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Endogenous galactose formation in galactose-1-phosphate uridyltransferase deficiency. |
Abstract Patients with classical galactosaemia (galactose-1-phosphate uridyltransferase (GALT) deficiency) manifest clinical complications despite strict dietary galactose restriction. Therefore the significance of endogenous galactose production has been assessed. Previous in vivo studies primarily focused on patients homozygous for the most common genetic variant Q188R but little is known about other genetic variants. In the present study the endogenous galactose release in a group of non-Q188R homozygous galactosaemic patients (n = 17; 4-34 years) exhibiting comparably low residual GALT activity in red blood cells was investigated. Primed continuous infusion studies with D-[1-13C]galactose as substrate were conducted under post-absorptive conditions and in good metabolic control. The results demonstrate that all patients exhibiting residual GALT activity of <1.5% of control showed a comparable pathological pattern of increased endogenous galactose release irrespective of the underlying genetic variations. Possible implications of the findings towards a more differentiated dietary regimen in galactosaemia are discussed. |
Effect of High-Dose Vitamin D3 on Hospital Length of Stay in Critically Ill Patients With Vitamin D Deficiency: The VITdAL-ICU Randomized Clinical Trial. |
Importance: Low vitamin D status is linked to increased mortality and morbidity in patients who are critically ill. It is unknown if this association is causal. Objective: To investigate whether a vitamin D3 treatment regimen intended to restore and maintain normal vitamin D status over 6 months is of health benefit for patients in ICUs. Design, Setting, and Participants: A randomized double-blind, placebo-controlled, single-center trial, conducted from May 2010 through September 2012 at 5 ICUs that included a medical and surgical population of 492 critically ill adult white patients with vitamin D deficiency (</=20 ng/mL) assigned to receive either vitamin D3 (n = 249) or a placebo (n = 243). Interventions: Vitamin D3 or placebo was given orally or via nasogastric tube once at a dose of 540 000 IU followed by monthly maintenance doses of 90 000 IU for 5 months. Main Outcomes and Measures: The primary outcome was hospital length of stay. Secondary outcomes included, among others, length of ICU stay, the percentage of patients with 25-hydroxyvitamin D levels higher than 30 ng/mL at day 7, hospital mortality, and 6-month mortality. A predefined severe vitamin D deficiency (</=12 ng/mL) subgroup analysis was specified before data unblinding and analysis. Results: A total of 475 patients were included in the final analysis (237 in the vitamin D3 group and 238 in the placebo group). The median (IQR) length of hospital stay was not significantly different between groups (20.1 days [IQR, 11.1-33.3] for vitamin D3 vs 19.3 days [IQR, 11.1-34.9] for placebo; P = .98). Hospital mortality and 6-month mortality were also not significantly different (hospital mortality: 28.3% [95% CI, 22.6%-34.5%] for vitamin D3 vs 35.3% [95% CI, 29.2%-41.7%] for placebo; hazard ratio [HR], 0.81 [95% CI, 0.58-1.11]; P = .18; 6-month mortality: 35.0% [95% CI, 29.0%-41.5%] for vitamin D3 vs 42.9% [95% CI, 36.5%-49.4%] for placebo; HR, 0.78 [95% CI, 0.58-1.04]; P = .09). For the severe vitamin D deficiency subgroup analysis (n = 200), length of hospital stay was not significantly different between the 2 study groups: 20.1 days (IQR, 12.9-39.1) for vitamin D3 vs 19.0 days (IQR, 11.6-33.8) for placebo. Hospital mortality was significantly lower with 28 deaths among 98 patients (28.6% [95% CI, 19.9%-38.6%]) for vitamin D3 compared with 47 deaths among 102 patients (46.1% [95% CI, 36.2%-56.2%]) for placebo (HR, 0.56 [95% CI, 0.35-0.90], P for interaction = .04), but not 6-month mortality (34.7% [95% CI, 25.4%-45.0%] for vitamin D3 vs 50.0% [95% CI, 39.9%-60.1%] for placebo; HR, 0.60 [95% CI, 0.39-0.93], P for interaction = .12). Conclusions and Relevance: Among critically ill patients with vitamin D deficiency, administration of high-dose vitamin D3 compared with placebo did not reduce hospital length of stay, hospital mortality, or 6-month mortality. Lower hospital mortality was observed in the severe vitamin D deficiency subgroup, but this finding should be considered hypothesis generating and requires further study. Trial Registration: clinicaltrials.gov Identifier: NCT01130181. |
Antibiotic consumption in relation to socio-demographic factors, co-morbidity, and accessibility of primary health care. |
Background: Differences in antibiotic consumption between individuals are not only due to differences in primary infection morbidity, other non-medical factors are important. Our objective was to investigate how socio-demographic factors, co-morbidity, and access to primary care affect antibiotic prescribing. Methods: The study population included all 2 078 481 persons in Sweden who received at least one antibiotic prescription during 2010, and an unmatched control population of 788 580 individuals. We used record linkage to obtain data on co-morbidity, various socio-demographic variables, and waiting times for doctor appointments in primary care. We used logistic regression to estimate odds ratios (ORs) for antibiotic prescription. Results: The results showed that over 20% of the population were prescribed antibiotics during 2010. Children aged 0-5 years, persons >/= 75 years of age, those living in urban areas, and women compared with men, received many prescriptions. Co-morbidity was a strong factor that determined the number of antibiotic prescriptions: those with Charlson's index >/= 3 had an OR of 3.03 (95% CI: 3.00-3.07) to obtain antibiotics in the adjusted analysis, compared with individuals without co-morbidity (Charlson's index 0). Short waiting times for a doctor's visit in primary care were associated with a higher number of antibiotic prescriptions. Individuals born in Sweden were prescribed more antibiotics compared with those born in another country. Specifically, persons born in any of the 27 EU countries (excluding Scandinavia) had an OR of antibiotic prescription of 0.78 (95% CI: 0.77-0.78) compared with native-born individuals. Conclusions: We conclude that non-medical factors strongly influence antibiotic prescriptions. |
Primary prevention of CVD: diet. |
INTRODUCTION: Diet is important in the cause of many chronic diseases. Individual change in dietary behaviour has the potential to decrease the burden of chronic disease, particularly cardiovascular disease (CVD). METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of dietary advice in generally healthy adults without existing CVD or increased CVD risk factors to improve cardiovascular outcomes (mortality, cardiovascular events, and cardiovascular risk factors)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 14 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: advice to increase fibre intake alone, advice to increase fruit and vegetable intake alone, advice to reduce and/or modify fat intake alone, and advice to reduce sodium intake alone. |
Evaluation of the Validity of Job Exposure Matrix for Psychosocial Factors at Work. |
OBJECTIVE: To study the performance of a developed job exposure matrix (JEM) for the assessment of psychosocial factors at work in terms of accuracy, possible misclassification bias and predictive ability to detect known associations with depression and low back pain (LBP). MATERIALS AND METHODS: We utilized two large population surveys (the Health 2000 Study and the Finnish Work and Health Surveys), one to construct the JEM and another to test matrix performance. In the first study, information on job demands, job control, monotonous work and social support at work was collected via face-to-face interviews. Job strain was operationalized based on job demands and job control using quadrant approach. In the second study, the sensitivity and specificity were estimated applying a Bayesian approach. The magnitude of misclassification error was examined by calculating the biased odds ratios as a function of the sensitivity and specificity of the JEM and fixed true prevalence and odds ratios. Finally, we adjusted for misclassification error the observed associations between JEM measures and selected health outcomes. RESULTS: The matrix showed a good accuracy for job control and job strain, while its performance for other exposures was relatively low. Without correction for exposure misclassification, the JEM was able to detect the association between job strain and depression in men and between monotonous work and LBP in both genders. CONCLUSIONS: Our results suggest that JEM more accurately identifies occupations with low control and high strain than those with high demands or low social support. Overall, the present JEM is a useful source of job-level psychosocial exposures in epidemiological studies lacking individual-level exposure information. Furthermore, we showed the applicability of a Bayesian approach in the evaluation of the performance of the JEM in a situation where, in practice, no gold standard of exposure assessment exists. |
