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Is high expression of mammalian target of rapamycin associated with better outcome for patients with early stage lung adenocarcinoma? Mammalian target of rapamycin (mTOR) is a key kinase downstream of phosphoinositide 3-kinase (PI3K)/AKT predominantly involved in translational control in the presence of nutrients and energy. Despite the well known role of mTOR in carcinogenesis, its prognostic potential in lung cancer has not been investigated. Here, we quantitatively assessed mTOR protein expression in two large data sets to investigate the impact of mTOR expression on patient survival. Automated quantitative analysis (AQUA), a fluorescent-based method for analysis of in situ protein expression, was used to assess mTOR expression in a training cohort of 167 lung cancer patients. An independent cohort of 235 lung cancer patients (from a second institution) was used for validation. Tumors expressed mTOR in the cytoplasm in 56% and 50% of the cases in training and validation cohorts, respectively; mTOR expression was not associated with standard clinical or pathologic characteristics. Patients with high mTOR expression had a longer median overall survival compared with the low expressers (52.7 versus 38.5 months; log rank P = 0.06), which was more prominent in the adenocarcinoma group (55.7 versus 38.88 months; log rank P = 0.018). Multivariate analysis revealed an independent lower risk of death for adenocarcinoma and adenocarcinoma stage IA patients with mTOR-expressing tumors (hazard ratio, 0.48; 95% confidence interval, 0.24-0.98; P = 0.04, and hazard ratio, 0.12; 95% confidence interval, 0.03-0.72; P = 0.019, respectively).

mTOR expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of lung adenocarcinoma patients as well as incorporation of mTOR into clinical decisions.

Does hypoxia exposure induce the emergence of fibroblasts lacking replication repressor signals of PKCzeta in the pulmonary artery adventitia? Cultured fibroblasts of hypoxia-stimulated remodelled pulmonary artery (PA) adventitia proliferate at a greater rate compared with those of normal adventitia. Since protein kinase C (PKC) zeta is a replication repressor of normal adventitial fibroblasts, we hypothesized that loss of the repressor activity of PKCzeta might contribute to increased rate of proliferation in adventitial cells of remodelled PA. Isolated PA adventitial fibroblasts of neonatal control (Fib-C) and chronic hypoxia-exposed (Fib-H) calves were used to test our hypothesis. For evaluation of the role of PKCzeta in hypoxia-induced vascular adventitial remodelling, expression and activation of PKCzeta were also examined in lung sections of Fib-C and Fib-H animals by immunoperoxidase staining. Although constitutively active PKCzeta expression attenuated DNA synthesis in Fib-C, it stimulated proliferation in Fib-H. PKCzeta-specific myristoylated pseudosubstrate peptide inhibitor (PKCzeta-PI) induced replication in Fib-C, whereas the inhibitor blocked DNA synthesis in Fib-H. Hypoxia stimulated PKCzeta as well as MAP kinase kinase (MEK)1/2 and extracellular signal-regulated kinase (ERK)1/2 phosphorylation in Fib-H cells. However, ERK1/2 activation was mediated by both MEK1/2-dependent and MEK1/2-independent PKCzeta-regulated mechanisms in hypoxia-exposed Fib-H. PKCzeta was selectively activated in the adventitial cells of the remodelled vascular wall, as demonstrated by strong immunoreactivity against the anti-phosphoPKCzeta antibody in the Fib-H lung sections.

PKCzeta acts as a replication repressor in Fib-C cells; however, the same isozyme mediates Fib-H proliferation. Thus, chronic exposure to hypoxia leads to the emergence of cells lacking anti-replication activity of PKCzeta in the PA adventitia.

Does mesenchymal stem cell irradiation in culture engage differential effect of hyper-fractionated radiotherapy for head and neck cancers? The purpose of this study was to challenge current knowledge on the potential therapeutic advantages of stem cells in radiotherapy by developing an in vitro model of the healthy tissue surrounding or replacing the widely resected tumor. After radical surgery, the start of radiotherapy is often delayed due to wound healing process, with potential loss of the opportunity for treating microscopic disease instead of macroscopic early recurrence. Hyperfractionated radiotherapy, contrary to the standard one, can extend the limits of radical surgery and shorten the gap before the onset of postoperative radiotherapy, with potential improvement in local control. By using both mesenchymal stem cells and pre-differentiated osteoblasts, cultured in proper pro-osteogenic media after cell irradiation, we investigated both the differences in the response to DNA damage between lineages undergoing differentiation in culture and the intensity of the mineralization process. Ionizing radiation stimulated stem cell proliferation and differentiation at 0.5 Gy and 1 Gy, thus confirming in vitro the clinical results of hyperfractionated irradiation randomized trials in head and neck cancers -HNCs-.

To our knowledge, this study is the first to investigate the biophysics of low dose gamma irradiation on stem cell culture, focusing on the potential applications in radiation oncology. For advanced oral cavity and oropharyngeal cancers, as radical surgery often implies major bone resection, the use of mesenchymal stem cells as bone reconstruction vectors might shorten the onset of adjuvant hyperfractionated radiotherapy which enhances the mineralization process. As postoperative radiotherapy has recently being revisited for osteosarcoma, this scenario could impact also on bone reconstruction process in this pathology.

Is the frequency of chromosome 7q interstitial deletions associated with B-cell lymphoproliferative disorders substantially high among hematological malignancies? To study the frequency of interstitial 7q deletions in B-cell lymphoproliferative disorders (B-LPDs). Cases were collected from the clinical laboratory diagnosis database at USLabs/LabCorp over the past two years (2002 to 2004). Cases that showed deletions in the long arm of chromosome 7 were then reviewed. Interstitial deletions in the long arm of chromosome 7 were further investigated according to the indications for clinical laboratory studies and flow cytometry findings. The final clinical diagnosis for each case was obtained from the referring physician. A total of 19,483 cases were included in this series. Eighty-five cases were observed to have either terminal or interstitial deletion in the long arm of chromosome 7. Of the 85 cases, 46 had interstitial deletions accounting for 54.1% of the 7q deletions combined. B-LPDs were found in 10 of the 46 cases, accounting for 21.7%. The B-LPDs associated with 7q interstitial deletions were diverse, including B-cell chronic lymphocytic leukemia (B-CLL) in five cases. The deleted region in the long arm of chromosome 7 in the 10 cases associated with B-LPDs was solely confined to the 7q22-q32 region.

(1) The frequency of 7q interstitial deletions associated with B-LPDs is substantially high; (2) 7q interstitial deletions are not uncommon in B-CLL.

Is cyr61/CCN1 involved in the pathogenesis of psoriasis vulgaris via promoting IL-8 production by keratinocytes in a JNK/NF-κB pathway? Interleukin-8 (IL-8) is an important factor in the pathogenesis of psoriasis vulgaris, which is characterized by proliferation of keratinocytes, neutrophil infiltration and angiogenesis. Cysteine-rich 61 (Cyr61/CCN1), a secreted extracellular matrix protein, is a novel proinflammatory factor. Whether Cyr61 is involved in the development of psoriasis vulgaris via IL-8 production remains unknown. In this study we explore the role of Cyr61 in IL-8 expression regulation in vivo and in vitro. Skin samples from normal donors and psoriasis vulgaris patients were examined the profile of Cyr61 and IL-8 using immunohistochemistry, real-time PCR and Western blotting. HaCaT cells were treated with Cyr61 and IL-8 expression was analyzed by real-time PCR and ELISA. Signal transduction pathways in Cyr61-induced IL-8 production were investigated by real-time PCR, western blotting, luciferase reporter assay or chromatin immunoprecipitation (ChIP) assay. IMQ-induced psoriasis-like mice were treated with anti-Cyr61monoclonal antibodies (mAb), or IgG1 as a control. We found that Cyr61 was abundant in the epidermis of patients with psoriasis vulgaris and positively correlated with the pathogenesis of skin lesions. Cyr61 induced IL-8 production by keratinocytes in a dose dependent manner. This IL-8 synthesis occurred in an IL-1β- and TNF-α- independent mode via PI3K, AKT and JNK activation, with binding of enhanced AP-1, C/EBPβ and NF-κB to sites located in the IL-8 promoter region. Treatment with anti-Cyr61 mAb led to reduction of MIP-2 level, decreased neutrophil infiltration, and attenuated inflammation in vivo.

Our results not only reveal a novel mechanism illustrating the role of Cyr61 in epidermis pathogenesis but also suggest that therapies targeting Cyr61 may represent a novel strategy in the treatment of psoriasis vulgaris.

Does recombination between homologous chromosomes play a dominant role in the formation of radiation-induced chromosomal aberrations? In mammalian cells, the relevance of homologous recombination in radiation-induced double-strand break (DSB) repair is not yet well understood. In the present work, the role of recombination between homologous chromosomes and homology-directed repair of DSB were studied, using X-ray-induced chromosomal aberrations as an end-point. Human-hamster hybrid cells containing one or two copies of human chromosome 8 were used. If recombination between homologous chromosomes plays a dominant role in DSB repair, it is expected that X-irradiation of cells with two copies of chromosome 8 would result in a lower frequency of aberrations involving this chromosome compared with cells with only one copy of chromosome 8. The aberrations involving human chromosome 8 were detected by fluorescence in situ hybridization (FISH). Furthermore, a comparison between the hamster cell line XR-C1 (defective in non-homologous repair), CHO-9 (the wild-type cells) and the cell line XR-C1#8 (in which the defect of XR-C1 is complemented by human chromosome 8) was made to determine, indirectly, the involvement of homology-directed recombination in DSB repair. The observed frequencies of aberrations per human chromosome 8 were not significantly different between cells containing one or two copies of this chromosome. The frequency of chromatid-type aberrations was doubled in XR-C1 cells compared with CHO-9 and XR-C1#8 cells.

In hamster cells, recombination between homologous chromosomes appears not to have a major role in the formation of radiation-induced chromosomal aberrations, while nonhomologous repair seems to be important in both the G and G2 phases of the cell cycle.

Does a single instillation of epirubicin after transurethral resection of bladder tumors prevent only small recurrences? We studied whether a single instillation of epirubicin after transurethral bladder tumor resection would influence the interval to and size of the first recurrence. A total of 404 patients from 13 hospitals were randomized to 1 instillation of 50 mg epirubicin or placebo within 6 hours after transurethral resection of bladder tumors. Of 155 evaluable patients in the epirubicin group 79 (51.0%) had recurrence compared to 95 of 152 (62.5%) in the placebo group (p = 0.04). Of the recurrences 63.3% were small (1 to 5 mm). Tumor size was unknown in 5 patients. Of 79 patients with recurrence in the epirubicin arm 33 (42.9%) vs 29 (31.5%) of 95 in the placebo arm had larger (more than 5 mm) first recurrences (p = 0.12). Approximately half of the patients with first recurrences were treated as outpatients and the other half spent a total of 145 days in the hospital with no difference between the groups.

We confirmed the results of previous studies showing that 8.5 patients must be treated with a single instillation to prevent 1 recurrence. Furthermore, our data may indicate that only small recurrences are prevented, which could easily be fulgurated using local anesthesia at followup cystoscopy. The benefit of single instillations can be questioned if this finding is confirmed by others.

Does computer modeling with randomized-controlled trial data inform the development of person-centered aged care homes? To answer questions on the essential components (services, operations and resources) of a person-centered aged care home (iHome) using computer simulation. iHome was developed with AnyLogic software using extant study data obtained from 60 Australian aged care homes, 900+ clients and 700+ aged care staff. Bayesian analysis of simulated trial data will determine the influence of different iHome characteristics on care service quality and client outcomes. Interim results: A person-centered aged care home (socio-cultural context) and care/lifestyle services (interactional environment) can produce positive outcomes for aged care clients (subjective experiences) in the simulated environment.

Further testing will define essential characteristics of a person-centered care home.

Does hyaluronan suppress lidocaine-induced apoptosis of human chondrocytes in vitro by inhibiting the p53-dependent mitochondrial apoptotic pathway? Intra-articular injection of local anesthetics (LAs) is a common procedure for therapeutic purposes. However, LAs have been found toxic to articular cartilage, and hyaluronan may attenuate this toxicity. In this study we investigated whether hyaluronan attenuated lidocaine-induced chondrotoxicity, and if so, to elucidate the underlying mechanisms. Human chondrocyte cell line SW1353 and newly isolated murine chondrocytes were incubated in culture medium containing hyaluronan and/or lidocaine for 72 h. Cell viability was evaluated using MTT assay. Cell apoptosis was detected with DAPI staining, caspase 3/7 activity assay and flow cytometry. Cell cycle distributions, ROS levels and mitochondrial membrane potential (ΔΨm) were determined using flow cytometry. The expression of p53 and p53-regulated gene products was measured with Western blotting. Lidocaine (0.005%-0.03%) dose-dependently decreased the viability of SW1353 cells. This local anesthetic (0.015%, 0.025%) induced apoptosis, G2/M phase arrest and loss of ΔΨm, and markedly increased ROS production in SW1353 cells. Hyaluronan (50-800 μg/mL) alone did not affect the cell viability, but co-treatment with hyaluronan (200 μg/mL) significantly attenuated lidocaine-induced apoptosis and other abnormalities in SW1353 cells. Furthermore, co-treatment with lidocaine and hyaluronan significantly decreased the levels of p53 and its transcription targets Bax and p21 in SW1353 cells, although treatment with lidocaine alone did not significantly change these proteins. Similar results were obtained in ex vivo cultured murine chondrocytes.

Hyaluronan suppresses lidocaine-induced apoptosis of human chondrocytes in vitro through inhibiting the p53-dependent mitochondrial apoptotic pathway.

Does in vivo airway eosinophil accumulation enhance antigen- or propranolol-induced bronchoconstriction in guinea pigs? Chronic airway eosinophil accumulation is characteristic of asthma. However, it remains unclear whether airway eosinophils enhance or reduce release of chemical mediators and/or action of the released mediators in the airways in vivo, because previous investigators have indicated that eosinophil-derived factors such as histaminase and arylsulfatase may alter the allergic reaction by metabolizing chemical mediators. Recently, we have developed a guinea pig model of propranolol-induced bronchoconstriction (PIB), which is mediated by lipid mediators such as thromboxane A2 (TxA2), cysteinyl leukotrienes (cLTs) and platelet activation factor (PAF). This study was conducted to explain the influence of airway eosinophil accumulation on antigen-induced bronchoconstriction and the following PIB, both of which are mediated by lipid mediators. Guinea pigs were transnasally treated with 75 microg/kg of polymyxin-B or vehicle twice a week for a total of 3 weeks. Guinea pigs were anesthetized and treated with diphenhydramine hydrochloride, and then artificially ventilated 24 h after the last administration of polymyxin-B or vehicle followed by passive sensitization. Propranolol at a concentration of 10 mg/ml was inhaled 20 min after an aerosolized antigen challenge. The proportion of eosinophils in bronchoalveolar lavage fluid obtained 15 min after the propranolol inhalation was significantly increased in guinea pigs treated with polymyxin-B compared with the vehicle. The polymyxin-B treatment did not affect antigen-induced bronchoconstriction or the following PIB.

We conclude that eosinophils accumulated in the airways by polymyxin-B does not affect release of chemical mediators induced by antigen or propranolol inhalation, or action of released mediators in vivo.

Is expression of complement and toll-like receptor pathway genes associated with malaria severity in Mali : a pilot case control study? The host response to infection by Plasmodium falciparum, the parasite most often responsible for severe malaria, ranges from asymptomatic parasitaemia to death. The clinical trajectory of malaria is influenced by host genetics and parasite load, but the factors determining why some infections produce uncomplicated malaria and some proceed to severe disease remain incompletely understood. To identify molecular markers of severe falciparum malaria, human gene expression patterns were compared between children aged 6 months to 5 years with severe and uncomplicated malaria who were enrolled in a case-control study in Bandiagara, Mali. Microarrays were used to obtain expression data on severe cases and uncomplicated controls at the time of acute disease presentation (five uncomplicated and five severe), 1 week after presentation (three uncomplicated and three severe) and treatment initiation, and in the subsequent dry season (late convalescence, four uncomplicated and four severe). This is a pilot study for the first use of microarray technology in Mali. Complement and toll-like receptor (TLR) pathways were differentially expressed, with severe cases showing higher expression of the C1q, TLR2, TLR4, TLR8, and CR1 genes. Other genes previously associated with malaria pathogenesis, GZMB, FOS and HSPA6, were also higher among severe cases. TLR2, TLR4, TLR8, CR1, GZMB, FOS, and HSPA6 genes were expressed at lower levels in severe cases at late convalescence.

Overexpression of genes previously associated with uncomplicated malaria was associated with severe disease. Low baseline expression of these genes may represent candidate markers for severe malaria. Despite the small sample size, results of this pilot study offer promising targets for follow-up analyses.

Does increased use of brachiocephalic arteriovenous fistulas improve functional primary patency? As vascular surgeons strive to meet the Fistula First Initiative, some authors have observed a decrease in arteriovenous fistula (AVF) maturation rates in association with an increase in AVF creation. In May 2012, we adopted a practice change in an attempt to maintain the same high level of AVF creation while leading to a decrease in fistula failures. A retrospective study was conducted of all dialysis access procedures performed by a single vascular surgeon before (period 1; before May 1, 2012) and after (period 2; after May 1, 2012) the change in practice pattern. The adopted change included favoring the brachiocephalic location unless the patient was an ideal anatomic candidate for a radiocephalic AVF, creating a larger and standardized arteriotomy, and using a large venous footplate whenever possible. The main outcome measure was primary functional patency at 1 year. Secondary outcome measures included primary patency at 1 year, time to maturation, type of fistula created, steal syndrome, and tunneled hemodialysis catheter infections. Of 213 vascular access procedures performed, 191 (90%) were AVFs. There was no difference in use of AVFs between period 1 (93% AVFs) and period 2 (88% AVFs; P = .2). Use of brachiocephalic AVFs increased from 38% in period 1 to 56% in period 2 (P = .01), with a corresponding trend toward a decrease in radiocephalic AVFs in period 2 (36% in period 1 to 27% in period 2; P = .2). Primary functional patency at 1 year was 47% in period 1 and 63% in period 2 (P = .03). Primary patency at 1 year was 51% in period 1 and 70% in period 2 (P = .001). Time to reach functional maturation was decreased in period 2 (median, 76 vs 82.5 days; P = .046). There was no difference in steal syndrome (P = 1.0), and the incidence of hemodialysis catheter infections was lower in period 2 (0 vs 7 [7%]; P = .006).

