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pubmed-1 | anxiety affects quality of life in those living with parkinson's disease (pd) more so than overall cognitive status, motor deficits, apathy, and depression [13]. although anxiety and depression are often related and coexist in pd patients, recent research suggests that anxiety rather than depression is the most prominent and prevalent mood disorder in pd [5, 6]. yet, our current understanding of anxiety and its impact on cognition in pd, as well as its neural basis and best treatment practices, remains meager and lags far behind that of depression. overall, neuropsychiatric symptoms in pd have been shown to be negatively associated with cognitive performance. for example, higher depression scores have been correlated with lower scores on the mini-mental state exam (mmse) [8, 9] as well as tests of memory and executive functions (e.g., attention) [1014]. likewise, apathy and anhedonia in pd patients have been associated with executive dysfunction [10, 1523]. however, few studies have specifically investigated the relationship between anxiety and cognition in pd. one study showed a strong negative relationship between anxiety (both state and trait) and overall cognitive performance (measured by the total of the repeatable battery for the assessment of neuropsychological status index) within a sample of 27 pd patients. furthermore, trait anxiety was negatively associated with each of the cognitive domains assessed by the rbans (i.e., immediate memory, visuospatial construction, language, attention, and delayed memory). two further studies have examined whether anxiety differentially affects cognition in patients with left-sided dominant pd (lpd) versus right-sided dominant pd (rpd); however, their findings were inconsistent. the first study found that working memory performance was worse in lpd patients with anxiety compared to rpd patients with anxiety, whereas the second study reported that, in lpd, apathy but not anxiety was associated with performance on nonverbally mediated executive functions and visuospatial tasks (e.g., tmt-b, wms-iii spatial span), while in rpd, anxiety but not apathy significantly correlated with performance on verbally mediated tasks (e.g., clock reading test and boston naming test). furthermore, anxiety was significantly correlated with neuropsychological measures of attention and executive and visuospatial functions. taken together, it is evident that there are limited and inconsistent findings describing the relationship between anxiety and cognition in pd and more specifically how anxiety might influence particular domains of cognition such as attention and memory and executive functioning. it is also striking that, to date, no study has examined the influence of anxiety on cognition in pd by directly comparing groups of pd patients with and without anxiety while excluding depression. given that research on healthy young adults suggests that anxiety reduces processing capacity and impairs processing efficiency, especially in the central executive and attentional systems of working memory [26, 27], we hypothesized that pd patients with anxiety would show impairments in attentional set-shifting and working memory compared to pd patients without anxiety. furthermore, since previous work, albeit limited, has focused on the influence of symptom laterality on anxiety and cognition, we also explored this relationship. seventeen pd patients with anxiety and thirty-three pd patients without anxiety were included in this study (see table 1). the cross-sectional data from these participants was taken from a patient database that has been compiled over the past 8 years (since 2008) at the parkinson's disease research clinic at the brain and mind centre, university of sydney. inclusion criteria involved a diagnosis of idiopathic pd according to the united kingdom parkinson's disease society brain bank criteria and were confirmed by a neurologist (sjgl). patients also had to have an adequate proficiency in english and have completed a full neuropsychological assessment. ten patients in this study (5 pd with anxiety; 5 pd without anxiety) were taking psychotropic drugs (i.e., benzodiazepine or selective serotonin reuptake inhibitor). patients were also excluded if they had other neurological disorders, psychiatric disorders other than affective disorders (such as anxiety), or if they reported a score greater than six on the depression subscale of the hospital anxiety and depression scale (hads). thus, all participants who scored within a depressed (hads-d>6) range were excluded from this study, in attempt to examine a refined sample of pd patients with and without anxiety in order to determine the independent effect of anxiety on cognition. this research was approved by the human research ethics committee of the university of sydney, and written informed consent was obtained from all participants. self-reported hads was used to assess anxiety in pd and has been previously shown to be a useful measure of clinical anxiety in pd. a cut-off score of>8 on the anxiety subscale of the hads (hads-a) was used to identify pd cases with anxiety (pda+), while a cut-off score of<6 on the hads-a was used to identify pd cases without anxiety (pda). this criterion was more stringent than usual (> 7 cut-off score), in effort to create distinct patient groups. the neurological evaluation rated participants according to hoehn and yahr (h&y) stages and assessed their motor symptoms using part iii of the revised mds task force unified parkinson's disease rating scale (updrs). in a similar way this was determined by calculating a total left and right score from rigidity items 3035, voluntary movement items 3643, and tremor items 5057 from the mds-updrs part iii (see table 1). processing speed was assessed using the trail making test, part a (tmt-a, z-score). attentional set-shifting was measured using the trail making test, part b (tmt-b, z-score). working memory was assessed using the digit span forward and backward subtest of the wechsler memory scale-iii (raw scores). language was assessed with semantic and phonemic verbal fluency via the controlled oral word associated test (cowat animals and letters, z-score). the ability to retain learned verbal memory was assessed using the logical memory subtest from the wechsler memory scale-iii (lm-i z-score, lm-ii z-score,% lm retention z-score). the mini-mental state examination (mmse) demographic, clinical, and neuropsychological variables were compared between the two groups with the independent t-test or mann whitney u test, depending on whether the variable met parametric assumptions. chi-square tests were used to examine gender and symptom laterality differences between groups. all analyses employed an alpha level of p<0.05 and were two-tailed. spearman correlations were performed separately in each group to examine associations between anxiety and/or depression ratings and cognitive functions. as expected, the pda+ group reported significant greater levels of anxiety on the hads-a (u=0, p<0.001) and higher total score on the hads (u=1, p<0.001) compared to the pda group (table 1). groups were matched in age (t(48)=1.31, p=0.20), disease duration (u=259, p=0.66), updrs-iii score (u=250.5, p=0.65), h&y (u=245, p=0.43), ledd (u=159.5, p=0.80), and depression (hads-d) (u=190.5, p=0.06). additionally, all groups were matched in the distribution of gender (= 0.098, p=0.75) and side-affected (= 0.765, p=0.38). there were no group differences for tmt-a performance (u=256, p=0.62) (table 2); however, the pda+ group had worse performance on the trail making test part b (t(46)=2.03, p=0.048) compared to the pda group (figure 1). the pda+ group also demonstrated significantly worse performance on the digit span forward subtest (t(48)=2.22, p=0.031) and backward subtest (u=190.5, p=0.016) compared to the pda group (figures 2(a) and 2(b)). neither semantic verbal fluency (t(47)=0.70, p=0.49) nor phonemic verbal fluency (t(47)=0.39, p=0.70) differed between groups. logical memory i immediate recall test (u=176, p=0.059) showed a trend that the pda+ group had worse new verbal learning and immediate recall abilities than the pda group. however, logical memory ii test performance (u=219, p=0.204) and logical memory% retention (u=242.5, p=0.434) did not differ between groups. there were also no differences between groups in global cognition (mmse) (u=222.5, p=0.23). participants were split into lpd and rpd, and then further group differences were examined between pda+ and pda. importantly, the groups remained matched in age, disease duration, updrs-iii, dde, h&y stage, and depression but remained significantly different on self-reported anxiety. lpda+ demonstrated worse performance on the digit span forward test (t(19)=2.29, p=0.033) compared to lpda, whereas rpda+ demonstrated worse performance on the digit span backward test (u=36.5, p=0.006), lm-i immediate recall (u=37.5, p=0.008), and lm-ii (u=45.0, p=0.021) but not lm% retention (u=75.5, p=0.39) compared to rpda. this study is the first to directly compare cognition between pd patients with and without anxiety. the findings confirmed our hypothesis that anxiety negatively influences attentional set-shifting and working memory in pd. more specifically, we found that pd patients with anxiety were more impaired on the trail making test part b which assessed attentional set-shifting, on both digit span tests which assessed working memory and attention, and to a lesser extent on the logical memory test which assessed memory and new verbal learning compared to pd patients without anxiety. taken together, these findings suggest that anxiety in pd may reduce processing capacity and impair processing efficiency, especially in the central executive and attentional systems of working memory in a similar way as seen in young healthy adults [26, 27]. although the neurobiology of anxiety in pd remains unknown, many researchers have postulated that anxiety disorders are related to neurochemical changes that occur during the early, premotor stages of pd-related degeneration [37, 38] such as nigrostriatal dopamine depletion, as well as cell loss within serotonergic and noradrenergic brainstem nuclei (i.e., raphe nuclei and locus coeruleus, resp., which provide massive inputs to corticolimbic regions). over time, chronic dysregulation of adrenocortical and catecholamine functions can lead to hippocampal damage as well as dysfunctional prefrontal neural circuitries [39, 40], which play a key role in memory and attention. recent functional neuroimaging work has suggested that enhanced hippocampal activation during executive functioning and working memory tasks may represent compensatory processes for impaired frontostriatal functions in pd patients compared to controls. therefore, chronic stress from anxiety, for example, may disrupt compensatory processes in pd patients and explain the cognitive impairments specifically in working memory and attention seen in pd patients with anxiety. it has also been suggested that hyperactivation within the putamen may reflect a compensatory striatal mechanism to maintain normal working memory performance in pd patients; however, losing this compensatory activation has been shown to contribute to poor working memory performance. anxiety in mild pd has been linked to reduced putamen dopamine uptake which becomes more extensive as the disease progresses. this further supports the notion that anxiety may disrupt compensatory striatal mechanisms as well, providing another possible explanation for the cognitive impairments observed in pd patients with anxiety in this study. noradrenergic and serotonergic systems should also be considered when trying to explain the mechanisms by which anxiety may influence cognition in pd. although these neurotransmitter systems are relatively understudied in pd cognition, treating the noradrenergic and serotonergic systems has shown beneficial effects on cognition in pd. selective serotonin reuptake inhibitor, citalopram, was shown to improve response inhibition deficits in pd, while noradrenaline reuptake blocker, atomoxetine, has been recently reported to have promising effects on cognition in pd [45, 46]. overall, very few neuroimaging studies have been conducted in pd in order to understand the neural correlates of pd anxiety and its underlying neural pathology. future research should focus on relating anatomical changes and neurochemical changes to neural activation in order to gain a clearer understanding on how these pathologies affect anxiety in pd. to further understand how anxiety and cognitive dysfunction are related, future research should focus on using advanced structural and function imaging techniques to explain both cognitive and neural breakdowns that are associated with anxiety in pd patients. research has indicated that those with amnestic mild cognitive impairment who have more neuropsychiatric symptoms have a greater risk of developing dementia compared to those with fewer neuropsychiatric symptoms. future studies should also examine whether treating neuropsychiatric symptoms might impact the progression of cognitive decline and improve cognitive impairments in pd patients. previous studies have used pd symptom laterality as a window to infer asymmetrical dysfunction of neural circuits. for example, lpd patients have greater inferred right hemisphere pathology, whereas rpd patients have greater inferred left hemisphere pathology. thus, cognitive domains predominantly subserved by the left hemisphere (e.g., verbally mediated tasks of executive function and verbal memory) might be hypothesized to be more affected in rpd than lpd; however, this remains controversial. it has also been suggested that since anxiety is a common feature of left hemisphere involvement [48, 49], cognitive domains subserved by the left hemisphere may also be more strongly related to anxiety. results from this study showed selective verbal memory deficits in rpd patients with anxiety compared to rpd without anxiety, whereas lpd patients with anxiety had greater attentional/working memory deficits compared to lpd without anxiety. although these results align with previous research, interpretations of these findings should be made with caution due to the small sample size in the lpd comparison specifically. recent work has suggested that the hads questionnaire may underestimate the burden of anxiety related symptomology and therefore be a less sensitive measure of anxiety in pd [30, 50]. in addition, our small sample size also limited the statistical power for detecting significant findings. based on these limitations, our findings are likely conservative and underrepresent the true impact anxiety has on cognition in pd. additionally, the current study employed a very brief neuropsychological assessment including one or two tests for each cognitive domain. future studies are encouraged to collect a more complex and comprehensive battery from a larger sample of pd participants in order to better understand the role anxiety plays on cognition in pd. another limitation of this study was the absence of diagnostic interviews to characterize participants ' psychiatric symptoms and specify the type of anxiety disorders included in this study. future studies should perform diagnostic interviews with participants (e.g., using dsm-v criteria) rather than relying on self-reported measures to group participants, in order to better understand whether the type of anxiety disorder (e.g., social anxiety, phobias, panic disorders, and generalized anxiety) influences cognitive performance differently in pd. one advantage the hads questionnaire provided over other anxiety scales was that it assessed both anxiety and depression simultaneously and allowed us to control for coexisting depression. although there was a trend that the pda+ group self-reported higher levels of depression than the pda group, all participants included in the study scored<6 on the depression subscale of the hads. controlling for depression while assessing anxiety has been identified as a key shortcoming in the majority of recent work. considering many previous studies have investigated the influence of depression on cognition in pd without accounting for the presence of anxiety and the inconsistent findings reported to date, we recommend that future research should try to disentangle the influence of anxiety versus depression on cognitive impairments in pd. considering the growing number of clinical trials for treating depression, there are few if any for the treatment of anxiety in pd. anxiety is a key contributor to decreased quality of life in pd and greatly requires better treatment options. moreover, anxiety has been suggested to play a key role in freezing of gait (fog), which is also related to attentional set-shifting [52, 53]. future research should examine the link between anxiety, set-shifting, and fog, in order to determine whether treating anxiety might be a potential therapy for improving fog. | research on the implications of anxiety in parkinson's disease (pd) has been neglected despite its prevalence in nearly 50% of patients and its negative impact on quality of life. previous reports have noted that neuropsychiatric symptoms impair cognitive performance in pd patients; however, to date, no study has directly compared pd patients with and without anxiety to examine the impact of anxiety on cognitive impairments in pd. this study compared cognitive performance across 50 pd participants with and without anxiety (17 pda+; 33 pda), who underwent neurological and neuropsychological assessment. group performance was compared across the following cognitive domains: simple attention/visuomotor processing speed, executive function (e.g., set-shifting), working memory, language, and memory/new verbal learning. results showed that pda+ performed significantly worse on the digit span forward and backward test and part b of the trail making task (tmt-b) compared to the pda group. there were no group differences in verbal fluency, logical memory, or tmt-a performance. in conclusion, anxiety in pd has a measurable impact on working memory and attentional set-shifting. | PMC5075302 |
pubmed-2 | small non-coding rnas are transcribed into mrna but remain untranslated in eukaryotic cells. they include sirna (small interfering rna), mirna (microrna), pirna (piwi-interacting rna) and snorna (small nucleolar rna). mirnas are a class of multifunctional singled-stranded small rna which are ~20 nt in length and regulate the stability or translational efficiency of targeted messenger rna depending on the base-pairing complementarity between the mirna and its target mrna [1, 2]. although over 1,000 mirna sequences have been identified from the tissues or cells of human origin and other species, as many as 1,000 to 10,000 mirnas per genome have been predicted [3, 4]. mirnas regulate a broad range of biological processes including timing of development, cell cycle progression, stem cell self-renewal, differentiation, cancer initiation, cancer cell proliferation, metastasis and apoptosis [511]. cancer is caused by multiple processes including uncontrolled cellular proliferation and inappropriate survival of apoptotic cells. many regulatory factors switch on or off genes that govern cell division and direct cellular proliferation. mirnas regulate gene expression and play important roles in the onset and progression of tumorigenesis. emerging evidence demonstrates the involvement of mirna in mammary gland tumorigenesis, functioning either as tumor suppressors or oncogenes. although the current treatment of radiation therapy, chemotherapy and hormone therapy slow mammary gland tumor growth, prolong survival and improve the quality of patients life, metastatic breast cancer still remains incurable due to our limited understanding of the molecular mechanisms through which tumorigenesis and metastasis occur. as small non-coding rnas regulate gene expression and tumorigenesis, they may represent a novel cancer therapy. unlike mrna, mirnas are transcribed but never translated. some mirnas are transcribed from non-coding regions between genes, deriving from independent transcription unit. other mirnas are transcribed together with coding mrnas from the coding region of the genome, deriving from the introns of gene transcripts [13, 14]. mirna gene copy number gain/loss and mirna gene mutation have been observed in breast cancer resulting in the aberrant expression of mirna. the first study about the altered expression of mirnas in human breast cancer patients and human breast cancer cell lines was reported in 2005 by lorio et al., in which 29 mirnas were identified with aberrant expression based on microarray and northern blot analysis of 76 breast tumor samples and 14 human breast cell lines. zhang and colleagues analyzed 283 human mirna genes on 55 human breast primary tumors and 18 human breast cancer cell lines using array-based comparative genomic hybridization. the results demonstrated a high frequency (~72.8%) of gene copy number abnormality in mirna-containing regions in human breast cancer. wang et al. collected 68 patients with newly diagnosed breast cancer and examined the expression of selected mirnas in tumor and adjacent non-tumor tissues. mir-21, mir-106a and mir-155 were significantly over-expressed in the tumor specimens compared with normal controls, whereas mir-126, mir-199a and mir-335 were significantly decreased in expression in the tumor samples. our studies of the mir-17-92 cluster demonstrated decreased expression of mir-17/20 in human breast cancer specimens compared with matching normal breast tissue from the same patient. subsequent analysis identified reduced mir-17/20 expression in node-positive compared with node-negative breast cancers and demonstrated that mir-17/20 inhibited breast cancer cell migration and invasion via a heterotypic signaling. although the tendency for a global decrease of mirna expression in human cancers originally suggested a general tumor suppressor function of mirnas, subsequent studies showing the aberrant expression of specific mirnas in breast cancer suggest mirna-specific roles in breast cancer onset and progression. many distinct mirnas have been shown to regulate breast cancer cell proliferation, apoptosis, cancer stem cell expansion, and tumorigenesis. mirna may function as either tumor suppressors or oncogenes depending on the cell type, culture conditions, target genes and pathway. the involvement of mirna in mammary gland tumorigenesis has been reviewed recently [21, 22]. le et al. described the expression pattern and regulatory network of key mirnas in breast cancer, including let-7, mir-34, mir-125, mir-200 family, mir-205, mir-21, mir-10 and the mir-17-92 cluster. adams et al. reviewed the mirna regulation of estrogen signaling pathway and erbb2/her signaling pathway in breast cancer. the understanding of how mirnas are involved in breast cancer through regulating the cell cycle remains rudimentary. herein we summarize the recent literature and research progress on the mechanism by which mirnas regulate the breast cancer cell cycle and cellular proliferation (fig. 1mirna regulation of mammary gland tumorigenesis in control of the cell cycle. through targeting different genes and different cyclin/cdk complexes, mir-17/20 and let-7 regulate the g1-s transition; mir-21 and mir-27a regulate the g2-m checkpoint mirna regulation of mammary gland tumorigenesis in control of the cell cycle. through targeting different genes and different cyclin/cdk complexes, mir-17/20 and let-7 