Serum Amyloid A and Clusterin as Potential Predictive Biomarkers for Severe Hand, Foot and Mouth Disease by 2D-DIGE Proteomics Analysis. |
Hand, foot, and mouth disease (HFMD) affects more than one million children, is responsible for several hundred child deaths every year in China and is the cause of widespread concerns in society. Only a small fraction of HFMD cases will develop further into severe HFMD with neurologic complications. A timely and accurate diagnosis of severe HFMD is essential for assessing the risk of progression and planning the appropriate treatment. Human serum can reflect the physiological or pathological states, which is expected to be an excellent source of disease-specific biomarkers. In the present study, a comparative serological proteome analysis between severe HFMD patients and healthy controls was performed via a two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) strategy. Fifteen proteins were identified as differentially expressed in the sera of the severe HFMD patients compared with the controls. The identified proteins were classified into different groups according to their molecular functions, biological processes, protein classes and physiological pathways by bioinformatics analysis. The up-regulations of two identified proteins, serum amyloid A (SAA) and clusterin (CLU), were confirmed in the sera of the HFMD patients by ELISA assay. This study not only increases our background knowledge about and scientific insight into the mechanisms of HFMD, but also reveals novel potential biomarkers for the clinical diagnosis of severe HFMD. |
Modulation of interhemispheric functional coordination in electroconvulsive therapy for depression. |
Considerable evidence suggests that depression is related to interhemispheric functional coordination deficits. For depression, electroconvulsive therapy (ECT) is the most rapid and effective therapy, but its underlying mechanism remains unknown. The aim of this study was to explore the impact of ECT on the interhemispheric functional coordination in depression patients. We used resting-state functional magnetic resonance imaging to observe the change of interhemispheric functional coordination with the method of voxel-mirrored homotopic connectivity (VMHC) in 11 depressed patients before and after ECT, compared with 15 healthy controls. The results showed that, compared with depression patients before ECT, VMHC was significantly increased in superior frontal gyri (BA 8), middle frontal gyri (two clusters: BA 8/9 and BA 10) and angular gyri (BA 39) in depression patients after ECT. Compared with healthy controls, VMHC in those areas was significantly lower in the middle frontal gyri (BA 8/9) and angular gyri (BA 39) in depression patients before ECT, but no significant difference was observed in the superior frontal gyri (BA 8) and middle frontal gyri (BA 10). There was no significant correlation between the changes of Hamilton Depression Rating Scale scores and changed VMHC values in those four areas in depression patients. The results suggest that ECT selectively modulated interhemispheric functional coordination in depression patients. Such may play an important mechanistic role in the treatment of depression, and may afford a useful avenue for optimizing treatment. |
Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure. |
A significant feature of the cortical neuropathology of schizophrenia is a disturbance in the biogenesis of short non-coding microRNA (miRNA) that regulate translation and stability of mRNA. While the biological origin of this phenomenon has not been defined, it is plausible that it relates to major environmental risk factors associated with the disorder such as exposure to maternal immune activation (MIA) and adolescent cannabis use. To explore this hypothesis, we administered the viral mimic poly I:C to pregnant rats and further exposed some of their maturing offsprings to daily injections of the synthetic cannabinoid HU210 for 14 days starting on postnatal day 35. Whole-genome miRNA expression analysis was then performed on the left and right hemispheres of the entorhinal cortex (EC), a region strongly associated with schizophrenia. Animals exposed to either treatment alone or in combination exhibited significant differences in the expression of miRNA in the left hemisphere, whereas the right hemisphere was less responsive. Hemisphere-associated differences in miRNA expression were greatest in the combined treatment and highly over-represented in a single imprinted locus on chromosome 6q32. This observation was significant as the syntenic 14q32 locus in humans encodes a large proportion of miRNAs differentially expressed in peripheral blood lymphocytes from patients with schizophrenia, suggesting that interaction of early and late environmental insults may affect miRNA expression, in a manner that is relevant to schizophrenia. |
Corneal blindness and xenotransplantation. |
Approximately 39 million people are blind worldwide, with an estimated 285 million visually impaired. The developing world shoulders 90% of the world's blindness, with 80% of causative diseases being preventable or treatable. Blindness has a major detrimental impact on the patient, community, and healthcare spending. Corneal diseases are significant causes of blindness, affecting at least 4 million people worldwide. The prevalence of corneal disease varies between parts of the world. Trachoma, for instance, is the second leading cause of blindness in Africa, after cataracts, but is rarely found today in developed nations. When preventive strategies have failed, corneal transplantation is the most effective treatment for advanced corneal disease. The major surgical techniques for corneal transplantation include penetrating keratoplasty (PK), anterior lamellar keratoplasty, and endothelial keratoplasty (EK). Indications for corneal transplantation vary between countries, with Fuchs' dystrophy being the leading indication in the USA and keratoconus in Australia. With the exception of the USA, where EK will soon overtake PK as the most common surgical procedure, PK is the overwhelming procedure of choice. Success using corneal grafts in developing nations, such as Nepal, demonstrates the feasibility of corneal transplantation on a global scale. The number of suitable corneas from deceased human donors that becomes available will never be sufficient, and so research into various alternatives, for example stem cells, amniotic membrane transplantation, synthetic and biosynthetic corneas, and xenotransplantation, is progressing. While each of these has potential, we suggest that xenotransplantation holds the greatest potential for a corneal replacement. With the increasing availability of genetically engineered pigs, pig corneas may alleviate the global shortage of corneas in the near future. |
Alterations at the Cross-Bridge Level Are Associated with a Paradoxical Gain of Muscle Function In Vivo in a Mouse Model of Nemaline Myopathy. |
Nemaline myopathy is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. The first disease causing mutation (Met9Arg) was identified in the gene encoding alpha-tropomyosinslow gene (TPM3). Considering the conflicting findings of the previous studies on the transgenic (Tg) mice carrying the TPM3Met9Arg mutation, we investigated carefully the effect of the Met9Arg mutation in 8-9 month-old Tg(TPM3)Met9Arg mice on muscle function using a multiscale methodological approach including skinned muscle fibers analysis and in vivo investigations by magnetic resonance imaging and 31-phosphorus magnetic resonance spectroscopy. While in vitro maximal force production was reduced in Tg(TPM3)Met9Arg mice as compared to controls, in vivo measurements revealed an improved mechanical performance in the transgenic mice as compared to the former. The reduced in vitro muscle force might be related to alterations occuring at the cross-bridges level with muscle-specific underlying mechanisms. In vivo muscle improvement was not associated with any changes in either muscle volume or energy metabolism. Our findings indicate that TPM3(Met9Arg) mutation leads to a mild muscle weakness in vitro related to an alteration at the cross-bridges level and a paradoxical gain of muscle function in vivo. These results clearly point out that in vitro alterations are muscle-dependent and do not necessarily translate into similar changes in vivo. |