Increasing brachiocephalic AVF creation and reducing our reliance on radiocephalic AVFs resulted in a significant increase in primary functional patency at 1 year. This was achieved while maintaining the same high percentage of fistulas, a lower rate of central catheter infections, and the same low incidence of steal syndrome.

Do oocytes from women of advanced reproductive age appear to have an increased risk of zona pellucida hardening? To test the hypothesis that very advanced reproductive age leads to an increased risk of zona pellucida hardening by comparing fertilization rates and rates of failed fertilization with conventional oocyte insemination vs intracytoplasmic sperm injection (ICSI). Women aged > or = 45 were given the option of ICSI vs conventional oocyte insemination in circumstances where there was no male factor present. They were advised of the theoretical benefit of ICSI overcoming zona hardening but also advised that ICSI might lower pregnancy rates and is more costly. There were 364 cycles evaluated and 74% chose ICSI. The failed fertilization rates were similar--28.4% (66/232) for ICSI vs 26.5% (35/132) for conventional insemination. The fertilization rates were similar 56.0% with ICSI vs 50.9% with conventional oocyte insemination.

Based on similar fertilization and failed fertilization rates in women aged > or = 45 undergoing IVF-ET, zona hardening does not appear to be a consequence of reproductive aging.

Does pre-dinner administration increase the efficacy of proton pump inhibitors on refractory GERD symptoms in connective tissue disease patients? A significant proportion of patients with connective tissue disease (CTD) have gastric esophageal reflux disease (GERD) symptoms despite receiving proton pump inhibitors (PPIs). Although pre-meal administration of PPIs is recommended in Western countries, the benefit of this administration timing in Japanese CTD patients with refractory GERD symptoms has not been proven. To determine whether pre-dinner administration of PPIs is more efficacious for refractory GERD symptoms in Japanese CTD patients. CTD patients receiving oral PPIs were instructed to take PPIs 1 h before dinner. Gastrointestinal symptoms were evaluated with frequency scale for the symptoms of GERD (FSSG) and gastrointestinal symptom rating scale (GSRS) before and after the intervention. Pre-dinner administration of PPIs significantly improved FSSG total score, from a median of 8 to 6.5 (P = 0.005). Pre-dinner administration was more effective in patients with overt GERD symptoms (from median 18 to 10, P < 0.001) than in those with mild GERD symptoms (from median 2 to 2, P = 0.201). In addition to reflux syndrome, pre-dinner administration of PPIs significantly decreased abdominal pain syndrome and constipation syndrome of GSRS.

Pre-dinner administration of PPIs may increase their efficacy in Japanese CTD patients with GERD, especially those with overt symptoms.

Do incontinent women have altered pelvic floor muscle contraction patterns? Pelvic floor exercises are invaluable for regaining continence but mechanisms are not fully understood. To contribute to the understanding of these mechanisms we investigated the contraction sequence of superficial vs deep pelvic floor muscles in 6 positions in continent and incontinent women. The onset of contraction of the superficial and deep pelvic floor muscles was recorded by perineal and intravaginal surface electromyography in 32 continent and 50 incontinent women. The agreement between perineal and intravaginal recordings was calculated with the kappa statistic and the percent of agreement. Differences in onset between superficial and deep pelvic floor muscle contractions are reported as the median and IQR. Perineal and intravaginal electromyography recordings used to define the onset of muscle activity showed a high level of agreement. In the continent group the superficial muscles almost always contracted before the deep muscles in all 6 positions. In the incontinent group the reverse sequence was observed in 3 of 6 positions. Higher and less consistent time differences in the onset of contraction of the 2 muscle layers were found in incontinent vs continent women.

Contractions of the superficial and deep pelvic floor muscles can be recorded by intravaginal or perineal electrodes. A consistent contraction sequence can be found in continent women but it is lacking in incontinent women. This might be a possible explanation for incontinence. Including differentiated muscle contraction exercises in pelvic floor muscle exercise programs may further optimize treatment outcomes.

Is neuropsychological performance within-person variability associated with reduced treatment consent capacity? The capacity of older adults to make healthcare decisions is often impaired in dementia and has been linked to performance on specific neuropsychological tasks. Within-person across-test neuropsychological performance variability has been shown to predict future dementia. This study examined the relationship of within-person across-test neuropsychological performance variability to a current construct of treatment decision (consent) capacity. Participants completed a neuropsychological test battery and a standardized capacity assessment. Standard scores were used to compute mean neuropsychological performance and within-person across-test variability. Assessments were performed in the participant's preferred location (e.g., outpatient clinic office, senior center, or home). Participants were recruited from the community with fliers and advertisements and consisted of men (N = 79) and women (N = 80) with (N = 83) or without (N = 76) significant cognitive impairment. Participants completed the MacArthur Competence Assessment Tool-Treatment and 11 neuropsychological tests commonly used in the cognitive assessment of older individuals. Neuropsychological performance and within-person variability were independently associated with continuous and dichotomous measures of capacity, and within-person neuropsychological variability was significantly associated with within-person decisional ability variability. Prevalence of incapacity was greater than expected in participants with and without significant cognitive impairment when decisional abilities were considered separately.

These findings are consistent with an emerging construct of consent capacity in which discrete decisional abilities are differentially associated with cognitive processes and indicate that the sensitivity and accuracy of consent capacity assessments can be improved by evaluating decisional abilities separately.

Is diurnal temperature range a risk factor for coronary heart disease death? Although the relation between day-to-day temperature change and coronary heart disease (CHD) mortality is well established, it is unknown whether temperature variation within 1 day, ie, diurnal temperature range (DTR), is an independent risk factor for acute CHD death. We used time-series and case-crossover approaches to assess the relation between DTR and daily CHD mortality between 2001 and 2004 in Shanghai, China. Specifically, we used exposures averaged over periods varying from 1 to 5 days to assess the effects of DTR on CHD mortality. We estimated the percent increase in the number of daily deaths related to CHD that were associated with DTR, after adjustment for daily meteorologic conditions (temperature and relative humidity) and levels of outdoor air pollutants. Both time-series and case-crossover analyses showed that DTR was significantly associated with the number of daily deaths related to CHD. A 1 degrees C increase in 2-day lagged DTR corresponded to a 2.46% (95% CI, 1.76% to 3.16%) increase in CHD mortality on time-series analysis, a 3.21% (95% CI, 2.23% to 4.19%) increase on unidirectional case-crossover analysis, and a 2.13% (95% CI, 1.04% to 3.22%) increase on bidirectional case-crossover analysis.

Our findings suggest that DTR is an independent risk factor for acute CHD death.

Does cHFR promoter methylation indicate poor prognosis in stage II microsatellite stable colorectal cancer? Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here, we examine the prognostic impact of promoter methylation in patients with CRC treated with surgery alone in the context of microsatellite instability (MSI), BRAF and KRAS mutations. One hundred and seventy-three CRCs were analyzed for promoter methylation of 19 tumor suppressor and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations. Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 [CL1, 57% (98/173) of CRCs], cluster 2 [CL2, 25% (43/173) of CRCs], and cluster 3 [CL3, 18% (32/173) of CRCs]. CL3 had the highest methylation index (0.25, 0.49, and 0.69, respectively, P = <0.01) and was strongly associated with CIMP (P < 0.01). Subgroup analysis for tumor stage, MSI, and BRAF status showed no statistically significant differences in survival between CL1, CL2, and CL3 nor between CIMP and non-CIMP CRCs. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, microsatellite stability (MSS), BRAF wild-type (WT) CRCs: multivariate Cox proportional HR = 3.89 [95% confidence interval (CI), 1.58-9.60, P < 0.01; n = 66] and HR = 2.11 (95% CI, 0.95-4.69, P = 0.068, n = 136) in a second independent population-based study.

CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF WT CRCs.

Does stimulus conditioned to foot-shock stress reinstate alcohol-seeking behavior in an animal model of relapse? Stress and conditioned responses to drug cues have been implicated as critical factors in relapse to drug use. In the animal literature, both the conditioned effects of drug-related stimuli and the unconditioned effects of foot-shock stress have been well documented to reinstate extinguished drug-seeking behavior. What has remained largely unexplored, however, is the significance of stimuli conditioned to foot-shock stress for the resumption of drug seeking. Additionally, although relapse is often the result of several risk factors acting in combination, the possibility that interactions among risk factors such as conditioned stress and drug cues may intensify drug-seeking behavior has received little experimental attention. The purpose of this study was to examine the individual and interactive effects of a stimulus conditioned to foot-shock stress (STRESS CS) and a stimulus conditioned to ethanol reward (EtOH CS) on the reinstatement of ethanol-seeking behavior following extinction. Male Wistar rats were trained to orally self-administer 10% ethanol on a fixed-ratio 3 schedule of reinforcement. The EtOH CS was established by response-contingently pairing 0.5 s illumination of a white cue light with each reinforced response. The STRESS CS was established by pairing a continuous white noise (70 dB) with intermittent foot shock (10 min; 0.5 mA; 0.5 s on; mean off period of 40 s). Ethanol dependence was induced by an ethanol vapor-inhalation procedure. After ethanol-maintained instrumental responding was extinguished by withholding ethanol and the EtOH CS, reinstatement tests were conducted. Both exposure to the STRESS CS and response-contingent presentation of the EtOH CS reinstated extinguished responding at the previously active, ethanol-paired lever without further ethanol availability. When response-contingent availability of the EtOH CS was preceded by exposure to the STRESS CS, interactive effects of these stimuli on responding were observed. However, both the individual and interactive effects of the STRESS CS and the EtOH CS reached statistical significance only in rats with a history of ethanol dependence but not in ethanol-nondependent rats.

The results confirm that both conditioned stress and ethanol cues elicit ethanol-seeking behavior and, more importantly, that these stimuli produce interactive effects resulting in an increased ethanol-seeking response. The findings also indicate that susceptibility to ethanol seeking induced by conditioned stress and alcohol cues depends significantly on the history of prior alcohol exposure.

Is postoperative pain after hip fracture procedure specific? Hip fracture patients experience high pain levels during postoperative rehabilitation. The role of surgical technique on postoperative pain has not been evaluated previously. One hundred and seventeen hip fracture patients were included in a descriptive prospective study. All patients received continuous epidural analgesia and were treated according to a standardized perioperative rehabilitation programme. Resting pain, pain on hip flexion, and walking were measured during daily physiotherapy sessions on a verbal five-point rating scale during the first four postoperative days. Patients were stratified into four groups according to surgical procedure: screws or pins, arthroplasty, dynamic hip screw (DHS), and intra-medullary hip screw (IMHS). Cumulated pain levels were significantly different between surgical procedures both for hip flexion (P=0.002) and for walking (P=0.02) with highest dynamic pain levels for patients who had either DHSs or IMHSs compared with arthroplasty or parallel implants. There were significant negative correlations between ambulatory capacity assessed by the cumulated ambulation score and both the dynamic cumulated pain scores on hip flexion (r=-0.43, P<0.001) and walking (r=-0.36, P=0.004).

Postoperative pain levels after surgery for hip fracture are dependent on the surgical procedure, which should be taken into account in future studies of analgesia and rehabilitation.

Does novel X-ray image noise reduction technology reduce patient radiation dose while maintaining image quality in coronary angiography? The consequences of high radiation dose for patient and staff demand constant improvements in X-ray dose reduction technology. This study assessed non-inferiority of image quality and quantified patient dose reduction in interventional cardiology for an anatomy-specific optimised cine acquisition chain combined with advanced real-time image noise reduction algorithms referred to as 'study cine', compared with conventional angiography. Fifty patients underwent two coronary angiographic acquisitions: one with advanced image processing and optimised exposure system settings to enable dose reduction (study cine) and one with standard image processing and exposure settings (reference cine). The image sets of 39 patients (18 females, 21 males) were rated by six experienced independent reviewers, blinded to the patient and image characteristics. The image pairs were randomly presented. Overall 85 % of the study cine images were rated as better or equal quality compared with the reference cine (95 % CI 0.81-0.90). The median dose area product per frame decreased from 55 to 26 mGy.cm(2)/frame (53 % reduction, p < 0.001).

This study demonstrates that the novel X-ray imaging technology provides non-inferior image quality compared with conventional angiographic systems for interventional cardiology with a 53 % patient dose reduction.

Do clinical mesenchymal stromal cell products undergo functional changes in response to freezing? Current methods of mesenchymal stromal cell (MSC) cryopreservation result in variable post-thaw recovery and phenotypic changes caused by freezing. The objective of this investigation was to determine the influence of ex vivo cell expansion on phenotype of MSCs and the response of resulting phenotypes to freezing and thawing. Human bone marrow aspirate was used. MSCs were isolated and cells were assessed for total count, viability, apoptosis and senescence over 6 passages (8-10 doublings/passage) in ex vivo culture. One half of cells harvested at each passage were re-plated for continued culture and the other half were frozen at 1°C/min in a controlled-rate freezer. Frozen samples were stored in liquid nitrogen, thawed and reassessed for total cell count, viability and senescence immediately and 48 h after thaw. Viability did not differ significantly between samples before freeze or after thaw. Senescence increased over time in pre-freeze culture and was significantly higher in one sample that had growth arrest both before freeze and after thaw. Freezing resulted in similar initial post-thaw recovery in all samples, but 48-h post-thaw growth arrest was observed in the sample with high senescence only.

High pre-freeze senescence appears to correlate with poor post-thaw function in MSC samples, but additional studies are necessary to obtain a sample sizes large enough to quantify results.

Is early neurologic examination reliable for prognostication in post-cardiac arrest patients who undergo therapeutic hypothermia? Recent advances in post-cardiac arrest (CA) care including therapeutic hypothermia (TH) have improved survival and favorable neurologic outcomes for survivors of CA. Survivors often present with deep coma and lack of brainstem reflexes, which are generally associated with adverse outcomes in many disease processes. Little is known regarding the role of initial emergency department (ED) neurological examination and its potential for prognostication. The purpose of this study is to determine if components of a standardized neurologic examination are reliable prognosticators in patients recently resuscitated from CA. We hypothesize that lack of neurologic function does not reliably predict an adverse outcome and, therefore, should not be used to determine eligibility for TH. A standardized neurologic examination was performed in the ED on a prospective, convenience cohort of post-CA patients presenting to a CA resuscitation center who would undergo a comprehensive postarrest care pathway that included TH. Data such as prior sedation or active neuromuscular blockade were documented to evaluate for the presence of possible confounders. Examination findings were then compared with hospital survival and neurologic outcome at discharge as defined by the cerebral performance category (CPC) score as documented in the institutional TH registry. Forty-nine subjects were enrolled, most of whom presented comatose with a Glasgow Coma Scale of 3 (n=41, 83.7%). Nineteen subjects (38.8%) had absence of all examination findings, of which 4 of 19 (21.1%) survived to hospital discharge. Of those with at least 1 positive examination finding, 13 of 30 subjects (43.3%) survived to hospital discharge. Subgroup analysis showed that 9 of the 19 patients with absence of brainstem reflexes did not have evidence of active neuromuscular blockade at the time of the examination; 2 of 9 (22.1%) survived to hospital discharge. Eight of these subjects in this group had not received any prior sedation; 1 of 8 (12.5%) survived to hospital discharge. Only 1 of the 17 subjects who survived was discharged with poor neurologic function with a CPC score=3, whereas all others who survived had good neurologic function, CPC score=1.

In this cohort of patients treated in a comprehensive postarrest care pathway that included TH, absence of neurologic function on initial ED presentation was not reliable for prognostication. Given these findings, clinicians should refrain from using the initial ED neurological examination to guide the aggressiveness of care or in counseling of family members regarding anticipated outcome.

Is complete revascularization a prerequisite for success in current transcatheter aortic valve implantation practice? This study sought to assess in patients undergoing transcatheter aortic valve implantation (TAVI), the prevalence and impact of incomplete coronary revascularization defined as >50% coronary artery or graft diameter stenosis on visual assessment of the coronary angiogram. TAVI is an established treatment option in elderly patients with aortic stenosis (AS) and a (very) high operative risk. Coronary artery disease (CAD) is often associated with AS. A single-center cohort of consecutive patients undergoing TAVI between November 2005 and June 2012 was evaluated for the presence of significant CAD. The decision to revascularize and pursue complete revascularization was made by heart team consensus. A total of 263 consecutive patients with a mean age of 80 ± 7 years and 51% male underwent TAVI with a median follow-up duration of 16 months (interquartile range: 4.2 to 28.1 months). Significant CAD with myocardium at risk was present in 124 patients (47%), 44 of whom had had previous coronary artery bypass grafting (CABG), and the median SYNTAX score in the 81 patients without previous CABG was 9.00 (2.38 to 15.63). Staged percutaneous coronary intervention (PCI) was planned in 19 (15%) and concomitant PCI with TAVI in 20 (16%). The median post-procedural residual SYNTAX score of patients without prior CABG was 5.00 (0.13 to 9.88). Overall, 99 patients (37%) (61 with no CABG and 38 CABG patients) had incomplete revascularization after TAVI. Revascularization status did not affect clinical endpoints. Kaplan-Meier survival curves for patients with and without complete revascularization demonstrated a 1-year mortality of 79.9% versus 77.4% (p = 0.85), respectively.

In an elderly patient population undergoing TAVI for severe AS, a judicious revascularization strategy selection by a dedicated heart team can generate favorable mid-term outcome obviating the need for complete coronary revascularization.

Does large-scale profiling of signalling pathways reveal an asthma specific signature in bronchial smooth muscle cells? Bronchial smooth muscle (BSM) cells from asthmatic patients maintain in vitro a distinct hyper-reactive ("primed") phenotype, characterized by increased release of pro-inflammatory factors and mediators, as well as hyperplasia and/or hypertrophy. This "primed" phenotype helps to understand pathogenesis of asthma, as changes in BSM function are essential for manifestation of allergic and inflammatory responses and airway wall remodelling. To identify signalling pathways in cultured primary BSMs of asthma patients and non-asthmatic subjects by genome wide profiling of differentially expressed mRNAs and activated intracellular signalling pathways (ISPs). Transcriptome profiling by cap-analysis-of-gene-expression (CAGE), which permits selection of preferentially capped mRNAs most likely to be translated into proteins, was performed in human BSM cells from asthmatic (n=8) and non-asthmatic (n=6) subjects and OncoFinder tool were then exploited for identification of ISP deregulations. CAGE revealed >600 RNAs differentially expressed in asthma vs control cells (p≤0.005), with asthma samples showing a high degree of similarity among them. Comprehensive ISP activation analysis revealed that among 269 pathways analysed, 145 (p<0.05) or 103 (p<0.01) are differentially active in asthma, with profiles that clearly characterize BSM cells of asthmatic individuals. Notably, we identified 7 clusters of coherently acting pathways functionally related to the disease, with ISPs down-regulated in asthma mostly targeting cell death-promoting pathways and up-regulated ones affecting cell growth and proliferation, inflammatory response, control of smooth muscle contraction and hypoxia-related signalization.