regulate the g1-s transition; mir-21 and mir-27a regulate the g2-m checkpoint cyclin d1 is either overexpressed or amplified in ~50% of breast cancer. the abundance of cyclin d1 is rate-limiting in breast cancer cellular proliferation and g1-s phase transition [23, 24]. in addition, cyclin d1 is a critical downstream target of erbb2-, ras- and -catenin- induced breast cancers, and is sufficient for the induction of mammary tumors when targeted to the mammary gland of mice. antisense inhibition of cyclin d1 expression in vivo suppressed the growth of neut-transformed mammary adenocarcinoma cells in nude mice. conserved sequences of the cyclin d1 3utr contain potential binding sites for multiple mirnas including mir-17/20/106, mir-15/16, mir-23 and let-7. mir-17/20 binds the cyclin d1 3utr, inhibiting the expression of cyclin d1, resulting in cell cycle arrest at the g1 phase and suppression of mcf-7 cell proliferation [18, 26]. the regulation of cyclin d1 expression by mir-17-92, as well as mir-15/16, was confirmed by deshpande et al.. the let-7 family functions as a tumor suppressor in a variety of cancers including lung, colon, ovarian and breast cancer. schultz et al. demonstrated the downregulation of cyclin d1 by mirna let-7 in control of cancer cell growth. the regulation of cyclin d1 by mirna is likely of broad importance as cyclin d1 encodes the regulatory subunit of a kinase that phosphorylates and inactivates the prb family proteins to inhibit dna synthesis, and phosphorylates nuclear respiratory factor 1 (nrf-1) to inhibit mitochondria biogenesis [32, 33]. furthermore, cyclin d1 promotes breast epithelial cell angiogenesis and migration, and promotes chromosomal instability which in turn contributes to tumorigenesis. the mir-221/222 cluster regulates the cell cycle, cell growth and epithelial-to-mesenchymal transition (emt) in breast cancer. mir-221/222 inhibited p27 and p57 abundance, facilitating g1-s phase transition, thereby promoting cancer cell proliferation [36, 37]. moreover, mir-221/222 may contribute to the aggressive clinical behavior of basal-like breast cancers. the breast cancer basal-like subtype-specific mirnas, mir-221 and mir-222, promote emt in breast cancer by targeting trps1 (trichorhinophalangeal syndrome type 1) which inhibits emt by repressing zeb2 expression. mir-221 and/or mir-222 expression in mcf-7 and t47d breast cancer cells decreased er expression associated with tamoxifen resistance. the onco-mirna mir-21 is overexpressed in a wide variety of cancers including breast cancer [40, 41]. mir-21 induced cellular proliferation, migration, invasion, emt, cancer stem cell characteristics and chemotherapy resistance in human breast cancer [42, 43]. high mir-21 level is associated with poor prognosis, advanced stage, positive lymph node status and reduced survival time in breast cancer. mir-21 promotes mcf-7 cellular proliferation in part through inhibiting the expression of a tumor suppressor gene programmed cell death 4 (pdcd4). in colon cancer, mir-21 participates in a dna damage-induced g2-m checkpoint through suppressing the cell cycle regulator cdc25a. a recent report demonstrated the mir-21 regulates the cell cycle through targeting cdc25a in mcf-7 breast cancer cells. with a potential anti-cancer chemical 3,3-diindolylmethane treatment, mir-27a expression is upregulated in human breast cancer cell lines. in mda-mb-231 cells, mir-27a negatively regulated the zinc finger zbtb10 gene and myt-1, thereby promoting breast cancer cell proliferation. mir-27a suppressed myt-1, increased cdc2/cyclin b activity and promoted the g2-m checkpoint in mda-mb-231 cells. thus, distinct mirnas affect key genetic targets that govern distinct cell-cycle checkpoints including cyclins, cdks, cdk inhibitors and the g2-m regulation apparatus. in addition to cell-cycle control, breast tumor onset and progression and breast tumor stem cells are also regulated by distinct mirnas. cancer stem cells (cscs) are characterized by their self-renewal capacity, an ability to differentiate into non-tumorigenic cell progeny, and their ability to seed tumors when transplanted into animal hosts. cell surface markers such as cd44, cd24, cd133, epithelial-specific antigen and aldehyde dehydrogenase-1 are frequently used to isolate and enrich cscs. the involvement of mirnas in regulating tumor formation by cscs or tumor-initiating cells (t-ic) has been widely investigated. let-7 expression is very low to undetectable level in embryonic stem cells (es cells) and increases with differentiation. a comparison of mirna expression between breast t-ic and non-t-ic demonstrated reduced let-7 expression in t-ic and increased abundance with differentiation. transduction of breast cscs with let-7 reduced the proportion of undifferentiated cells, inhibited cell proliferation, mammosphere formation, and tumor formation in vivo. clarke and colleagues identified 37 mirnas which were differentially expressed between human breast cscs (cd44cd24lineage) and lineage nontumorigenic breast cancer cells. the mir-200 family members were downregulated in human breast cscs and normal mammary stem/progenitor cells. expression of mir-200 inhibited breast cancer stem cell expansion in vitro, and suppressed the tumor formation ability of human breast cancer stem cell in vivo. ectopic mir-34c expression reduced breast t-ics self-renewal, inhibited emt and suppressed tumor cell invasiveness via silencing notch4. zhu et al. found the reduced mir-128 expression in human breast t-ic was accompanied by bmi-1 and abcc5 overexpression, and associated with chemotherapeutic resistance and poor survival. enforced mir-128 expression increased the sensitivity of breast cancer cells to doxorubicin-induced apoptosis and dna damage. emerging evidence has demonstrated the importance of cscs in cancer initiation, cancer metastasis and drug resistance. cscs are believed to be one of the most promising targets for cure of cancer. the discovery that non-coding rnas regulate cscs widens our understanding of cscs, and may provide potential novel strategies for breast cancer therapy. deletion of chromosome 6q, including region 6q14-q16, is frequently observed in breast cancer. the small non-coding snorna u50 is a candidate tumor suppressor gene in the 6q14-16 region, playing a role in the development and/or progression of breast cancer. genomic deletion and transcriptional downregulation of snorna u50 was detected in breast cancer cell lines. re-expression of snorna u50 inhibited colony formation of the human breast cancer cells hs578 t and mda-mb-231. pirnas are small non-coding rna that form rna-protein complexes through interactions with piwi proteins. pirna was initially discovered in germ line cells, and considered as germ line-specific small rnas. emerging evidence indicates that pirna expression occurs in somatic cells [57, 58] and piwil2 expression has been identified in human breast cancer cells. high-throughput deep sequencing identified a group of small rnas matching pirna sequences in human breast cancer tissues and breast cancer cell lines. the study of these non-coding small rnas in human cancer is just starting. the identification of the expression signature of these non-coding small rnas in breast cancer subtypes, and an understanding of their functional significance to oncogene expression, tumor initiation and tumor cell metastasis may shed important new perspectives on the role of these non-coding small rnas in breast cancer. small non-coding rna-based diagnostic and therapeutic applications for human cancer are expected in the near future. although tumor-targeted delivery and local administration are still major challenges to the practical application of gene therapy for cancer, mirna-based cancer therapeutic approaches are being established and tested in animal models. synthetic mirna mimics or mirna expression vectors have been successfully applied to restore or overexpress mirna in vitro. chemically modified lna anti-sense mirna inhibitor and other approaches have been used to block mirna function in cells. kim et al. recently reported significant anti-tumor effect of virus-mediated delivery of mir-145 combined with 5-fu to treat breast cancer. intranasal delivery of let-7 and intravenous delivery of mir-34a mimics for non-small-cell lung cancer treatment and a virus-mediated delivery of mir-26a for liver cancer treatment in mouse model demonstrate the promise of mirna for treatment of cancer. dysregulated expression of mirnas has implicated components of the non-coding genome as either oncogenes or tumor suppressors of breast cancer. experimental evidence has shown specific mirnas regulating the initiation, progression, metastasis and drug resistance of breast cancer via control of the cell cycle, altering cellular proliferation, altering cellular apoptosis and/or controlling the population of tumor stem cells. dysregulated mirna expression has also been observed in cancer associated fibroblasts (caf) and in the systemic circulation [65, 66]. the circulating mirnas have the potential to serve as novel diagnostic and prognostic biomarkers for breast cancer. a specific subset of dysregulated mirnas in breast cancer cells may serve as targets for gene therapy either alone or as an adjuvant treatment to current clinical protocols for breast cancer patients. | small non-coding rnas include sirna, mirna, pirna and snorna. the involvement of mirnas in the regulation of mammary gland tumorigenesis has been widely studied while the role for other small non-coding rnas remains unclear. here we summarize the involvement of mirna in breast cancer onset and progression through regulating the cell cycle and cellular proliferation. the regulation of breast cancer stem cells and tumor regeneration by mirna is reviewed. in addition, the emerging evidence demonstrating the involvement of pirna and snorna in breast cancer is briefly described. | PMC3309138 |
pubmed-3 | ohss is a serious complication of ovulation induction, occurring in 1-10% of in vitro fertilization patients (rizk and aboulghar, 1991; brinsden et al., 1995). this iatrogenic condition has a spectrum of clinical and laboratory manifestations ranging from mild to severe, even life-threatening conditions (rizk et al., 1990). among the serious manifestations of ohss are ascites and pleural effusion (rizk and smitz, 1992). vascular endothelial growth factor has emerged as one of the factors most likely involved in the pathophysiology of ohss (geva and jaffe, 2000; rizk and aboulghar, 2010). vascular endothelial growth factor is an angiogenic cytokine that is a potent stimulator of the vascular endothelium and appears to play an integral role in follicular growth, corpus luteum function and ovarian angiogenesis (rizk et al., 1997). vascular endothelial growth factor causes increased capillary permeability with its sequelae of ascites and possible pleural effusion (rizk et al., 1997; gomez et al., 2002). human chorionic gonadotrophin is thought to play a crucial role in the development of ohss (rizk et al. two distinct forms of severe ohss have been described: early and late forms (papanikolaou et al., 2005; mathur et al., 2000). early ohss is caused by the administration of exogenous human chorionic gonadotrophin (hcg) and it starts before the 10th day after oocyte retrieval, while the late form is the result of endogenous human chorionic gonadotrophin release in the event of pregnancy, and it starts after the 10th day following oocyte aspiration (papanikolaou et al., 2005; such strategies included the use of low dose gonadotropins and frequent monitoring during controlled ovarian stimulation, cycle cancellation, coasting, freeze all embryos and the use of gonadotropin releasing hormone (gnrh) agonist as an oocyte trigger in gnrh antagonist cycles (rizk et al. the use of antagonist in the luteal phase with total freeze of embryos to prevent severe ohss has also been suggested (lainas et al., 2012). such strategies should be used especially in patients at high risk for developing severe ohss, including those who are young, have low body weight, have polycystic ovary syndrome, those who experience high estradiol levels, rapidly increasing estradiol levels, high number of follicles during controlled ovarian stimulation and those with high number of oocytes retrieved (rizk and aboulghar, 1999; delvigne, 2009). dopamine agonists have been proposed for the prevention of ohss in women at high risk. however, the study by lvarez et al. (2007) suggested that it was only effective in reducing the incidence of moderate ohss, but not in its severe form (alvarez et al., 2007). low-dose aspirin therapy and doxycycline have also been suggested to inhibit angiogenesis (fainaru et al., 2009). (2011) believes that the concept of an ohss-free clinic has become a reality. the authors suggest that this approach should include pituitary down-regulation using a gnrh antagonist, ovulation triggering with a gnrh agonist and vitrification of oocytes or embryos (devroey et al., 2011). severe and critical forms of ohss are associated with significant ascites (golan et al., 1989; rizk et al., ascites results in an increased abdominal pressure compromising venous return, cardiac output and renal perfusion (navot et al. paracentesis is frequently needed, as prompt drainage of fluid produces a significant clinical and biochemical improvement, including spontaneous diuresis and hastening the resolution process (rizk et al., multiple paracenteses may be required to relieve symptoms and avoid serious sequelae of hemoconcentration, hypotension, decreased renal perfusion and severe respiratory compromise. instead of multiple interventions, the placement of a catheter temporarily for a few days will permit complete drainage through one procedure (rizk and aboulghar, 1999). pigtail catheters have been used for drainage in various clinical situations. in a previous study we described the use of percutaneous placement of a pigtail catheter for drainage of ascites caused by severe/critical ohss (abuzeid et al., 2003). in this study we established the efficacy and safety of pigtail catheter drainage in the management of severe/critical ohss in patients who underwent in vitro fertilization and embryo transfer at our centre between 1999 and 2001 on both inpatient and outpatient basis. the aim of the current study was to evaluate the role of the pigtail catheter drainage in outpatient management of patients with early onset severe ohss. this is a retrospective study that included all patients who underwent in vitro fertilization and developed severe or critical ohss by the golan classification (golan et al., 1989) in the period between 2004 and 2009. all patients underwent an ultrasound evaluation which documented the presence of severe ascites and bilateral ovarian enlargement. all patients presented with shortness of breath, marked abdominal distension, nausea, weight gain and lower abdominal pain. thirteen patients complained of vomiting, and 3 patients reported decreased urine output (less than 720 cc per 24 hours) and had haemoglobin 15 g/dl. all 33 patients were offered treatment using pigtail catheter insertion as an alternative to trans-vaginal paracentesis. blood studies including a complete blood count, creatinine, electrolytes, serum albumin and total protein, and coagulation panel were ordered prior to the procedure. all 33 patients were rehydrated with intravenous crystalloid solutions (0.9% normal saline). care was taken to give the patient the same amount of fluid as the amount that was drained from the peritoneal cavity. all pigtail catheter placements were performed in the operating room at our surgical centre. the catheter (6-0 french, 2.0 mm, boston scientific, quincy, ma, usa) was introduced utilizing a non-disposable metal gamete intra-fallopian treatment (gift) trocar and cannula (embryon gift catheter, ivf online, gilford, ct, usa) which was introduced into the largest accessible ascitic fluid pocket in the upper outer quadrant of the abdominal wall under local anaesthesia and trans-abdominal ultrasound guidance. the trocar was then removed and a glide wire (boston scientific corp., watertown, ma, usa) was threaded through the gift canula. the canula was removed with care so as to keep the glide wire in the peritoneal cavity. the pigtail catheter was guided into the peritoneal cavity by the wire after removal of the stylet of the pigtail catheter. the catheter was anchored to the skin using 2-0 silk suture and it was supported by gauze, which was covered by a tegaderm. the catheter was connected to a three-way stop cock which was connected to a drainage bag. initial amount of drained fluid was calculated and subsequently the patients were trained to drain 1000 cc per day (500 cc in the morning and 500 cc in the evening). one liter normal saline and 500 cc of 6% hydroxyethyle starch solution (hespan) was administered to the patient on the same day of pigtail catheter placement. any patient with critical ohss according to the golan classification, or those in whom the presenting symptoms and signs did not completely subside after drainage of ascitic fluid and iv fluid replacement, were admitted to the hospital for observation and further management. all other patients were sent home. once there was minimal or no drainage from the catheter, the patient returned to the office for removal of the catheter. the patients were encouraged to drink plenty of fluids and to increase their protein intake. all patients kept a diary for body weight, abdominal girth, and urine output before and after the procedure. patients were seen in the office as needed for evaluation and hydration with normal saline. demographic data including mean age (years), duration of infertility (years), bmi (kg/m2) and aetiology of infertility are illustrated in table i. ovarian stimulation data including number of treatment days, total dose of recombinant follicle stimulating hormone, hormone serum levels, endometrial thickness, number of follicles and number of patients receiving only 5000 iu of human chorionic gonadotrophin is illustrated in table ii. our data include the number of patients requiring early versus late placement of pigtail catheter, mean amount of ascitic fluid drained immediately after pigtail placement, number of days of pigtail catheter drainage and the number of days between oocyte retrieval and the onset of severe ohss symptoms requiring pigtail placement. table iii also illustrates the number of patients who underwent coasting, number of patients who received prophylactic hespan on day of egg retrieval. values are expressed as mean+standard deviation values are expressed as mean+standard deviation: rfsh=recombinant fsh; hmg =human menopausal gonadotropins; hcg=human chorionic gonadotropin; e2=estradiol values are expressed as mean+standard deviation three patients (9%) required an early placement of a pigtail catheter while 30 patients (91%) had late placement of the catheter (table iii). twenty-nine patients (88%) were managed on an outpatient basis without any complications. four patients (12%) required hospital admission for 1-7 days (3+2.7), three for associated severe pleural effusion requiring thoracentesis. these three patients were admitted to the hospital immediately after insertion of the pigtail catheter for management of severe pleural effusion and careful observation. one patient was admitted 48 hours after insertion of the pigtail catheter for work up for chest pain, all tests were negative. navot et al., 1992; rizk and aboulghar, 1999), but perhaps the most accepted classification of ohss is the one described by golan et al as mild, moderate and severe (golan et al., 1989). however, clinicians should be aware that ohss is a dynamic condition and moderate ohss may progress to severe ohss within hours (rizk and aboulghar, 1999; rizk, 2009). therefore, the practice committee of the american society for reproductive medicine (asrm) proposed a classification for ohss of mild, worsening and serious (the practice committee of the american society for reproductive medicine, 2008). recognizing the patients at high-risk, prevention and early recognition are the most important steps in the management of ohss (rizk, 2006). however, severe forms of ohss, especially late onset type that occurs when patients are pregnant, most likely will continue to happen, albeit at much lower rate, unless one reverts to a total freeze of all embryos after the use of gnrh agonist as a trigger shot in a gnrh antagonist cycle (donoso and devroey, 2013; devroey et al., 2011). traditional treatment consists mainly of supportive management until spontaneous resolution occurs (rizk, 1994). although moderate ohss does not usually require intervention, outpatient monitoring is essential to identify progression to a severe form (rizk, 2006). patients with moderate ohss can be managed on an outpatient basis by adequate hydration and close daily monitoring of weight gain and abdominal girth to detect progression to severe ohss, and to provide intervention, if required (rizk, 2010). patients presenting with severe forms of ohss are usually managed on inpatient basis and most patients with critical ohss are admitted to intensive care units for aggressive supportive measures to avoid maternal morbidity and mortality (the practice committee of the american society for reproductive medicine, 2008). correction of hypovolemia, electrolyte imbalance and hypoalbuminemia are the basic principles during the treatment of severe ohss (rizk, 1994, 2006; myrianthefs et al., 2000). (1992) suggested that paracentesis is the single most important treatment modality in life-threatening ohss not controlled by medical therapy. paracentesis and removal of ascites result in relieving the pressure on the inferior vena cava and improvement in venous return, cardiac output and renal perfusion (padilla et al., 1990). therefore, prompt drainage of fluid produces significant clinical and biochemical improvement, including spontaneous diuresis and hastening the resolution process (abuzeid et al., 2003; the practice committee of the american society for reproductive medicine, 2008). it is also possible that removal of ascites decreases the amount of vegf and its effects on vascular permeability. therefore ultrasound guided drainage of the ascitic fluid should be performed in severe cases of ohss with respiratory distress, oliguria or severe abdominal pain (padilla et al., 1990). this can be done either trans-vaginally (aboulghar et al., 1990) or trans-abdominally (padilla et al., 1990). however, recurrence of ascites is common in severe cases of ohss. placement of a pigtail catheter has been proposed by some investigators to allow drainage of ascitic fluid whenever it accumulates without the need for further surgical procedures (abuzeid et al., 2003). in a previous study we reported the use of percutaneous pigtail catheter for drainage of ascites in severe ohss as an alternative to repeated paracentesis (abuzeid et al., 2003). this procedure is relatively simple and requires a short period of time as compared to the time needed to gradually aspirate any fluid accumulation transvaginally. immediate relief of symptoms and signs of severe ohss after pigtail catheter insertion was an important finding. in addition, the ease by which any accumulated ascitic fluid was drained resulted in a faster resolution of ohss (abuzeid et al., no infection was reported (abuzeid et al., 2003). in that study the first 13 patients they were discharged home with the pigtail catheter in place and managed on an outpatient basis until ohss subsided; thereafter