The Use of Surrogate Endpoints in Regulating Medicines for Cardio-Renal Disease: Opinions of Stakeholders. |
AIM: There is discussion whether medicines can be authorized on the market based on evidence from surrogate endpoints. We assessed opinions of different stakeholders on this topic. METHODS: We conducted an online questionnaire that targeted various stakeholder groups (regulatory agencies, pharmaceutical industry, academia, relevant public sector organisations) and medical specialties (cardiology or nephrology vs. other). Participants were enrolled through purposeful sampling. We inquired for conditions under which surrogate endpoints can be used, the validity of various cardio-renal biomarkers and new approaches for biomarker use. RESULTS: Participants agreed that surrogate endpoints can be used when the surrogate is scientifically valid (5-point Likert response format, mean score: 4.3, SD: 0.9) or when there is an unmet clinical need (mean score: 3.8, SD: 1.2). Industry participants agreed to a greater extent than regulators and academics. However, out of four proposed surrogates (blood pressure (BP), HbA1c, albuminuria, CRP) for cardiovascular outcomes or end-stage renal disease, only use of BP for cardiovascular outcomes was deemed moderately accurate (mean: 3.6, SD: 1.1). Specialists in cardiology or nephrology tended to be more positive about the use of surrogate endpoints. CONCLUSION: Stakeholders in drug development do not oppose to the use of surrogate endpoints in drug marketing authorization, but most surrogates are not considered valid. To solve this impasse, increased efforts are required to validate surrogate endpoints and to explore alternative ways to use them. |
Modes of Transmission of Influenza B Virus in Households. |
INTRODUCTION: While influenza A and B viruses can be transmitted via respiratory droplets, the importance of small droplet nuclei "aerosols" in transmission is controversial. METHODS AND FINDINGS: In Hong Kong and Bangkok, in 2008-11, subjects were recruited from outpatient clinics if they had recent onset of acute respiratory illness and none of their household contacts were ill. Following a positive rapid influenza diagnostic test result, subjects were randomly allocated to one of three household-based interventions: hand hygiene, hand hygiene plus face masks, and a control group. Index cases plus their household contacts were followed for 7-10 days to identify secondary infections by reverse transcription polymerase chain reaction (RT-PCR) testing of respiratory specimens. Index cases with RT-PCR-confirmed influenza B were included in the present analyses. We used a mathematical model to make inferences on the modes of transmission, facilitated by apparent differences in clinical presentation of secondary infections resulting from aerosol transmission. We estimated that approximately 37% and 26% of influenza B virus transmission was via the aerosol mode in households in Hong Kong and Bangkok, respectively. In the fitted model, influenza B virus infections were associated with a 56%-72% risk of fever plus cough if infected via aerosol route, and a 23%-31% risk of fever plus cough if infected via the other two modes of transmission. CONCLUSIONS: Aerosol transmission may be an important mode of spread of influenza B virus. The point estimates of aerosol transmission were slightly lower for influenza B virus compared to previously published estimates for influenza A virus in both Hong Kong and Bangkok. Caution should be taken in interpreting these findings because of the multiple assumptions inherent in the model, including that there is limited biological evidence to date supporting a difference in the clinical features of influenza B virus infection by different modes. |
In Silico, Experimental, Mechanistic Model for Extended-Release Felodipine Disposition Exhibiting Complex Absorption and a Highly Variable Food Interaction. |
The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog's plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability. |
Caenorhabditis elegans: A Simple Nematode Infection Model for Penicillium marneffei. |
Penicillium marneffei, one of the most important thermal dimorphic fungi, is a severe threat to the life of immunocompromised patients. However, the pathogenic mechanisms of P. marneffei remain largely unknown. In this work, we developed a model host by using nematode Caenorhabditis elegans to investigate the virulence of P. marneffei. Using two P. marneffei clinical isolate strains 570 and 486, we revealed that in both liquid and solid media, the ingestion of live P. marneffei was lethal to C. elegans (P<0.001). Meanwhile, our results showed that the strain 570, which can produce red pigment, had stronger pathogenicity in C. elegans than the strain 486, which can't produce red pigment (P<0.001). Microscopy showed the formation of red pigment and hyphae within C. elegans after incubation with P. marneffei for 4 h, which are supposed to be two contributors in nematodes killing. In addition, we used C. elegans as an in vivo model to evaluate different antifungal agents against P. marneffei, and found that antifungal agents including amphotericin B, terbinafine, fluconazole, itraconazole and voriconazole successfully prolonged the survival of nematodesinfected by P. marneffei. Overall, this alternative model host can provide us an easy tool to study the virulence of P. marneffei and screen antifungal agents. |
Global Financing and Long-Term Technical Assistance for Multidrug-Resistant Tuberculosis: Scaling Up Access to Treatment. |
Thomas Hwang and Salmaan Keshavjee argue that a market-based strategy combined with long-term in-country technical assistance should be used to scale-up access to the treatment of multi-drug resistant tuberculosis Please see later in the article for the Editors' Summary. |
Genotyping of the Duffy Blood Group among Plasmodium knowlesi-Infected Patients in Malaysia. |
The Duffy blood group is of major interest in clinical medicine as it plays an important role in Plasmodium knowlesi and Plasmodium vivax infection. In the present study, the distribution of Duffy blood group genotypes and allelic frequencies among P. knowlesi infected patients as well as healthy individuals in Peninsular Malaysia were determined. The blood group of 60 healthy blood donors and 51 P. knowlesi malaria patients were genotyped using allele specific polymerase chain reaction (ASP-PCR). The data was analyzed using Fisher's exact test in order to assess the significance of the variables. Our results show a high proportion of the FY*A/FY*A genotype (>85% for both groups) and a high frequency of the FY*A allele (>90% for both groups). The FY*A/FY*A genotype was the most predominant genotype in both infected and healthy blood samples. The genotype frequency did not differ significantly between the donor blood and the malaria patient groups. Also, there was no significant correlation between susceptibility to P. knowlesi infection with any Duffy blood genotype. |
Annotated Chemical Patent Corpus: A Gold Standard for Text Mining. |
Exploring the chemical and biological space covered by patent applications is crucial in early-stage medicinal chemistry activities. Patent analysis can provide understanding of compound prior art, novelty checking, validation of biological assays, and identification of new starting points for chemical exploration. Extracting chemical and biological entities from patents through manual extraction by expert curators can take substantial amount of time and resources. Text mining methods can help to ease this process. To validate the performance of such methods, a manually annotated patent corpus is essential. In this study we have produced a large gold standard chemical patent corpus. We developed annotation guidelines and selected 200 full patents from the World Intellectual Property Organization, United States Patent and Trademark Office, and European Patent Office. The patents were pre-annotated automatically and made available to four independent annotator groups each consisting of two to ten annotators. The annotators marked chemicals in different subclasses, diseases, targets, and modes of action. Spelling mistakes and spurious line break due to optical character recognition errors were also annotated. A subset of 47 patents was annotated by at least three annotator groups, from which harmonized annotations and inter-annotator agreement scores were derived. One group annotated the full set. The patent corpus includes 400,125 annotations for the full set and 36,537 annotations for the harmonized set. All patents and annotated entities are publicly available at www.biosemantics.org. |