These first-time results can now be exploited toward development of novel therapeutic strategies targeting ISP signatures linked to asthma pathophysiology.

Does curcumin inhibit cellular cholesterol accumulation by regulating SREBP-1/caveolin-1 signaling pathway in vascular smooth muscle cells? To investigate the protective effect and the possible mechanism of curcumin on anti-atherosclerosis. Morphological changes of atherosclerotic lesions taken from apoE knockout (apoE-/-) mice were determined by hematoxylin- eosin staining. Intracellular lipid droplets and lipid levels were assayed by oil red O staining and HPLC. The protein expression of caveolin-1 was quantified by Western blotting. Translocation and the expression of sterol response element-binding protein-1 (SREBP-1) were indirectly detected by an immunofluorescence analysis. The administration of 20 mg. kg(-1 ). d(-1 )curcumin to apoE-/- mice for 4 months induced a 50% reduction of atherosclerotic lesions and yielded a 5- fold increase in the caveolin-1 expression level as compared to the model group. Rat vascular smooth muscle cells (VSMC) pretreated with 50 mg/L ox-lipid density lipoprotein(ox-LDL) for 48 h increased cellular lipid contents, and stimulated SREBP-1 translocation, but decreased the caveolin-1 expression level. Lipid-loaded cells exposed to curcumin at various concentrations (12.5, 25, and 50 micromol/L) for different durations (0, 6, 12, 24, and 48 h) significantly diminished the number and area of cellular lipid droplets, total cholesterol, cholesterol ester, and free cholesterol accompanying the elevation of the caveolin-1 expression level (approximately 3-fold); the translocation of SREBP-1 from the cytoplasm to the nucleus was inhibited compared with the models. Lipid-loaded VSMC exposed to N-acetyl- Leu-Leu-norleucinal, a SREBP-1 protease inhibitor, showed increased nuclear translocation of SREBP-1, reduced caveolin-1 expression level, and upregulated cellular lipid levels.

Curcumin inhibits ox-LDL-induced cholesterol accumulation in cultured VSMC through increasing the caveolin-1 expression via the inhibition of nuclear translocation of SREBP-1.

Does hemoglobin Raleigh result in factitiously low hemoglobin A1c when evaluated via immunoassay analyzer? Glycosylated hemoglobin (HbA1c) is commonly used to assess long-term blood glucose control in patients with diabetes mellitus. Numerous conditions including hemoglobinopathies can alter HbA1c measurements and cause misleading results. To report a 13-year-old male with Type 1 diabetes mellitus who had low HbA1c measurements, despite persistent hyperglycemia. HbA1c was initially measured by immunoassay. Hb electrophoresis was then employed to assess potential Hb variants. Electrospray ionization (ESI) tandem mass spectrometry of isolated Hb and gene sequencing of the Hbβ gene were used to specifically identify the Hb variant. HbA1c measurement by immunoassay revealed an unusually low HbA1c of 3.9%. Hb electrophoresis revealed an aberrant Hb. The ESI mass spectrum of the intact Hb sample revealed a variant β-chain of 15,881 Da, 14 Da heavier than the mass of the normal Hb β-chain (15,867 Da). Sequence analysis of the 965.45 Da peptide suggested a substitution of valine (Val) to acetylated alanine (Ala). The DNA sequence of the patient's Hbβ gene revealed a single-base heterozygous mutation (GTG to GCG) at Base 2 of the codon of the first amino acid, producing a Val→Ala substitution, previously termed Hb-Raleigh. Because the acetylated N-terminal amino acid of the Hb-Raleigh β chain cannot be glycated, the HbA1c immunoassay will result in falsely low HbA1c levels.

In managing diabetic patients, knowledge of hemoglobinopathies influencing HbA1c determination methods is essential because hemoglobin variants may cause mismanagement of diabetes. Unusual results should prompt further analysis for a hemoglobinopathy as the potential cause of aberrant results.

Does high-quality chronic care delivery improve experiences of chronically ill patients receiving care? Investigate whether high-quality chronic care delivery improved the experiences of patients. This study had a longitudinal design. We surveyed professionals and patients in 17 disease management programs targeting patients with cardiovascular diseases, chronic obstructive pulmonary disease, heart failure, stroke, comorbidity and eating disorders. Patients completed questionnaires including the Patient Assessment of Chronic Illness Care (PACIC) [T1 (2010), 2637/4576 (58%); T2 (2011), 2314/4330 (53%)]. Professionals' Assessment of Chronic Illness Care (ACIC) scores [T1, 150/274 (55%); T2, 225/325 (68%)] were used as a context variable for care delivery. We used two-tailed, paired t-tests to investigate improvements in chronic illness care quality and patients' experiences with chronic care delivery. We employed multilevel analyses to investigate the predictive role of chronic care delivery quality in improving patients' experiences with care delivery. Overall, care quality and patients' experiences with chronic illness care delivery significantly improved. PACIC scores improved significantly from 2.89 at T1 to 2.96 at T2 and ACIC-S scores improved significantly from 6.83 at T1 to 7.18 at T2. After adjusting for patients' experiences with care delivery at T1, age, educational level, marital status, gender and mental and physical quality of life, analyses showed that the quality of chronic care delivery at T1 (P < 0.001) and changes in care delivery quality (P < 0.001) predicted patients' experiences with chronic care delivery at T2.

This research showed that care quality and changes therein predict more positive experiences of patients with various chronic conditions over time.

Does methylphenidate treatment affect mitogen-activated protein kinase activation in the striatum of young rats? Methylphenidate (MPD) is a drug prescribed for the treatment of attention deficit/hyperactivity disorder and its therapeutic effect is attributed to the inhibition of dopamine. Young male Wistar rats were administered MPD (1, 2, 5, or 10 mg/kg) once a day or an intraperitoneal injection of saline for 28 days (chronic treatment) or for 1 day (acute treatment). Two hours after the last administration the animals were decapitated and their striatum was dissected. In this work, we show that continued treatment with MPD is capable of modifying the levels of phosphorylation of proteins JNK1/2 (c-Jun amino-terminal kinases 1 and 2) and ERK1/2 (extracellular signal-regulated kinases 1 and 2). Whereas the level of phosphorylation of protein ERK increased significantly, that of proteins JNK1/2 diminished.

The alteration in the level of activation of mitogen-activated protein kinases can be a molecular mechanism through which MPD exerts its therapeutic effect.

Does a decrease in spatially resolved near-infrared spectroscopy-determined frontal lobe tissue oxygenation by phenylephrine reflect reduced skin blood flow? Spatially resolved near-infrared spectroscopy-determined frontal lobe tissue oxygenation (ScO2) is reduced with administration of phenylephrine, while cerebral blood flow may remain unaffected. We hypothesized that extracranial vasoconstriction explains the effect of phenylephrine on ScO2. We measured ScO2 and internal and external carotid as well as vertebral artery blood flow in 7 volunteers (25 [SD 4] years) by duplex ultrasonography during IV infusion of phenylephrine, together with middle cerebral artery mean blood velocity, forehead skin blood flow, and mean arterial blood pressure. During phenylephrine infusion, mean arterial blood pressure increased, while ScO2 decreased by -19% ± 3% (mean ± SE; P = 0.0005). External carotid artery (-27.5% ± 3.0%) and skin blood flow (-25.4% ± 7.8%) decreased in response to phenylephrine administration, and there was a relationship between ScO2 and forehead skin blood flow (Pearson r = 0.55, P = 0.042, 95% confidence interval [CI], = 0.025-0.84; Spearman r = 0.81, P < 0.001, 95% CI, 0.49-0.94) and external carotid artery conductance (Pearson r = 0.62, P = 0.019, 95% CI, 0.13 to 0.86; Spearman r = 0.64, P = 0.012, 95% CI, 0.17-0.88).

These findings suggest that a phenylephrine-induced decrease in ScO2, as determined by INVOS-4100 near-infrared spectroscopy, reflects vasoconstriction in the extracranial vasculature rather than a decrease in cerebral oxygenation.

Is cardiac mortality higher around Christmas and New Year 's than at any other time : the holidays as a risk factor for death? Research published in Circulation has shown that cardiac mortality is highest during December and January. We investigated whether some of this spike could be ascribed to the Christmas/New Year's holidays rather than to climatic factors. We fitted a locally weighted polynomial regression line to daily mortality to estimate the number of deaths expected during the holiday period, using the null hypothesis that natural-cause mortality is unaffected by the Christmas/New Year's holidays. We then compared the number of deaths expected during the holiday period, given the null hypothesis, with the number of deaths observed. For cardiac and noncardiac diseases, a spike in daily mortality occurs during the Christmas/New Year's holiday period. This spike persists after adjusting for trends and seasons and is particularly large for individuals who are dead on arrival at a hospital, die in the emergency department, or die as outpatients. For this group during the holiday period, 4.65% (+/-0.30%; 95% CI, 4.06% to 5.24%) more cardiac and 4.99% (+/-0.42%; 95% CI, 4.17% to 5.81%) more noncardiac deaths occur than would be expected if the holidays did not affect mortality. Cardiac mortality for individuals who are dead on arrival, die in the emergency department, or die as outpatients peaks at Christmas and again at New Year's. These twin holiday spikes also are conspicuous for noncardiac mortality. The excess in holiday mortality is growing proportionately larger over time, both for cardiac and noncardiac mortality.

Our findings suggest that the Christmas/New Year's holidays are a risk factor for cardiac and noncardiac mortality. There are multiple explanations for this association, including the possibility that holiday-induced delays in seeking treatment play a role in producing the twin holiday spikes.

Does sleep restriction decrease the physical activity of adults at risk for type 2 diabetes? To test the hypothesis that recurrent sleep curtailment will result in decreased physical activity in adults at risk for type 2 diabetes. Two-condition 2-period randomized crossover study. University General Clinical Research Center. Eighteen healthy patients with parental history of type 2 diabetes (9 females and 9 males, age 27 yr [standard deviation 3], body mass index 23.7 [2.3] kg/m²). Two week-long inpatient sessions with 8.5 or 5.5-hr nighttime sleep opportunity. Participants who exercised regularly (39%) could follow their usual exercise routines during both sessions. Sleep and total body movement were measured by wrist actigraphy and waist accelerometry. Subjective mood and vigor was assessed using visual analog scales. The main outcome was the comparison of total activity counts between sleep conditions. Ancillary endpoints included changes in sedentary, light, and moderate plus vigorous activity, and their association with changes in mood and vigor. Daily sleep was reduced by 2.3 hr (P < 0.001) and total activity counts were 31% lower (P = 0.020) during the 5.5-hr time-in-bed condition. This was accompanied by a 24% reduction in moderate-plus-vigorous activity time (P = 0.005) and more sedentary behavior (+21 min/day; P = 0.020). The decrease in daily activity during the 5.5-hr time-in-bed condition was seen mostly in participants who exercised regularly (-39 versus -4% in exercisers versus nonexercisers; P = 0.027). Sleep loss-related declines in physical activity correlated strongly with declines in subjective vigor (R = 0.90; P < 0.001).

Experimental sleep restriction results in decreased amount and intensity of physical activity in adults at risk for type 2 diabetes.

Is promoter polymorphism at the tumour necrosis factor/lymphotoxin-alpha locus associated with type of diabetes but not with susceptibility to sight-threatening diabetic retinopathy? To investigate, in a large cohort of 2494 individuals with diabetes mellitus, whether functional single nucleotide polymorphisms in the promoter region of tumour necrosis factor (TNF) and lymphotoxin-alpha (LTA) genes are associated with type of diabetes or presence of diabetic retinopathy. A total of 334 type 1 diabetes and 999 type 2 diabetes participants with sight-threatening diabetic retinopathy, and 260 type 1 diabetes and 901 type 2 diabetes participants with no diabetic retinopathy or minimal non-proliferative diabetic retinopathy, were genotyped for two single nucleotide polymorphisms (rs1800629 and rs361525). The A allele of rs1800629 was associated with type 1 diabetes (p < 0.001; odds ratio = 0.62). After adjustment for age, sex, diabetes duration, HbA1c, hypertension and nephropathy, no significant association was found between rs1800629 or rs361525 and sight-threatening diabetic retinopathy.

An association between the A allele of rs1800629 and type of diabetes was found. No association was found between two promoter variants of TNF and LTA, and diabetic retinopathy in a large cohort of Caucasian patients with type 1 diabetes and type 2 diabetes.

Does eating in the absence of hunger during childhood predict self-reported binge eating in adolescence? The objectives of the current study were to examine whether eating in the absence of hunger (EAH) at age 7 predicted reports of self-reported binge eating at age 15 and to identify factors among girls with high-EAH that moderated risk of later binge eating. Subjects included 158 girls assessed at age 7 and age 15. Logistic regression was used to predict binge eating at age 15 from calories consumed during EAH at age 7. A series of logistic regressions were used to examine the odds of reporting binge eating given levels of risk factors (e.g., anxiety) among those with high-EAH in childhood. Girls' EAH intake predicted reports of binge eating at age 15; after adjusting for age 7 BMI, for each additional 100kcal consumed, girls were 1.7 times more likely to report binge eating in adolescence. Among those with high-EAH, BMI, anxiety, depression, dietary restraint, emotional disinhibition, and body dissatisfaction all predicted binge eating.

EAH during childhood predicted reports of binge eating during adolescence; girls with elevated BMI, negative affect, and maladaptive eating- and weight-related cognitions were at increased risk. High-EAH in childhood may be useful for indicating those at risk for developing binge eating.

Does use of a novel polyp `` ruler snare '' improve estimation of colon polyp size? Prior studies have demonstrated that endoscopists' estimates of polyp size are imprecise. The aim of this study was to determine whether a modified polypectomy "ruler snare" improves the accuracy of assessment of polyp size in real time without the use of additional devices. Ten artificial polyps of predetermined sizes (4 to 25 mm) were affixed to the inside of a colon model. A standard polypectomy snare was modified by adding 5-mm graduated markings to the distal end of the plastic sheath. Study participants estimated the sizes of the artificial polyps during simulated colonoscopies, first using a standard snare and then with the modified ruler snare. Thirty-four private practice and academic gastroenterologists participated in the study. Endoscopists' ability to accurately classify polyps by size (diminutive, small, or large) improved from 48.5% to 60.3% with the ruler snare (P = .002). The greatest improvement in precision was seen among the large polyps, where accuracy increased from 35.9% to 58.2% with use of the ruler snare (P < .0001). Participants underestimated polyp size by a mean of 3.6 mm (interquartile range, -5 to -2 mm) with the standard snare and 1.8 mm (interquartile range, -3 to 0 mm) with the ruler snare, which corresponded to a 44.2% improvement in accuracy with the ruler snare (P < .05).

The modified ruler snare improved polyp size assessment compared with a standard snare, particularly with large polyps. Overall, although size estimation continues to be imprecise, the addition of calibrated markings to a polypectomy snare is a simple and likely low-cost means to improve neoplasia surveillance recommendations.

Do mathematical models to predict long bone lengths by transvaginal scan at 11-16 weeks ' gestation? To propose a new mathematical model to estimate the length of fetal long bones in early pregnancy that can be used in the routine clinical setting. In a group of 400 singleton normal fetuses, referred for transvaginal ultrasound examination between 11 and 16 weeks' gestation prior to genetic amniocentesis, a regression analysis was performed to evaluate the relationship between femur length (FLl) (mm) and biparietal diameter (BPD) (mm) and gestational age (GA) (days), as well as between humerus length (HL) (mm) and BPD (mm) and GA (days). The confidence intervals (CIs) of the predicted values for different values of BPD and for different gestational periods and CIs for the regression coefficients are stated as the mean +/- SD of standardized residuals. The accuracy of our best models obtained were evaluated at each gestational week between 11 and 16 with a 10% error cut-off limit. The best relationships between FL and HL versus BPD and GA are: expected FL = -16.92108 + 0.4569402 BPD +0.171617 GA (R(2) = 0.86) and expected HL = -16.28531 + 0.4283019 BPD + 0.1696017 GA (R(2) = 0.88), respectively. When a cut-off limit of 10% in estimating fetal long bones was utilized, the mathematical models revealed a good accuracy particularly at 13-14 weeks' gestation, a period when transvaginal biometric and morphologic examination is advisable and the highest percentage of scans are performed.

Our proposed two linear models had a very good ability to estimate FL and HL and, due to the simplicity of the calculations, would be particularly useful in the routine clinical setting.

Does [ The active metabolite of leflunomide A771726 inhibit proliferation and collagen synthesis of hepatic stellate cell ]? To investigate the effect of the metabolite of leflunomide, A771726,on proliferation and collagen synthesis of hepatic stellate cell (HSC). HSC and Kupffer cells were isolated from the rat liver by collagenase IV and pronase perfusion, and purified by density gradient separation. The effects of A771726 on cell proliferation and collagen synthesis were examined by 3H-thymidine and 3H-proline incorporation assays, respectively. The TGF-beta, TNF-alpha and IL-1 levels in Kupffer cell conditioned medium (KCCM) were determined by enzyme-linked immunosorbent assay (ELISA). HSC and Kupffer cells in rat liver were well separated. The KCCM of CCl4-injured rats had significant stimulation effect on proliferation and collagen synthesis of HSC in primary culture. Addition of A771726 (0.001-10 micromol/Lein HSC culture stimulated by KCCM significantly inhibited proliferation and collagen synthesis of HSC. Furthermore, the elevated TGF-beta, TNF-alpha and IL-1 levels in KCCM of CCl4-injured rats were significantly reduced in A771726 treatment groups.

A771726 has markedly inhibitory effect on proliferation and collagen synthesis of HSC and secretion of TGF-beta,TNF-alpha and IL-1 from Kupffer cells.