the catheter was removed. the last 13 patients were managed on an outpatient basis without any problem (abuzeid mi, et al., 2003). our previous study confirmed the safety and effectiveness of the pigtail catheter for the management of severe ohss. therefore, we embarked on the current study to evaluate the role of pigtail catheter drainage in outpatient management of patients with severe ohss syndrome. in the current study we demonstrated that patients who were diagnosed very early with severe ohss can be managed safely and effectively on outpatient basis using pigtail catheter drainage, iv fluid replacement and careful monitoring. although all 33 patients presented with shortness of breath, marked abdominal distension, nausea, weight gain and lower abdominal pain, and 13 of them complained of vomiting, (all are criteria for hospital admission according to the practice committee of the american society for reproductive medicine on ohss), 30 patients were sent home as their presenting symptoms were relieved. early diagnosis and intervention resulted in rapid elimination of the symptoms of severe ohss and normalization of vital signs, which allow us to manage the patients on outpatient basis. the pigtail catheter placements were performed without complications and patients were discharged home after a few hours of observation. the patients who needed hospital admission were those with associated severe pleural effusion requiring thoracentesis. another patient was admitted to the hospital for 1 day for work up for chest pain and possible diagnosis of pulmonary embolism. once pulmonary embolism was ruled out, she was discharged home with a pigtail catheter in place and she was managed on outpatient basis. outpatient management of ohss has no place in those who fail to have complete resolutions of their symptoms, or those with severe hyperproteinuria or electrolyte imbalance. certainly it has no place in patients with critical ohss such as those with severe pleural effusion, diminished urine output, severe hemoconcentration and those at increased risk of thromboembolic risks (rizk, 2010). it is imperative to stress that such a protocol can only be used in patients who are motivated, reliable and have the necessary support at home to allow them to return to the clinic or go to the emergency room if the need arises. it also requires dedicated in vitro fertilization nurses to educate and follow up the patient on a daily basis. contrary to other reports that state that access to intravenous albumin is a critical part of outpatient management for severe ohss, we did not use any albumin replacement (lincoln et al., 2002). the reason behind the use of intravenous albumin is to increase intravascular oncotic pressure, thereby curtailing the exodus of free water from the intravascular space. in our study we used hespan instead of albumin, as some investigators have shown that it is beneficial in reducing the incidence of severe ohss (youssef et al., 2011). by increasing the intravascular oncotic pressure in addition, the majority of our patients had late onset ohss as a result of pregnancy. hespan should be used with caution in patients with late onset ohss only when benefits outweigh risks.it is a fact that outpatient management of early severe ohss is a common practice among infertility specialists after trans-vaginal aspiration of ascitic fluid and iv fluid hydration. outpatient management by repeated abdominal or trans-vaginal paracentesis has been reported to be safe, effective and cost effective (lincoln et al., 2002; shrivastav et al., 1994; fluker et al., 2000 (1994) were the first to suggest that day care management in patients with severe ohss with abdominal paracentesis and iv hydration was simple, safe and effective compared with traditional treatment with in-patient hospitalization and supportive measures. (2002) concluded that the need for hospitalization for hyperstimulated patients can be minimized by outpatient management of severe ohss with trans-vaginal culdocentesis and rehydration with crystalloids and albumin. (2000) advocated in a pilot study an active management strategy for moderate ohss, which involved early paracentesis designed to minimize the progression from moderate to severe ohss, instead of late paracentesis aimed at speeding up recovery in severely ill patients. (2010) concluded that early outpatient paracentesis for moderate to severe ohss is the most cost effective management plan when compared with traditional conservative inpatient therapy. (2009) reported a large series of patients with severe ohss in whom the vast majority were successfully managed as outpatients with use of aggressive trans-vaginal paracentesis (smith et al., 2009). despite the findings in our study it is important to emphasize that ohss remains a serious disorder with the potential for rapid deterioration, requiring hospitalization and intensive treatment of a critically ill patient. the life-threatening complications of ohss are secondary to thromboembolism or compromised pulmonary or cardiovascular function and multi-organ failure. there have been isolated reports of women dying from the complications associated with ohss. the mortality rate related to ohss is very low and was estimated by brinsden et al. more recently, reports regarding maternal mortality rates due to ohss in the netherlands and united kingdom demonstrate an incidence of approximately 3 deaths per 100,000 in ivf cycles (braat et al., 2006; lewis, 2007). eleven lethal complications of assisted reproductive technology have been documented and summarized by braat et al. several investigators reported sporadic fatality as a result of ohss due to adult respiratory distress syndrome, massive pulmonary oedema, myocardial infarction, and carotid artery occlusion resulting in cerebral infarction. in this study we describe a modified technique of what interventional radiologists usually use for pigtail catheter placement. we observed that in the obese patients the metal introducer provided in the pigtail catheter kit is difficult to use; instead we used the non disposable gamete intra-fallopian treatment trocar and cannula to facilitate the introduction of the catheter through the abdominal wall of such patients. this technique helps to manage the patients in the office without the need for sending her to the hospital for an interventional radiologist to place the catheter. however, the patients in this study were identified from our in vitro fertilization database; the study included every patient who developed severe/critical ohss. in addition, the lack of a control group that was managed without pigtail catheter placement limits the conclusions that can be drawn from our study. in summary, drainage of ascitic fluid in patients with severe/critical ohss is an important step in the management of this condition (rizk, 2010). the placement of a pigtail catheter resulted in a safe and effective outpatient management of the majority of patients with severe ohss. however, outpatient management of this potentially fatal condition requires clear understanding that rapid deterioration may occur, which may necessitate hospitalization and intensive treatment of a critically ill patient (rizk, 2006, 2010). patients with critical ohss and those with persistence of symptoms of severe ohss despite insertion of a pigtail catheter and drainage of ascitic fluid should be admitted to the hospital for inpatient management. | objective: to evaluate the efficacy and safety of outpatient management of severe ovarian hyperstimulation syndrome (ohss) requiring placement of a pigtail catheter. methods: retrospective analysis of thirty-three consecutive patients who underwent in-vitro fertilization (2003-2009) and developed severe/critical ohss requiring placement of a pigtail catheter. patients who were managed on outpatient basis were monitored by frequent office visits, daily phone calls, and received iv normal saline for hydration when required. results: in 3 patients (9.1%) ohss started early, requiring placement of a pigtail catheter 4.3+0.6 days after retrieval. in 30 patients (90.9%) ohss started late (14 4 days after retrieval). the mean amount of ascitic fluid drained immediately after placement of the catheter was 2085 1018 cc. the pigtail catheter was removed after 7.8 5.3 days. of the 31 patients who had embryo transfer (two had total freeze), 84% conceived. twenty-nine patients (88%) were managed on outpatient basis without any complications. four patients required hospital admission for 1-7 days (3.0 2.7). one patient with severe ohss was admitted for work up for chest pain. three patients with critical ohss with severe pleural effusion requiring thoracentesis were admitted for supportive measures. conclusion: the placement of a pigtail catheter resulted in safe and effective outpatient management for the majority of patients with severe ohss. | PMC4086000 |
pubmed-4 | the family is the cornerstone of human social support network and its presence is essential in everyone s life. changes inevitably occur in families with illness and hospitalization of a family member. in other words, among the sources of stress for families are accidents leading to hospitalization particularly intensive care unit (icu). statistics show that 8% of hospital beds in the united states are occupied by the intensive care units. stress in the family while the patient is in the icu can disrupt the harmony power of the family members and finally, it may causes disturbances in the support of the patient. in addition to the various sources of stress in intensive care units such as the patient s fear of death, financial problems, lack of awareness about the environment and etc., their satisfaction level is another important source of stress for the patient s family. today, the family needs of hospitalized patients in the icu are summarized in five sections. these factors may include receiving assurance, staying close to the patient, receiving information, feeling comfortable and receiving support. however, in many cases, the patient s family needs and their expectations in the icu will not be fulfilled which will cause dissatisfaction. since, how families deal with mental stress is the most important components of comprehensive care, it should be known that attention to the family needs of the patients hospitalized in intensive care units could increase their satisfaction and thus a reduction in stress disorders. studies showed that the nurses in particular sections focus primarily on the patient and the disease. therefore, attention to the families should be considered as an important part in patient management. effective interventions targeted at the needs and expectations of family members should help to reduce the stress and improve their satisfaction. fox et al. stated that the needs of the family members were not often overlooked by the nurses. however, the nurses spend a lot of time with the patients and their families and are in a good position to assess their needs and plan for meeting these needs with appropriate interventions. the reason of investigating the satisfaction of the families of the patients in the icu is that the patients are facing life-threatening illness experiences and complex treatments, different technologies and different equipment are used for them. these cases could potentially lead to the dissatisfaction of their families. in the meantime, the families of trauma and neurosurgical patients are more vulnerable than the other groups of patients. they need supports that are more emotional and should be accepted by the icu staff. today, there are many theories expressed that in intensive care units, the patient and his family should be considered as a single unit. by providing care to this unit, the aim of this study was to analyze the satisfaction of the families of icu patients. the tool of society of critical care medicine s family needs assessment (sccmfna) (which has been validated in 1998 by johnson) was used in that study. the results showed that most of the family satisfaction was related to the communication and patient care and the lowest level of satisfaction was about the ability of staff to patients family comfort. bailey et al. have conducted a study in 2009 with the purpose of investigating the relationship between informational support to families of special care patients and their anxiety and satisfaction. they showed that there is a direct link between the informational support and their satisfaction. the study of fumis et al. in 2008 also showed that the increase in the availability of physicians for giving the information to the patient s family and as well as nurses efforts to provide understandable explanations about the patient s condition to them will increase the patient s family satisfaction. this clinical trial was performed with respect to the existing gap for a study carried out for investigating the interventions for the satisfaction of the patients in the special care units and their families in iran. the purpose of the study was to determine the effectiveness of nursing interventions based on family needs on family satisfaction level of hospitalized patients in the neurosurgery intensive care unit of al-zahra hospital in 2010. the statistical research community was the families of hospitalized patients in neurosurgery intensive care unit of al-zahra (sa) hospital, isfahan, iran from may to september 2010. with respect to inclusion criteria, the families of 64 patients were selected with simple sampling. after obtaining the informed consents from the hospitalized patients, by using the envelopes, which were prepaid by using a table of random numbers, they were divided into two groups (intervention and control). the inclusion criteria was included as the following cases: to be a first-degree member of the family, to be older than 18 years, willing to participate in the study, having the power to speak and write in farsi, to be hospitalized one day before the study, lack of physical or mental problem in the family member, no responsibility for the care of another patient, introduced as the first person responsible for the patient care. obtaining the written informed consent, completion of the questionnaires about demographic information and the families satisfaction were performed in the second day of hospitalization of the patients in icu in both groups. johnson questionnaire for the satisfaction of the family of icu patients was used to measure the family satisfaction. the rating of the questionnaire was performed by using the likert scale with four options of 0 to 4 as follows: almost all the time (3 scores), often (2 scores), only occasionally (1 score) and never (zero score). johnson s questionnaire was the modified type of multer patient s family needs, which was evaluated in various scientific researches and there are extensive evidences for its validity. the interventions were performed in the second and the third day of hospitalization of the patient in the neurosurgery icu by the researcher in the morning shift for the intervention group. thus, the researcher provided understandable explanations about the disease to the patient s family and answered honestly to the questions about the patient and the disease. the researcher ensured them for providing the best care in the section and spoke about the prognosis of the disease. the researcher took the family member to the patient s room and gave the necessary information about the room space, equipment, personnel departments and the actions that were done for the patient. the patient family member was contacted if there was a change in the patient condition. they let the family help the patient in some cases of the public health (such as hand and foot massage and giving food). locations of rest, nutrition, prayer room, bathroom and buffet of the hospital were introduced to them. the telephone numbers of hospitals and wards (and if necessary, the social worker and supervisor) were given. various departments and personnel of the hospital were taught to accept the families and communicate with them. the hospital social worker was introduced and if necessary, the patient s family was allowed to express their feelings. these interventions were performed in the evening shift of the second and the third day of the patient reception. the actions were carried out by the fellow researcher. while, for the control group, only the routine work was done. on the fourth day, the satisfaction survey was completed by the selected family member in both of the intervention and control groups. statistical methods used in this study were 2 test, man-whitney, independent student s t-test and paired t-tests. the findings did not show statistically significant difference in the demographic characteristics of the intervention and control groups, such as: age (p<0.99), gender (p<0.79), marital status (p<0.41), educational level (p<0.12) and relation with patient (p<0.54). as shown in table 1, there was no significant difference in the mean satisfaction score before the intervention in the intervention and control groups (p>0.05). the mean satisfaction score after the intervention in the intervention group was significantly more than the control group (p<0.001). the mean satisfaction score in the intervention group after the intervention was significantly higher than before the intervention (p<0.001). there was no significant difference in the mean satisfaction score in the control group before and after the intervention (p>0.05) (table 2). comparison of mean satisfaction score (100 *) of participants in the intervention and control groups the mean of satisfaction score changes of the studied subjects in the intervention and control groups after intervention the results of the present study showed that the nursing interventions based on the family needs increased the patient s family satisfaction in the neurosurgery intensive care unit of al-zahra hospital. due to the differences in the study design, study population, the number of samples and methods of intervention, it would be difficult to compare the results. in chien et al. study, the results showed that performing the training based on the patients family needs in the icu, decreased the anxiety and increased their satisfaction. in the study of myhren et al. indicated that effective communication of the staff with the families of icu patients would increase their satisfaction. in the study by rosher and robinson, it showed that involving the families in patient care led to increase their satisfaction than before the intervention. the mentioned results were consistent with the results of this study, because all of these interventions were some parts of the interventions performed in this study. however, the study of steele et al. indicated that clinical training had no impact on the family satisfaction of the patient hospitalized in the icu. therefore, there was no statistically significant difference in the satisfaction level in the control and intervention group. in this study, it was shown that the use of nursing interventions based on family needs (confidence, support, information, proximity and convenience) had significant impact on the family satisfaction of the patient hospitalized in intensive care unit. they should be based on the family investigation and recognition and their priority needs should be determined in order to cause the greatest satisfaction. the icu nurses must also accept their role in the care of patient s family members. the findings of this study could be a basis for performing further studies about family needs of the patients in the icu especially with the different forms of culture and economy. consequently, the increase in family satisfaction of patients can reduce the stress disorders and improve their mental state and ultimately better support of the patient by the family. this study only examined the effect of nursing interventions in the first days of hospitalization on the satisfaction of the families but the effects on the patient s entire hospitalization period has not been assessed. by performing other researches in this field, it would be possible to compare the differences in the effects of nursing interventions based on the needs of families in the early days and the whole period of the patient s hospitalization. | background: since the family is a social system, the impairment in each of its component members may disrupt the entire family system. one of the stress sources for families is accidents leading to hospitalization particularly in the intensive care unit (icu). in many cases, the families needs in patient care are not met that cause dissatisfaction. since the nurses spend a lot of time with patients and their families, they are in a good position to assess their needs and perform appropriate interventions. therefore, this study was conducted to determine the effectiveness of nursing interventions based on family needs on family satisfaction level of hospitalized patients in the neurosurgery icu. materials and methods: this clinical trial was conducted in the neurosurgery icu of al-zahra hospital, isfahan, iran in 2010. sixty four families were selected by simple sampling method and were randomly placed in two groups (test and control) using envelopes. in the test group, some interventions were performed to meet their needs. in the control group, the routine actions were only carried out. the satisfaction questionnaire was completed by both groups two days after admission and again on the fourth day. findings:both of the intervention and control groups were compared in terms of the mean satisfaction scores before and after intervention. there was no significant difference in mean satisfaction scores between test and control groups before the intervention. the mean satisfaction score significantly increased after the intervention compared to the control group. conclusions:nursing interventions based on family needs of hospitalized patients in the icu increase their satisfaction. attention to family nursing should be planned especially in the icus. | PMC3702150 |