CT-Based Attenuation Correction in I-123-Ioflupane SPECT. |
PURPOSE: Attenuation correction (AC) based on low-dose computed tomography (CT) could be more accurate in brain single-photon emission computed tomography (SPECT) than the widely used Chang method, and, therefore, has the potential to improve both semi-quantitative analysis and visual image interpretation. The present study evaluated CT-based AC for dopamine transporter SPECT with I-123-ioflupane. MATERIALS AND METHODS: Sixty-two consecutive patients in whom I-123-ioflupane SPECT including low-dose CT had been performed were recruited retrospectively at 3 centres. For each patient, 3 different SPECT images were reconstructed: without AC, with Chang AC and with CT-based AC. Distribution volume ratio (DVR) images were obtained by scaling voxel intensities using the whole brain without striata as reference. For assessing the impact of AC on semi-quantitative analysis, specific-to-background ratios (SBR) in caudate and putamen were obtained by fully automated SPM8-based region of interest (ROI) analysis and tested for their diagnostic power using receiver-operator-characteristic (ROC) analysis. For assessing the impact of AC on visual image reading, screenshots of stereotactically normalized DVR images presented in randomized order were interpreted independently by two raters at each centre. RESULTS: CT-based AC resulted in intermediate SBRs about half way between no AC and Chang. Maximum area under the ROC curve was achieved by the putamen SBR, with negligible impact of AC (0.924, 0.935 and 0.938 for no, CT-based and Chang AC). Diagnostic accuracy of visual interpretation also did not depend on AC. CONCLUSIONS: The impact of CT-based versus Chang AC on the interpretation of I-123-ioflupane SPECT is negligible. Therefore, CT-based AC cannot be recommended for routine use in clinical patient care, not least because of the additional radiation exposure. |
[State of the art treatment of progressive or refractory multiple myeloma.] |
Multiple myeloma (MM) is with an incidence of 4-6/100 000 inhabitants a fairly frequent malignancy of B cells. The incidence increases markedly with age. In this review changes in the treatment of relapsed / refractory myeloma during the last decade have been analysed. The present standard of care in the progressive or refractory myeloma was elaborated by the working group "Refractory Multiple Myeloma" using an extensive literature search for studies published between 2003 and 2013. Outside of clinical trials, high-dose therapy with stem cell transplantation is recommended in fit patients up to 75 years without significant comorbidities. Ongoing studies address the question about the least toxic and the most effective treatment. Therefore, inclusion of patients in therapeutic trials and use of novel agent combinations is highly recommended, e. g. with 3rd generation-IMIDs (pomalidomide), new proteasome inhibitors, such as carfilzomib, ixazomib or oprozomib, antibodies, such as elotuzumab, daratumumab or SAR650984, siltuximab, tabalumab, denosumab, romosozumab, BTK-, HSP-inhibitors and other innovative phase I/II agents. Conclusion: Based on new insights in the pathogenesis of the disease, treatment options for MM have changed significantly in recent years. There is a significantly larger treatment diversity, i. e. more MM-active agents and combinations are available today. Even with relapsed MM, patients with the disease often live longer and have fewer complications. |
[Symptomatic therapy of SIADH in small cell lung cancer by tolvaptan.] |
History and clinical findings: A 69-year-old woman with small cell lung cancer presented in the emergency ward because of severe back pain. She had received tolvaptan treatment in hospital for paraneoplastic SIADH but had discontinued the drug after discharge from hospital 3 days ago. Restriction of fluid intake was not tolerated. Investigations: Consistent with SIADH, there were profound hyponatraemia, elevated urine osmolality and urine sodium. Treatment and course: After a generalized seizure triggered by hyponatraemia, tolvaptan was reintroduced in addition to radiochemotherapy. Serum sodium concentration increased and finally returned to normal. Conclusion: If restriction of fluid intake is not tolerated by the patients the vasopressin antagonist tolvaptan provides an alternative symptomatic treatment of paraneoplastic SIADH. |
Serum Concentrations of Prostate-Specific Antigen Measured Using Immune Extraction, Trypsin Digestion, and Tandem Mass Spectrometry Quantification of LSEPAELTDAVK Peptide. |
Context.-Prostate-specific antigen (PSA) is a 34-kDa glycoprotein with chymotrypsin-like enzyme activity that circulates both in free forms and complexed to various enzyme inhibitors including antichymotrypsin and alpha2-macroglobulin. Prostate-specific antigen bound to alpha2-macroglobulin is not detected by commercial PSA immunoassays. Objective.-To develop a mass spectrometry assay that detects the same forms of PSA as the immunoassays, which could serve as a reference for harmonizing PSA immunoassays. Design.-Prostate-specific antigen was immune extracted from serum, trypsin was digested, and the LSEPAELTDAVK peptide was quantitated on an API 5000 spectrometer. Calibrators were made by adding 10% free and 90% antichymotrypsin-bound PSA to female sera. The assay was standardized to the World Health Organization 96/670 reference standard. Validation of clinical utility and comparisons with 2 immunoassays (Roche cobas and Beckman Access) were performed using frozen sera aliquots from 100 men undergoing prostate biopsy (50 negative, 50 with cancer) and 5 serial samples collected over time from 5 men with advanced prostate cancer. Results.-The antibody extraction efficiency was greater than 99%. The assay has an analytic range from 1.2 to 76 ng/mL, with precision ranging from 8.6% at 1.5 ng/mL to 5.4% at 27 ng/mL. The mass spectrometry assay correlated well with 2 immunoassays. All 3 assays showed statistically equivalent separation of prostate cancer from benign disease using receiver operating characteristic curve analysis. Conclusions.-This mass spectrometry assay can reliably measure PSA concentrations in human serum and could serve as a reference standard for harmonizing PSA immunoassays. |
Proximal Tubulopathies Associated With Monoclonal Light Chains: The Spectrum of Clinicopathologic Manifestations and Molecular Pathogenesis. |
Context.-Lesions associated with monoclonal light and heavy chains display a variety of glomerular, tubular interstitial, and vascular manifestations. While some of the entities are well recognized, including light and heavy chain deposition diseases, AL (light chain) and AH (heavy chain) amyloidosis, and light chain ("myeloma") cast nephropathy, other lesions centered on proximal tubules are much less accurately identified, properly diagnosed, and adequately understood in terms of pathogenesis and molecular mechanisms involved. These proximal tubule-centered lesions are typically associated with monoclonal light chains and have not been reported in patients with circulating monoclonal heavy chains. Objective.-To determine the incidence of proximal tubulopathies in a series of patients with monoclonal light chain-related renal lesions and characterize them with an emphasis on clinical correlations and elucidation of molecular mechanisms involved in their pathogenesis. Design.-A study of 5410 renal biopsies with careful evaluation of light microscopic, immunofluorescence, and electron microscopic findings was conducted to identify these monoclonal light/heavy chain-related lesions. In selected cases, ultrastructural immunolabeling was performed to better illustrate and understand molecular mechanisms involved or to resolve specific diagnostic difficulties. Results.-In all, 2.5% of the biopsies were diagnosed as demonstrating renal pathology associated with monoclonal light or heavy chains. Of these, approximately 46% were classified as proximal tubule-centered lesions, also referred to as monoclonal light chain-associated proximal tubulopathies. These proximal tubulopathies were divided into 4 groups defined by characteristic immunomorphologic manifestations associated with specific clinical settings. Conclusions.-These are important lesions whose recognition in the different clinical settings is extremely important for patients' clinical management, therapeutic purposes, and prognosis. These entities have been segregated into 4 distinct variants, conceptualized morphologically and clinically. Specific mechanisms involved in their pathogenesis are proposed. |