Does reduced NO-cGMP signaling contribute to vascular inflammation and insulin resistance induced by high-fat feeding? Diet-induced obesity (DIO) in mice causes vascular inflammation and insulin resistance that are accompanied by decreased endothelial-derived NO production. We sought to determine whether reduced NO-cGMP signaling contributes to the deleterious effects of DIO on the vasculature and, if so, whether these effects can be blocked by increased vascular NO-cGMP signaling. By using an established endothelial cell culture model of insulin resistance, exposure to palmitate, 100 micromol/L, for 3 hours induced both cellular inflammation (activation of IKK beta-nuclear factor-kappaB) and impaired insulin signaling via the insulin receptor substrate-phosphatidylinositol 3-kinase pathway. Sensitivity to palmitate-induced endothelial inflammation and insulin resistance was increased when NO signaling was reduced using an endothelial NO synthase inhibitor, whereas endothelial responses to palmitate were blocked by pretreatment with either an NO donor or a cGMP analogue. To investigate whether endogenous NO-cGMP signaling protects against vascular responses to nutrient excess in vivo, adult male mice lacking endothelial NO synthase were studied. As predicted, both vascular inflammation (phosphorylated I kappaB alpha and intercellular adhesion molecule levels) and insulin resistance (phosphorylated Akt [pAkt] and phosphorylated eNOS [peNOS] levels) were increased in endothelial NO synthase(-/-) (eNOS(-/-)) mice, reminiscent of the effect of DIO in wild-type controls. Next, we asked whether the vascular response to DIO in wild-type mice can be reversed by a pharmacological increase of cGMP signaling. C57BL6 mice were either fed a high-fat diet or remained on a low-fat diet for 8 weeks. During the final 2 weeks of the study, mice on each diet received either placebo or the phosphodiesterase-5 inhibitor sildenafil, 10 mg/kg per day orally. In high-fat diet-fed mice, vascular inflammation and insulin resistance were completely prevented by sildenafil administration at a dose that had no effect in mice fed the low-fat diet.

Reduced signaling via the NO-cGMP pathway is a mediator of vascular inflammation and insulin resistance during overnutrition induced by high-fat feeding. Therefore, phosphodiesterase-5, soluble guanylyl cyclase, and other molecules in the NO-cGMP pathway (eg, protein kinase G) constitute potential targets for the treatment of vascular dysfunction in the setting of obesity.

Are nADPH oxidase ( NOX ) isoforms inhibited by celastrol with a dual mode of action? Celastrol is one of several bioactive compounds extracted from the medicinal plant Tripterygium wilfordii. Celastrol is used to treat inflammatory conditions, and shows benefits in models of neurodegenerative disease, cancer and arthritis, although its mechanism of action is incompletely understood. Celastrol was tested on human NADPH oxidases (NOXs) using a panel of experiments: production of reactive oxygen species and oxygen consumption by NOX enzymes, xanthine oxidase activity, cell toxicity, phagocyte oxidase subunit translocation, and binding to cytosolic subunits of NOX enzymes. The effect of celastrol was compared with diphenyleneiodonium, an established inhibitor of flavoproteins. Low concentrations of celastrol completely inhibited NOX1, NOX2, NOX4 and NOX5 within minutes with concentration-response curves exhibiting higher Hill coefficients and lower IC₅₀ values for NOX1 and NOX2 compared with NOX4 and NOX5, suggesting differences in their mode of action. In a cell-free system, celastrol had an IC₅₀ of 1.24 and 8.4 µM for NOX2 and NOX5, respectively. Cytotoxicity, oxidant scavenging, and inhibition of p47(phox) translocation could not account for NOX inhibition. Celastrol bound to a recombinant p47(phox) and disrupted the binding of the proline rich region of p22(phox) to the tandem SH3 domain of p47(phox) and NOXO1, the cytosolic subunits of NOX2 and NOX1, respectively.

These results demonstrate that celastrol is a potent inhibitor of NOX enzymes in general with increased potency against NOX1 and NOX2. Furthermore, inhibition of NOX1 and NOX2 was mediated via a novel mode of action, namely inhibition of a functional association between cytosolic subunits and the membrane flavocytochrome.

Are plasma concentrations of afamin associated with the prevalence and development of metabolic syndrome? Afamin is a human plasma vitamin E-binding glycoprotein primarily expressed in the liver and secreted into the bloodstream. Because little is known about (patho)-physiological functions of afamin, we decided to identify phenotypes associated with afamin by investigating transgenic mice overexpressing the human afamin gene and performing large-scale human epidemiological studies. Transgenic mice overexpressing afamin revealed increased body weight and serum concentrations of lipids and glucose. We applied a random-effects meta-analysis using age- and sex-adjusted baseline and follow-up investigations in the population-based Bruneck (n=826), Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR; n=1499), and KOoperative Gesundheitsforschung in der Region Augsburg (KORA) F4 studies (n=3060). Mean afamin concentrations were 62.5±15.3, 66.2±14.3, and 70.6±17.2 mg/L in Bruneck, SAPHIR, and KORA F4, respectively. Per 10 mg/L increment in afamin measured at baseline, the number of metabolic syndrome components increased by 19% (incidence rate ratio=1.19; 95% confidence interval [CI], 1.16-1.21; P=5.62×10(-64)). With the same afamin increment used at baseline, we observed an 8% gain in metabolic syndrome components between baseline and follow-up (incidence rate ratio=1.08; 95% CI, 1.06-1.10; P=8.87×10(-16)). Afamin concentrations at baseline were highly significantly related to all individual metabolic syndrome components at baseline and at follow-up. This observation was most pronounced for elevated waist circumference (odds ratio, 1.79; 95% CI, 1.54-2.09; P=4.15×10(-14) at baseline and odds ratio, 1.46; 95% CI, 1.31-1.63; P=2.84×10(-11) for change during follow-up) and for elevated fasting glucose concentrations (odds ratio, 1.46; 95% CI, 1.40-1.52; P=1.87×10(-69) and odds ratio, 1.46; 95% CI, 1.24-1.71; P=5.13×10(-6), respectively).

This study in transgenic mice and >5000 participants in epidemiological studies shows that afamin is strongly associated with the prevalence and development of metabolic syndrome and all its components.

Is coincident pre-diabetes associated with dysregulated cytokine responses in pulmonary tuberculosis? Cytokines play an important role in the pathogenesis of pulmonary tuberculosis (PTB)--Type 2 diabetes mellitus co-morbidity. However, the cytokine interactions that characterize PTB coincident with pre-diabetes (PDM) are not known. To identify the influence of coincident PDM on cytokine levels in PTB, we examined circulating levels of a panel of cytokines in the plasma of individuals with TB-PDM and compared them with those without PDM (TB-NDM). TB-PDM is characterized by elevated circulating levels of Type 1 (IFNγ, TNFα and IL-2), Type 17 (IL-17A and IL-17F) and other pro-inflammatory (IL-1β, IFNβ and GM-CSF) cytokines. TB-PDM is also characterized by increased systemic levels of Type 2 (IL-5) and regulatory (IL-10 and TGFβ) cytokines. Moreover, TB antigen stimulated whole blood also showed increased levels of pro-inflammatory (IFNγ, TNFα and IL-1β) cytokines as well. However, the cytokines did not exhibit any significant correlation with HbA1C levels or with bacterial burdens.

Our data reveal that pre-diabetes in PTB individuals is characterized by heightened cytokine responsiveness, indicating that a balanced pro and anti - inflammatory cytokine milieu is a feature of pre-diabetes--TB co-morbidity.

Is early brain pseudoatrophy while on natalizumab therapy due to white matter volume changes? Investigation of atrophy data from a pivotal natalizumab trial has demonstrated an increased rate of volume loss, compared to placebo, after the first year of therapy. It was considered to be probably due to a pseudoatrophy effect. To assess grey and white matter volume changes and their relation to global brain volume changes and to baseline inflammation, for patients under natalizumab therapy. We selected 45 patients on natalizumab therapy for at least 24 months, with magnetic resonance imaging (MRI) scans at baseline, 12 and 24 months. We calculated the percentage brain volume change (PBVC) for the first and second year, using SIENA software. Grey and white matter fractions (GMF and WMF, respectively) for the first year were calculated with SPM5, using lesion masks. After quality checks, six patients were excluded. We studied the predictive variables of change in brain volumes. The PBVC decrease was faster during the first year (-1.10% ± 1.43%), as compared to the second (-0.51% ± 0.96%) (p = 0.037). These differences were more marked in patients with baseline gadolinium-enhancing lesions (p = 0.005). Mean GMF and WMF changes during the first year of treatment were +1.15% (n.s.) and -1.72% (p = 0.017), respectively. The presence of active lesions at baseline MRI predicted PBVC (p = 0.022) and WMF change (p = 0.026) during the first year of treatment, after adjusting for age and corticosteroid treatment. No predictors were found for GMF volume changes.

Early brain volume loss during natalizumab therapy is mainly due to WMF volume loss and it is related to the inflammatory activity present at the onset of therapy. We found that the pseudoatrophy effect is mostly due to white matter volume changes.

Are patients with chronic heart failure encountered in daily clinical practice different from the `` typical '' patient enrolled in therapeutic trials? The aim of this study was to compare the clinical characteristics of patients enrolled in randomized clinical trials on congestive heart failure treatment with those of real-world patients encountered in daily clinical practice. We searched the Cochrane review methodology, Medline and SilverPlatter databases to obtain the clinical characteristics of both patients enrolled in therapeutic clinical trials and real-world patients with heart failure. We selected 27 clinical trials, and 8 prospective epidemiological studies or registries published between 1987 and 2001 which enrolled 53,859 and 18,207 patients, respectively. On average, compared to real-world heart failure patients, patients enrolled in clinical trials were younger (63 +/- 10 vs 75 +/- 11 years respectively, p < 0.0001), and more likely to be male (72 vs 54% respectively, p < 0.0001). Clinical trial patients showed a lower ejection fraction (26 +/- 7 vs 38 +/- 15% respectively, p < 0.0001) but a lower prevalence of NYHA functional class III-IV (62 vs 75% respectively, p < 0.0001) than real-world patients. In clinical trial patients, the prevalence of ischemic heart disease (67 vs 42% respectively, p < 0.0001) and a history of previous myocardial infarction (62 vs 42% respectively, p < 0.0001) were higher than in real-world patients. Conversely, the prevalence of chronic atrial fibrillation (12 vs 31% respectively, p < 0.0001) and of diabetes (22 vs 24% respectively, p < 0.02) was lower in trial patients than in real-world patients.

Our data suggest that most clinical trials on congestive heart failure, on which the guidelines for clinical practice are based, have generally included patients who are not representative of the whole spectrum of patients actually managed in clinical practice.

Is reduction of albumin urinary excretion associated with reduced cardiovascular events in hypertensive and/or diabetic patients . A meta-regression analysis of 32 randomized trials? The association between renal dysfunction and risk of cardiovascular (CV) events and mortality has been reported in several studies. However, it is unclear whether reduction in urinary albumin excretion (UAE) is associated with reduced risk of clinical events. Therefore, we sought to investigate, in a meta-regression analysis of randomized studies enrolling hypertensive and/or diabetic patients, whether changes in UAE are associated with changes in CV outcomes and all-cause mortality. MEDLINE, ISI Web of Science, Cochrane Database and Scopus were searched for randomized trials enrolling more than 200 diabetic and/or hypertensive patients, reporting UAE at baseline and at end of follow-up and CV events [CV death, myocardial infarction (MI), and stroke], as well all-cause mortality. Thirty-two trials enrolling 80,812 participants were included in analyses. Meta-regression analysis showed that each 10% reduction of UAE was significantly associated with 13% reduction of MI (Regression Coefficient [RC]:0.0055; 95% Confidence Interval [CI]:0.0014 to 0.0095; p=0.010), with 29% reduction of stroke (RC:0.0124; CI:0.0030 to 0.0218; p=0.013) and with 14% reduction of the composite outcome (CV death, MI, stroke)(RC:0.0059; CI:0.0027 to 0.0090; p=0.001), whereas not significantly associated with all-cause (RC:0.0028; CI:-0.0047 to 0.0103; p=0.486) and CV mortality (RC:0.0028; CI:-0.0047 to 0.0103; p=0.447). Results were mostly confirmed by sensitivity analysis. No heterogeneity or publication bias was detected.

Reduction in UAE is associated with reduced risk of MI and stroke in diabetic and/or hypertensive patients. These findings suggest that UAE changes may represent a valuable intermediate end-point for CV risk evaluation in clinical practice.

Does ultrasonic tissue characterization predict left ventricular remodeling in patients with acute anterior myocardial infarction after primary coronary angioplasty? The aim of this study was to assess the role of cyclic variation (CV) of myocardial integrated backscatter (IBS) in the prediction of left ventricular (LV) remodeling in patients with anterior acute myocardial infarction (AMI) after primary coronary angioplasty. Some studies have shown that the CV of myocardial IBS predicts myocardial viability for patients with AMI. We recorded short-axis IBS images within 24 hours of angioplasty in 80 patients with anterior AMI. Two parameters were measured: the magnitude of CV and the normalized time delay (NTD). The increase in LV end-diastolic volume (LVEDV) at 4 weeks (DeltaLVEDV) was defined as LV remodeling (>20% increase from baseline). Patients were divided into two groups according to LV remodeling status: the remodeling group (n = 41) and the nonremodeling group (n = 39). There was a significant difference in the magnitude of CV between the two groups (5.11 +/- 1.47 vs 5.96 +/- 189 dB, P < .05), and the NTD was significantly different in the two groups (1.57 +/- 0.31 vs 1.23 +/- 0.32, P < .0001). The correlation between the magnitude of CV and DeltaLVEDV was significant but weak (r = -0.338, P < .01). There was significant correlation between NTD and DeltaLVEDV (r = 0.443, P < .0001). Using NTD greater than 1.35 as the optimal cutoff, the sensitivity, specificity, and positive and negative predictive values to predict LV remodeling were 82%, 86%, 87%, and 80%, respectively.

Myocardial IBS, especially NTD, is useful for predicting LV remodeling in patients with AMI after primary coronary angioplasty.

Is [ Expression of programmed cell death 4 protein closely correlated with laryngeal squamous cell carcinomas ]? To study whether programmed cell death 4 (PDCD4) is involved in the development and progression of laryngeal squamous cell carcinomas (LSCC). The expressions of PDCD4 protein were examined by immunohistochemical staining and Western blot in LSCC tissues and their surrounding laryngeal normal mucosa tissues. The positive rate of PDCD4 protein in LSCC was significantly lower than that in the laryngeal normal mucosa tissues by immunohistochemical staining (P<0.01). No correlation was found between positive expression of PDCD4 and gender, age, tumor site, TNM stage, but there was significant correlation between positive expression of PDCD4 from differentiation grading and lymphatic matastasis. Meanwhile,we got the similar results by Western blot (P<0.01).

The low expression of PDCD4 protein is closely related to the development and progression of LSCC. PDCD4 might be a novel molecular marker for prognosticating metastases and prognosis of LSCC.

Does stable-State Midrange-Proadrenomedullin Level be a Strong Predictor of Mortality in Patients With COPD? Midrange-proadrenomedullin (MR-proADM) has been shown to be elevated in patients hospitalized for an acute exacerbation of COPD (AECOPD) and in patients with community-acquired pneumonia. When measured during AECOPDs, MR-proADM has also been shown to be a predictor of mortality. We hypothesized that MR-proADM levels measured in a stable state could also predict mortality. We included 181 patients in whom we had paired plasma samples for MR-proADM determinations during a stable state and at hospitalization for an AECOPD when they also produced sputum. Time to death or censoring was compared between patients with MR-proADM above or below the median of 0.71 nmol/L. The predictive value of MR-proADM for survival was determined by calculating the C statistic. Patients with COPD and MR-proADM levels > 0.71 nmol/L in the stable state had a threefold-higher risk of dying than did patients with MR-proADM levels < 0.71 nmol/L (hazard ratio, 2.98 [95% CI, 1.51-5.90]; C statistic, 0.76). The corrected OR for 1-year mortality was 8.90 (95% CI, 1.94-44.6) in patients with high MR-proADM levels measured in the stable state, compared with patients with low levels measured in the stable state.

MR-proADM measured in the stable state appeared to be a strong predictor of mortality in patients with COPD. MR-proADM is far easier to measure than other predictors of mortality in COPD, such as BMI, airflow obstruction, dyspnea, and exercise capacity score.

Does adenovirus-mediated Bak gene transfer induce apoptosis in mesothelioma cell lines? Conventional treatment for mesothelioma is largely ineffective. We therefore evaluated the novel approach of adenoviral gene transfer of the proapoptotic Bcl-2 family member Bak in mesothelioma cancer cell lines, which are sensitive and resistant to adenoviral p53. Binary adenoviral Bak (Ad/GT-Bak and Ad/GV16) and LacZ (Ad/GT-LacZ and Ad/GV16) vectors were used for transduction of the mesothelioma cell lines I-45 (p53 resistant) and REN (p53 sensitive). Protein levels were determined by Western blotting. Apoptosis was assessed by morphologic changes, caspase-3 cleavage, and fluorescence-activated cell sorter analysis of subdiploid populations. Cell viability was determined with the XTT assay. Statistical analysis was performed with analysis of variance and the Student t test. High levels of Bak gene transfer were seen after coadministration of Ad/GT-Bak and Ad/GV16 in both mesothelioma cell lines. Apoptosis was induced 24 hours after Bak but not LacZ gene transfer ([Bak: I-45, 36%; REN, 25%] vs [LacZ: I-45, 1%; REN, 3%], P <.05]) in p53-sensitive (REN) and p53-resistant (I-45) cell lines. Cellular viability was significantly decreased 48 to 72 hours after Bak gene transfer compared with control vector in both cell lines (72 hours: Bak I-45, 1.4% +/- 1.0%, and Bak REN, 4.7% +/- 1%, vs Lac-Z I-45, 83% +/- 3%, and Lac-Z REN, 100% +/- 1%; P <.05).

Adenovirus-mediated overexpression of the Bak gene induces apoptosis and decreased cellular viability in p53-sensitive and p53-resistant mesothelioma cells. These data suggest that the gene transfer of proapoptotic Bcl-2 family members may represent a novel gene therapy strategy to treat mesothelioma.