pubmed-5 | rising levels of obesity are becoming a worldwide phenomenon and are increasingly identified as a health problem across the globe [14]. higher weight has been associated with adverse health indicators and outcomes, including cardiovascular disease [512], stroke [5, 13], cognitive and functional decline [1418], metabolic syndrome [19, 20], inflammation [21, 22], and mortality [20, 2325]. obesity among aging populations is relatively recent and aging among people who have been obese for much of their lives is also a new phenomenon. from 1980 to 2004, the prevalence of obesity in the us has continued to rise from about 17% to 25% for men aged 5059. while obesity in england has also increased during this period, from approximately 9% in 1980 to 15% in 2004 for men aged 5564, the level of obesity remains much lower in england. additionally, the difference in obesity between the us and england is more pronounced for women. the level of obesity in us women was about 24% in 1980 and rose to 37% in 2004 (age 5059); in england, levels for women were 9% in 1980 and 14% in 2004 (age 5564). the aim of this paper is to investigate differences in how obesity relates to indicators of physiological dysregulation in men and women of diverse populations. this comparison will lead to an improved understanding of how obesity might be differentially related to health and mortality across cultures and lifestyles. obesity was relatively rare in most populations until the second part of the last century, but it has now become common in many countries. the us population is recognized as among the most obese in the world, although many other countries are now approaching the us level and most countries are experiencing increasing obesity. this worldwide obesity epidemic began with the epidemiological revolution and the virtual elimination of infectious disease; the decline in manual labor needed to provide sustenance with the industrial revolution; and the increasing availability and decreasing cost of food [2729]. obesity reflects some combination of calorie intake, diet content, and amount of physical activity. in some cultures, lack of physical activity can be a more important determinant of obesity; in other cultures, overeating or food composition may be the more important determinant of obesity. it is also true that within countries, individuals could differ in the causes of obesity. for instance, changes in activity might be more characteristic of women or men resulting in different reasons for obesity by gender. these differences may affect how obesity is related to other risk factors for poor health, and it may determine the overall health risk associated with obesity. if physical activity is maintained, the overall effect of obesity may be less than if the activity is not. one indication of the cause of obesity may be the relationship between waist size and weight [30, 31]. in societies where obese people are more physically active, waist size of the obese waist circumference has also been linked to late life mortality, where high waist circumference has been associated with increased mortality among men and women in the netherlands, while high bmi was not associated with mortality. this paper builds upon current obesity research by using both bmi and waist circumference to quantify obesity in order to determine how a combined indicator of weight and adiposity is related to physiological dysregulation in populations with different cultures, diets, behaviors, and epidemiological histories. obesity has been related to many indicators of physiological dysregulation including cardiovascular risk factors such as hypertension and metabolic dysregulation in lipid levels or insulin resistance. most studies that investigate the differences in biological risk associated with excess weight have examined western populations [33, 36]. comparative studies on the health risks associated with obesity that examined the us and england reported that obese americans had an increased risk of diabetes and a higher waist circumference [37, 38]. these studies suggested that differences in physical activity, diet, and social environments may explain these national differences. while these differences have been observed between the us and england, these two western countries have roughly similar life expectancy, levels of living, history, and culture even while the us has poorer health by a number of indicators of disease prevalence and biological risk [36, 39]. comparative studies of the links between obesity and health outcomes and risk factors for obesity comparing western and non-western countries indicate important differences in the causes and consequences of obesity. a comparison of the association of disease with overweight and obesity in japan and the us indicated that the associations were stronger in the us than in japanese women and that there was no association in japanese men. links between social, demographic, and behavioral risk factors for obesity also differ markedly in japan, korea, and the us. the availability of biomarker data from taiwan a middle-income country undergoing rapid economic growth, increasing obesity, and with life expectancy recently increasing to levels similar to that of the us and england allows for investigation of the biological risk associated with obesity in a population characterized by very different cultural, behavioral, socioeconomic, and dietary parameters. we examine how elevated weight and obesity (using an indicator that considers both bmi and waist circumference) relate to having levels defined as clinical risk for cardiovascular, metabolic, and inflammatory markers in three aging societies that are now relatively similar in life expectancy but that differ in the timing of the epidemiological transition and obesity epidemic, history of economic development, socioeconomic levels, general lifestyle habits, health behaviors, and health care systems: the us, england, and taiwan. finding differences in the relationship between obesity and indicators of physiological dysregulation in these three aging societies will clarify whether increases in weight gain are equally problematic across all countries. we use data from three nationally representative samples: the us national health and nutrition examination survey (nhanes, 20032006; n=3855), the english longitudinal study of ageing (elsa, 2004-2005; n=9139), and the social environment and biomarkers of aging study (sebas) in taiwan (2000; n=1023). these surveys collect information on demographics, as well as anthropometric, physical, and biological measures. every year, approximately 5,000 individuals undergo detailed interviews and medical examinations, which include collection of several physiological measures. nhanes utilizes a complex sampling design, and when weights are applied, the sample is representative of the noninstitutionalized american population. we use the 20032006 data since nhanes data is released in two-year intervals, and this sample is centered on 2004-2005, which matches the period in which elsa was collected. for nhanes, we use individual-level data based on a sample of 1,513 fasting individuals aged 54 and older. elsa includes participants drawn from households responding to the health survey for england (hse) in 1998, 1999, and 2001 and is representative of the english population aged 50 and older. the core elsa sample (wave 1: 2002-2003) includes people living in an hse responding household who were born prior to march 1, 1952, and their partners who could be under age 50. wave 4 of elsa (2008-2009), which includes a nurse visit, includes wave 1 core members, if they are still alive and do not refuse further contact after the first interview at wave 1. it also includes a refresher sample to maintain the age structure of the sample (in waves 3 and 4), and their partners. for elsa, we use individual-level data based on a sample of 7,384 individuals aged 54 and older. sebas is drawn from a follow-up survey of the survey of health and living status of the near elderly and elderly in taiwan (also known as the taiwan longitudinal study of aging (tlsa)), a nationally representative survey of taiwanese adults (including institutionalized individuals) collected in 1989, 1993, 1996, 1999, and 2000. in 2000, a subsample of individuals was randomly selected for inclusion in sebas. sebas consists of adults aged 54 and older in 2000, with in-home interviews and medical exams taken in a hospital. for sebas, the sample averages 66.8 years of age in england, and the us and taiwan mean age is about the same (table 1). there are more men in taiwan (56%) and england (53%) and fewer in the us (44%). we examine the following indicators of physiological dysregulation often associated with obesity and also associated with increased risk for multiple adverse health outcomes and obesity [43, 44]: (1) cardiovascular markers: high systolic (sbp) and diastolic blood pressure (dbp); (2) metabolic markers: high levels of blood lipids (total and low-density lipoprotein (ldl) cholesterol, and fasting triglycerides), low levels of high-density lipoprotein (hdl) cholesterol, and high fasting glucose and glycated hemoglobin; (3) high levels of inflammatory markers c-reactive protein (crp; available in nhanes and elsa) and interleukin-6 (il-6; available in sebas), as crp and il-6 have been positively associated with bmi. for each indicator we use clinical cutpoints or widely used research-based cutpoints to indicate high levels of risk which are shown in table 1 [39, 43, 45]. there has been debate as to the best indicator of obesity: body mass index (bmi) or waist circumference. waist circumference is thought to be a better measure of abdominal adiposity than bmi and a better indicator of risk of poor health outcomes, including all-cause and cardiovascular mortality [46, 47]. for this reason we investigate the association between bmi and biomarkers across categories of bmi (underweight<18.5 kg/m, normal and overweight 18.529.9 kg/m, obese 3034.9 kg/m, and very obese 35 kg/m) and waist circumference categorized as normal or high waist (high waist: men 120 cm, women 88 cm). we create a composite measure of obesity and adiposity by categorizing individuals into five groups: (1) underweight and normal waist (all underweight individuals had a normal waist circumference), (2) normal/overweight bmi (termed normal bmi) and normal waist circumference (reference group), (3) normal/overweight bmi (termed normal bmi) and high waist circumference (termed high waist), (4) obese and high waist (all obese individuals had a high waist circumference), and (5) very obese. we also evaluate an alternate definition for obesity in taiwan based on bmi 27, as it has been suggested by some that obesity levels should be differentially defined for asians [48, 49]. a similar composite measure of obesity and adiposity was calculated using this alternate definition of bmi in taiwan. because these risk factors are all assumed to be associated with obesity and because dysregulation in multiple physiological systems has been shown to predict many of the poor health risk outcomes associated with aging, we also create two summary measures of risk based on the total number of at-risk levels of biomarkers, either 9 or 8. because crp values for sebas are not available, this measure is not included in the 9-item summary measure for taiwan, but a summary measure (range 09) was calculated for taiwan using il-6, another indicator of inflammation, instead of the crp values included for the us and england. a second alternate summary measure of biological risk, excluding the inflammatory marker (range 08), biological risk summary scores were computed for individuals who had missing values on no more than 3 biological markers. we examine multiple covariates in our investigation of the relationship between obesity and biological risk. self-reported use of antihypertensives was determined in all three countries, and use of lipid-lowering statins was only asked in the us sample. dichotomous variables were created to indicate whether the respondent reported being a current smoker and participating in at least moderate physical activity for exercise (e.g., brisk walking, running, or swimming) in the past 30 days (for the us and england) or generally exercising once a week (for taiwan). we use logistic regression models to determine the odds of having at-risk levels of a specific biomarker for obese men and women among the three populations. for all countries, the comparison group for bmi and waist circumference is the normal bmi and normal waist group. the regressions included indicators of age, use of antihypertensives, current smoking status, and having exercised in the past 30 days. ordinary least squares (ols) regression models were used to determine the relationship between the summary measures of biological risk and the composite measure of obesity and adiposity. we begin by examining national differences in the high risk levels of individual biomarkers (table 1). low levels or high risk levels of hdl cholesterol are also more common in taiwan. high total and ldl cholesterol is more common among the english; lower levels of plasma glucose, crp, and glycated hemoglobin are also characteristic of the english. few adults in england have elevated levels of fasting glucose (2.2%), while this is observed in 17.3% and 13.2% of american and taiwanese adults. most people in this age range are in the normal to overweight category (64.7%, 67.2%, and 89.4% in the us, england, and taiwan, respectively) (table 2(a)). americans are more likely to be obese (33.7%) compared to the english (32.1%) and taiwanese (7.2%). among the obese, americans are much more likely to be very obese: 13.4% of the total us sample, 10.1% in england, and about 1% in taiwan. both among the obese and very obese, the average bmi is higher in the us and england compared to taiwan. few are underweight in any country (1.7%, 0.8%, and 3.4% in the us, england, and taiwan, resp.). when we examine waist circumference, the us has the highest average waist circumference, with 65.5% of americans, 55.9% of english, and 15.8% of taiwanese having a high waist size (table 2(a)). this means that high waist characterizes a substantial number of those who would be categorized as normal weight in the us and england. among those in the normal and overweight group about half (49.5%) of americans and a third (36.4%) of the english almost all obese individuals have a high waist in the us and england (98.3% in the us and 96.5% in england), but only 78.4% of the obese in taiwan also have a high waist. when we use the alternate obese cutpoint of 27 kg/m in taiwan, less than half of the obese individuals have a high waist (not shown here). americans exhibit the highest proportion of the older population taking antihypertensive medication (47.1%) (table 1). the percentage who reports taking antihypertensives is lower in england (32.0%) and taiwan (28.6%). americans are more likely to be current smokers (24.5%) than persons in taiwan (22.5%) and england (13.9%). more than half of the population in all countries report having exercised in the past 30 days, with more english exercising (82.2%) compared to taiwan (61.4%) and the us (58.5%). men with normal bmi and high waist have a greater likelihood than men with normal bmi and normal waist size of having high-risk levels of triglycerides in all three countries. in the us and england, men with high waist are more likely to have high levels of glycosylated hemoglobin and higher crp; fasting glucose is also elevated among this group in the us (table 3(a)). men who are obese in the us have fewer elevated risk factors than those with high waist who are not obese; in the us, obese men are only more likely than normal weight men without high waist to have elevated glycated hemoglobin, fasting glucose and crp. english men who are obese have more elevated risk: both blood pressure indicators, hdl cholesterol, triglycerides, glycated hemoglobin, and crp. very obese men in england have the same elevated risk factors with the exception of dbp. very obese men in the us are more likely to have elevated fasting glucose in addition to crp and glycated hemoglobin. english and taiwanese women with normal weight and high waist are more likely to have elevated sbp, dbp, and glycosylated hemoglobin; only british women with higher waist have significantly elevated triglycerides and only the taiwanese women had more hdl risk. high risk crp is more common among both american and english women with normal bmi and high waist, and this risk of elevated crp is also higher in the obese and very obese (table 3(b)). obese women in britain had elevations in the same markers as normal bmi and high waist english women, while obese women in the us only have elevated fasting glucose, glycated hemoglobin, and crp; obese women in taiwan only had high dbp. with the exception of taiwan, levels of the inflammatory markers (crp in the us and england; il-6 in taiwan) are more likely to be elevated among persons with a high waist and normal bmi, obese or very obese, compared to their normal bmi and normal waist counterparts. among men, an increase in the biological risk summary score (range 09) is associated with having a high waist relative to being of normal bmi and normal waist in all three countries (table 4(a)). being obese or very obese is also related to a higher biological risk summary score (09) for men in the us and england. these equations explain 6 to 11 percent of the variance in the summary indicator of biological risk. these relationships are similar for women (table 4(b)), with one exception: obese taiwanese women do not have a significantly increased biological risk compared to their normal weight and normal waist counterparts. when we consider the alternate summary score that excludes our indicators of inflammation (range 08), being obese or very obese is no longer associated with a higher biological risk summary score in us men compared to men with a normal bmi and normal waist when controls for health behaviors and medication use are included (table 5(a)). the size of the effects of the obesity categories is reduced on the 8-indicator summary measure in both england and the us, indicating the strong link between crp and obesity. the r is also reduced in these equations for england and the us. for taiwan, women in england and taiwan, but not women in the us, with a higher waist but who are not obese have significantly higher physiological dysregulation compared to their normal bmi and normal waist counterparts. obese women in all three countries have elevated risk and the very obese have even higher risk (table 5(b)). the alternate biological risk summary measure (08) yields different relationships between weight and physiological dysregulation in the us and taiwan. in the us, only very obese women have a higher alternate biological risk summary score (08). in taiwan, obese and normal bmi and high waist women exhibit higher alternate biological risk summary scores compared to their normal bmi and normal waist counterparts, except when smoking status, physical activity, and use of hypertensives are included. figures 1(a) and 1(b) illustrate the predicted alternate biological risk score (08) for each weight category for men and women (respectively) aged 65 who are nonsmokers, do not engage in physical activity, and are currently taking antihypertensive medication. this figure allows for country comparisons of individuals with these characteristics within each weight category and across weight categories. the predicted values indicate that the us has the highest biological risk score within each respective weight category among men and women of the same age and lifestyle behaviors. with the exception of women in the normal bmi and high waist group, england has the second highest biological risk score within each weight category, followed by taiwan. among 65-year-old women with the noted lifestyle behaviors and with a normal bmi and high waist when we consider the alternate bmi cutpoint for obesity in taiwan (bmi 27 kg/m), our findings for the individual biomarkers and summary measures of biological risk are similar to using the bmi 30 kg/m cutoff for taiwan except that the category normal weight with high waist no longer differs from the omitted category (results not shown). this study observes three general findings about how biological risk is associated with obesity in three countries that differ in lifestyle and culture. first, obesity is associated with physiological dysregulation in all countries with differences in the links between specific indicators of biological risk and obesity. generally, obesity in england is associated with hypertension, dyslipidemia, and elevated glycated hemoglobin; americans who are obese are not more likely to have hypertension. in taiwan, obese women are more likely to have elevated dbp and obese men have an increased risk of elevated triglycerides and glycated hemoglobin compared to their nonobese, normal waist counterparts. our biological risk summary scores indicate that at all levels of weight physiological dysregulation was highest in the us, followed by england (with one exception), with taiwanese exhibiting the lowest biological risk in all groups among the three countries. second, these relationships remain after controlling for demographic factors, participation in physical activity, and other behavioral factors. third, similar to obese older adults, high waist individuals with normal bmi also exhibit greater physiological dysregulation in all countries compared to their normal bmi and normal waist counterparts. our finding of a higher physiological dysregulation, as shown by the alternate biological risk summary score, in taiwan compared to the us and england could be due to a couple of potential explanations. the prevalence of obesity in the us and england is much higher than in taiwan, indicating an earlier initial rise in obesity relative to taiwan. from 1978 to 2002, the proportion of obese americans and britons exhibited stark increases (1332% and 623% for men and women, resp.). the estimates for obesity prevalence in taiwan indicate a recent increase for men but not women. from 19931996 to 2000-2001, the age-adjusted prevalence of obesity rose from 10.5% to 15.9% for men and declined from 13.2% to 10.7% in women. it may be that the lower levels of risk among older adults who have lived longer years with obesity could be a reflection of better pharmacologic control of physiological dysregulation (e.g., through statin use), which may in turn confer less biological risk in these populations compared to populations of currently obese taiwanese adults who may have more recently begun living with obesity. a second reason for the observed country differences in obesity may be due to differences in dietary habits and lifestyle. the us and england are two modern, western populations whose diets have been influenced by increased industrialization and have over time come to be characterized by high glycemic loads and high fatty acid composition. taiwan, on the other hand, represents a country that has experienced the effects of the industrial and scientific revolutions later than that of the us and england but is currently rapidly undergoing economic development and demographic change. the recent economic changes in taiwan may indicate that obese older adults in taiwan have more recently begun to consume high-fat diets, which could result in greater initial physiological dysregulation associated with access to western-influenced dietary habits. despite controlling for lifestyle behaviors thought to be linked with health, the country differences in obesity and physiological regulation remain. moreover, the consideration of antihypertensives does not alter our substantive conclusions on these associations. this suggests that despite the greater use of medications to treat hypertension in the us, obesity among americans is associated with greater overall biological risk than the other two countries. this is supported by findings from the general population of americans relative to england, which report that the us is faced with greater health disadvantages than england in adulthood and across the life span. we also note differences in biological profiles of obese individuals between the two westernized countries: the us and england. the excess risk of hypertension associated with obesity in england was not found in the us. these differences may be due to the higher use of medications among americans compared to the english, with about 16% more men and 18% more women in the us aged 65+taking antihypertensive medication compared to their british counterparts. the greater use of hypertensive medications in the us is also noted when compared to japan and countries across europe. two notable differences in country patterns of the relationship between obesity and physiological dysregulation by sex are found. among men in england and taiwan, the order of magnitude of physiological dysregulation increases with higher weight categories; however, this