Langerhans Cell Histiocytosis Involving the Gastrointestinal Tract. |
Langerhans cell histiocytosis is a rare disease with a variable clinical presentation, and its prognosis and treatment depend on the extent and severity of disease. Although the pathogenesis of Langerhans cell histiocytosis has been debated in the past, recent evidence suggests that it is a neoplastic proliferation potentially derived from a myeloid-lineage precursor. Involvement of the gastrointestinal tract in Langerhans cell histiocytosis is exceedingly rare and is most often encountered in the pediatric population, in the setting of systemic disease. This is illustrated using a case of Langerhans cell histiocytosis involving the esophagus in a 59-year-old woman who presented with dysphagia, in which molecular testing documented a BRAF V600E mutation. We review the features and implications of this diagnosis. |
Lobular Neoplasia: Morphology and Management. |
Context.-Lobular neoplasia encompasses a spectrum of disease, including atypical lobular hyperplasia and lobular carcinoma in situ. Although classic forms of lobular neoplasia are predominantly heralded as a risk marker, the pleomorphic form of lobular carcinoma in situ is generally regarded as a more aggressive subtype and a possible cancer precursor, and thus is treated in a manner more similar to ductal carcinoma in situ than classic forms of lobular neoplasia. Objective.-To focus on the morphologic spectrum of lobular neoplasia as highlighted by 3 cases and current management recommendations. Areas of diagnostic challenge and controversy are addressed. Data Sources.-A review of the pertinent published literature and current national guidelines was conducted. Conclusions.-Correct classification of classic lobular neoplasia and pleomorphic lobular carcinoma in situ is critical because of differences in clinical management, with current treatment strategies focused on risk reduction for patients with classic lobular neoplasia and eradication of the lesion for those with pleomorphic lobular carcinoma in situ. |
Neutrophilic Panniculitis: Algorithmic Approach to a Heterogeneous Group of Disorders. |
Context.-Neutrophilic panniculitis encompasses an etiologically and morphologically heterogeneous group of disorders. Correct histopathologic diagnosis is important in identifying certain systemic diseases and guiding appropriate treatment. Objective.-To review the clinical and histopathologic features of different types of neutrophilic panniculitis, and to provide a diagnostic algorithm for these disorders. Data Sources.-A review of the literature with emphasis on the distinguishing features of different entities was performed. Conclusions.-Evaluation for neutrophilic panniculitis entails paying close attention to the pattern of inflammation, the type of fat necrosis present, any evidence of vascular damage, and other relevant histopathologic features. An algorithmic approach integrating all histopathologic, clinical, and laboratory findings is required for correct diagnosis. |
Clear Cell Melanoma: A Cutaneous Clear Cell Malignancy. |
Clear cell melanoma is a rare clear cell malignancy. Accurate diagnosis of clear cell melanoma requires integration of immunohistochemical and morphologic findings, with molecular studies to rule out clear cell sarcoma. The differential diagnosis includes melanoma, carcinoma, perivascular epithelioid cell tumor, and epidermotropic clear cell sarcoma. We use a case of a lesion on the helix of an 86-year-old man as an example. Histologic examination revealed an ulcerated clear cell malignant tumor. Tumor cell cytoplasm contained periodic acid-Schiff-positive, diastase-sensitive glycogen. Tumor cells showed positive labeling for S100, HMB-45, and Melan-A, and negative labeling for cytokeratins, p63, and smooth muscle actin. Molecular studies demonstrated BRAF V600E mutation, copy gains at the 6p25 (RREB1) and 11q13 (CCND1) loci, and absence of EWSR1-ATF1 fusion. These findings supported a diagnosis of clear cell melanoma. The rare pure clear cell morphology occurs due to accumulation of intracytoplasmic glycogen. We review the differential diagnosis of clear cell melanoma and describe the utility of immunohistochemical and molecular studies in confirming this diagnosis. |
Selected Inflammatory Imitators of Mycosis Fungoides: Histologic Features and Utility of Ancillary Studies. |
Mycosis fungoides is the most common primary cutaneous lymphoma; however, it remains a significant diagnostic challenge, in part because of the overlap with several inflammatory dermatoses. Despite advances in immunohistochemistry and molecular diagnostics, false-positive, false-negative, and indeterminate diagnoses are not uncommon. In most cases, the overall balance of morphologic, immunophenotypic, and genetic features must be considered carefully because there are few sensitive and specific clues to the diagnosis. Moreover, an appropriate clinical presentation is essential to the diagnosis and helps to favor or exclude inflammatory/reactive processes. Herein, we discuss 3 important inflammatory dermatoses that may closely simulate mycosis fungoides, and we review the use of ancillary studies in these challenging cases. |
Controversies and Considerations in the Diagnosis of Primary Cutaneous CD4 Small/Medium T-Cell Lymphoma. |
Context.-Primary cutaneous CD4+ small/medium T-cell lymphoma is a provisional and controversial entity with a broad differential diagnosis. Despite being an uncommon lymphoma, it is a frequent diagnostic consideration in cutaneous biopsies with a dense lymphoid infiltrate because it shows overlapping features with reactive lymphoid hyperplasia (pseudolymphoma) and a variety of other primary cutaneous and systemic lymphomas. However, proper classification of this process is important for determining patient prognosis and treatment options. Objective.-To review the clinical, morphologic, immunophenotypic, and genetic features of primary cutaneous CD4+ small/medium T-cell lymphoma and contrast those features with entities in the differential diagnosis. Data Sources.-Applicable literature will be reviewed with emphasis on current controversies and distinguishing characteristics. Conclusions.-Although many consider primary cutaneous CD4+ small/medium T-cell lymphoma to be indistinguishable from reactive lymphoid hyperplasia/pseudolymphoma, it can be differentiated from other primary cutaneous and systemic lymphomas. Patients with solitary lesions of primary cutaneous CD4+ small/medium T-cell lymphoma generally have an excellent prognosis. Nevertheless, a subset of patients who have been reported to meet criteria for this lymphoma have followed a more-aggressive course; however, those patients show some differing clinical, morphologic, and immunophenotypic features. |
Transient Abnormal Myelopoiesis in Neonates: GATA Get the Diagnosis. |
Transient abnormal myelopoiesis occurs exclusively in patients with Down syndrome (constitutional trisomy 21), manifests in the neonatal period, and is characterized by circulating megakaryoblasts with varied degrees of multisystem organ involvement. In most cases, this process resolves spontaneously by 3 to 6 months of age, but for some, the disease can be fatal. Affected patients are particularly prone to develop acute megakaryoblastic leukemia in early childhood. Somatic GATA1 mutations are believed to be pivotal in the development of transient abnormal myelopoiesis and have proven to be a marker of clonal identity in its evolution to megakaryoblastic leukemia. We describe a study case of transient abnormal myelopoiesis and review the clinical manifestations, laboratory features, natural history, molecular genetics, and postulated disease pathogenesis of this disorder. |