Do patients with severe obstructive sleep apnea syndrome and elevated high-sensitivity C-reactive protein need priority treatment? To evaluate the clinical factors predicting the significantly elevated high-sensitivity C-reactive protein (hs-CRP) concentrations, defined herein as hs-CRP > or = 3 mg/L, in adult males with untreated obstructive sleep apnea syndrome (OSAS). Cross-sectional study. Tertiary referral center. Sixty-five consecutive male patients with newly diagnosed OSAS were enrolled to receive complete medical history review, physical examination, in-laboratory overnight polysomnography, and hs-CRP test. The patients had no current or history of cardiovascular disease. The patients had a mean age of 38.2 +/- 9.9 years, body mass index (BMI) of 27.4 +/- 3.5 kg/m(2), and Epworth Sleepiness Scale (ESS) of 11.3 +/- 4.6. The serum levels of hs-CRP were assessed using peripheral venous blood samples. Twenty-three percent of the overall patients had significantly elevated serum levels of hs-CRP. The increase of hs-CRP correlated fairly with BMI, apnea-hypopnea index (AHI), tonsil size, and ESS (r = 0.450, 0.398, 0.393, and 0.300, respectively; all P < or = 0.05) after adjustment for conventional coronary heart disease risk factors. However, only the AHI could predict for significantly elevated hs-CRP after stepwise multiple linear regression (R(2) = 0.251, P < 0.001).

Patients in this study with hs-CRP > or = 3 mg/L were more prevalent in the severe OSAS group. This observation suggests that the severe OSAS patients need to have their cardiovascular statuses evaluated by use of an hs-CRP screening test.

Does religious activity improve life satisfaction for some physicians and older patients? To assess religious perceptions and activities of physicians and older patients and to determine whether religious activities are associated with life satisfaction. A cross-sectional survey of practicing Virginia internists and psychiatrists and hospitalized or institutionalized (nursing home) older adults. One hundred randomly sampled practicing physicians and 55 hospitalized or institutionalized older patients. A mailed survey was used for the physicians and a structured interview for the patients. All subjects provided information pertaining to demographics and life satisfaction using the Life Satisfaction Index (LSI-B). For physicians or patients who engaged in any religious activity, the Intrinsic/Extrinsic Religiosity (I/E-R) scale was used. Of the 100 physicians (49 internists and 51 psychiatrists) who answered the survey (50% response rate), 75% used religious activity as a coping resource (39% somewhat, 36% definitely). There was a positive correlation between intrinsic religious activity (e.g., prayer, Bible reading) and life satisfaction (r = .293, P = .042). Of the 55 patients interviewed, 47 (86%) used religion as a coping resource, and intrinsic religious activity was positively associated with life satisfaction (r = .843, P < .001). Even after controlling for age, gender, health, and marital status, intrinsic religious activity remained a predictor of higher life satisfaction.

Intrinsic religious activity is associated positively with life satisfaction in physicians and ill older adults.

Does e-cadherin protein expression predict prostate cancer salvage radiotherapy outcomes? Radiotherapy for biochemical prostate cancer recurrence after prostatectomy achieves durable salvage rates of only 40% to 50%. Improved methods of identifying patients unlikely to benefit from salvage radiotherapy are needed. Altered expression of the adhesion molecule E-cadherin may be associated with the invasive and metastatic phenotype. We examined the relationship between E-cadherin expression and outcomes after salvage radiotherapy. E-cadherin expression was examined by immunohistochemistical analysis of a tissue microarray of prostatectomy tissues from patients who underwent salvage radiotherapy. The relation between E-cadherin staining, other risk factors and biochemical failure after salvage radiotherapy was analyzed using Kaplan-Meier and Cox regression methods. Of 37 analyzable cases 25 showed aberrant E-cadherin expression, while the remainder had normal expression. At a median clinical followup of 40 months univariate analysis demonstrated that E-cadherin staining was not associated with Gleason score, extracapsular extension, surgical margin status, pre-prostatectomy or pre-radiotherapy prostate specific antigen, complete biochemical response after radiotherapy or adjunctive hormonal therapy but it was associated with seminal vesicle invasion. Two-year failure-free survival was 55% in patients with aberrant E-cadherin expression compared with 92% in patients with normal E-cadherin expression (p = 0.02). Multivariate analysis confirmed that aberrant E-cadherin expression was associated with salvage radiotherapy failure (p = 0.03).

Aberrant E-cadherin staining is associated with increased biochemical failure rates after salvage radiotherapy. Patients with biochemical failure after prostatectomy and aberrant E-cadherin expression are likely to have subclinical disseminated disease. Early systemic therapy may be warranted in these patients.

Does transoral laser microsurgery elevate fundamental frequency in early glottic cancer? To evaluate the long-term voice characteristics and quality of life of early glottic cancer patients after definitive treatment. Case series with chart review in a tertiary care medical center in Taiwan. Forty-two consecutive patients who received radiation therapy (RT) or transoral laser microsurgery (TLM) for early glottic cancer over 12 months were evaluated for voice laboratory data and quality-of-life measurements. Twenty-four patients received RT, and 18 underwent TLM. There was no difference between the two groups on acoustic and aerodynamic voice measures except for modal fundamental frequency in males. In the Functional Assessment of Cancer Therapy-Head and Neck survey, the TLM group had better communication than the RT group, but there were no differences in voice quality and strength. There was also no significant difference in the Voice Handicap Index 10 evaluation.

Male patients who received TLM have higher modal fundamental frequency than male patients who received RT and norms. Voice-related life quality is similar in patients regardless of RT or TLM treatment for early glottic cancer, but those who receive TLM have better communication abilities than those who receive RT.

Does the endogenous NOS inhibitor asymmetric dimethylarginine ( ADMA ) predict LV mass independent of afterload? Nitric oxide (NO) is a modulator of left ventricular hypertrophy (LVH) and myocardial relaxation. The impact of NO availability on development of LVH has never been demonstrated in humans. We tested the hypotheses that elevation of asymmetric dimethylarginine (ADMA) concentrations (biochemical marker of decreased NO generation), and impairment of vascular responsiveness to NO donor GTN, would each predict the presence of LVH and associated LV diastolic dysfunction in a normal aging population. In 74 subjects aged 68±6 years, LV volumes and mass indexed to height(2.7) (LVMI) were calculated from cardiac MRI. Despite the absence of clinically-defined LVH, there was a relationship (r=0.29; p=0.01) between systolic BP and LVMI. Both elevation of ADMA levels to the highest quartile or impairment of GTN responsiveness (determined by applanation tonometry) to the lowest quartile were determinants of LVMI independent of systolic BP (p=0.01 and p=0.03, respectively). Filling pressure (E/E' ratio from echocardiography) was increased in patients with impaired vascular NO responsiveness (p<0.05) irrespective of LVMI. ADMA remained a significant determinant of LVMI on multivariate analysis.

These data imply that NO bioavailability within the myocardium modulates earliest stages of LVH development and facilitates development of diastolic dysfunction at a given LV mass.

Does proprioceptive neck influence modify the information about tilt direction coded by the cerebellar anterior vermis? To verify whether the direction of head tilt coded by the population response of Purkinje (P) cells located in the cerebellar anterior vermis is modified by the relative position of the body with respect to the head. In decerebrate cats, the responses of P cells to wobble of the whole animal were analyzed in order to compute the response vectors of the same cells to the labyrinthine input. These response vectors were used to evaluate the population response (vector) of all the recorded neurons to head tilt in specific directions. When the head was aligned with the body, the direction of the population vector closely corresponded to that of head tilt. A 30 degree body-to-head rotation to the left or right around a C1-C2 vertical axis modified the response vectors of most of the recorded neurons, leading to reciprocal deviations of the population vector from the direction of head tilt of approximately 30 degrees.

We propose that information from neck receptors regulates the convergence of labyrinthine signals with different spatial and temporal properties on corticocerebellar units, thus allowing the P-cell population to code the direction of body tilt.

Is the `` second gas effect '' a valid concept? To determine whether the "second gas effect" is valid, we determined the pharmacokinetics of 0.2% enflurane with or without 80% N2) (n = 7 each) under controlled constant volume ventilation in 14 young healthy male patients before their operations. The alveolar (end-tidal) concentration (FA) and inspired concentration (FI) at the mouthpiece and the arterial blood concentration of enflurane were measured, and the ratio of FA to FI was calculated. The FA/FI of enflurane increased rapidly during the first few minutes of administration and then increased slowly. No significant difference was found in the FA/FI between the two groups at any time point (P > 0.05). The arterial blood concentrations of enflurane increased progressively and were not significantly different between the two groups at any time point (P > 0.05). The results indicate that, at high concentrations, N2O neither facilitated the increase of FA nor enhanced the uptake of a companion gas. The second gas effect is a nonexistent phenomenon in clinical practice because the concentrating effect is very weak and the augmentation effect is nonexistent under controlled ventilation.

We studied the effects of N2O on the ratio of alveolar (end-tidal) concentration to inspired concentration of the second gas (enflurane) and on its blood concentration in humans. Nitrous oxide did not affect the alveolar or blood concentration of the second gas under controlled constant volume ventilation. The "second gas effect" is not a valid concept.

Does new genotyping method discover sustained nosocomial Pseudomonas aeruginosa outbreak in an intensive care burn unit? Pseudomonas aeruginosa is a leading cause of healthcare-associated infections in the intensive care unit (ICU). To investigate an unexplained increase in the incidence of P. aeruginosa recovered from clinical samples in the ICU over a two-year period. After unsuccessful epidemiological investigation by conventional tools, P. aeruginosa clinical isolates of all patients hospitalized between January 2010 and July 2012 were typed by a novel double-locus sequence typing (DLST) method and compared to environmental isolates recovered during the investigation period. In total, 509 clinical isolates from 218 patients and 91 environmental isolates were typed. Thirty-five different genotypic clusters were found in 154 out of 218 patients (71%). The largest cluster, DLST 1-18, included 23 patients who were mostly hospitalized during overlapping periods in the burn unit. Genotype DLST 1-18 was also recovered from floor traps, shower trolleys and the shower mattress in the hydrotherapy rooms, suggesting environmental contamination of the burn unit as the source of the outbreak. After implementation of appropriate infection control measures, this genotype was recovered only once in a clinical sample from a burned patient and twice in the environment, but never thereafter during a 12-month follow-up period.

The use of a novel DLST method allowed the genotyping of a large number of clinical and environmental isolates, leading to the identification of the environmental source of a large unrecognized outbreak in the burn unit. Eradication of the outbreak was confirmed after implementation of a continuous epidemiological surveillance of P. aeruginosa clones in the ICU.

Do multiple microRNAs regulate human FOXP2 gene expression by targeting sequences in its 3 ' untranslated region? Mutations in the human FOXP2 gene cause speech and language impairments. The FOXP2 protein is a transcription factor that regulates the expression of many downstream genes, which may have important roles in nervous system development and function. An adequate amount of functional FOXP2 protein is thought to be critical for the proper development of the neural circuitry underlying speech and language. However, how FOXP2 gene expression is regulated is not clearly understood. The FOXP2 mRNA has an approximately 4-kb-long 3' untranslated region (3' UTR), twice as long as its protein coding region, indicating that FOXP2 can be regulated by microRNAs (miRNAs). We identified multiple miRNAs that regulate the expression of the human FOXP2 gene using sequence analysis and in vitro cell systems. Focusing on let-7a, miR-9, and miR-129-5p, three brain-enriched miRNAs, we show that these miRNAs regulate human FOXP2 expression in a dosage-dependent manner and target specific sequences in the FOXP2 3' UTR. We further show that these three miRNAs are expressed in the cerebellum of the human fetal brain, where FOXP2 is known to be expressed.

Our results reveal novel regulatory functions of the human FOXP2 3' UTR sequence and regulatory interactions between multiple miRNAs and the human FOXP2 gene. The expression of let-7a, miR-9, and miR-129-5p in the human fetal cerebellum is consistent with their roles in regulating FOXP2 expression during early cerebellum development. These results suggest that various genetic and environmental factors may contribute to speech and language development and related neural developmental disorders via the miRNA-FOXP2 regulatory network.

Is traditional dietary pattern of South America linked to breast cancer : an ongoing case-control study in Argentina? Several studies have shown the effect of dietary patterns on breast cancer risk, but none has been conducted in Argentina. The aim of this study was to extract dietary patterns from Food Frequency Questioner, to estimate their effect on breast cancer occurrence while taking into account aggregation factors (family history of breast cancer) and to explore the sensitivity of the estimates to changes in the assumptions. A principal component exploratory factor analysis was applied to identify dietary patterns, which were then included as covariates in a multilevel logistic regression. Family history of BC was considered as a clustering variable. A multiple probabilistic sensitivity analysis was also performed. The study included 100 cases and 294 controls. Four dietary patterns were identified. Traditional (fat meats, bakery products, and vegetable oil and mayonnaise) (OR III tertile vs I 3.13, 95% CI 2.58-3.78), Rural (processed meat) (OR III tertile vs I 2.02, 95% CI 1.21-3.37) and Starchy (refined grains) (OR III tertile vs I 1.82, 95 % CI 1.18-2.79) dietary patterns were positively associated with BC risk, whereas the Prudent pattern (fruit and non-starchy vegetables) (OR III tertile vs I 0.56, 95% CI 0.41-0.77) showed a protective effect. For Traditional pattern, the median bias-adjusted ORs (3.52) were higher than the conventional (2.76).

While the Prudent pattern was associated with a reduced risk of BC, Traditional, Rural and Starchy patterns showed a promoting effect. Despite the threats to validity, the nature of associations was not strongly affected.

Is dementia strongly associated with 90-day mortality in lobar cerebral amyloid angiopathy related intra-cerebral haemorrhage? While evidence suggests that lobar intracerebral haemorrhage (ICH) is linked with dementia and cognitive impairment, the association between cognition and mortality risk from ICH is unclear. To examine the association between dementia or cognitive impairment and short- and medium-term mortality post ICH. Patients with primary ICH were classified into lobar and non-lobar ICH using radiological criteria. Patients' characteristics and radiological measures were collected at the baseline along with history of dementia and cognitive impairment. Mortality risks at 7, 30, 60, and 90 days were assessed using multiple logistic regression adjusting for potential confounders identified as significant associates in univariate models. A total of 136 patients (males 50%, mean age 77 years, SD 10) were included in this study. Out of 53 (39%) patients with lobar ICH 47 (89%) were classified as having possible and 6 (11%) as probable cerebral amyloid angiopathy (CAA). In lobar ICH the prevalence of history of dementia or cognitive impairment, confusion at presentation, previous ICH, multiple haemorrhages, and initial haematoma volume were significantly higher (p<0.05). In lobar ICH the significant mortality predictors (p<0.05) were history of dementia or cognitive impairment (90 days), prior antiplatelet use (60 and 90 days), initial haematoma volume (60 days), male sex (30 and 60 days), age (30, 60, 90 days), and low Glasgow Coma Scale (GCS) (7 and 30 days). In non-lobar ICH prior use of anticoagulation, initial haematoma volume, low GCS and age were significant mortality predictors (p<0.05).

A history of dementia or cognitive impairment is more common in lobar CAA-related ICH and it is a medium-term mortality predictor in lobar ICH but not in deep non-lobar ICH.

Does periodontal treatment need in a native island community in Colombia determined with CPITN? To identify the prevalence and different degrees of periodontal disease in an isolated community (Isla Grande, Colombia) with no dental services and low educational level with the use of CPITN, and to establish periodontal treatment needs in different age groups. Of 116 people examined, 0.9% were in periodontal health (CPITN value 0), 18.1% had gingival bleeding (CPITN value 1), 51.7% had supra or subgingival calculus (CPITN value 2), 18.1% presented pockets 3.5-5.0 mm deep (CPITN value 3), and 11.2% had pathological pockets of 5.5mm or deeper (CPITN value 4). No clear differences were observed between sexes.

This study shows that 81% of the sample has some type of periodontal treatment need, with 69.8% of them requiring periodontal treatment that may be supplied by a hygienist and 11.2% requiring specialised treatment. Implementation of oral health education and oral prevention programmes was recommended to the authorities for this community.

Does the traditional Japanese medicine hangeshashinto alleviate oral ulcer-induced pain in a rat model? Recent studies have demonstrated that mouthwash made with the traditional Japanese medicine hangeshashinto exhibits anti-inflammatory action and alleviates oral mucositis scores, including pain complaints, in patients undergoing chemoradiotherapy. However, no study has demonstrated the mechanism underlying how hangeshashinto provides pain relief in oral ulcers. The analgesic effects on pain-related behaviors following the topical application of hangeshashinto were evaluated in an oral ulcer rat model treated with acetic acid using recently developed methods. Indomethacin, the representative anti-inflammatory agent, was intraperitoneally administered. The tissue permeability of the oral mucosa was histologically evaluated after applying the fluorescent substance FluoroGold. The topical application of hangeshashinto in ulcerative oral mucosa suppressed mechanical pain hypersensitivity over 60 min, without any effects on healthy mucosa. The same drug application also inhibited oral ulcer-induced spontaneous pain. Indomethacin administration failed to block the mechanical pain hypersensitivity, though it did largely block spontaneous pain. Topical anesthesia with lidocaine showed hyposensitivity to mechanical stimulation in healthy mucosa. In the ulcer regions in which the oral epithelial barrier was destroyed, deep parenchyma was stained with FluoroGold, in contrast to healthy oral mucosa, in which staining was limiting to the superficial site.

Hangeshashinto leads to long-lasting analgesic effects, specifically in the ulcer region by destroying the epithelial barrier. Hangeshashinto alleviates oral ulcer-induced pain in inflammation-dependent and/or independent manner.

Are coagulofibrinolytic changes after isolated head injury different from those in trauma patients without head injury? To test the hypothesis that tissue factor release, thrombin activation, fibrin formation, and fibrinolysis after an isolated head injury are equal to those in patients without head injury, as well as to investigate the precise time course of the coagulation and fibrinolytic abnormalities after head injury, we performed prospective and retrospective studies. In the prospective study, 5 patients with isolated head injury and 11 trauma patients without head injury took part in this study. Tissue factor antigen concentration, prothrombin fragment F1+2, thrombin antithrombin complex, fibrinopeptide A, and fibrin degradation products (D-dimer) were measured on the day of admission, and days 1, 2, 3, and 4 after admission. The levels of all five hemostatic molecular markers were markedly elevated on the day of admission, and then gradually decreased to day 4. The levels and the time course of these hemostatic markers in patients with isolated head injury were not different from those in the control patients. The same incidence of disseminated intravascular coagulation between the two groups was also observed. In the retrospective study, the records of fibrinopeptide Bbeta15-42, plasmin antiplasmin complex, plasminogen activator inhibitor-1 antigen concentration (PAI-1 antigen), and PAI-1 activity in 76 trauma patients were reviewed. On the basis of the exclusion criteria, 9 patients with isolated head injury and 30 control patients were selected for the study group. Fibrinopeptide Bbeta15-42 and plasmin antiplasmin complex markedly elevated on the day of admission, then decreased on day 1, and tended to increase to day 5. Markedly elevated PAI-1 antigen and PAI-1 activity on the day of admission significantly decreased on day 1 and recovered to the normal values on day 5. The changes of these molecular markers in patients with isolated head injury were equal to those in the control patients.