is not observed for us men. this difference may be due to our inability to consider statin use in england and taiwan, which may be particularly important in the relationship between obesity and physiological dysregulation for men. conversely, the importance of considering statin use may be less vital to understanding the country differences in the association between obesity and physiological dysregulation among women, given that the relationship for women is more consistent across countries, namely in the us and england. women, underweight corresponds with higher biological risk (though nonsignificant) compared to women with normal bmi and normal waist. underweight among men in taiwan is significantly associated with much lower biological risk than their normal bmi and normal weight counterparts. further studies will be required to explore possible explanations for these differences in physiological dysregulation. the higher biological risk observed among normal bmi and high waist individuals relative to normal bmi and normal waist older adults builds upon previous studies that report on alternate indicators of body shape, which vary across countries. the importance of waist circumference is underscored by our current study, as well as a growing body of literature on the predictive value of waist circumference on indicators of health. higher rates of diabetes among older americans compared to britons have been accounted for by high waist circumference as opposed to bmi differences. additionally, increasing waist circumference is more predictive of greater risk of incident diabetes than bmi in middle-aged british men (and the european prospective investigation into cancer and nutrition (epic)-potsdam study). waist circumference, as an indicator of central fat mass, is thought to be more strongly associated with disease risk, and in our case with physiological dysregulation, compared to bmi, which is considered a cruder index of adiposity. banks and colleagues cite differences in physical activity, diet and greater psychosocial environmental challenges in america compared to england as potential mechanisms linking central adiposity and type 2 diabetes. our study considers some of these possible mechanisms (e.g., physical activity and antihypertensive use) but finds that they explain little of the relationship between biological risk and adiposity among the three countries. together, these results highlight the importance of considering waist circumference in investigating the links between indicators of health and adiposity. our finding of the biological risks associated with obesity among older taiwanese adults underscores the growing concern for risks associated with obesity in countries rapidly undergoing modernization. in comparing the biological risk of obese individuals among the three countries, we are able to use these international comparisons to our advantage to examine how differences in modernization influence the health of older adults in different populations this may have potential health policy implications that underscore the importance of addressing and controlling the rising obesity epidemic that has become most widespread in countries, like the us and england, that have long experienced high economic growth and in countries currently undergoing rapid economic development. the increasing use of biological information to inform our understanding of health represents an innovative method in biodemography that will further contribute to the testing of current comparative theory and the potential creation of new paradigms surrounding the influence of modernization on health. first is the use of a broad range of biological markers across three large-scale population surveys. the inclusion of biological information as objective precursors of health allows, to some extent, a fairly comparable comparison of indicators of health across the different populations. an exception to this uniform comparison of biomarkers across the three surveys is our use of inflammatory marker crp in the us and england and our inclusion of a different marker of inflammation (il-6) in taiwan. of note, crp seems to be more strongly associated with obesity than il-6. a growing body of literature has made distinctions between bmi and waist circumference, namely, suggesting that waist circumference is a better indicator of abdominal obesity, which in turn has been associated with obesity-related health risks. our findings generally report a similar association between increased biological risk and (1) normal bmi and high waist and (2) obese and high waist. using the us nhanes, reported that when both waist circumference and bmi were included in their analyses, only waist circumference was a significant predictor of comorbidity. although this and other studies have suggested that waist circumference may be a better indicator of obesity and risk for adverse health outcomes, our study finds the two indicators to be similarly associated with biological risk across the three countries. first, we examine population-based data from three countries at a single time point. future studies of longitudinal data will allow for further investigations of the potential role of obesity on biological risk observed in the current associations. second, we do not have measures of some lifestyle and medical behaviors for some of the datasets (e.g., statin use), which likely influence the relationship between obesity and biological risk. as such, we are unable to include such factors in our analyses of all three countries. it is possible that these lifestyle behaviors are key explanatory factors to the noted cross-country differences in obesity-related biological risk. the cross-country differences in the relationship between increased biological risk for individuals who are obese and have a high waist underscore potential differences in health and lifestyle behaviors. these behaviors may be a result of country differences in economic development that we are not able to observe in this study. the country differences in the links between obesity and physiological dysregulation are particularly marked when comparing obesity among taiwanese older adults relative to westernized populations, such as the us and england. further examination of these relationships over time and across other countries will contribute to our understanding of the potential factors responsible for these country-specific variations in biological risk, as obesity becomes increasingly more prevalent and older adults in various countries live more years with obesity and increased adiposity. | excess weight has generally been associated with adverse health outcomes; however, the link between overweight and health outcomes may vary with socioeconomic, cultural, and epidemiological conditions. we examine associations of weight with indicators of biological risk in three nationally representative populations: the us national health and nutrition examination survey, the english longitudinal study of ageing, and the social environment and biomarkers of aging study in taiwan. indicators of biological risk were compared for obese (defined using body mass index (bmi) and waist circumference) and normal weight individuals aged 54 +. generally, obesity in england was associated with elevated risk for more markers examined; obese americans also had elevated risks except that they did not have elevated blood pressure (bp). including waist circumference in our consideration of bmi indicated different links between obesity and waist size across countries; we found higher physiological dysregulation among those with high waist but normal bmi compared to those with normal waist and normal bmi. americans had the highest levels of biological risk in all weight/waist groups. cross-country variation in biological risk associated with obesity may reflect differences in health behaviors, lifestyle, medication use, and culture. | PMC3679767 |
pubmed-6 | many studies have not been reported in literature for lumbar discectomy by destandau endospine system. we report a series of 300 patients operated for lumbar dissectomy by destandau endospine system. a total of 300 patients suffering from lumbar disc herniations were operated between january 2002 and december 2008. technique comprised localization of symptomatic level followed by insertion of an endospine system devise through a 15 mm skin and fascial incision. endoscopic discectomy is then carried out by conventional micro disc surgery instruments by minimal invasive route. the results were evaluated by macnab's criteria after a minimum followup of 12 months and maximum up to 24 months. based on modified macnab's criteria, 90% patients had excellent to good, 8% had fair, and 2% had poor results. the complications observed were discitis and dural tear in five patients each and nerve root injury in two patients. 90% patients were able to return to light and sedentary work with an average delay of 3 weeks and normal physical activities after 2 months. the advantages of use of minimal invasive spinal surgical techniques in treatment of lumbar disc herniation is small incision, limited tissue disruption, enhanced visualization due to better magnification and illumination, shorter hospital stay, and faster recovery time.13 among many posterior spinal endoscopic systems used for disc surgery, destandau endospine system and foley and smith's metrx system are seen as viable alternatives to open disc surgery.46 the aim of this study was to present results in 300 patients operated by edoscopic discectomy and to discuss technical points to shorten the learning curve. a total of 475 patients suffering from different type and level of lumbar disc herniation with radiculopathy and degenerative lumbar canal stenosis were operated between january 2002 and december 2008. the inclusion criteria were patients having lumbar disc prolapse with unilateral radiculopathy, on clinical evaluation, positive straight leg raise or femoral stretch test, and identification of a single nerve root lesion on mri. patients with bilateral symptoms, double root involvement, cauda equina syndrome and whose clinical symptoms did not match mri picture were excluded from present study. all these patients had fair trial of conservative treatment in the form of rest, medication (nsaid), activity modification, and physiotherapy (minimum 6 weeks) before they were advised to undergo surgery. however, in present study, none of the patients opted for surgery at 6 weeks after completion of conservative treatment. there were 206 males and 94 females aged between 18 to 72 years (mean, 38.4 years). levels operated upon included l1-l2 (n=3), l2-l3 (n=2), l3-l4 (n=6), l4-l5 (n=205), and l5-s1 (n=84). there were 235 extruded, 20 contained, 15 foraminal, and 30 sequestrated herniations. results were evaluated as poor, fair, and good or excellent using modified macnab's criteria. modified macnab's grading was as follows: excellent-no pain/restriction of activity and being able to do all activities; good-occasional pain with relief of presenting symptoms and returning to work with some modification; fair-some improved functional capacity but still handicapped or unemployed; and poor results-having objective symptoms of root involvement or repeat surgery at the index level. the clinical material included preoperative history, physical examination, plain x-rays and mri studies of lumbosacral spine, laboratory tests, and intraoperative video documentation. postoperative follow-up was carried out on third day, 2 weeks, 6 weeks, 3, 6, 12, and 24 months. it consists of endospine tube, trocar, and working insert [figure 1a and b]. one port for 0 degree endoscope, second for suction cannula, third port (biggest) for working instrument, and fourth port for dural and nerve root retractor. the procedure of discectomy can be carried out under general, spinal, epidural, or local anesthesia. the operative technique consists of knee chest positioning after administration of anesthesia followed by level localization by localization devise [figure 1c]. at marked point, 15 mm skin incision is made aponeurosis is incised using mayo's scissors; 1.5 cm wide periosteal elevator is used to elevate paravertebral muscles subperiostealy, thus exposing the interlaminar window and part of the affected side facet. (a) clinical photograph showing patient positioning and level marking (b) destandau endospine system (c) iitv picture of marked level (d) position of endospine tube (e) endoscopic view of decompressed nerve root the endospine tube with trocar is pushed through the incision in the direction of posterior arch over interlaminar window followed by withdrawal of trocar. the working insert any soft tissue bulging in the mouth of tube is removed till boundaries of interlaminar window such as superior and inferior lamina, facet joint are clearly visualized [figure 1e]. this follows part resection of inferior margin of the superior lamina followed by excision of ligamentum flavum leading to exposure of the dural sac and nerve root under endoscopic vision. once the nerve root has been accurately identified, it is retracted using a nerve root retractor.. it also helps to keep the field dry. depending on local findings, discectomy involving the extraction of the nucleus pulposus once satisfactory nerve root decompression is achieved, endospine tube along with working insert is withdrawn. aponeurosis is sutured using vicryl fine suture followed by closure of the skin in a subcuticular fashion. a water-impermeable dressing (a) preoperative sagittal t2wi mri of prolapsed l5-s1 disc (b) postoperative sagittal t2wi mri of l5-s1 disc after endoscopic discectomy at 2 years follow up (c) axial t2wi mri section at l5-s1 disc after endoscopic discectomy at 2 years follow up shows no compression these patients were followed up on third day, 2 weeks, 6 weeks, 3, 6, 12, and 24 months. patients were followed up for minimum of one year and maximum of 2-year duration. on second visit on third day, wound was inspected for any drainage or evidence of infection. complains about fever, backache, and leg discomfort at final follow-up, 90% patients were relieved of sciatica and were satisfied with procedure. 285 patients were operated as day care cases and were mobilized and discharged same evening from day care facility. based on modified macnab's criteria 90% patients had excellent to good, 8% had fair, and 2% had poor results. five patients who had interaoperative minor dural tears were hospitalized and were observed for any dural leak. causative factor for dural tears in present study were as follows: three patients had dural rent due to forceful retraction of dura and nerve root by dural and nerve root retractor. this was observed in patients in whom there was significant posterolateral herniation resulting in tenting of dura and nerve root at recess. in this situation, authors have found gentle mobilization of nerve root and dura by nerve root hook or approaching and debulking the offending disc through axilla before proceeding with retraction of nerve root and discectomy. this happened when kerrison rongeur was used to open the tight recess resulting in dural tear and nerve root injury. these dural tears were managed by water tight closure of muscle, fascia, and skin and bed rest for duration of one week. superficial delayed wound healing was observed in 20 patients, which healed in 21 days by regular dressings rest and administration of antibiotics. the diagnosis of postsurgical discitis was based on mainly clinical grounds and laboratory evidence of raised counts, esr, and c-reactive proteins. clinical criteria included recurrence of severe and unrelenting back pain within first week of surgery, keeping patient awake at night after initial recovery. no biopsy of disc was resorted to; however, mri of lumbosacral spine was ordered in all these patients which did not contribute much to the diagnosis. lizolid 600 mg/bd) for first week followed by oral antibiotics for 5 weeks. all these patients responded well to antibiotics and no further intervention of any kind was carried out. after initial back pain for 6 weeks, these patients had occasional residual backache which was treated by analgesics, activity modification, lumbar support, and rest during subsequent follow-up visits. nerve root injuries (n=2) were encountered while trying to do a medial facetectomy to open the recess by a kerrison rongeur causing severe laceration of nerve root. however, nerve root was in continuity., patties were used for gentle retraction and procedure of discectomy was successfully completed endoscopically without resorting to open discectomy. 276 patients were able to return to sedentary work with an average delay of 2 weeks, except 24 patients who had complains of backache, occasional leg discomfort, discitis, and nerve root injuries. medial facetectomy was resorted to in 59 patients to open the recess to decompress the nerve root in addition to discectomy. mixter and barr7 discovered the pathophysiology of discogenic sciatica and suggested laminectomy and discectomy as operative treatment. the overall results of standard discectomy range from 68 to 95% in different series.8 the operative microscope and microsurgical techniques were developed in mid-1960 's by yasargil and krayenbuhl910 and these techniques revolutionized spine surgery leading to smaller incisions, less blood loss, increased visualization of site of pathology, decreased hospitalization, shorter postoperative recovery, and earlier return to activities compared with previous operative interventional techniques. the results of microdiscectomy also range from 85 to 98%.1113 katayama et al.14 compared the results of open vs gold standard microdiscectomy and observed no difference between the surgical outcomes in both the groups but microdiscectomy gave better lighting, magnification, and therefore decreased the length of incision and tissue invasion. microdiscectomy also allowed the patients to return to early work with lesser use of narcotic medication. microendoscopic dissectomy (med) combines standard microsurgical technique with an endoscope, enabling the surgeons to address all types of disc herniations including decompression of nerve root and lateral recess. chemonucleolysis was reported by smith.15 nonetheless, based upon various randomized clinical trials, the efficacy of chemonucleolysis compared with more traditional and open procedures for the operative treatment of lumbar disc herniations remained speculative.16 the use of percutaneous nucleotomy, laser discectomy, and intradiscal electrothermal annuloplasty (idet) compared with microdiscectomy remains unclear, and it is attributed to the lack of high-quality studies.17 conclusions about the efficacy of some of the aforementioned minimally invasive procedures (e.g., chemonucleolysis, apd, idet) were questionable with regard to disc-related pathology.18 therefore, lumbar microdiscectomy remained the gold standard for addressing a herniated or sequestrated intervertebral disc; however, a movement toward more minimally invasive approaches that would yield superior outcomes, while minimizing excessive soft and bony tissue removal and minimizing soft tissue trauma, were sought. as such, an evolution in procedures toward smaller incisions, less tissue trauma, and quicker return to daily activities took center stage in spine surgery. the use of muscular retractor system was reported initially by faubert and caspar.1920 perez-curet and fessler,21 described for the first time a myriad of spine pathologies that could be addressed using tubeology. though from our initial experience, endospine technique is minimal invasive, but limitation of study has been lack of comparison with gold standard microscopic discectomy technique. however, in a study by shin et al.,22 15 cases each were compared of med and microscopic group (md). the mean cpk-mm levels were lower for the med group than for the md group at both 3 (576.1286.3 iu/l compared with 968.1377.8 iu/l) and 5 days (348.1231.0 iu/l compared with 721.7463.2) postoperatively (p<0.05). the mean vas scores for postoperative back pain were lower in the med group than in the md group, both at 1 (3.32.3 compared with 5.81.5) and 5 days (1.91.1 compared with 3.61.1) postoperatively (p<0.01). aforementioned authors concluded that the med procedure is less invasive than md, and causes less muscle damage and backache. the 90% excellent results in present study is comparable with other surgical procedures for herniated lumbar discs such as those of destandau, perez-cruet et al., and their average surgical time was 66 minutes, average blood loss was 22 ml, average hospital stay was 7.7 hours, complication rate was 5%, reoperation rate was 4%, and average return to work was 17 days with excellent result in 94% patients. average operative time was 50 minutes average blood loss was 45 ml (range, 30-70 ml). return to work (21 days) and overall results (90%) which are comparable. in another prospective and randomized evaluation of surgical treatment for lumbar disc herniation by hermantin et al.,24 satisfactory results of 97% in endoscopic group (n=30) and 93% in open laminectomy group (n=30) were reported. however, in endoscopic group, these authors had excluded large central herniations and extra ligamentous herniations between l5 and first sacral vertebra. however, present endoscopic technique could be used for all levels and all type of herniations. in our current series, there was 5% discitis and 5% incidence of dural injury. caspar and ebling,2526 authors have reported reoperation rate of 5.5, 5.7, and 3%, respectively. another measure of success is reflected by the patient's ability to return to previous employment. our patients returned to previous employment on an average at 15 days with restriction to avoid heavy manual work for 2 months. discectomy (med) by endospine system has claimed even lesser tissue invasion than microdiscectomy with even smaller skin incision, lesser use of analgesics, and early return to work. least tissue invasion is established by many reports comparing the postoperative mri signal of paraspinal muscles,27 intraoperative electromyographic findings establishing less invasion to nerve roots,28 and by measuring serum levels of biochemical parameters reflective of a postoperative inflammatory reaction and damage to the paravertebral muscles.29 our personal opinion is similar, though this was not the parameter studied in our series. minimal invasive microendoscopic decompression technique has been used not only for paracentral disc herniations, but also for all types including far lateral, cephalad, caudal migrated, and central and recurrent disc herniations.3032 one of the driving forces behind the minimal invasive spine surgery is economics, shorter hospital stay, reduced postoperative morbidity, and quicker recovery times. in our series, 90% patients were operated as day care cases. posterior paraspinous process endoscopic access to lumbar disc herniation requires creation of working space where no or little space existed before. internal view of operating site is magnified and well illuminated. with advent of this system, discectomy can be done as day care procedure ensuring reduced postoperative morbidity, minimal or no hospitalization, less pain, and faster recovery. with proper patient selection, discectomy and adequate nerve root decompression by doing foraminotomy or opening a lateral recess stenosis by minimally invasive technique can be achieved with this system. however, the endospine system has been excellent modality to address discogenic radiculopathy and to decompress lumbar canal stenosis. many surgeons are convinced of advantages of the system and have included this system as part of their inventry. however, due to difficulty in orientation with scope and two-dimensional vision, availability of less space, frustrating and steep learning curve, and inability to master hand eye coordination, majority of surgeons are not able to continue with the technique. the patience and persvrance to work through narrow confines and work closely with a surgeon who has mastered the technique is the key to learn. second step would be to become comfortable with 2 dimensional vision of endoscopic camera and to master orientation, triangulation. depth perception in these techniques comes from experience rather than observation; hence, surgeon keen to learn these techniques must combine these procedures during early phase of learning with standard procedures he is doing in his clinical practice. gradually, as surgeons master the learning curve, he will be able to use this as treatment method for his patients. there is also a need to establish cadaveric labs and dummy models on line of arthroscopic learning centers where surgeons can practice hands-on cadavers and models to improve triangulation, depth perception, and hand eye coordination. | background: posterior endoscopic discectomy is an established method for treatment of lumbar disc herniation. many studies have not been reported in literature for lumbar discectomy by destandau endospine system. we report a series of 300 patients operated for lumbar dissectomy by destandau endospine system. materials and methods: a total of 300 patients suffering from lumbar disc herniations were operated between january 2002 and december 2008. all patients were operated as day care procedure. technique comprised localization of symptomatic level followed by insertion of an endospine system devise through a 15 mm skin and fascial incision. endoscopic discectomy is then carried out by conventional micro disc surgery instruments by minimal invasive route. the results were evaluated by macnab's criteria after a minimum followup of 12 months and maximum up to 24 months. results:based on modified macnab's criteria, 90% patients had excellent to good, 8% had fair, and 2% had poor results. the complications observed were discitis and dural tear in five patients each and nerve root injury in two patients. 90% patients were able to return to light and sedentary work with an average delay of 3 weeks and normal physical activities after 2 months. conclusion:edoscopic discectomy provides a safe and minimal access corridor for lumbar discectomy. the technique also allows early postoperative mobilization and faster return to work. | PMC3270611 |