Diagnosis of Splenic B-Cell Lymphomas in the Bone Marrow: A Review of Histopathologic, Immunophenotypic, and Genetic Findings. |
Splenic B-cell lymphomas are a heterogeneous group of diseases comprising several entities that exhibit overlapping features. Diagnosis of these lymphomas has been reliant on the histopathologic examination of the spleen. However, with advances in diagnostic modalities and therapy, splenectomy is not commonly performed, and diagnosis and subclassification must be rendered based on the blood and bone marrow findings. In this brief review, we summarize the morphologic, immunophenotypic, and genetic findings of splenic B-cell lymphomas in the blood and bone marrow. |
Diffuse Large B-Cell Lymphoma of the Prostate. |
In this article, we review prostatic lymphomas and discuss the differential diagnosis of high-grade malignant neoplasms of the prostate. We illustrate this with a case of a 46-year-old man seen with lower urinary tract obstruction who had diffuse involvement by a high-grade malignancy on prostate biopsy. Morphologic evaluation and immunohistochemistry were consistent with diffuse large B-cell lymphoma of the prostate. Workup with positron emission tomography-computed tomography demonstrated intensely hypermetabolic lymph nodes in the mediastinum, as well as widespread osseous involvement and involvement of the pancreatic tail, prostate, and urinary bladder, suggesting secondary prostatic involvement by a nodal lymphoma. Lymphomas of the prostate are uncommon in surgical pathology practice and usually represent secondary involvement from leukemia/lymphoma at a more typical site. Chronic lymphocytic leukemia/small lymphocytic lymphoma is the most common subtype. |
Diagnosis of Metastatic Renal Cell Carcinoma on Fine-Needle Aspiration Cytology. |
Fine-needle aspiration has assumed an increasingly important role in the diagnosis and management of patients with advanced stage cancer. Given its predilection for metastases to distant sites and organs at the time of presentation, metastatic renal cell carcinoma (RCC) is not infrequently encountered in the setting of fine-needle aspiration for initial diagnosis. In some instances, fine-needle aspiration may be the only opportunity to obtain diagnostic tissue to diagnose and subclassify RCC. Therefore, cytopathologists and cytotechnologists should be familiar with and recognize the cytomorphology of RCC and the ancillary studies that can be used to confirm and subclassify RCC. Herein, we describe a case of metastatic RCC initially diagnosed on fine-needle aspiration, discuss the cytomorphologic features of RCC subtypes, and review pertinent ancillary immunohistochemical and cytogenetic adjuncts. |
Inflammatory Myofibroblastic Tumor of the Bladder. |
We illustrate a case of an inflammatory myofibroblastic tumor (IMT) involving the bladder in a woman with dysuria and review the literature and differential diagnosis. Inflammatory myofibroblastic tumor, also referred to as pseudosarcomatous myofibroblastic proliferation, is a rare lesion that can arise in the genitourinary system and is characterized by a fascicular arrangement of myofibroblasts with admixed inflammatory cells and slitlike vessels. Urinary bladder IMT can be a diagnostic pitfall because its histologic features (brisk mitoses, invasion into muscularis propria, and prominent nucleoli) can mimic malignancy. The differential diagnosis of urinary bladder IMT includes sarcomatoid carcinoma and leiomyosarcoma. Diagnostic features such as bland nuclear chromatin, ganglion-like cells, pale eosinophilic cytoplasm with long processes, overexpression of anaplastic lymphoma kinase (immunohistochemistry or gene rearrangement studies), and the absence of atypical mitoses help distinguish IMT from its malignant mimics. Current controversies regarding postoperative spindle cell nodule and IMT are discussed. |
Pseudocarcinomatous Hyperplasia of the Urinary Bladder. |
We review the morphology and differential diagnoses of pseudocarcinomatous hyperplasia of the bladder, using a study case to illustrate the discussion. Pseudocarcinomatous hyperplasia is a rare, reactive response to an ischemic insult, classically to radiation therapy, and consists of proliferative, pseudoinfiltrative urothelial nests within the stroma. The presence of background radiation therapy-related changes, such as numerous dilated thrombosed vessels, reactive-appearing endothelial and stromal cells, edema, and hemorrhage, can provide clues to the diagnosis. The main differential diagnoses include invasive urothelial carcinoma and the nested variant of urothelial carcinoma; morphologic features, such as the presence or absence of background therapy-related changes and the architecture and the cytologic atypia of the nests, can help distinguish between pseudocarcinomatous hyperplasia and urothelial carcinoma. |
Correlation of Proteinuria with Podocyte Foot Process Effacement in IgA Nephropathy: An Ultrastructural Study. |
Abstract Background: Proteinuria is an uncommon clinical manifestation of IgA nephropathy and is usually seen in cases with severe lesions like endocapillary proliferation. However, it is occasionally seen even with cases with mild glomerular manifestations and may even be of nephrotic range. Predictor: Podocyte foot process effacement. Outcome: Severity of proteinuria. Measurements: Podocyte foot process effacement was measured. Morphometric analysis was performed on transmission electron microscope images using a computerized digital photomicrograph system (BioWizard 4.2 Image analysis software, New Delhi, India). Proteinuria was measured quantitatively assigned into five grades. Results: It was found that as the extent of proteinuria increased, the effacement ratio also increased, and this was most significant between "no" proteinuria and the rest of the categories. Conclusion: Nephrotic presentation in IgA nephropathy is a known phenomenon and in certain cases may show near normal glomerular morphology with severe foot process effacement on EM being the only significant finding to explain the proteinuria. Proteinuria in these cases shows a significant correlation with degree of foot process effacement. Renal biopsy is important in these cases because they are known to have a better prognosis and are usually steroid responsive. |
Features of the biotechnologically relevant polyamide family "cyanophycins" and their biosynthesis in prokaryotes and eukaryotes. |
Abstract Cyanophycin, inclusions in cyanobacteria discovered by the Italian scientist Borzi in 1887, were characterized as a polyamide consisting of aspartic acid and arginine. Its synthesis in cyanobacteria was analyzed regarding growth conditions, responsible gene product, requirements, polymer structure and properties. Heterologous expression of diverse cyanophycin synthetases (CphA) in Escherichia coli enabled further enzyme characterization. Cyanophycin is a polyamide with variable composition and physiochemical properties dependent on host and cultivation conditions in contrast to the extracellular polyamides poly-gamma-glutamic acid and poly--l-lysine. Furthermore, recombinant prokaryotes and transgenic eukaryotes, including plants expressing different cphA genes, were characterized as suitable for production of insoluble cyanophycin regarding higher yields and modified composition for other requirements and applications. In addition, cyanophycin was characterized as a source for the synthesis of polyaspartic acid or N-containing bulk chemicals and dipeptides upon chemical treatment or degradation by cyanophycinases, respectively. Moreover, water-soluble cyanophycin derivatives with altered amino acid composition were isolated from transgenic plants, yeasts and recombinant bacteria. Thereby, the range of dipeptides could be extended by biological processes and by chemical modification, thus increasing the range of applications for cyanophycin and its dipeptides, including agriculture, food supplementations, medical and cosmetic purposes, synthesis of the polyacrylate substitute poly(aspartic acid) and other applications. |
Trends in the resistance profiles of Acinetobacter baumannii endemic clones in a university hospital of Argentina. |