We systematically elucidated the time course of coagulation and fibrinolysis after isolated head injury. We further demonstrated that changes in coagulofibrinolytic and antifibrinolytic systems in patients with isolated head injury are not different from those in patients without head injury.

Does anaphase lagging mainly explain chromosomal mosaicism in human preimplantation embryos? Cleavage stage embryos as well as postimplantation embryos have been studied extensively over the years. However, our knowledge with respect to the chromosomal constitution of human embryos at the blastocyst stage is still rudimentary. In the present paper, a large series of human blastocysts was examined by means of fluorescent in situ hybridization (FISH). It was found that only one in four blastocysts (25%) displayed a normal chromosomal pattern. We defined a group of blastocysts (26%) displaying a simple mosaic chromosome pattern (different cell lines resulting from one chromosomal error), an about equally large group of blastocysts (31%) displaying a complex mosaic chromosome pattern, and a smaller group of blastocysts (11%) showing a chaotic chromosome distribution pattern. Six per cent of all blastocysts analysed could not be assigned one of the previously mentioned chromosomal patterns.

Anaphase lagging appeared to be the major mechanism through which human embryos acquire a mosaic chromosome pattern during preimplantation development to the blastocyst stage.

Does cyanidin-3-O-beta-glucoside inhibit LPS-induced expression of inflammatory mediators through decreasing IkappaBalpha phosphorylation in THP-1 cells? As a common phytochemical, cyanidin 3-O-beta-glucoside (C3G) has a role in inhibiting inflammatory mediators; however, its mechanism of action remains unclear. The purpose of this study was to explore the effect of C3G on lipopolysaccharide (LPS)-stimulated TNFalpha and IL-6 expression in the human monocyte/macrophage cell line THP-1, and to explore the mechanisms involved. Differentiated THP-1 cells were treated with different concentrations of C3G (0.005, 0.05, 0.5,10 microM) in the absence or presence of 1 ng/mL LPS. mRNA expression levels were detected by real time PCR, and secretion of TNFalpha and IL-6, phosphorylated IkappaBalpha, and nuclear factor-kappa B (NF-kappaB) P65 were monitored by ELISA or Western blotting analysis. The role of an inhibitor of IkappaBalpha phosphorylation, BAY 11-7082, in C3G inhibition of LPS-induced cytokines expression was investigated. C3G (0.05-0.5 microM) treatment significantly inhibited LPS-stimulated TNFalpha and IL-6 mRNA expression and secretion of these proteins by THP-1 cells. Phosphorylation of IkappaBalpha and NF-kappaB nuclear translocation could be blocked by 0.5 microM C3G. BAY 11-7082 treatment abolished C3G-induced reduction of TNFalpha and IL-6.

Our results suggest that C3G exerts its anti-inflammatory effect through inhibiting IkappaBalpha phosphorylation, thereby suppressing NF-kappaB activity in THP-1 cells.

Does production of IL1-beta by ovarian cancer cells induce mesothelial cell beta1-integrin expression facilitating peritoneal dissemination? A crucial step in the metastatic spread of ovarian cancer (OC) is the adhesion and implantation of tumor cells to the peritoneal mesothelium. In order to study this step in the cascade, we derived a pro-metastatic human ovarian carcinoma cell line (MFOC3) from the non-metastatic FOC3 line. Molecular profiling of the isogeneic lines identified differentially expressed genes, and investigation for a role in dissemination for specific factors was achieved by development of a co-culture adhesion assay utilizing monolayers of human mesothelial cells. After murine intraperitoneal inoculation, the FOC3 cell line formed no metastases, but the MFOC3 subline formed metastases in > 80% of SCID mice. MFOC3 cells also adhered 2-3 times more avidly to mesothelial monolayers. This adhesion was inhibited by neutralizing antibodies to IL-1β and enhanced by recombinant IL-1β (p < 0.01). IL-1β induced mesothelial cell β1-integrin, and an antibody to this subunit also inhibited the adhesion of MFOC3 to mesothelial cells in vitro and significantly reduced metastases in vivo. Immunohistochemical analysis of a cohort of 96 ovarian cancer cases showed that negative IL-1β expression was significantly associated with an improved overall survival rate.

These results suggest that a IL-1β/β1-integrin axis plays a role in ovarian tumor cell adhesion to mesothelia, a crucial step in ovarian cancer dissemination.

Is retinal sensitivity a valuable complementary measurement to visual acuity -- a microperimetry study in patients with maculopathies? To evaluate changes in macular sensitivity, as measured with microperimetry, among patients with maculopathy and stable visual acuity (VA). Macular sensitivity was assessed using the Spectral OCT/SLO™ microperimetry (OCT/SLO, Optos Plc., Dunfermline, UK) in 25 eyes (16 patients) with maculopathy and stable VA (<5 letters change in ETDRS score) at two consecutive clinic visits. To take the limits of the test-retest repeatability of the OCT/SLO into account, coefficient of repeatability (CoR) was employed to estimate the probability of the sensitivity changes being secondary to measurement noise. The point sensitivity changes were statistically significant (Wilcoxon signed-rank test, P < 0.001). Seventy-seven points (11 %) out of a total of 700 sensitivity points had a genuine sensitivity change, with a mean increase of 8.6 ± 2.6 dB in 35 points and a mean decrease of 7.9 ± 2.2 dB in 42 points.

Point-to-point change in macular sensitivity can be used as a biomarker of changes in disease activity in patients with maculopathy, and can be more accurate than either mean sensitivity or BCVA in detection of changes in macular function. The measurement variability should be considered when observing the local sensitivity changes.

Does obesity have no effect on outcomes following unicompartmental knee arthroplasty? Although obesity has historically been described as a contraindication to UKA, improved outcomes with modern UKA implant designs have challenged this perception. The purpose of this study was to assess the influence of obesity on the outcomes of UKA with a robotic-assisted system at a minimum follow-up of 24 months with the hypothesis that obesity has no effect on robotic-assisted UKA outcomes. There were 746 medial robotic-assisted UKAs (672 patients) with a mean age of 64 years (SD 11) and a mean follow-up time of 34.6 months (SD 7.8). Mean overall body mass index (BMI) was 32.1 kg/m Patient BMI did not influence the rate of revision surgery to TKA (5.8 %) or conversion from InLay to OnLay design (1.7 %, n.s.). Mean postoperative Oxford knee score was 37 (SD 11) without correlation with BMI (n.s.). The type of prosthesis (InLay/OnLay) regardless of BMI had no influence on revision rate (n.s.). BMI did not influence 90-day readmissions (4.4 %, n.s.), but showed significant correlation with higher opioid medication requirements and a higher number of physical therapy session needed to reach discharge goals (p = 0.031).

These findings suggest that BMI does not influence clinical outcomes and readmission rates of robotic-assisted UKA at mid-term. The classic contraindication of BMI >30 kg/m

Are the mitogen-activated protein kinases p38 and ERK1/2 increased in lesional psoriatic skin? Alterations in specific signal transduction pathways may explain the hyperproliferation and abnormal differentiation of the keratinocytes as well as the increased expression of inflammatory cytokines seen in psoriasis. Major signalling pathways used by eukaryotic cells to transduce extracellular signals into cellular responses impinge on the mitogen-activated protein kinases (MAPKs). To investigate the expression of the MAPK p38, extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) in psoriatic skin. Keratome biopsies were taken from patients with plaque-type psoriasis. Western blot analysis was used to determine p38, ERK and JNK activity and protein levels, whereas kinase assays were used to examine the kinase activity of p38. We demonstrated increased levels of the phosphorylated forms of p38 and ERK1/2 in lesional psoriatic skin compared with nonlesional psoriatic skin. No abnormality was found in the activation and expression of JNK1/2. Ex vivo kinase assays confirmed the increased activation of p38, and furthermore demonstrated increased kinase activity of the p38 isoforms p38alpha, p38beta and p38delta in lesional compared with nonlesional psoriatic skin. p38gamma was not detected in the psoriatic skin. Clearance of the psoriatic lesions, induced by climatotherapy at the Dead Sea for 4 weeks, led to a normalization in the activity of both p38 and ERK1/2.

Taken together, our results demonstrate that the activity of the MAPKs p38alpha, p38beta and p38delta and ERK1/2 are increased in lesional psoriatic skin compared with nonlesional psoriatic skin, and that clearance of psoriasis normalizes the p38 and ERK1/2 activity. Thus, p38 and ERK1/2 might be potential targets in the treatment of psoriasis.

Do norgestimate and medroxyprogesterone acetate attenuate the atheroprotective effects of 17beta-estradiol in ovariectomized , apolipoprotein E-deficient mice? To determine whether progestins counteract the cardioprotective effects of estrogen. Controlled animal study. Academic laboratory environment. Female apolipoprotein E-deficient mice. Mice were randomly assigned to groups receiving a sham operation plus placebo pellet, bilateral gonadectomy plus placebo pellet, or gonadectomy plus one of nine combinations of estrogen/progestin SC pellets. Total plasma cholesterol, body weight, fat depot weight, uterine weight and size, and the cross-sectional area of fatty streaks in the aortic sinus were measured in each animal. After 8 weeks of treatment, plasma cholesterol levels were significantly higher only in the ovariectomized and sham-operated animals that received placebo pellets. No differences in plasma cholesterol were observed relative to the type or amount of progestin administered. There was a reduction in fatty streaks in all of the hormone treatment groups as compared with both the ovariectomized and sham-operated animals that received placebo pellets.

There were no significant differences in lesion area in response to estrogen alone or to estrogen plus the different types and doses of progestins.

Does blood leucocyte telomere DNA content predict vascular telomere DNA content in humans with and without vascular disease? Previous studies have suggested that reduced telomere length in circulating leucocytes in humans is associated with premature vascular disease and by implication, accelerated vascular ageing. Importantly, a link between telomere length in circulating leucocytes and the blood vessel wall has never been established. We, thus, investigated the relationship between vascular wall and circulating leucocyte telomere length in humans with and without overt vascular disease. Aortic biopsies and paired blood leucocytes were obtained from 20 patients with asymptomatic abdominal aortic aneurysms (AAAs), undergoing elective open repair, and 12 morphologically normal aortas from a group of cadaveric organ donors of similar mean age. Telomere content was compared by quantitative PCR and expressed as telomere:genomic DNA ratio. The telomere:genomic DNA content was significantly reduced in wall biopsies of AAA vs. normal aorta, and this difference remained after adjusting for age and gender. There were strong correlations between leucocyte and vascular telomere content when the AAA and control groups were analysed either separately or grouped irrespective of the presence of vascular disease (r = 0.62, P < 0.001).

The findings demonstrate that leucocyte DNA content is predictive of vascular telomere content and is an accurate surrogate for human vascular age.

Are polymorphisms in the 5 ' region of the CD14 gene associated with eczema in young children? Variants in the CD14 gene (CD14) are hypothesized to be associated with atopic disorders. However, most studies have only investigated one polymorphism in this gene. We sought to study the association of 5 single nucleotide polymorphisms (SNPs) in the 5' flanking region of CD14 with eczema and serum IgE levels in young children. We genotyped 5 SNPs in an approximately 6.5-kb region in the 5' region of CD14 in 344 2-year-old white children from 2 birth cohorts in the northeastern United States. We examined the relation of both single SNPs and haplotypes in CD14 with the atopic outcomes. Two SNPs were significantly associated with eczema. In dominant models adjusted for potential confounders, SNP rs2569193 was associated with significantly decreased risk for eczema (odds ratio [OR] for CT/TT vs CC, 0.5; 95% CI, 0.3-0.8), whereas SNP rs2569190 (also reported as the C-159T) was associated with significantly increased risk for eczema (OR for CT/TT vs CC, 2.3; 95% CI, 1.4-3.8). The CT/TT genotypes of SNP rs2569190 also had higher geometric means of serum IgE than the CC genotype (24.6 vs 15 IU/mL, P = .025). Haplotype analyses provided results similar to those of the single SNP analyses.

Our results contradict previous reports that have found a protective effect of the T allele of SNP rs2569190 (C-159T) against atopic disorders. Nevertheless, these results confirm the importance of polymorphisms in CD14 in the development of atopy, and future studies of this gene region will need to account for linkage disequilibrium and environmental exposures unique to the study population.

Do viral factors correlate with hepatitis B e antigen seroconverson in patients with chronic hepatitis B? Seroconversion (SC) from hepatitis B envelope antigen (HBeAg) to anti-HBe usually indicates lower viral loads, resolved hepatitis activity and improved long-term outcomes. However, the role of viral factors in the development of SC remains largely unknown. We thus comprehensively studied these factors in 25 patients with sustained HBeAg SC and seven control patients with sustained loss of HBeAg. We determined viral factors in serum samples obtained 1 year before, 6 months before, 3 months before, at the time of, 6 months after and 1 year after HBeAg SC or HBeAg loss. Precore A1896 and basal core promoter T1762/A1764 mutants were determined by polymerase chain reaction (PCR)-based assays. Serum HBV levels were determined by a real-time PCR assay. We found that decline of serum viral load, frequently accompanied by hepatitis exacerbation, occurred within 1 year before HBeAg SC. The proportions of precore and BCP mutations also increased gradually throughout the process of HBeAg SC. The virologic features were similar between HBeAg SC group and HBeAg loss group. Before HBeAg SC or loss, genotype B patients had higher serum viral loads and lower proportions of BCP mutation compared with genotype C patients.

Our findings suggested that viral factors correlate with the development of sustained HBeAg SC or loss.

Does reduced vital capacity lead to exercise intolerance in patients with ankylosing spondylitis? It is well-known that pulmonary function is altered in patients with ankylosing spondilitis (AS) owing mainly to the restriction of chest expansion. In addition to musculoskeletal factors, development of pulmonary function abnormalities may also deteriorate exercise tolerance of the patients. The aim of this study was to examine the pulmonary function and exercise tolerance of AS patients. A case controlled study. Outpatient clinic of an university hospital. Twenty-two men with the diagnosis of definite AS and 20 healthy controls matched according to age, sex, smoking habits and physical activity level were enrolled in this study. After a detailed physical examination, pulmonary function and exercise tolerance were assessed by "Sensormedics-Vmax 229" ergospirometry system. Maximal exercise testing was performed on a cycle ergometer using "10 watt ramp" protocol. Patients with AS had lower chest expansion, vital capacity and exercise tolerance than healthy subjects. Exercise tolerance strongly correlated with the patients' age, disease duration, chest expansion, modified Schober test, and vital capacity. In stepwise regression analysis, the best regression model for explaining the total variation of exercise tolerance selected only vital capacity as an independent variable (R²=54.9%).

Rather than musculoskeletal manifestations, exercise intolerance was mainly explained by pulmonary function impairment in AS patients.

Are methamphetamine and sildenafil ( Viagra ) use linked to unprotected receptive and insertive anal sex , respectively , in a sample of men who have sex with men? There is evidence that methamphetamine and sildenafil (Viagra) use are associated with sexual risk behaviour among men who have sex with men (MSM). We investigated the association of methamphetamine, sildenafil, and other substance use with unprotected receptive and insertive anal sex among MSM by conducting an encounter specific analysis. Data were from a cross sectional, community based survey of MSM in San Francisco regarding behaviour during their most recent anal sex encounter. Mulitvariate regression analysed independent associations of specific substance use and demographic variables with unprotected anal sex behaviours. The sample (n = 388) was diverse in race/ethnicity, age, income, education, HIV status, and homosexual/bisexual identification. More than half (53%) reported unprotected anal sex, including insertive (29%) and receptive (37%) during their most recent anal sex encounter; 12% reported unprotected insertive and 17% reported unprotected receptive anal sex with an HIV discordant or unknown partner. Methamphetamine was used by 15% and sildenafil was used by 6% of the men before or during the encounter; 2% used both drugs. In multivariate analysis controlling for demographic factors and other substance use, methamphetamine use was associated with unprotected receptive (odds ratio (OR), 2.03; 95% confidence interval (CI), 1.09 to 3.76) and sildenafil use was associated with unprotected insertive (OR, 6.51; CI, 2.46 to 17.24) anal sex. Effects were stronger with HIV discordant or unknown sex partners specifically.

Encounter specific associations of methamphetamine and sildenafil use with unprotected receptive and insertive anal sex, respectively, indicate the importance of assessment specificity and tailoring risk reduction efforts to address certain drugs and sexual behavioural roles among MSM.

Do [ Chorioamnionitis and early-onset neonatal sepsis significantly affect levels of interleukin-6 in very low birth weight neonates ]? To determine the influence of maternal chorioamnionitis and neonatal sepsis on interleukin-6 (IL-6) levels in cord blood and in blood obtained from very low birth weight (VLBW) infants within the first two hours of life. Prospective clinical study. Institute for the Care of Mother and Child, Prague. We measured the serum levels of IL-6 in 30 consecutive VLBW infants born in our institute. IL-6 levels were evaluated in cord blood and in neonatal blood within 2 hours after delivery. Maternal chorioamnionitis and neonatal sepsis within the first 72 hours of life were monitored. Maternal chorioamnionitis was detected in 7 of 30 patients (23.3%). There was no significant increase in IL-6 level in cord blood of newborns with maternal chorioamnionitis (p = 0.42). Serum level of IL-6 in this group did not differ from the level in newborns of mothers without signs of intraamniotic infection (p = 0.39). Neonatal early-onset sepsis was diagnosed in 7 of 30 patients (23.3%). There was no influence of neonatal sepsis on IL-6 level in cord blood (p = 0.98) and IL-6 level in neonatal blood (p = 0.19). We did not find any correlation between the group "chorioamnionitis positive" and "sepsis positive" (p = 0.31).

IL-6 in cord blood or in neonatal blood within 2 hours of life was not enough sensitive and specific marker of maternal chorioamnionitis as well as for early-onset neonatal sepsis in the group of very low birth weight infants.