pubmed-7 | squamous cell carcinoma of the head and neck (hnscc) is a heterogeneous disease that includes tumors arising from the mucosal epithelial surface of the oral cavity, oropharynx, hypopharynx, and larynx. although these tumors originate within different anatomic sites within the upper aerodigestive tract, they are histologically identical (95% of hnscc are squamous cell carcinomas), share common etiologic risk factors and overlapping metastatic target site profiles (reviewed in [13]). recent genetic analysis of human head and neck tumors has revealed common molecular alterations including p53 mutation, p14arf, and p16 methylation, as well as cyclin d and egfr amplification [36]. despite these similarities, the distinct anatomic subsites are associated with differing rates of regional metastasis for example, vocal cord lesions tend to metastasize less frequently than oropharyngeal or hypopharyngeal lesions. this variation may be attributed to differing densities of lymph draining vessels within each of the relevant subsites. patients who exhibit metastases into the regional nodal basin exhibit a 50% decrease in survival irrespective of treatment [715]. currently, it is the 5th leading cause of cancer by incidence and the 6th leading cause of cancer mortality in the world [16, 17]. recurrent and/or metastatic hnscc patients have a poor prognosis, with a median survival of less than 1-2 years [18, 19]. several lines of evidence indicate that cancer is a disease resulting from dynamic changes in the genome that promote the progressive transformation of normal human cells into highly malignant derivatives [20, 21]. during this process, cancer cells acquire several unique capabilities including self-sufficiency in response to growth signals, insensitivity to antigrowth signals, evasion of programmed death (apoptosis), limitless replicative potential, sustained angiogenesis as well as invasion and metastasis, reprogramming of energy metabolism, and avoiding immune destruction [21, 22]. detailed global genomic analyses of several human tumors has revealed that certain classes of signaling proteins appear to be targeted more frequently by oncogenic mutations. receptor tyrosine kinases (rtks) are a good example. of the 59 transmembrane rtks identified to date, dysregulation of ~30 rtks are associated with neoplastic transformation and cancer progression [2325]. interestingly, ninety percent of primary head and neck squamous cell cancers, irrespective of subsite, have alterations in members of the epidermal growth factor (egf) family of receptor tyrosine kinases (erbbs), in particular erbb1/egfr. ten to fifteen percent of tumors will also have an alteration in another egfr family member, the erbb2/her2/neu receptor [27, 28]. these findings suggest a strong etiologic role for rtk dysregulation in this type of tumors. given this association, patients with head and neck squamous cell cancers are well positioned to benefit from existing and future molecular targeted agents directed against oncogenic rtks such as egfr (reviewed in). rtks are a family of transmembrane proteins that mediate many important physiological processes in both normal and cancerous cells. ligand binding to the extracellular domain of rtks induces receptor dimerization and activation of rtk activity. subsequent autophosphorylation of the receptor at specific tyrosine residues within the cytoplasmic domain generates binding sites for proteins that relay downstream biological signals to regulate protein function, protein-protein interactions, and gene expression. under physiological conditions, rtk dysregulation can occur through several mechanisms including gene amplification or rtk overexpression, chromosomal translocation to produce constitutively active rtks, gain of function mutations or deletions that promote ligand-independent rtk activity, escape from negative regulatory mechanisms or local environmental changes, all of which lead to potent oncogenic signaling and hence neoplastic growth. these complex signaling networks use multiple factors to drive the outcome of rtk signaling. although often depicted as linear pathways, they actually represent an integrated network with various modes of cross-talk, overlapping and distinct functions. known signaling pathways involved in head and neck tumorigenesis include the phosphatidylinositol-3-kinase (pi3k)-akt-mammalian target of rapamycin (mtor), signal transducer and activator of transcription (stats) and raf kinase-mitogen-activated protein kinase kinase (mek)-p42/p44 mitogen activated protein kinase (mapk) signaling pathways [1, 30]. this review highlights three rtk signaling pathways involved in head and neck squamous cell carcinoma; egfr, the type 1 insulin-like growth factor receptor (igf-1r) and the hepatocyte growth factor (hgf) receptor (met). this short review will explore the relative contribution of each signaling axis to disease progression, potential modes of cross-talk, and targeted clinical approaches under investigation for disease management. the egfr family of rtks is comprised of four different receptors known as erbb1 (also referred to as egfr), erbb2 (her2/neu in rodents), erbb3 (her3), and erbb4 (her4) (reviewed in [3133]). each receptor, with the exception of erbb3, contain an intracellular tyrosine kinase domain that is activated by binding to extracellular egf-like ligands, which result in receptor dimerization and hence activation of downstream signaling cascades including mapk, pi3k/akt and stat signaling. eleven egf-like ligands have been identified to date that can be categorized into four groups those that bind egfr only (egf, transforming growth factor alpha (tgf), and amphiregulin), those that bind to egfr and her4 (heparin binding-egf, betacellulin and epiregulin), those binding directly to either her3 and her4 (neuregulin 1 and neuregulin 2) and her4 binding only (neuregulin 3 and neuregulin 4) (reviewed in). epigen, the most recently discovered member of the egf-like ligand family appears to be a low affinity and broad specificity ligand that effectively activates egfr. erbb2 is considered a ligand-less coreceptor as it does not have any known ligands that bind directly with high affinity, despite its established role as a potent oncogene in several cancer types including breast, colorectal, nonsmall cell lung carcinoma (nsclc) and hnscc [36, 37]. aberrant egfr activity has been strongly linked to the etiology of 5890% of hnscc [26, 38]. these rates can vary due to the inclusion of cancers from different subsites within the head and neck, methods used to assess gene amplification and tumor scoring methods. in contrast to lung adenocarcinomas in which activating egfr mutations result in ligand-independent signaling [3943], such activating egfr mutations are infrequent in hnscc [44, 45]. egfr gene amplification resulting in upwards of 12 copies per cell has been reported in hnscc patients compared to copy numbers detected in normal mucosa from noncancer patients. this and other pathways of ligand-independent receptor activation that do not require egfr overexpression have been characterized as the likely drivers of egfr activity in hnscc. egfr gene amplification remains a strong indicator for poor patient survival, radioresistance, and locoregional failure [4749]. egfr overexpression is detected in healthy mucosa in cancer patients (field cancerization) that will increase in proportion to observed histological abnormalities such as hyperplasia, carcinoma in situ and invasive carcinoma, indicating that it is an early event in hnscc. accordingly, significant effort has focused on egfr signaling as a therapeutic target for treating hnscc patients. cetuximab, matuzumab and nimotuzumab represent humanized antiegfr antibodies, whereas gefitinib and erlotinib are small tyrosine kinase inhibitors (tkis) (figure 1). cetuximab (erbitux) competitively inhibits endogenous ligand-binding to egfr and thereby inhibits subsequent receptor activation [5053]. cetuximab is a valuable treatment option in head and neck patients as it synergizes with current treatment modalities. cetuximab enhances the effects of many standard cytotoxic agents, including cisplatin (the conventional platinum-fluorouracil chemotherapeutic), and in combination with chemotherapy it can elicit antitumor responses in tumors that previously failed to respond to that chemotherapy. notably, cetuximab did not dramatically exacerbate the common toxic effects associated with radiotherapy of the head and neck, including mucositis, xerostomia, dysphagia, pain, weight loss, and performance status deterioration. cetuximab has been approved for use in combination with radiation for treating patients with locally advanced hnscc and as monotherapy for patients with recurrent hnscc. matuzumab (formerly emd 72000) binds to egfr with high specificity and affinity to block receptor signaling, and also modulates antibody-dependent cellular cytotoxicity (adcc) when combined with cetuximab [5860]. phase i clinical trials report excellent antitumor activity of matuzumab against several human tumor types including head and neck cancers. a randomized phase iib, four-arm, open-label study recently assessed the safety and efficacy of nimotuzumab in combination with radiation therapy (rt) or chemoradiation therapy (crt) in patients with advanced (stage iii or iva) hnscc. the addition of nimotuzumab to both the radiation and chemoradiation regimens was reported to improve the overall response rate, survival rate at 30 months, median progression-free survival and median overall survival. a combined group analysis of the nimotuzumab arms versus the non-nimotuzumab arms demonstrated a significant difference in overall survival favoring nimotuzumab. this study is compelling as patient response rates compare favorably with studies combining cetuximab with radiotherapy, but with fewer side effects. gefitinib (iressa) is a small molecule tki-targeted to the intracellular active site for phosphorylation that has been tested in clinical trials involving hnscc patients, as a single agent or in combination with radiation treatment. unfortunately, gefitinib has shown limited clinical efficacy with response rates of 1015% [63, 64]. erlotinib is a selective inhibitor of the egfr that also shows antitumor activity in hnscc comparable to standard combination chemotherapy. another promising rtk under preclinical and clinical evaluation for head and neck cancers includes the igf-1r (reviewed in [66, 67]). two ligands, insulin-like growth factor 1 (igf1) and igf2 bind to igf-1r. ligand binding to the igf-1r stimulates its intrinsic tyrosine kinase activity, activating downstream signaling networks including ras-raf, mapk and erk, and pi3k (figure 1) to drive cellular functions such as cell growth, survival and differentiation. it is widely accepted that the igf-axis activates antiapoptotic signaling, which in turn upregulates the pi3k-akt and mapk pathways in cancer cells. additionally, igf-ir also regulates vascular endothelial growth factor (vegf) production, suggesting a role in tumor angiogenesis. several studies indicate that igf-1r is overexpressed and functional in 94% of hnscc patient samples [70, 71]. consistent with this, igf-ir signaling significantly enhances the proliferation, motility and tumorigenicity of human head and neck cancer cell lines. igf-1r down regulation in a hnscc cell line using antisense oligonucleotides resulted in a dose-dependent decrease in cellular proliferation, induction of apoptosis, caspase activation and reduced expression of proangiogenic cytokines such as vegf. interest in targeting the igf-1r in hnscc was bolstered by the observation that treatment of head and neck cancer cells with either igf or egf resulted in igf-ir and egfr heterodimerization [71, 72]. however, only igf resulted in the phosphorylation of both receptors. using a mouse xenograft model for hnscc, treatment with antibodies against igf-1r, egfr or it remains to be determined whether cellular cross-talk between igf-1r and egfr has an important role in determining the biological aggressiveness of hnscc or resistance to egfr-targeted therapies. several monoclonal antibodies and tkis for igf-1r have been tested in preclinical studies and early phase clinical studies. however, the efficacy of igf-1r-targeted therapy for treating patients with hnscc, particularly cross-talk with egfr, warrants further investigation. to date, the effect of blocking oncogenic igf-1r and egfr signaling have been studied more extensively in breast cancer cell lines [7375]. treatment with gefitinib and ag1024, a tki for igf-1r reduced cell proliferation when used as single agents and showed an additive effect when used in combination [76, 77]. targeting igf-1r and egfr signaling is currently under evaluation in hormone-sensitive metastatic breast cancer using the igf-1r inhibitor osi-906 and the egfr tki erlotinib, although results are not yet available (http://www.clinicaltrials.gov/, identifier nct01205685). similarly, an exploratory study to assess the modulation of biomarkers in hnscc patients treated preoperatively with cetuximab and/or imc-a12, a humanized antiigf-1r monoclonal antibody is currently underway (http://www.clinicaltrials.gov/, identifier nct00617734). these studies will be critical for evaluating whether the use of anti-igf-1r and egfr-targeted treatments will be more effective than single-agent modalities for treating patients with hnscc. the met receptor is a single pass transmembrane protein that upon binding its ligand hgf also known as scatter factor-promotes increased cell proliferation, survival and motility (reviewed in [78, 79]). hgf is the only physiological ligand for met and is secreted as an inactive precursor polypeptide chain by mesenchymal cells. hgf is proteolytically cleaved to form an active/heterodimer by a number of serine proteases including urokinase plasminogen activator (upa), tissue-type plasminogen activator (tpa), coagulation factors x. xi and xii. met is a disulphide-linked/heterodimer derived from the proteolytic cleavage of a 170 kda precursor. the chain and n-terminal region of the -chain form sema domain, a seven -propeller structure in which blades 2 and 3 bind to hgf. the sema domain is flanked by a cysteine-rich region followed by four immunoglobulin repeats. it is proposed that the cysteine-rich region and immunoglobulin repeat domains undergo a conformational change following hgf binding allowing for met dimerization [80, 81]. binding of hgf to met results in receptor autophosphorylation at key catalytic residues and subsequent recruitment of several cytosolic signaling molecules that are shared with the egfr and igf-1r signaling pathways, including the grb2/sos complex, the p85 regulatory subunit of pi3k, gab1 and jak/stat3 (figure 1). subsequent activation of the mapk and jun-n-terminal kinase (jnk) pathways is responsible for the mitogenic and motogenic properties of met/hgf signaling resulting in invasive growth, depending on the physiological setting. increased met signaling in human cancers can be the result of enhanced ligand-binding (autocrine and paracrine), met overexpression or missense mutations that often induce constitutive kinase activity, failure of met down regulation and interactions with other cell surface receptors such as egfr (reviewed in [8284]). met is overexpressed in 84% of hnscc patient samples. interestingly, amplification of the met gene (> 10 copies per cell) is present only in 3 of 23 (13%) tumor tissues. hgf overexpression is detected in 45% of hnsccs, suggesting that hgf functions predominantly in a paracrine manner to drive met signaling in these cancers. moreover, high levels of hgf are detected in hnscc patient plasma samples supporting the idea that ligand availability is not a limiting factor for met activation. mutations in the met ligand-binding domain (t230m/e168d), transmembrane or jm domain (r988c, t1010i) and the tyrosine kinase domain (t1275i, v14333i) have also been identified in hnscc tumor samples, although their relative contribution to hnscc progression remains to be determined. two somatic met mutations have been detected in hnscc that result in constitutively active receptor signaling that confers an invasive phenotype when ectopically expressed in cell lines. the y1230c mutation confers anchorage-independent growth and an invasive phenotype in transfected cells, whereas the y1235d met mutation stimulates epithelial cells to invade reconstituted basement membrane in the absence of hgf. in the case of the mety1235d mutation, genomic analyses of hnscc patient samples detected the presence of this mutant allele in 50% of metastatic tumors versus 26% in primary tumors, raising the possibility that this could be a critical genetic lesion for the acquisition of a metastatic phenotype. alternatively, increased met signaling could afford hnscc a selective advantage for growth and/or survival in metastatic sites, such as the lymph node and lung. indeed several studies indicate that met overexpression correlates highly with lymph node metastasis, pathologic stage, and disease reoccurrence [8891]. moreover, patient survival was significantly reduced in biopsy samples with positive met expression relative to negative met expression, suggesting the association of met with hnscc disease progression. consistent with these findings, treatment with the tki pf-2341066 caused a significant reduction in tumor growth, a high level of apoptosis and cellular debris within the tumor using a xenograft animal model for hnscc. selective inhibitors of met/hgf signaling include humanized monoclonal antibodies for hgf and met, and small-molecule tyrosine kinase inhibitors directed against met (figure 1). although their efficacy for treating a variety of solid tumors is increasingly recognized, we await results of preclinical and clinical trials for head and neck cancer that are ongoing. the humanized antibody amg 102 shows high potency towards the mature and processed form of hgf with no detected effects on proteolytic activation of prohgf. amg 102 interferes with met signaling, by competing with hgf for binding to the chain of the met receptor. in phase i clinical studies in patients with advanced solid tumors, 70% of patients had a best response in terms of achieving stable disease [93, 94]. importantly, no antiamg 102 antibodies were detected and circulating hgf levels were dose dependent. another promising clinical therapeutic is the one-armed 5d5 humanized antibody (oa5d5/metmab) directed against met. metmab binds met with high affinity, preventing hgf binding, met phosphorylation, receptor internalization and downstream signaling events and has been shown to inhibit tumor growth in animal models by more than 95% [95, 96]. metmab is currently in phase i/ii human clinical trials in comparison with erlotinib in patients with nsclc (http://www.clinicaltrials.gov/, identifier nct00854308). future clinical trials will be required to determine the suitability of amg102 and metmab as either single agents or combinatorial therapeutics for treating hnscc patients. foretinib (formerly xl880) is a tki whose primary targets include met and vegf, and to a lesser extent the platelet-derived growth factor (pdgf) receptor, ron, kit and tie2 rtks. foretinib recently completed phase ii clinical trials in head and neck patients (http://www.clinicaltrials.gov/, identifier nct00725764). interim results suggest that after 12 months, 12 of 18 patients had stable disease. a phase i dose-escalation study of the safety and pharmacokinetics of xl184 administered orally to patients with advanced malignancies (showed that, on average, patients survived for more than 3 months with several up to 6 months while on treatment) (reviewed in). due to encouraging data from this study, a randomized phase iii trial of xl184 in hnscc patients was initiated to investigate xl184 as a first-line treatment (compared with placebo) for survival benefit to patients with hnscc (http://www.clinicaltrials.gov/, identifier nct00704730). arq197 (arqule) is a nonatp-site competitive, selective small molecule inhibitor of the met intracellular region. although the mechanism of arq197 is presently unknown, the results of phase i trials suggest potential antiinvasive activity for this compound. overall, met, and hgf-targeted therapies have been well tolerated in clinical trials with negligible toxicities. however, it remains to be determined whether met is a better therapeutic target than hgf. clearly, in patients where met is activated by autocrine hgf secretion, both hgf and met targeted therapies may prove to be more efficacious treatment options. acquired resistance is likely the result of several mechanisms including (1) egfr mutations initially present as well as those acquired during therapy, (2) receptor independent activation of downstream