A total of 925 Acinetobacter spp. isolates were collected from routine clinical samples of patients admitted to the university hospital of Buenos Aires city during the period 2004-2012. From this collection, 129 isolates identified as Acinetobacter baumannii were selected for molecular studies. Minimal inhibitory concentrations (MICs) of antimicrobials were determined by agar dilution method. Colistin (COL) heteroresistance was investigated by means of population analysis studies. PCR-based methods were used for epidemiological analysis and for the screening of carbapenemases and the blatetB gene. We have observed a steady rise in the MIC50 of imipenem (IMI)-resistant isolates and an increment in the presence of blaOXA-23-like gene (74-100%) as well. A rapid increasing rate of minocycline (MIN) resistance and a rise of the MIC50 of the resistant isolates have been detected since the year 2008. All isolates harboured the tet (B) gene. An increase in the value of the tigecycline (TIG) MIC was seen from the year 2007 onwards. This loss of activity was observed among different clones. A rise of COL heteroresistance from 46.4% in 2004 to 95% in 2012 was detected. During this period, COL consumption also increased (11.1-fold). However, COL resistance remained sporadic. |
A Growth Factor-Induced, Spatially Organizing Cytoskeletal Module Enables Rapid and Persistent Fibroblast Migration. |
Directional migration requires robust front/back polarity. We find that fibroblasts treated with platelet-derived growth factor (PDGF) and prepolarized by plating on a fibronectin line substrate exhibit persistent migration for hours. This does not occur in the absence of PDGF or on uniformly coated fibronectin substrates. Persistent migration arises from establishment of two functional modules at cell front and back. At the front, formation of a zone containing podosome-like structures (PLS) dynamically correlates with low RhoA and myosin activity and absence of a contractile lamella. At the back, myosin contractility specifically controls tail retraction with minimal crosstalk to the front module. The PLS zone is maintained in a dynamic steady state that preserves size and position relative to the cell front, allowing for long-term coordination of front and back modules. We propose that front/back uncoupling achieved by the PLS zone is crucial for persistent migration in the absence of directional cues. |
How Kinetochores CCAN Resist Force. |
Kinetochores orchestrate chromosome segregation during mitosis and must cope with dynamic forces generated by attached microtubules. In this issue of Developmental Cell, Suzuki et al. (2014) demonstrate that the constitutive centromere-associated network (CCAN) displays a complex architecture that plays a crucial role in resisting these forces. |
Diabetic pregnancy: an overview of current guidelines and clinical practice. |
PURPOSE OF REVIEW: We review the recent changes in diagnostic criteria of gestational diabetes mellitus (GDM), describe problems with maintaining and monitoring adequate blood glucose, especially in type 1 diabetes, and provide a brief overview of the currently approved glucose-lowering therapies in pregnancy. RECENT FINDINGS: After the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, the definition of GDM was revised under the auspices of the International Association of Diabetes and Pregnancy Study Groups. The guidelines, with minor modifications, were endorsed by WHO in 2013. Intensive debate continues, focused on the expected large increase in prevalence of GDM and shortage of experimental evidence of clinical benefits from the new diagnostic criteria. Despite a very good glycaemic control, the prevalence of macrosomia remains high. This indicates a serious deficiency in current monitoring tools and the available therapies. So far, the only glucose-lowering medications approved for use during pregnancy are insulins. SUMMARY: The HAPO study provides a very suggestive evidence for a strong, continuous association of maternal glucose levels with an increased risk of excessive foetal weight gain. The new definition of GDM results in higher healthcare expenditure, but remains cost-effective. The current therapeutic goals require careful revision to further reduce the risk of adverse outcomes. New glucose-monitoring strategies and markers, and approval of new pharmacotherapies are needed. |
STAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy. |
Chemoradiotherapy (CRT) represents a standard treatment for many human cancers, frequently combined with radical surgical resection. However, a considerable percentage of primary cancers are at least partially resistant to CRT, which represents a substantial clinical problem, because it exposes cancer patients to the potential side effects of both irradiation and chemotherapy. It is therefore exceedingly important to determine the molecular characteristics underlying CRT-resistance and to identify novel molecular targets that can be manipulated to re-sensitize resistant tumors to CRT. In this review, we highlight much of the recent evidence suggesting that the signal transducer and activator of transcription 3 (STAT3) plays a prominent role in mediating CRT-resistance, and we outline why inhibition of STAT3 holds great promise for future multimodal treatment concepts in oncology. |
The Future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy. |
The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care. |
Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance. |
The phenomenon of multidrug resistance (MDR) has attenuated the efficacy of anticancer drugs and the possibility of successful cancer chemotherapy. ATP-binding cassette (ABC) transporters play an essential role in mediating MDR in cancer cells by increasing efflux of drugs from cancer cells, hence reducing the intracellular accumulation of chemotherapeutic drugs. Interestingly, small-molecule tyrosine kinase inhibitors (TKIs), such as AST1306, lapatinib, linsitinib, masitinib, motesanib, nilotinib, telatinib and WHI-P154, have been found to have the capability to overcome anticancer drug resistance by inhibiting ABC transporters in recent years. This review will focus on some of the latest and clinical developments with ABC transporters, TKIs and anticancer drug resistance. |
SUMO and KSHV Replication. |
Small Ubiquitin-related MOdifier (SUMO) modification was initially identified as a reversible post-translational modification that affects the regulation of diverse cellular processes, including signal transduction, protein trafficking, chromosome segregation, and DNA repair. Increasing evidence suggests that the SUMO system also plays an important role in regulating chromatin organization and transcription. It is thus not surprising that double-stranded DNA viruses, such as Kaposi's sarcoma-associated herpesvirus (KSHV), have exploited SUMO modification as a means of modulating viral chromatin remodeling during the latent-lytic switch. In addition, SUMO regulation allows the disassembly and assembly of promyelocytic leukemia protein-nuclear bodies (PML-NBs), an intrinsic antiviral host defense, during the viral replication cycle. Overcoming PML-NB-mediated cellular intrinsic immunity is essential to allow the initial transcription and replication of the herpesvirus genome after de novo infection. As a consequence, KSHV has evolved a way as to produce multiple SUMO regulatory viral proteins to modulate the cellular SUMO environment in a dynamic way during its life cycle. Remarkably, KSHV encodes one gene product (K-bZIP) with SUMO-ligase activities and one gene product (K-Rta) that exhibits SUMO-targeting ubiquitin ligase (STUbL) activity. In addition, at least two viral products are sumoylated that have functional importance. Furthermore, sumoylation can be modulated by other viral gene products, such as the viral protein kinase Orf36. Interference with the sumoylation of specific viral targets represents a potential therapeutic strategy when treating KSHV, as well as other oncogenic herpesviruses. Here, we summarize the different ways KSHV exploits and manipulates the cellular SUMO system and explore the multi-faceted functions of SUMO during KSHV's life cycle and pathogenesis. |
Positron Emission Tomography (PET) in Oncology. |