Does [ Research on ginsenosides composition in wild ginseng leave in different growing years ]? To analyze ginsenosides composition in wild ginseng leaves with different growth years. The analysis was performed on Acquity UPLC BEH Shield RP18 (2.1 mm x 100 mm, 1.7 microm) column, the mobile phase was acetonitrile-0.05% formic acid solution in gradient elution mode. The detection wavelength was at 203 nm. The flow rate was 0.4 mL x min(-1) and column temperature was set at 30 degrees C. Thirteen ginsenosides were determined by the established UPLC method. In 5-17th growth year ginseng leaf samples cultivated simulating wild conditions, the contents of ginsenosides in the 14th year have the highest content.

The established method is simple, accurate and reliable, can be used in ginsenosides determination and fingerprint research of Panax crude drug. The result provides reliable data for the accumulation of ginsenosides and sustainable utilization of ginseng resources.

Does up-regulation of CNDP2 facilitate the proliferation of colon cancer? Cytosolic nonspecific dipetidase (CN2) belongs to the family of M20 metallopeptidases. It was stated in previous articles that higher expression levels of CN2 were observed in renal cell carcinoma and breast cancer. Our study explored the correlation between CN2 and colon carcinogenesis. We analysed the relationship between 183 patients clinicopathological characteristics and its CN2 expression. To detect the levels of CN2 in colon cancer cell lines and colon cancer tissues by western blot. To verify cell proliferation in colon cancer cells with knockdown of CNDP2 and explore the causes of these phenomena. The expression levels of CN2 in clinical colon tumors and colon cancer cell lines were significantly higher than that in normal colon mucosa and colon cell lines. The difference in CN2 levels was associated with tumor location (right- and left-sided colon cancer), but there was no significant association with age, gender, tumor size, tumor grade, tumor stage or serum carcinoembryonic antigen (CEA). Knockdown of CNDP2 inhibited cell proliferation, blocked cell cycle progression and retarded carcinogenesis in an animal model. The signaling pathway through which knockdown of CNDP2 inhibited cell proliferation and tumorigenesis involved in EGFR, cyclin B1 and cyclin E.

Knockdown of CNDP2 can inhibit the proliferation of colon cancer in vitro and retarded carcinogenesis in vivo.

Are the two authentic methionine aminopeptidase genes differentially expressed in Bacillus subtilis? Two putative methionine aminopeptidase genes, map (essential) and yflG (non-essential), were identified in the genome sequence of Bacillus subtilis. We investigated whether they can function as methionine aminopeptidases and further explored possible reasons for their essentiality or dispensability in B. subtilis. In silico analysis of MAP evolution uncovered a coordinated pattern of MAP and deformylase that did not correlate with the pattern of 16S RNA evolution. Biochemical assays showed that both MAP (MAP_Bs) and YflG (YflG_Bs) from B. subtilis overproduced in Escherichia coli and obtained as pure proteins exhibited a methionine aminopeptidase activity in vitro. Compared with MAP_Bs, YflG_Bs was approximately two orders of magnitude more efficient when assayed on synthetic peptide substrates. Both map and yflG genes expressed in multi-copy plasmids could complement the function of a defective map gene in the chromosomes of both E. coli and B. subtilis. In contrast, lacZ gene transcriptional fusions showed that the promoter activity of map was 50 to 100-fold higher than that of yflG. Primer extension analysis detected the transcription start site of the yflG promoter. Further work identified that YvoA acted as a possible weak repressor of yflG expression in B. subtilis in vivo.

Both MAP_Bs and YflG_Bs are functional methionine aminopeptidases in vitro and in vivo. The high expression level of map and low expression level of yflG may account for their essentiality and dispensality in B. subtilis, respectively, when cells are grown under laboratory conditions. Their difference in activity on synthetic substrates suggests that they have different protein targets in vivo.

Does heat stress limit infarct size in the isolated perfused rabbit heart? Heat stress, with the expression of heat stress proteins, has been shown to protect the rabbit heart in vitro against global ischaemia/reperfusion injury, though no benefit is apparent in an in vivo rabbit model of infarct size. The aim of this study was therefore to investigate this discrepancy and to discover whether heating itself has any effect which could negate the protection derived from myocardial stress protein synthesis. (1) To ascertain whether heat stress could limit infarct size in the absence of blood, isolated buffer perfused hearts, with or without prior heat stress, were subjected to 45 min of regional ischaemia and 120 min reperfusion, and the resulting infarct size was expressed as a percentage of the risk area (I/R%). (2) The observations were repeated in an isolated blood perfused heart model in which a support rabbit (heat stressed or control) was used to perfuse the isolated heart. In the buffer perfused heart, prior heat stress reduced I/R from 70.8(SEM 4.4)%, n = 10, in controls to 51.5(5.7)%, n = 12 (p < 0.05). In hearts perfused by support rabbits, prior heat stress reduced I/R [from 34.7(3.7)%, n = 16, to 23.5(3.3)%, n = 15 (p < 0.05)] only when the perfusing rabbit was a control (not heat stressed). If the perfusing rabbit had been heated, I/R was greater in both heat stressed and control hearts [51.9(7.0)% and 44.9(3.3)%, p < 0.05 v control support rabbit].

Heat stress limits infarct size in this rabbit model. However it appears to have additional adverse effects, probably on the blood, which may override any benefit associated with myocardial stress protein synthesis.

Is regional control preserved after dose de-escalated radiotherapy to involved lymph nodes in HPV positive oropharyngeal cancer? To analyze a cohort of patients with HPV positive, oropharyngeal squamous cell carcinoma (OPSCC) treated with lower radiation dose to clinically involved lymph nodes. We retrospectively identified patients with HPV positive, OPSCC treated with definitive chemoradiotherapy (70-74.4Gy) to the primary site and, since a post-radiation neck dissection was planned, 54Gy to the involved nodal areas. Neck dissection was ultimately omitted in all cases due to complete response. All patients were treated with a 3 field approach with sequential boost plans. Composite plans were generated retrospectively and primary tumor and lymph node GTVs were contoured and nodes were expanded by 5mm to form a CTV. Mean dose, dose to 95% (D95) and dose to 99% (D99) were determined. Fifty patients treated from 2008 to 2010 with 113 involved nodes were identified. The median age was 57years, and 6%, 46%, and 48% were current, former, and never smokers. Ninety percent of patients received concurrent cisplatin based chemotherapy. Median D95 and D99 to involved nodes were 59.8Gy and 55.9Gy respectively. At a median follow up of 54.1months, two patients developed nodal failure and four developed metastatic disease. Five year loco-regional control, disease free survival and overall survival were 96%, 81% and 86% respectively.

In this exploratory analysis, regional lymph node control in HPV positive oropharyngeal cancer was not compromised by dose de-escalated radiotherapy to involved nodes in the setting of concurrent cisplatin based chemotherapy.

Is paraoxonase-1 associated with oxidative stress , fibrosis and FAS expression in chronic liver diseases? We previously reported that paraoxonase-1 activity measurement may be useful for the evaluation of liver diseases. Because oxidative stress plays a role in liver apoptosis, and lipid peroxides are hydrolyzed by paraoxonase-1, we have extended our studies to explore the relationships between this enzyme and oxidative stress, fibrosis and apoptosis. We measured paraoxonase-1 activity and concentration, soluble FAS concentration, serum fibrosis markers, and total peroxides in a group of patients with minimal hepatic changes (n=25), chronic hepatitis (n=51), or liver cirrhosis (n=17). We also measured the Knodell activity index in liver biopsies and performed FAS and PON1 immunostaining. Patients with liver diseases showed an increase in soluble FAS, fibrosis markers and paraoxonase-1 concentrations, as well as a decrease in PON1 activity. Paroxonase-1 activity and concentration were correlated with soluble FAS (r=-0.43, P<0.001 and r=0.27, P=0.007, respectively). Paraoxonase-1 concentration showed a significant inverse association with FAS immunostaining (P=0.013) and a direct association with PON1 immunostaining (P<0.001).

These results suggest an active role of PON1 in the regulation of oxidative stress, fibrosis and hepatic cell apoptosis in chronic liver diseases.

Does dynamic Contrast-Enhanced Magnetic Resonance Imaging suggest Normal Perfusion in Normal-Appearing White Matter in Multiple Sclerosis? Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system and has been associated with reduced perfusion in normal-appearing white matter (NAWM). The magnitude of this hypoperfusion is unclear. The present study aims to quantify NAWM perfusion with dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in patients with relapsing-remitting (RR) MS and in a control group. The statistical power of a DCE-MRI acquisition to reveal hypoperfusion in MS was estimated using a Monte Carlo simulation: synthetic tissue curves with a contrast-to-noise ratio of 8 were generated for MS patients and control group using perfusion values reported in previous studies. A compartment-uptake model was fitted to these curves, yielding estimates of cerebral blood flow (CBF), cerebral blood volume (CBV), and permeability-surface area product (PS). This was repeated 1000 times. Mean and standard deviation of the resulting distributions were used to calculate the statistical power of a DCE-MRI study to detect perfusion differences between 16 control subjects and 24 MS subjects.In an institutional review board-approved study, patients with RR-MS (n = 24; mean age, 36 years; 17 women, mean Enhanced Disability Status Scale score, 3.25) and patients without history or symptoms of neurological disorder (n = 16; mean age, 49 years; 9 women) underwent a DCE-MRI examination with a previously established MRI protocol (3D SPGR sequence; 2.1 seconds temporal resolution; 44 slices; spatial resolution, 1.7 × 1.7 × 3 mm). Regions were defined manually in the middle cerebral artery; in the frontal, periventricular, and occipital NAWM; in the pons; and in the thalamus, and CBF, CBV, and PS were quantified using a compartment-uptake model.Parameter differences between MS and control groups were evaluated using a mixed linear model with subjects as random effect and controlling for age and sex. A P value of less than 0.05 was considered to indicate statistical significance. For all but one of previously reported effect sizes, the simulation study estimated a statistical power of 80% to 100% to detect reduced CBF in MS. In the patient study, mean (standard deviation) CBF in NAWM was 11.0 (15.1) and 10.4 (8.2) mL/100 mL per minute in the MS and control groups, respectively. Mean CBV in NAWM was 0.50 (0.45) mL/100 mL in the MS group and 0.48 (0.28) mL/100 mL in the control group. Mean values of PS in NAWM were 0.002 mL (0.027)/100 mL per minute in the control group and -0.001 (0.015) mL/100 mL per minute in the MS patients. Differences between patient groups were not statistically significant for CBF, CBV, mean transit time, and PS (P = 0.44, P = 0.20, P = 0.78, P = 0.66, respectively). In both groups, the influence of age on any parameter was nonsignificant. Cerebral blood flow and CBV in the thalamus and pons were significantly higher than in NAWM regions (P < 1e-4); mean transit time was significantly shorter than in NAWM (P < 1e-4). Permeability-surface area product was not significantly different from zero (P > 0.25) in all evaluated regions.

Despite high statistical power, we could not confirm previous reports of NAWM hypoperfusion in MS. This indicates that, at least in our patient cohort, potential hypoperfusion is much less pronounced than reported in previous studies.

Does hepatic gene expression profiling reveal protective responses in Atlantic salmon vaccinated against furunculosis? Furunculosis, a disease caused with gram negative bacteria Aeromonas salmonicida produces heavy losses in aquaculture. Vaccination against furunculosis reduces mortality of Atlantic salmon but fails to eradicate infection. Factors that determine high individual variation of vaccination efficiency remain unknown. We used gene expression analyses to search for the correlates of vaccine protection against furunculosis in Atlantic salmon. Naïve and vaccinated fish were challenged by co-habitance. Fish with symptoms of furunculosis at the onset of mass mortality (LR - low resistance) and survivors (HR - high resistance) were sampled. Hepatic gene expression was analyzed with microarray (SFA2.0 - immunochip) and real-time qPCR. Comparison of LR and HR indicated changes associated with the protection and results obtained with naïve fish were used to find and filter the vaccine-independent responses. Genes involved in recruitment and migration of immune cells changed expression in both directions with greater magnitude in LR. Induction of the regulators of immune responses was either equal (NFkB) or greater (Jun) in LR. Expression levels of proteasome components and extracellular proteases were higher in LR while protease inhibitors were up-regulated in HR. Differences in chaperones and protein adaptors, scavengers of reactive oxygen species and genes for proteins of iron metabolism suggested cellular and oxidative stress in LR. Reduced levels of free iron and heme can be predicted in LR by gene expression profiles with no protection against pathogen. The level of complement regulation was greater in HR, which showed up-regulation of the components of membrane attack complex and the complement proteins that protect the host against the auto-immune damages. HR fish was also characterized with up-regulation of genes for proteins involved in the protection of extracellular matrix, lipid metabolism and clearance of endogenous and exogenous toxic compounds. A number of genes with marked expression difference between HR and LR can be considered as positive and negative correlates of vaccine protection against furunculosis.

Efficiency of vaccination against furunculosis depends largely on the ability of host to neutralize the negative impacts of immune responses combined with efficient clearance and prevention of tissue damages.

Is the functional HERG variant 897T associated with Conn 's adenoma? Aldosterone secreting adenomas (aldosteronomas) have an unknown molecular origin. Ion channel currents are involved in signal transduction leading to aldosterone synthesis and secretion. HERG (human-ether-a-go-go-related gene) encodes for a potassium channel responsible for the outward rectifying delayed current and it is mutation prone. When mutated it causes most of the familial forms of both long QT and short QT syndromes. Abnormal repolarization in glomerulosa cells might increase aldosterone secretion or induce a proliferative advantage. The aims of this study were to: (1) evaluate HERG expression in aldosteronomas; (2) search for HERG somatic mutations; and (3) determine whether there is any relationship between the common HERG functional variant (A2690C, leading from lysine 897 to threonine, K897T) and aldosteronoma. Aldosteronoma and blood samples from 17 patients were studied to evaluate HERG expression, full-length HERG complementary DNA sequencing, and genotyping for K897T alleles. The prevalence of HERG 897 alleles was also tested in a control population and a population consisting entirely of hypertensive individuals. HERG was expressed in all aldosteronomas analysed. HERG somatic mutations were not detected. The 897T variant of HERG was significantly more common among patients with aldosteronoma (897T allele 41%) than in patients with moderate-severe essential hypertension (897T allele 20%, P = 0.007) or in the control population (897T allele 12%, P < 0.0001). The 897T/T genotype was present in 24% of the aldosteronoma patients versus 7% (P = 0.040) and 3% (P = 0.001) in essential hypertension and in the control population, respectively. When the chi test was performed considering the three groups together, the significance was similar (for alleles P < 0.0001 and for genotypes P = 0.004).

The common functional HERG variant 897T may predispose to the development of aldosteronoma.

Is 25-Hydroxyvitamin D closely related with the function of the pancreatic islet β cells? This study is to investigate the relationship between 25-Hydroxyvitamin D (25-OH-D) and pancreatic islet β cell function under different glucose tolerance statuses in China. Totally, 180 patients with type 2 diabetes mellitus (DM group), 178 patients with impaired fasting glucose/impaired glucose tolerance (IFG/IGT group), and 160 normal control subjects (NGT group) were included to measure their body parameters and biochemical parameters. In oral glucose tolerance test, fasting serum 25-OH-D was assessed by the enzyme-linked immunosorbent assay (ELISA). Homeostasis model assessment for insulin resistance (Homa-IR), insulin acuity index (IAI), β-cell function index (Homa-BCF) as well as secretion index (IS) were determined. The levels of 25-OH-D, IAI and Homa-BCF in the DM group and IFG/IGT group were significantly lower than that in NGT group (P < 0.05). Homa-IR in DM group and IFG/IGT group was significantly higher than that in the NGT group (P < 0.05). Pearson correlation analysis and partial correlation analysis showed that 25-OH-D was positively correlated with fasting insulin (FINS) and Homa-BCF (P < 0.05). Multiple stepwise regression analysis showed that 25-OH-D was one of the influential factors of pancreatic islet β cell function in patients with type 2 diabetes mellitus.

Our results suggest that 25-OH-D is closely related with the function of the pancreatic islet β cells and is one of the influential factors of pancreatic islet β cell function.

Is the Mini-Mental State Exam ( MMSE ) sensitive to cognitive impairment in bariatric surgery candidates? Cognitive dysfunction is common among bariatric surgery candidates and associated with poorer weight loss outcomes. Identification of a brief screening measure to detect cognitive impairment in this population is needed, because comprehensive neuropsychological evaluations may not be available in all clinical settings. The present study examined the utility of the Mini-Mental State Examination (MMSE) for detecting cognitive impairment in 30 bariatric surgery candidates by comparing impairment on the MMSE (at varying cutoffs) to impairment on a comprehensive neuropsychological test battery. Results indicated that the MMSE showed low sensitivity and specificity in identifying impairment, even at the more stringent MMSE cutoffs of 27 and 28.

These findings suggest that the MMSE is a poor screener for cognitive impairment in bariatric surgery candidates. Future research is needed to identify or develop cognitive screeners for use in this population.

Does a standardized kudzu extract ( NPI-031 ) reduce alcohol consumption in nontreatment-seeking male heavy drinkers? We previously demonstrated that short-term treatment with a standardized kudzu extract (NPI-031) reduced alcohol drinking by men and women in a natural setting. The present study was conducted in nontreatment-seeking heavy drinkers to assess the safety and efficacy of 4 weeks of kudzu extract in an outpatient setting. This randomized between-subject, double-blind, placebo-controlled study involved 2 weeks of baseline, 4 weeks of treatment, and 2 weeks of follow-up. Seventeen men (21-33 years) who reported drinking 27.6 ± 6.5 drinks/week with a diagnosis of alcohol abuse/dependence took either kudzu extract (250 mg isoflavones, t.i.d.) or matched placebo on a daily basis. They reported alcohol consumption and desire to use alcohol using a wrist actigraphy device; twice weekly laboratory visits were scheduled to monitor medication adherence and adverse events. Medication adherence was excellent and there were no adverse events and changes in vital signs, blood chemistry, and renal or liver function. There was no effect on alcohol craving, but kudzu extract significantly reduced the number of drinks consumed each week by 34-57 %, reduced the number of heavy drinking days, and significantly increased the percent of days abstinent and the number of consecutive days of abstinence.