signaling cascades, (3) cross-talk with other rtks and converging signaling pathways and (4) environmental factors including inflammatory agents and viral infection. resistance to cetuximab has been associated with the coexpression of the truncated egfr mutant, egfrviii with wild-type egfr. egfrviii is the result of an in frame deletion of exons 27 spanning the extracellular ligand-binding domain. the deletion results in a truncated egfr receptor that signals in a ligand-independent manner. egfrviii expression has been detected in 42% of hnscc patient samples, and closely correlates with increased hnscc cell proliferation in vitro and increased tumor growth using in vivo xenograft models. egfrviii preferentially activates the pi3k pathway instead of the ras/raf/mek pathway, which is activated by wild-type egfr. of particular interest to the therapeutic treatment of hnscc, egfrviii expression decreases the proliferative response of egfr expressing tumor cells to cetuximab treatment relative to vector control cells. in a recent study, egfrviii cells were shown to be resistant to the antiinvasive effects of cetuximab due to an increase in phosphorylation of stat3 rather than increased pi3k signaling. egf-induced expression of the stat3 target gene hif1 was abolished by cetuximab in hnscc cells expressing wild-type egfr under hypoxic conditions, but not in egfrviii-expressing hnscc cells [102, 103]. these data suggest a role for egfrviii in mediating hnscc resistance to cetuximab. despite egfrs critical role in the development of hnscc, clinical data indicate modest clinical benefits for locoregional control and survival of head and neck cancer patients treated with egfr-targeted therapies. hnscc patients resistant to cetuximab, often succumb to local tumor recurrence as well as regional and distant metastasis. the addition of cetuximab to radiation therapy was reported to show improved locoregional disease control, progression-free survival, and overall survival in patients with locally advanced hnscc. however the data revealed a disproportionate benefit of cetuximab with radiotherapy to oropharyngeal cancer patients when compared to patients treated with hyperfractionated radiotherapy. accumulating evidence suggests that human papilloma virus (hpv) 16 status (hpv+) is an important prognostic factor associated with a favorable outcome in a subset of head and neck cancers, including oropharyngeal and tonsilar cancers. hpv+ tumors tend to have unique genetic aberrations including decreased egfr expression, whereas increased igf-1r levels characteristic of hnscc appear to be independent of hpv status. clinically, hpv+ tumors are characterized by more favorable patient prognosis regarding disease-free survival as well as overall survival [104, 105], possibly as a result of increased genomic stability associated with global gene hypermethylation in hpv+ tumors. thus it will be interesting to determine whether hpv+ status explains some of the benefits derived from the addition of cetuximab to radiotherapy in this subset of hnscc patients. at present, there are few clinical indicators of which hnscc patients will most likely respond to egfr-targeted therapies. accordingly, strategies to optimize egfr-targeted therapy remain an active area of research. additional mechanisms that result in egfr activation include activating mutations in downstream signaling components or cross-talk between different rtk pathways. activating mutations in the pi3ka oncogene occurs in 10% of hnscc tumors whereas elevated levels of phosphorylated stat3 correlates with lymph node metastasis and poor patient prognosis [108110]. conversely, h-ras mutations are infrequent in hnscc cases (less than 5%), although a higher incidence has been detected in asian populations and correlates with areca nut chewing [111, 112]. met signaling has been shown to contribute to resistance in cell lines derived from multiple tumor types including breast, gastric and lung. in one key study, nsclc with activating mutations in the egfr acquire resistance to the tki gefitinib and erlotinib, by amplification of the met gene to maintain akt and her3 signaling. these studies underscore the role of cross-talk between rtks to preferentially signal through the pi3k-akt survival pathway as a mechanism for acquired drug resistance. the relevance of met as a mechanism for escape from egfr-targeted therapy in head and neck cancers remains to be determined. hypoxia results in the transcriptional upregulation of met gene expression via hif1 in a number of tumors including head and neck, often downstream of egfr signaling. in normoxia, hydroxylation of 2 prolines in hif1 enables its binding to the von hippel-lindau tumor suppressor protein (pvhl) linking hif1 to a ubiquitin ligase complex. during hypoxia, minimal or no hydroxylation occurs enabling hif1 to avoid proteasomal degradation and dimerize to other hif family members such as hif1 and coactivators, to form an active transcriptional hif complex on the hypoxia response element (hre) of target genes such as met. the ubiquitin ligase catalyzes polyubiquitination of hif1 targeting it for proteasomal degradation. under hypoxic conditions, increased met signaling directs the invasive growth program, enabling cells to invade more oxygenated tissues. since met has been reported to promote invasive and angiogenic effects in the tumor microenvironment, the use of hgf/met inhibitors may afford a means of impairing tissue colonization as well as tumor vascularization in head and neck cancer patients. studies on other solid tumor types, most notably glioblastoma, indicate a role for igf-1r upregulation in resistance to egfr-targeted therapies. igf-1r mediates resistance to anti-egfr therapy in primary glioblastoma through the continued activation of the pi3k/akt survival pathway. the apparent cooperation between igf-1r and egfr in promoting hnscc pathogenesis as well as resistance to egfr-targeted therapy, suggests an advantage to cotargeting these signaling axes for the treatment of head and neck cancers. to date, the effect of blocking oncogenic igf-1r and egfr signaling have been studied more extensively in breast cancer lines. treatment with gefitinib and ag1024, a tki for igf-1r reduced cell proliferation when used as single agents and showed an additive effect when used in combination [76, 77]. targeting igf-1r and egfr signaling is currently under evaluation in hormone-sensitive metastatic breast cancer using the igf-1r inhibitor osi-906 and the egfr tki erlotinib, although results are not yet available (http://www.clinicaltrials.gov/, identifier nct01205685). similarly, an exploratory study to assess the modulation of biomarkers in hnscc patients treated preoperatively with cetuximab and/or imc-a12, a humanized antiigf-1r monoclonal antibody is currently underway (http://www.clinicaltrials.gov/, identifier nct00617734). these studies will be critical for evaluating whether the use of antiigf-1r and egfr-targeted treatments will be more effective than single-agent modalities for treating patients with hnscc. targeted therapies that block egfr, met, and igf-1r signaling in head and neck cancers continue to show promising results in preclinical studies and clinical trials. however, it is difficult to predict which patients are most likely to benefit from these therapeutics and potential side effects during long-term in vivo use. given the interplay between these rtk signaling pathways and the mediocre results obtained with monotherapy regimens thus far, clinical trials will be required to determine how egfr-, met-, and igf-1r-targeted therapies can be used in combination in order to definitively abrogate their common downstream oncogenic signaling networks. although gaps in our knowledge concerning the role of met and igf-1r in head and neck tumorigenesis, as well as acquired resistance to antiegfr therapies remain to be addressed, efforts to translate current information towards clinical applications continue to be impressive. | molecular therapeutics for treating epidermal growth factor receptor-(egfr-) expressing cancers are a specific method for treating cancers compared to general cell loss with standard cytotoxic therapeutics. however, the finding that resistance to such therapy is common in clinical trials now dampens the initial enthusiasm over this targeted treatment. yet an improved molecular understanding of other receptor tyrosine kinases known to be active in cancer has revealed a rich network of cross-talk between receptor pathways with a key finding of common downstream signaling pathways. such cross talk may represent a key mechanism for resistance to egfr-directed therapy. here we review the interplay between egfr and met and the type 1 insulin-like growth factor receptor (igf-1r) tyrosine kinases, as well as their contribution to anti-egfr therapeutic resistance in the context of squamous cell cancer of the head and neck, a tumor known to be primarily driven by egfr-related oncogenic signals. | PMC3135278 |
pubmed-8 | global and regional left ventricular (lv) functions are well-known indicators of cardiac disease. quantitative values of ventricular volumes and of myocardial mass are independent predictors of morbidity and mortality in patients with coronary artery disease. classically, echo has been used to evaluate lv volume and function because it is relatively inexpensive and noninvasive. however, a component of operator dependence and poor contrast between blood and myocardium are considerable limitations of this technique. cardiac magnetic resonance imaging (mri) is considered the clinical gold standard for lv function assessment, but it is expensive, of limited availability, and can not be performed in patients with implanted pacemakers or defibrillators. in recent years, multidetector ct (mdct) has gained acceptance as a promising imaging method for coronary arteries. mdct acquired in a single breath-hold with retrospective electrocardiogram (ecg) gating can cover the entire heart with 1-mm slice thickness with a temporal resolution of 125-250 ms. when performed for coronary imaging, this method provides excellent opportunity to create, image reformation in any desired plane, including anatomically optimized long axis, short axis, or four-chamber views. diastolic and systolic images can easily be produced from the same data set with a retrospective ecg-gating technique, thus obtaining lv end-diastolic and end-systolic volumes (edvs and esvs). mdct has a potential of being utilized as tool for the combined assessment of the coronary anatomy and lv function. in addition, ventricular wall motion can be assessed visually by the use of cine loop displays of multiple cardiac phases. recently we observed increasing tendency for utilizing low radiation dose, prospective gating for coronary angiography, thus limiting possibility of volumetric assessment of ventricular function. however, a small number of patients may need a retrospective gating, thus providing possibility of reconstructions in various phases of cardiac activity. according to published reports, measurements for various lv functional parameters with mdct were well-correlated and agree with measurements obtained with mri, two-dimensional transthoracic echocardiography (2d-tte), and ecg-gated single photon emission ct (spect). experience with 64-slice mdct for cardiac function assessment remains limited by small patient numbers and the inclusion of homogeneous patient populations. the purpose of this study was to assess lv ejection fraction (lvef) using 64-slice as a byproduct of mdct coronary examination and to compare efficacy of technique with 2d-tte in a heterogeneous patient population. also, review the role of mdct lv function with a relation to evolution in the technology of coronary mdct imaging. study included 113 patients referred for 64-slice mdct coronary angiography for evaluation of coronary artery disease. all patients were scanned on 64 slice ge-helical ct (ge high speed advantage) scanner and had an echo done within 1 week of the ct scan. this prospective study was approved by the institutional review board and written informed consent was obtained from all patients. patients with absolute contraindication to contrast or radiation were excluded from the study. in patients with relative contraindications such as atopy, asthma, and renal failure scan was performed if the benefit of examination outweighed the risk in such patients. patients with arrhythmias and ectopic heart beats were excluded as stable heart rate is required for ct coronary angiogram. apart from the routine contraindications, patients with pacemaker and ventricular septal defect were excluded from the study as successful segmentation of the lv blood pool is not possible in these patients due to artifacts and incorrect segmentation by software. all patients undergoing ct coronary angiogram, who had heart rate of more than 60 bpm, were premedicated with 50-200 mg oral b adrenergic blocking agent: metoprolol, 1-h prior to the study. a 60-120 mg calcium channel blocker: diltiazem, cta was performed with contrast volume of 1.2 ml/kg body weight of iohexol 350. the intravenous contrast agent was followed by 30 ml of saline chaser bolus at the same injection rate. scan parameters were 0.35 s rotation time, 120 kv tube voltage, 600-800 effective ma, 0.6 mm collimation, and a helical pitch of 0.22:1. the image acquisition was caudocranial for post-coronary artery bypass grafting (cabg) patients and craniocaudal for the rest of the patients. no complications encountered in any of the patients. retrospectively, ecg-correlated image reconstruction was performed. the reconstruction was performed with the reconstruction window starting at 10% of r-r interval and up to 90% r-r interval with increment of 10%. this included data sets reconstructed in systole, if diastolic data sets showed motion artifact. diastolic and systolic axial image sets were then transferred to the scanner's workstation-ge advanced workstation advantage windows 4.4 p. image data were evaluated with a prototype version of a commercially available program (auto ejection fraction, circulation; ge medical solutions) that performs a fully automatic segmentation of the blood volume in the lv by defining the mitral valve plane and the lv. the software uses this mitral valve plane as an upper boundary for the segmentation of the lv. the software identifies the hinges of the mitral and aortic valve leaflets closest to the ventricle wall and selects these as defining points for the plane [figure 1a]. all ct scans were analyzed according to this method, which allowed for optimal segmentation of the lv. papillary muscles were automatically excluded from the blood pool, which allows for precise determination of blood volume in the lv. multiplanar reformats are then performed by the software in long and short axes of left ventricle. the long axis image is obtained parallel to the interventricular septum connecting the lv apex and the middle level of mitral valve. the short axis images are obtained parallel to the plane of mitral valve [figure 1b]. lv=left ventricular (b) line perpendicular to long axis of left ventricle (parallel to mitral valve) plane for short axis images once the region of interest is finalized, the edv and esv are measured by this software using simpson's method by summing the endocardial area of all lv ed and es short-axis slices multiplied by the slice thickness [figure 2a and b]. the stroke volume (sv) and ef were automatically calculated from these values and displayed by the software [figure 3a d]. (a) lv short axis image in diastole (b) short axis image in systole 3d display of volumetric data in different patients. (a) patient 1: left ventricular ejection fraction by ct 58.4% (echo 58%). (b) patient 2: left ventricular ejection fraction by ct 55.7% (echo 53%). (c) patient 3: left ventricular ejection fraction by ct 60.0% (echo 60%). (d) patient 4: left ventricular ejection fraction by ct 38.3% (echo 35%). 3d=three-dimensional, echo=echocardiography, ct=computed tomography two-dimensional echo examination was performed either 1 week before or after coronary cta in either of two ultrasound units, an acuson sequoia (siemens medical systems usa, mountain view, ca) or a ge vivid 3 (ge healthcare, milwaukee, wi). images were obtained using a 3.5 mhz transducer and images were acquired in standard apical and parasternal two- and four-chamber views. the chamber and wall dimensions were measured using standard recommendations for chamber quantification in consensus. results on continuous measurements are presented on mean sd (min max) and results on categorical measurements are presented in number (%). the mean standard deviation (sd) lvef calculated by clinical echo similarly mean sd of lvef calculated by fully automated software based on cta data was obtained [table 2]. agreement for lvef was determined by the use of pearson's regression analysis [figure 4] and calculating correlation coefficient (r). bland-altman analysis [figure 5] was used to compare the lvef measured with mdct and that with 2d-tte. mountain plot [figure 6] was used to see the relationship between two groups. echo-ejection fraction (ef) mean standard deviation (sd): 58.67 4.53, echo=echocardiography ct-ejection fraction (ef) mean standard deviation (sd): 58.93 5.43, ct=computed tomography pearson regression analysis between echo-ef and ct-ef. r=pearson correlation coefficient, p=p-value, ef=ejection fraction bland and altman showing the correlation of echo-ef and ct-ef sd=standard deviation mountain plot showing the correlation of echo-ef and ct-ef. in our study, 86 (76.1%) were males and 27 (23.9%) were females. the mean age of the patients was 51.19 10.10 years and majority of subjects belonged to age group between 51 and 60 years. 28.3% were between 41 and 50 years, 15.9% subjects were between 61 and 70 years, and 12.4% subjects between 31 and 40 years. most of the patients had at least one symptom, the commonest being chest pain in 88 (77.9%) cases. the most common coronary risk factor association was hypertension, accounting for 77.9% of the cases. the mean heart rate of the patients at the time of scan was 61.5 8.6 bpm with maximum patients having a heart rate range of 61-70 bpm. the mean lvef calculated by clinical echo was 58.67 4.53% with maximum number of patients having an ef range of 56-60%. the mean lvef calculated by fully automated software based on cta data was 58.93 5.43% with maximum number of patients having an ef range of 61-65%. in our study using the fully automated software, the pearson's regression analysis showed a good interstudy correlation, with a correlation coefficient of 0.503 (p<0.001). bland-altman analysis showed a trend towards mdct resulting in slightly higher values for lvef when compared with echo; however, this observation was not statistically significant. the mountain plot analysis reinforced that ef measured by ct correlated well with that measured by echo. mdct coronary angiography has emerged as a valuable technique for the evaluation of coronary artery disease in patients with low to intermediate pretest probability of ischemic heart disease. utilizing analytic software, gated volumetric ct data can be processed to provide quantitative functional analysis of the lv in patients with coronary artery disease. we were able to obtain satisfactory artifact free datasets from 113 consecutive subjects who underwent coronary cta. all of our patients were either known cases of coronary artery disease or had suggestive clinical symptoms. patients with pacemaker, ventricular septal defect were excluded from the study as successful segmentation of the lv blood pool was not possible. achieving a stable heart rate for the examination was variable component of the examination. however, no examination had to be postponed or cancelled due to this limitation. our study using automated software showed a good interstudy correlation, with a correlation coefficient of 0.503 (p<0.001). the bland-altman plot revealed a slight mean difference between ef measurements on ct and echo with most differences falling within two sds of the mean. hence, we found that software is user-friendly and capable of providing good reproducibility for ef measurements in comparison with echo. in a previous study by krishnam et al., similar results were recorded, though the number of subjects was small. in a study by cury et al., a trend of mdct slightly underestimating lvef compared with tte was observed. we observed a trend towards mdct resulting in slightly higher values for lvef when compared with echo, contrary to expected mild reduction in beta blocked patients. trend however was not statistically significant, could be due to recognized limitation of evaluation technique leading to over or underestimation. mean difference in ef measurements between cta and echo is small; although standard deviation of the mean difference is quite high, leading to wide limits of agreement. possibly observation results from the fact that the ef measurements from echo were obtained in a clinical setting, on visual estimation and calculation of ef using simpson's method based on geometrical assumptions. our observations are in accordance with the previous studies of 64-slice coronary ct, confirming that lvef estimation is feasible with the mdct data and may be regarded as a useful clinical index, correlating with results of echo. there are studies with semiautomated software for quantitative functional analysis of lv with user defined mitral valve plane and an arbitrary point within the lv, with the option to expand or reduce the area of segmentation. many earlier studies have compared the use of 4-, 8-, and 16-slice ct scanners for evaluation of lv volumes. larger detector configuration in 64-slice ct scanner, has the advantage of being faster, capable of smaller slice thickness and higher temporal resolution. relatively higher radiation dose results from the protocol optimized for thin slice high-resolution imaging of the coronary arteries. the ecg-dependent tube current modulation is currently the most effective tool for dose reduction and may reduce patient dose by up to 50%. it is important to note that two points of the cardiac cycle (end-systole and end-diastole) with modulation of tube current were not used in our study because ecg-gated dose modulation was only applicable to 50-90% of the rr interval on ecg. if the aim is to evaluate coronary arteries only, it is recommended to use an ecg-dependent dose modulation technique or newer prospective gated techniques. new developments in mdct technology is allowing examination of patients with higher heart rates and reducing the dose of beta-blockers. presently, mdct examination is possible which contains all the phases with a considerably lower dose of the order of 2-3.3 msv. the software identifies the lv blood pool based on hounsfield unit values and continuity of adjacent voxels. in patients with a ventricular septal defect, there is contrast opacification in both ventricles and a bridge of contrast through the septal defect. therefore, the software identifies the right and lv blood pools as a single chamber, resulting in incorrect segmentation and thus inaccurate assessment of lv functional parameters. in patient with pacemakers, software identifies a pacemaker wire as high-density contrast and segments the pacing wire as part of the ventricle, resulting in failed segmentation. the version of the software used for this study it was not able to segment the myocardium in order to quantify the lv myocardial mass, which may be important