Since its introduction in the early nineties as a promising functional imaging technique in the management of neoplastic disorders, FDG-PET, and subsequently FDG-PET/CT, has become a cornerstone in several oncologic procedures such as tumor staging and restaging, treatment efficacy assessment during or after treatment end and radiotherapy planning. Moreover, the continuous technological progress of image generation and the introduction of sophisticated software to use PET scan as a biomarker paved the way to calculate new prognostic markers such as the metabolic tumor volume (MTV) and the total amount of tumor glycolysis (TLG). FDG-PET/CT proved more sensitive than contrast-enhanced CT scan in staging of several type of lymphoma or in detecting widespread tumor dissemination in several solid cancers, such as breast, lung, colon, ovary and head and neck carcinoma. As a consequence the stage of patients was upgraded, with a change of treatment in 10%-15% of them. One of the most evident advantages of FDG-PET was its ability to detect, very early during treatment, significant changes in glucose metabolism or even complete shutoff of the neoplastic cell metabolism as a surrogate of tumor chemosensitivity assessment. This could enable clinicians to detect much earlier the effectiveness of a given antineoplastic treatment, as compared to the traditional radiological detection of tumor shrinkage, which usually takes time and occurs much later. |
Off-Label Prescription of Genetically Modified Organism Medicines in Europe: Emerging Conflicts of Interest? |
Abstract Recently, the first human medicine containing a genetically modified organism (GMO medicine) was authorized for use in the European market. Just as any medicinal product, the market authorization for a GMO medicine contains a precise description of the therapeutic use for which the medicinal product is intended. Within this use, the application of the GMO medicine is permitted, without the need for the institution to obtain a specific permit. In practice, however, medicinal products are also frequently prescribed for treatment outside the registered therapeutic use, a practice that is referred to as "off-label use." While off-label use of conventional medicines is permitted and has been very useful, the off-label use of GMO medicines is not covered in the European Union (EU) legislation or guidelines and falls under each member state's national environmental legislation. This implies that in the Netherlands and most other EU member states, an environmental permit will be required for any institution that uses the GMO medicine outside the registered application(s). In the Netherlands, this permit is identical to the permits required for the execution of clinical trials involving nonregistered GMOs. The application procedure for such permit is time-consuming. This process can therefore limit the therapeutic options for medical professionals. As a consequence, desired treatment regimens could be withheld for certain patient (groups). To make future off-label use of GMO medicines permissible in a way that is acceptable for all stakeholders, regulators should adopt a proactive attitude and formulate transparent legislative procedures for this. Only then the field can maintain the public acceptance of GMO medicines, while maintaining the freedom to operate of medical professionals. |
Standing on the Shoulders of Pinel, Freud, and Kraepelin: A Historiometric Inquiry Into the Histories of Psychiatry. |
History of psychiatry can provide us with a map of the evolution of the practice and identify its major figures. A historiometric approach was taken to available history of psychiatry texts and a historical dictionary. Reliability was tested against data from the journal History of Psychiatry. Those cited in all historical accounts are characterized as major figures, whereas those cited in at least 60% of the sources are considered significant figures. An index of eminence is calculated for each significant figure. The Cronbach's alpha was 0.89. Seventy-four significant figures were identified, of which 18 are considered major figures. Among these, Freud, Pinel, and Kraepelin have the highest eminence-in that order. Pinel, Freud, and Kraepelin represent key moments in three epochs in the history of psychiatry: the asylum era, the first biological psychiatry, and the psychoanalytical period, respectively. The most recent historical periods are not well represented in histories of psychiatry. |
Differences Between Patients With Schizophrenia With and Without Co-Occurring Methamphetamine Use Disorders in a Taiwanese Public Psychiatric Hospital. |
This study aimed to examine the factors related to and the outcomes of schizophrenic patients with co-occurring methamphetamine use disorders (MUDs). All schizophrenic patients discharged from a psychiatric hospital between January 1, 2006, and December 31, 2006, were monitored. This study compared the important demographic and clinical variables between patients with co-occurring MUDs and those without, and postdischarge measured time to rehospitalization during a 1-year period. Seven hundred fifty-six patients were included in this study. Of these patients, 88 (11.6%) reported the use of methamphetamine. Univariate analyses indicated that male sex, low educational level, discharge against medical advice, missed first appointment after discharge, co-occurring other illicit substance use disorder, age (younger), diazepam equivalents prescribed at discharge (higher), number of previous admissions within the past 5 years (higher), and length of hospital stay (longer) were predictive of patients with co-occurring MUDs. There were also significant differences in time to rehospitalization between these two groups during the follow-up periods. Many factors can be identified in schizophrenic patients with co-occurring MUDs. Furthermore, schizophrenic patients with co-occurring MUDs were more likely to be rehospitalized. Future studies in many different mental health systems are needed before these findings can be generalized. |
Is Ankle Contracture After Stroke Due to Abnormal Intermuscular Force Transmission? |
Contracture after stroke could be due to abnormal mechanical interactions between muscles. This study examined if ankle plantarflexor muscle contracture after stroke is due to abnormal force transmission between gastrocnemius and soleus muscles. Muscle fascicle lengths were measured from ultrasound images of soleus in 5 subjects with stroke and ankle contracture and 6 able-bodied subjects. Changes in soleus fascicle length or pennation during passive knee extension at fixed ankle angle were assumed to indicate intermuscular force transmission. Changes in soleus fascicle length or pennation were adjusted for changes in ankle motion. Subjects with stroke had significant ankle contracture. After adjustment for ankle motion, 9 of 11 subjects demonstrated small changes in soleus fascicle length with knee extension, suggestive of intermuscular force transmission. However the small changes in fascicle length may have been artifact caused by movement of the ultrasound transducers. There were no systematic differences in change in fascicle length (median between-group difference adjusting for ankle motion = -0.01, 95%CI -0.26 to 0.08 mm/degree of knee extension) or pennation (-0.05, 95%CI -0.15 to 0.07 degree/degree of knee extension). This suggests ankle contractures after stroke were not due to abnormal (systematically increased or decreased) intermuscular force transmission between gastrocnemius and soleus. |
Visualization of different characteristics of cerebrospinal fluid with acute encephalopathy and febrile seizures using pattern recognition analysis of H NMR. |
Background:In acute encephalopathy, deterioration of the condition can be rapid and early intervention is essential to prevent progression of the disease. However, in the acute period, differentiating acute encephalopathy from febrile seizures is difficult. Thus, an early diagnostic marker has been sought to enable early intervention. Proton nuclear magnetic resonance (1H NMR) spectroscopy is used to study the chemical characteristics of biological fluids such as cerebrospinal fluid (CSF). The purpose of this study was to ascertain if pattern recognition of 1H NMR spectra could differentiate CSF obtained from patients with acute encephalopathy and febrile seizures.Methods:CSF was obtained from patients with acute encephalopathy (n = 4), complex febrile seizures (n = 9) and simple febrile seizures (n = 9).Results:NMR spectra of CSF did not visually differ across the three groups. Spectral data were analyzed by partial least squares discriminant analysis and visualized by plotting the partial least squares scores of each sample. The three patient groups clustered separately on the plots.Conclusion:In this preliminary study, we were able to visualize different characteristics of CSF obtained from patients with acute encephalopathy and simple and complex febrile seizures using pattern recognition analysis of 1H NMR data.Pediatric Research (2014); doi:10.1038/pr.2014.141. |