A standardized formulation of kudzu extract produced minimal side effects, was well-tolerated, and resulted in a modest reduction in alcohol consumption in young nontreatment-seeking heavy drinkers. Additional studies using treatment-seeking alcohol-dependent persons will be necessary to determine the usefulness of this herbal preparation in reducing alcohol use in other populations.

Does exercise training improve the soleus muscle morphology in experimental diabetic nerve regeneration? In this study we evaluate the effects of exercise training (10 weeks) on soleus muscle morphology in diabetic nerve regeneration after injury by sciatic nerve crush. Wistar rats were assigned to either a non-diabetic (n = 6), non-diabetic injured (n = 6), diabetic (n = 6), diabetic injured (DC; n = 9), or trained diabetic injured group (TDC; n = 7). Muscle transverse sections were used for morphometric and ultrastructural analyses. Higher fiber density and smaller average myofiber area were observed in the DC and TDC (P < 0.05) groups compared with the other groups. This atrophic pattern was partially reversed in TDC. There was misalignment of the sarcomeres and structural alterations in the blood vessels, sarcolemma, nucleus, and mitochondria in the DC animals. The myofibers and blood vessels had a similar normal appearance in the TDC group. In addition, polyribosomes, rough sarcoplasmic reticulum, developed Golgi apparatus, and new myofibrils were observed.

Sciatic nerve injury was found to promote soleus muscle atrophy and ultrastructural alterations in experimental diabetic nerve regeneration, which were partially reversed by exercise training.

Does pretreatment serum anti-müllerian hormone predict long-term ovarian function and bone mass after chemotherapy for early breast cancer? Administration of chemotherapy to premenopausal women shortens their reproductive lifespan by depleting nonrenewable oocytes. Preservation of fertility is a priority for many such women, and identification of women at risk of infertility is therefore important. However, age is the only patient characteristic currently recognized to be predictive of long-term ovarian function after chemotherapy. Our objective was to assess markers of ovarian reserve and age as long-term predictors of ovarian function after chemotherapy. We conducted a prospective, longitudinal study at a university hospital and research institute. Patients included women who were premenopausal at the time of diagnosis of early breast cancer. Ovarian function was assessed at 5 yr follow-up in relation to pretreatment hormonal and ultrasound markers of ovarian reserve. Forty-two women received (neo-)adjuvant chemotherapy. Continuing menses 4-5 yr after diagnosis closely reflected ovarian activity as assessed by a range of serum markers, including estradiol, inhibin B, FSH, and anti-müllerian hormone (AMH). Pretreatment serum AMH, FSH, antral follicle count, and age predicted late ovarian activity by univariate analysis. However, only AMH was predictive in a multivariate logistic regression (odds ratio = 13.0; 95% confidence interval = 2.5-66.7); 0.71 ng/ml gave peak likelihood ratio of 7.0 with 54% sensitivity and 92% specificity. Bone mineral density fell over the 4-5 yr after diagnosis with greater loss in women with lower ovarian activity. Higher pretreatment AMH was associated with lower bone mineral density at both lumbar spine and hip at 5 yr (P < 0.02).

Measurement of AMH at cancer diagnosis predicts long-term ovarian function after chemotherapy. Use of this in clinical practice may allow better prediction of chemotherapy-related risk to future fertility.

Does a single nucleotide polymorphism within the novel sex-linked testis-specific retrotransposed PGAM4 gene influence human male fertility? The development of novel fertilization treatments, including in vitro fertilization and intracytoplasmic injection, has made pregnancy possible regardless of the level of activity of the spermatozoa; however, the etiology of male-factor infertility is poorly understood. Multiple studies, primarily through the use of transgenic animals, have contributed to a list of candidate genes that may affect male infertility in humans. We examined single nucleotide polymorphisms (SNPs) as a cause of male infertility in an analysis of spermatogenesis-specific genes. We carried out the prevalence of SNPs in the coding region of phosphoglycerate mutase 4 (PGAM4) on the X chromosome by the direct sequencing of PCR-amplified DNA from male patients. Using RT-PCR and western blot analyses, we identified that PGAM4 is a functional retrogene that is expressed predominantly in the testes and is associated with male infertility. PGAM4 is expressed in post-meiotic stages, including spermatids and spermatozoa in the testes, and the principal piece of the flagellum and acrosome in ejaculated spermatozoa. A case-control study revealed that 4.5% of infertile patients carry the G75C polymorphism, which causes an amino acid substitution in the encoded protein. Furthermore, an assay for enzymatic activity demonstrated that this polymorphism decreases the enzyme's activity both in vitro and in vivo.

These results suggest that PGAM4, an X-linked retrogene, is a fundamental gene in human male reproduction and may escape meiotic sex chromosome inactivation. These findings provide fresh insight into elucidating the mechanisms of male infertility.

Is antenatal indomethacin tocolysis associated with an increased need for surgical ligation of patent ductus arteriosus in preterm infants? To examine the effect of antenatal indomethacin (AI) exposure on the incidence, response to postnatal indomethacin (PI), and need for surgical ligation of patent ductus arteriosus (PDA) in preterm infants. We performed a retrospective matched cohort study of infants born at < or = 30 weeks' gestation after exposure to AI administered because of preterm labour. Control subjects were infants unexposed to AI but with similar gestational age and birth weight. We compared the incidence of PDA, response to treatment with PI, and surgical PDA ligation rate between the two groups. There was no difference in the incidence of PDA between AI infants (67.6%) and control subjects (66.6%). Only 22 of 54 (41%) infants in the AI group responded to PI therapy for symptomatic PDA closure, compared to 34 of 52 (65%) infants in the control group (P = 0.012). Thirty-two (59%) infants in the AI group required surgical PDA ligation after indomethacin therapy, compared with 18 infants in the control group (35%) (P = 0.01). Multivariate logistic regression analysis showed that AI exposure was independently associated with surgical ligation of PDA (adjusted odds ratio 3.07; 95% CI 1.46 to 6.45).

In infants born preterm (< or = 30 weeks) with a PDA, antenatal exposure to indomethacin was associated with an increased rate of therapeutic failure of PI and an increased rate of surgical PDA ligation compared with controls without such antenatal exposure.

Does a Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs allow Prediction of Human Brain Target Site Concentrations? Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition. A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments. The effect of active drug transporters was also accounted for. Subsequently, the model was translated to predict human concentration-time profiles for acetaminophen and morphine, by scaling or replacing system- and drug-specific parameters in the model. A common model structure was identified that adequately described the rat pharmacokinetic profiles for each of the nine drugs across brain compartments, with good precision of structural model parameters (relative standard error <37.5%). The model predicted the human concentration-time profiles in different brain compartments well (symmetric mean absolute percentage error <90%).

A multi-compartmental brain pharmacokinetic model was developed and its structure could adequately describe data across nine different drugs. The model could be successfully translated to predict human brain concentrations.

Are children with Down syndrome high-risk for severe respiratory syncytial virus disease? To assess Down syndrome as an independent risk factor for respiratory syncytial virus (RSV) hospitalization in children younger than 3 years of age and to evaluate illness severity. A retrospective cohort study of children enrolled in the military health system database was conducted. The effect of Down syndrome on RSV hospitalization was assessed by Cox proportional hazards model, while we controlled for risk factors. Disease severity was assessed by length of hospital stay, need for respiratory support, and age at hospitalization. The study included 633 200 children and 3 209 378 person-years. Children with Down syndrome had a hospitalization rate of 9.6% vs 2.8% in children without Down syndrome. Down syndrome had a greater adjusted hazard ratio (HR) for RSV hospitalization than most risk factors, 3.46 (95% CI 2.75-4.37). A sensitivity analysis demonstrated HR 3.21 (95% CI 2.51-4.10) for patients with Down syndrome ages 0-23 months and HR 5.07 (95% CI 2.21-11.59) ages 24-36 months. The median (IQR) length of stay of children with and without Down syndrome was 4 days (2-7) and 2 days (1-4) (P < .001). Patients with Down syndrome had a greater risk of requiring respiratory support (relative risk 5.5; 95% CI, 2.5-12.3). The median (IQR) ages at admission for children with and without Down syndrome were 9.8 months (5.5-17.7) and 3.5 months (1.7-8.7) (P < .001).

Down syndrome is independently associated with an increased risk for RSV hospitalization. Children with Down syndrome are older at time of RSV hospitalization and have more severe RSV illness than children without Down syndrome. This increased risk for hospitalization continues beyond 24 months.

Are biliary carcinoembryonic antigen levels a marker for cholangiocarcinoma? Cholangiocarcinoma develops in 5% to 15% of patients with choledochal cysts, sclerosing cholangitis, and intrahepatic stones. The detection of cholangiocarcinoma in patients with premalignant biliary conditions has been difficult. Serum levels of carcinoembryonic antigen (CEA) have been neither sensitive nor specific for the diagnosis of cholangiocarcinoma. However, CEA has been shown to be present in cholangiocarcinomas by immunohistochemical staining. Therefore, we measured the level of CEA excreted in bile in patients with benign strictures, premalignant biliary diseases, and cholangiocarcinoma. Bile was obtained from transhepatic stents in patients with benign biliary strictures (34), choledochal cysts (5), primary sclerosing cholangitis (6), intrahepatic cholelithiasis (5), and perihilar cholangiocarcinoma (25). Samples were analyzed for CEA using a solid phase, two-site immunoenzymetric assay. Biliary CEA levels were significantly elevated (P < 0.01) in patients with cholangiocarcinoma (50.2 +/- 5.8 ng/mL) and intrahepatic cholelithiasis (57.4 +/- 10.4 ng/mL) compared with patients with benign strictures (10.1 +/- 3.9 ng/mL). Patients with sclerosing cholangitis (21.6 +/- 3.9 ng/mL) and choledochal cysts (20.0 +/- 16.5 ng/mL) had intermediate levels. In 5 patients undergoing resection of perihilar cholangiocarcinomas, the mean biliary CEA level decreased from a preoperative level of 46.8 +/- 6.7 ng/mL to a postoperative level of 11.3 +/- 5.6 ng/mL (P < 0.02). In 4 patients with progression of cholangiocarcinoma, biliary CEA increased from a mean of 53.3 +/- 6.9 ng/mL to 98.3 +/- 12.2 ng/mL (P < 0.02) over a mean interval of 9.5 months.

Increased levels of CEA can be detected in the bile of patients with chlolangiocarcinoma. Monitoring these levels may have a role in the management of cholangiocarcinoma as well as premalignant biliary conditions such as choledochal cysts and sclerosing cholangitis.

Do `` Maybe they have found something new '' participants ' views on returning cohort psychosocial survey results? Although greater attention is currently being paid to participants in research, no studies have dealt so far with the issue of returning aggregate psychosocial results to cohort participants. (i) To explore participants' views about disclosure of the aggregate results of a French national psychosocial cohort survey on the epidemiology of preventive behaviour in women from families with a hereditary breast cancer risk. (ii) To assess whether it is worth consulting participants before designing the disclosure process. A qualitative study using semi-structured face-to-face interviews and a thematic analysis based on Grounded Theory methods. Nineteen interviews were conducted with cancer-free female BRCA mutation carriers/non-carriers aged 31-79 who had participated in a cohort survey by answering self-administered questionnaires. Participants showed considerable interest in the issue of result disclosure. The preferences expressed about disclosure were rarely relevant to the topic investigated, however, as they often focused on medical knowledge about BRCA and not on the psychosocial findings obtained. This confusion may have been due to the participants' experience of the survey procedures, including its longitudinal nature, the occurrence of very few interactions with the investigators and the wide range of topics addressed in the questionnaires.

Investigators should ascertain participants' expectations and preferences by consulting them before disclosing the results obtained. Although the disclosure process may not meet participants' expectations completely, consultation is the key to preventing them from having irrealistic expectations about the information they are going to receive.

Is mucinous histology a risk factor for nodal metastases in endometrial cancer? Mucinous adenocarcinoma of the endometrium (MUC) is a rare histological variant of endometrial carcinoma accounting for 1-9% of endometrioid tumors. Few studies have characterized its clinical behavior. This is a case-control study at a single institution comparing the risk factors and clinical course of MUC relative to endometrioid adenocarcinoma. A case-control study was performed including patients treated for endometrial cancer between 1996 and 2006. 41 cases of mucinous adenocarcinoma were identified. Each case was matched with two controls of endometrioid histology by age and histological grade. Cases and controls were compared with regard to known risk factors for endometrial cancer and the extent of disease at diagnosis. Chi-square tests were used to compare proportions and Student's t-tests for the comparison of means. Multivariate regression was used to identify the independent predictors of lymph node metastases. Overall survival was calculated using the Kaplan-Meier method and compared with the Log-rank test. p<.05 was considered significant for all tests. Cases and controls were matched by age and FIGO grade and were found to be similar in regard to ethnicity, body mass index and medical history. No significant difference in myometrial invasion (MI)>50% or the presence of lymph-vascular space invasion was found between cases and controls, however, 17% of patients with MUC had lymph node metastases compared to 3% of controls (p=.01). Multivariate analysis controlling for both tumor grade and depth of MI identified mucinous histology as an independent predictor of lymph node metastasis (p=.02). There was no difference in adjuvant treatment, recurrence rate or survival between the two groups.

Mucinous differentiation was found to be an independent predictor of lymph node metastasis in the study population. Comprehensive surgical staging including retroperitoneal node dissection should be strongly considered in all endometrial cancer patients with predominantly mucinous histology.

Does peptide deformylase inhibitor actinonin reduce celastrol 's HSP70 induction while synergizing proliferation inhibition in tumor cells? Celastrol is a promising anti-tumor agent, yet it also elevates heat shock proteins (HSPs), especially HSP70, this effect believed to reduce its anti-tumor effects. Concurrent use of siRNA to increase celastrol's anti-tumor effects through HSP70 interference has been reported, but because siRNA technology is difficult to clinically apply, an alternative way to curb unwanted HSP70 elevation caused by celastrol treatment is worth exploring. In this work, we explore three alternative strategies to control HSP70 elevation: (1) Searching for cancer cell types that show no HSP70 elevation in the presence of celastrol (thus recommending themselves as suitable targets); (2) Modifying HSP70-inducing chemical groups, i.e.: the carboxyl group in celastrol; and (3) Using signaling molecule inhibitors to specifically block HSP70 elevation while protecting and/or enhancing anti-tumor effects. The first strategy was unsuccessful since celastrol treatment increased HSP70 in all 7 of the cancer cell types tested, this result related to HSF1 activation. The ubiquity of HSF1 expression in different cancer cells might explain why celastrol has no cell-type limitation for HSP70 induction. The second strategy revealed that modification of celastrol's carboxyl group abolished its ability to elevate HSP70, but also abolished celastrol's tumor inhibition effects. In the third strategy, 11 inhibitors for 10 signaling proteins reportedly related to celastrol action were tested, and five of these could reduce celastrol-caused HSP70 elevation. Among these, the peptide deformylase (PDF) inhibitor, actinonin, could synergize celastrol's proliferation inhibition.

Concurrent use of the chemical agent actinonin could reduce celastrol's HSP70 elevation and also enhance proliferation inhibition by celastrol. This combination presents a novel alternative to siRNA technology and is worth further investigation for its potentially effective anti-tumor action.

Is co-morbid cardiovascular disease and depression : sequence of disease onset linked to mental but not physical self-rated health . Results from a cross-sectional , population-based study? Self-rated health has been linked to important health and survival outcomes in individuals with co-morbid depression and cardiovascular disease (CVD). It is not clear how the timing of depression onset relative to CVD onset affects this relationship. We aimed to first identify the prevalence of major depressive disorder (MDD) preceding CVD and secondly determine whether sequence of disease onset is associated with mental and physical self-rated health. This study utilised cross-sectional, population-based data from 224 respondents of the 2007 Australian National Survey of Mental Health and Wellbeing (NSMHWB). Participants were those diagnosed with MDD and reported ever having a heart/circulatory condition over their lifetime. Age of onset was reported for each condition. Logistic regression was used to explore differences in self-rated mental and physical health for those reporting pre-cardiac and post-cardiac depression. The proportion of individuals in whom MDD preceded CVD was 80.36% (CI: 72.57-88.15). One-fifth (19.64%, CI: 11.85-27.42) reported MDD onset at the time of, or following, CVD. After controlling for covariates, the final model demonstrated that those reporting post-cardiac depression were significantly less likely to report poor self-rated mental health (OR:0.36, CI: 0.14-0.93) than those with pre-existing depression. No significant differences were found in self-rated physical health between groups (OR:0.90 CI: 0.38-2.14).

MDD is most common prior to the onset of CVD. Further, there is an association between pre-morbid MDD and poorer self-rated mental health. To our knowledge, this is the first time this has been demonstrated in a national, population-based survey. As self-rated health has been shown to predict important outcomes such as survival, we recommend that those with MDD be identified as vulnerable to CVD onset and poorer health outcomes.

Do eBER2 RNA-induced transcriptome changes identify cellular processes likely targeted during Epstein Barr Virus infection? Little is known about the physiological role of the EBER1 and 2 nuclear RNAs during Epstein Barr viral infection. The EBERs are transcribed by cellular RNA Polymerase III and their strong expression results in 106 to 107 copies per EBV infected cell, making them reliable diagnostic markers for the presence of EBV. Although the functions of most of the proteins targeted by EBER RNAs have been studied, the role of EBERs themselves still remains elusive. The cellular transcription response to EBER2 expression using the wild-type and an internal deletion mutant was determined. Significant changes in gene expression patterns were observed. A functional meta-analysis of the regulated genes points to inhibition of stress and immune responses, as well as activation of cellular growth and cytoskeletal reorganization as potential targets for EBER2 RNA. Different functions can be assigned to different parts of the RNA.

These results provide new avenues to the understanding of EBER2 and EBV biology, and set the grounds for a more in depth functional analysis of EBER2 using transcriptome activity measurements.

Is pulmonary hypertension in patients with advanced heart failure associated with increased levels of interleukin-6? Inflammatory, endothelial and neurohormonal biomarkers are involved in heart failure (HF) and pulmonary hypertension (PH) pathogenesis. To study these biomarkers in PH due to advanced HF. Thirty adults with HF were included. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), endothelin-1 and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were measured in peripheral vein and pulmonary artery during right heart catheterisation. IL-6, TNF-α, hsCRP and NT-proBNP correlated with pulmonary pressures independent of ventricular function, HF etiology and vascular bed. IL-6 was independent predictor of systolic pulmonary artery pressure (sPAP).

Inflammatory biomarkers correlate to PH severity. IL-6 predicts sPAP in advanced HF.