in certain cardiac diseases such as hypertrophic cardiomyopathy. it is important to note that cardiac mri is considered as a gold standard for lv function assessment. cardiac mri (cmri) provides excellent temporal and spatial resolution, image acquisition in any desired plane, and a high degree of accuracy and reproducibility. concerning quantitative measurements cine mri technique is potentially the most comprehensive cardiac imaging modality available because of its excellent contrast between blood-filled ventricles and the surrounding myocardium. yamamuro et al., have shown high linear correlation between ef measurements on ct and on mri. the temporal resolution of many available mdct is still considerably lower than that of echo and cine mri. this lower temporal resolution can make evaluation of isovolumetric ed and es phases of the cardiac cycle, and thus ef, less precise. there is considerable improvement in temporal resolution of mdct with improvement in gantry rotation, multiple and partial segment processing techniques. tr of 80-250 ms has been achieved in state of the art units. though it is short of fluoroscopic resolution, currently available options are more than sufficient for motion free systolic and diastolic cardiac imaging with heart rate below 100/min. additionally, the use of a b-blocker to reduce the heart rate to less than 65 bpm can influence the functional parameters that are to be measured. beta blocker do influence the lvef, lead to underestimation. overestimation or underestimation of the lv volume has been reported because of the different criteria for selecting the endocardial boundary or the inclusion/exclusion of papillary muscle. ideally estimation of the real-ef from all 20 phases is more precise; however, this significantly increases effort and processing time. effect of beta-blocker has to be factored in interpretation of ef by mdct. introduction of new ct imaging methods, including dual source ct in clinical practice will overcome these two problems significantly owing to its two-fold increase in temporal resolution. also, newer options in mdct technology may partially obviate need for use of beta blockers. functional parameters derived from 2d-tte are compared with ct derived 3d volumetric data, which are not strictly comparable. our study design did not allow realistic comparison of mdct and echo lv volume data. it would be interesting to compare the same for assessment of accuracy of respective data. with evolution of speckle-tracking 3d echography and new low radiation, high tr scanning such studies are possible. the delay time between ct and echo and premedication with -blockers could have changed myocardial contraction and lv volumes as measured with the two methods. in the present set up, the number of patients referred to coronary angiography who will have volumetric data will be significantly smaller, limiting the application of this utility to a smaller offset of patients. the radiation issue will certainly be an important consideration to use this technique in the larger group of patients. emerging new applications of echography in the form of 2d and 3d speckle-tracking echo certainly will have a greater role to play in the future noninvasive assessment of the myocardial function. in conclusion our study confirms useful complementary functional information in coronary cta datasets, using fully automated analysis software for rapid assessment of lvef. it is irrational to utilize mdct alone to assess lv function in clinical patients, given the radiation exposure involved. however, additional clinically useful information from a clinically indicated coronary ct examination with a lowest possible radiation dose is invaluable in patients known or suspected of ischemic heart disease. validating consistency of results with mri will further lend support to the use of mdct derived results. going forward with changing trends in ccta imaging, it is conceivable that number of patients undergoing cta with retrospective gating will substantially be reduced, thus limiting the functionality to a small group of patients. | background: coronary computed tomography angiography (ccta) is a frequently performed examination for coronary artery disease. when performed with retrospective gating, there is an opportunity to derive functional parameters of left ventricle utilizing automated software. complementary information, if validated with established standards, will enhance the total value of study. objective:study evaluates the usefulness of fully automated software for the assessment of left ventricular ejection fraction (lvef) using 64-slice ccta data and to correlate ct results with echocardiography (echo). role of ct derived lv function is reviewed in the light of emerging technologies and recent developments in multidetector ct (mdct). materials and methods: a total of 113 patients referred for mdct ccta for evaluation of coronary artery disease. all patients were scanned on 64 slice ge-helical ct scanner and had an echo done within 1 week of the ct scan. retrospectively electrocardiogram (ecg)-correlated image reconstruction was performed with the reconstruction at 10% r-r interval increment. axial image sets were analyzed with advanced workstation using a program-auto ejection fraction, circulation: ge medical solutions. results:the mean lvef calculated by clinical echo was 58.6 4.5% and by fully automated software based on cta data was 58.9 5.4%. the pearson's regression analysis showed a large correlation, with a correlation coefficient of 0.503 (p<0.001). bland-altman analysis showed a trend towards mdct resulting in slightly higher values for lvef when compared with echo. conclusion:the fully automated software is simple, reliable, and user-friendly, and can provide rapid assessment of lv functional parameters with good reproducibility. despite of good correlation, fewer patients are likely to benefit, in future, from this function due to smaller number of patients undergoing ccta with retrospective gating. | PMC5353405 |
pubmed-9 | moraxella catarrhalis is a gram-negative, aerobic diplococcus human mucosal pathogen which causes middle ear infections in infants and children [13], and it is one of the three major causes of otitis media along with streptococcus pneumonia and haemophilus influenzae. although moraxella catarrhalis is frequently found as a commensal of the upper respiratory tract, recently it has emerged as a genuine pathogen and is now considered an important cause of upper respiratory tract infections in healthy children and elderly people, lower respiratory tract infections in adults with chronic obstructive pulmonary disease [1, 5], and hospital-acquired pneumonia. amikacin, cefixime, fosfomycin, cefuroxime, cotrimoxazole, doxycycline, and erythromycin resistant strains of moraxella catarrhalis were isolated and the widespread production of a -1actamase enzyme renders the bacterium resistant to the penicillin [79]. this has led to the search for new and effective therapeutic alternatives among natural compounds. plants remain an important source of diverse chemical entities which have been used as drugs or provide scaffolds from which new drugs have been derived. the selection of a suitable candidate species for investigations can be done on the basis of long-term use by humans. this approach is based on an assumption that the active compounds isolated from such plants are likely to be safer than those derived from plant species with no history of human use. aristolochia is an important genus in the family of aristolochiaceae and is widespread across tropical asia, africa, and south america. it is used in traditional medicine as a gastric stimulant and in the treatment of cancer, lung inflammation, dysentery, and snakebites. it is also used in the treatment of tumors and malaria and for fevers, but its usage as an antimalarial is not recommended in its crude form. aristolochia bracteolata showed a definite positive effect on wound healing, with significant increase in the level of powerful antioxidant enzymes. the whole plant was used as a purgative, antipyretic, and anti-inflammatory. organic solvent extracts of the plant showed antibacterial activities while the water extract showed antifungal activity. although aristolochia has been used for thousands of years in many cultures for many indications due to its various pharmacological activities, it was later discovered that consuming these plants can certainly be dangerous. the genus of aristolochia contains a naturally carcinogenic compound aa which has been shown to be the cause of so-called chinese herb nephropathy or aa nephropathy [19, 20], and mutations in the cells of people who consume it, causes more mutations than two of the best-known environmental carcinogens: tobacco smoke and uv light [21, 22]. there are many cases of nephropathy reported in the literature caused by the systemic and long term application of chinese snakeroot (aristolochia fangchi); this highlighted the risk of using preparations which contain aristolochic acids. although aristolochia is being known in many countries that is containing a toxic compound aa, but this has not stopped it from being a popular herbal remedy for thousands of years. it is still extensively used in india and in traditional chinese medicine for slimming, menstrual symptoms, and rheumatism. it is also widespread used in sudan and other african countries as one of the most effective herbal remedies for infectious diseases. therefore, it was our objective to assess the potential antimicrobial activity of aristolochia bracteolata using a bioassay-guided fractionation, in order to produce pure compound that can act as the lead compound in developing new, safe, and effective drug to replace the use of the harmful crude plant material. sephadex lh-20 (pharmacia fine chemical co. ltd) was used for column chromatography. precoated silica gel plates (merck, kieselgel 60 f254, 0.25 mm) and precoated rp-18 f254s plates (merck) were used for thin-layer chromatography (tlc) analysis. high resolution fab-ms and esi-ms were recorded on jeol jms700n and jms-100td, respectively. h- and c-nmr, h-h cosy, noesy, hsqc, and hmbc spectra were recorded with a unity plus 500 spectrometer (varian inc., u.s.a.) operating at 500 mhz for h and 125 mhz for c, respectively. h-nmr chemicals shifts are expressed in values referring to the solvent peak h 2.49 for dmso and coupling constants are expressed in hz. c-nmr chemical shifts are expressed in values referring to the solvent peak c 39.5 for dmso. piperonylic acid was purchased from commercial sources (tci) and used without further purification. the plant material (whole) was collected in the period from (october to december 2012) from khartoum state in sudan. standard strains: moraxella catarrhalis (gtc 01544), klebsiella pneumoniae (atcc 13883), escherichia coli (k12), salmonella typhimurium (atcc 14028), streptococcus pyogenes (atcc 19615), streptococcus agalactiae (atcc 13813), staphylococcus epidermidis (atcc 12228), neisseria lactamicus (atcc 23970), enterobacter cloacae, (atcc 23355), bacillus subtilis (atcc 6633), staphylococcus aureus (209p), and pseudomonas aeruginosa (ifo 3445).clinical strains: moraxella catarrhalis, bacillus cereus, aeromonas hydrophila, salmonella typhi, vibrio cholerae, and yersinia enterocolitica. standard strains: moraxella catarrhalis (gtc 01544), klebsiella pneumoniae (atcc 13883), escherichia coli (k12), salmonella typhimurium (atcc 14028), streptococcus pyogenes (atcc 19615), streptococcus agalactiae (atcc 13813), staphylococcus epidermidis (atcc 12228), neisseria lactamicus (atcc 23970), enterobacter cloacae, (atcc 23355), bacillus subtilis (atcc 6633), staphylococcus aureus (209p), and pseudomonas aeruginosa (ifo 3445). clinical strains: moraxella catarrhalis, bacillus cereus, aeromonas hydrophila, salmonella typhi, vibrio cholerae, and yersinia enterocolitica. in addition to a sea urchin (anthocidaris crassispina) derived bacillus sp. which obtained from the laboratory in medical plants garden, nagasaki university.(c)fungal strains: the fungal strains used were aspergillus niger (nbrc 33023), penicillium crustosum (nbrc 33015), schizophyllum commune (nbrc 30749), trichophyton concentricum (nbrc 31068), and candida albicans (nbrc 10108). fungal strains: the fungal strains used were aspergillus niger (nbrc 33023), penicillium crustosum (nbrc 33015), schizophyllum commune (nbrc 30749), trichophyton concentricum (nbrc 31068), and candida albicans (nbrc 10108). the air-dried powdered whole plant (200 g) was exhaustively extracted with cold maceration method with sufficient quantity of 70% methanol for 7 days at room temperature. the methanolic extract was passed through whatman number 1 filter paper (whatman england) and the concentrated extract (40 g) was digested with 100 ml distilled water and successively partitioned with n-hexane (4 400 ml), chloroform (3 400 ml), ethyl acetate (5 400 ml), and n-butanol (2 400 ml). each fraction was concentrated under reduced pressure to a constant weight to give the corresponding n-hexane fraction (0.4 g), chloroform fraction (2 g), ethyl acetate fraction (0.7 g), n-butanol fraction (6 g), and aqueous fraction (30 g). the most active fraction against bacillus sp. and m. catarrhalis (chloroform fraction) was subjected to sephadex lh20 column chromatography to give three subfractions (a-c). fraction (b) was resubjected again to sephadex lh20 to afford very active and pure compound aa-1 (150 mg). to the solution of aa-1 (50 mg; 0.23 mmol) in dimethylformamide (dmf), 1 ml potassium carbonate was added (95 mg; 0.69 mmol). to the resulting suspension iodomethane was added (72 l; 1.15 mmol) and stirred for 8 hours. the reaction mixture was poured onto water (10 ml) and ethyl acetate (20 ml). the organic layer was washed with 1 m hcl (10 ml) three times and then with brine (10 ml) once. after removal of solvent under reduced pressure, the residue was purified by silica-gel chromatography (chloroform-methanol) to afford the titled ester (88%). h-nmr (400 mhz, cdcl3, tms, r.t.) (ppm): 3.88 (3h, s), 4.06 (3hs), 6.38 (2h, s), 7.11 (1h, d, j=7.8 hz), 7.72 (1h, dd, j=7.8 hz, 8.0 hz), 7.77 (1h, s), 8.70 (1h, d, j=8.0 hz), and 8.83 (1h, s). suspension of the tested bacteria (100 l of 10 cfu/ml) was spread onto solid media plates. the sterile paper discs (6 mm in diameter) which were impregnated with the plant extract (14 mg) and pure compound (10100 g) were placed aseptically over the bacterial culture on nutrient agar plates. after incubation at 37c for 24 hours, the zone of inhibition around the discs was measured by millimeter scale. sterile, blank paper discs impregnated with only sterile solvents served as negative control each time. the sterile paper discs (6 mm in diameter) which were impregnated with individual extract were placed on the inoculated plates. these plates were incubated for 2472 h at 2528c and the growth was evaluated visually by comparing a particular plate with the negative control plates (having only test fungi). the antifungal activity was evaluated by measuring the inhibition zone diameter (in millimeter) observed. the mic and mbc values were determined by broth dilution method in accordance with clsi methodology. bacterial strains were cultured for 24 h at 37c on nutrient broth and then suspended in sterile distilled water to give a final inoculum concentration of 1.5 1.0 10 cfu/ml. dilutions ranging from 1.56 to 400 g/ml of the compound were prepared in tubes including broth and dmso 10% (v/v), in addition to one negative control (broth+dmso 10% v/v+test microorganism) to ensure that the final concentration of dmso in the assays did not interfere with the bacterial growth and one sterility control (broth+dmso 10% v/v+test compound). a 100 l suspension of test microorganism was added to individual tubes and incubated at 37c for 24 h. the mic of the compound was defined as the lowest concentration that inhibited the visible bacterial growth and the mbc was defined as the lowest concentration that prevented the growth of the organism after subculture onto antibiotic-free plates. initial steps in new drug discovery involve identification of new chemical entities, which can be either sourced through chemical synthesis or can be isolated from natural products through biological activity guided fractionation. bioassay-guided fractionation of the identified plant may lead to standardized extract or isolated bioactive lead compounds as the new drug. the whole plant of aristolochia bracteolata was extracted successively with meoh and subjected to liquid-liquid fractionation with n-hexane, chloroform, ethyl acetate, and n-butanol. the resulting fractions were tested for antibacterial and antifungal activities. the crude extract and chloroform fraction were significantly active against sea urchin-derived bacillus sp. and both standard strain and clinical isolates of moraxella catarrhalis and were moderately active against s. aureus, b. subtilis, and ps. the n-hexane fraction had moderate activity against s. aureus and b. subtilis while ethyl acetate fraction showed moderate activity against ps. the crude extract failed to inhibit the growth of all test fungi in addition to the following bacterial strains: klebsiella pneumoniae, escherichia coli, salmonella typhimurium, streptococcus pyogenes, streptococcus agalactiae, staphylococcus epidermidis, neisseria lactamicus, enterobacter cloacae, bacillus cereus, aeromonas hydrophila, salmonella typhi, vibrio cholerae, and yersinia enterocolitica. the chloroform soluble fraction was therefore selected for further chromatographic separations and resulted in the isolation of known compound aa-1 (figure 1). aa-1 showed strong activity against moraxella catarrhalis (standard strain and clinical isolates) and sea urchin-derived bacillus sp. (table 2), with equal mic and mbc values of 25 and 50 g/ml. both the piperonylic acid moiety of aa-1 (figure 1) and aa-1-methyl ester showed no activity against bacteria (table 2), which suggests that the coexistence of phenanthrene ring and free carboxylic acid is essential for aa-1 antibacterial activity. bioguided fractionation of methanolic extract of aristolochia bracteolata led to isolation of aa-1 and its structure was elucidated by interpretation of its nmr and ms data and by comparison with those reported in the literature. electrospray ionization mass spectrometry (esims) showed pseudomolecular ion signal at m/z 364.03 [m+na] and high resolution fast atom bombardment mass spectrometry (hr-fabms) afforded m+1 ion signal at m/z 342.0620 which was corresponding to the molecular formula c17h12no7 (calculated for 342.06138). h nmr and c-nmr spectra were matched with those of aa-1 which were previously reported. two weak signals which did not show any correlation with proton in hsqc and hmbc spectroscopy were considered as quaternary carbons at positions 5 (124.3 ppm) and 6 (143.5 ppm), respectively. laboratories of the world have found literally thousands of phytochemicals which have inhibitory effects on all types of microorganisms in vitro. more of these compounds should be subjected to animal and human studies to determine their effectiveness in whole-organism systems, including in particular toxicity studies and an examination of their effects on beneficial normal microbiota. in spite of the fact that herbal remedy is a mixture of many chemicals in unknown doses and might result in unpleasant side effects, many people believe that treatments that are natural are somehow magically safe and effective. aristolochia is used in traditional medicine for the treatment of various diseases [13, 15], including those associated with bacteria. this study showed clearly that the excellent effect of aristolochia in treating such diseases is due to the toxic compound aa-1. although aa-1 is highly effective in killing m. catarrhalis, it is ineffective against the other microorganisms tested. this highlights the importance of m. catarrhalis in discovering the cellular target of aa-1 and the mechanism of aa-1 toxicity. the widespread use of aristolochia is not sufficient to ensure that it is effective or even that it is safe. therefore, hit-to-lead exploration is necessary to identify related compounds with low toxicity, low cost, and improved potency that can replace the use of the harmful crude plant material. it is impossible to ban the use of these remedies, especially in the rural areas in sudan and other african countries; therefore, we strongly recommend educating the public of the risks versus the benefits of aristolochia and gradually replacing them with either economical new drugs or standardized extracts and homogenous batches of other plant material with known levels of safe active constituents. using bioassay-guided fractionation technique, the present study directly linked the antibacterial activity of aristolochia bracteolata to the aa-1. although aa-1 had strong activity against m. catarrhalis, it had a narrow spectrum of activity than expected based on the activity of the crude extract from which it was isolated or from its traditional usage. this may be the result of synergism between different compounds in the complex extracts or may be due to placebo effect. | a bioassay-guided fractionation of methanol extract of aristolochia bracteolata whole plant was carried out in order to evaluate its antimicrobial activity and to identify the active compounds in this extract. antibacterial and antifungal activities of methanol extract against gram-positive, gram-negative, and fungal strains were investigated by the agar disk diffusion method. among the strains tested, moraxella catarrhalis and sea urchin-derived bacillus sp. showed the highest sensitivity towards the methanol extract and hence they are used as test organisms for the bioassay-guided fractionation. from this extract, aristolochic acid 1 (aa-1) has been isolated and has showed the greatest antibacterial activity against both standard strain and clinical isolates of moraxella catarrhalis with equal minimum inhibitory concentration (mic) and minimum bactericidal concentration (mbc) values of 25 and 50 g/ml. modification of the aa-1 to aa-1 methyl ester completely abolished the antibacterial activity of the compound and the piperonylic acid moiety of aa-1 which suggested that the coexistence of phenanthrene ring and free carboxylic acid is essential for aa-1 antibacterial activity. | PMC4745564 |
pubmed-10 | "anti-neutrophil cytoplasmic antibodies (ancas) correlate well with a wide spectrum of vasculitis ma(...TRUNCATED) | "we herein report an unusual case of an infected descending aortic pseudoaneurysm with luminal patho(...TRUNCATED) | PMC5216144 |
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Original data from: https://github.com/armancohan/long-summarization
The first 3000 rows of the test split of the original dataset were processed and filtered as follows.
- In the original dataset, some sentences appear several times in the same article, even if they're only contained once in the original research paper. For this reason, all dataset rows where the same sentence appeared more than once where removed.
- In the original dataset, every sentence is a separate string, and these strings are contained in arrays. Therefore, all these strings were merged in order to create one single string for each article body and one other for each article abstract.
- All line breaks were removed.
- Unnecessary spaces (e.g. before points or commas) were removed.
- The dataset was filteder by article and summary length.
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