4th Global CRO Council for Bioanalysis: coadministered drugs stability, EMA/US FDA guidelines, 483s and carryover

The Global CRO Council for Bioanalysis (GCC) was formed in September 2010. Since then, the representatives of the member companies come together periodically to openly discuss bioanalysis and the regulatory challenges unique to the outsourcing industry. The 4th GCC Closed Forum brought together experts from bioanalytical CROs to share and discuss recent issues in regulated bioanalysis, such as the impact of coadministered drugs on stability, some differences between European Medicines Agency and US FDA bioanalytical guidance documents and lessons learned following recent Untitled Letters. Recent 483s and agency findings, as well as issues on method carryover, were also part of the topics discussed.     

Current indications and contraindications for liver transplantation

Survival rates after liver transplantation have improved steadily because of earlier referral and timely evaluation, judicious patient selection, improved surgical techniques, superior immunosuppressive regimens, and effective prevention of perioperative opportunistic infections. Indications and contraindications for liver transplantation are undergoing constant modifications with the goal of improving survival and functional status of patients who have end-stage liver disease or acute liver failure. Potential candidates for liver transplantation should meet minimal listing criteria and not have contraindications to liver transplantation. Currently, the Model for End-stage Liver Disease score is used for organ allocation, but it may have future application in patient-selection criteria.     

Fish intake and LPA 93C>T polymorphism: gene-environment interaction in modulating lipoprotein (a) concentrations

High plasma lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for atherosclerotic diseases. To date, no effective intervention strategies on reducing Lp(a) concentrations have been reported. The aim of the study was to evaluate the possible modulation of two polymorphisms of LPA gene (LPA 93C>T and LPA 121G>A) and nutritional habits on Lp(a) concentrations. We studied 647 healthy Italian subjects (260 M; 387 F) with a median age of 48 years (range: 19-78) enrolled in an epidemiological study conducted in Florence, Italy. A linear regression analysis showed a significant negative influence of fish intake (beta=-0.174+/-0.084; p=0.04) on Lp(a) concentrations, after adjustment for smoking habit, C-reactive protein serum concentrations, dietary habits and LDL-cholesterol concentrations. With regard to LPA polymorphisms, LPA 93C>T polymorphism resulted to significantly affect Lp(a) circulating concentrations in a dose-dependent manner, with lower concentrations shown by subjects carrying the T rare allele, whereas no significant influence of LPA 121G>A polymorphism on Lp(a) concentrations was observed. Moreover, by analyzing the possible interplay between LPA 93C>T and dietary fish intake, a significant interaction between these two determinants in lowering Lp(a) concentrations was reported. In addition, lower Lp(a) concentrations were observed in subjects carrying the T allele of the LPA 93C>T polymorphism and consuming a high intake of fish with respect to those being in the highest tertile of fish consumption but homozygotes for the common allele of the polymorphism. In conclusion, this study reported a significant interaction of daily fish intake and LPA 93C>T polymorphism in decreasing Lp(a) concentrations.     

Genomic differences between guinea pig lethal and nonlethal Marburg virus variants

The complete genome sequences of 2 closely related plaque-derived variants of Marburg virus (MARV) species Lake Victoria marburgvirus, strain Musoke, indicate only a few regions of the RNA genome as underlying the differences between the 2 viruses. One variant is >90% lethal for guinea pigs and the other much less virulent, when guinea pigs are challenged with 1000 pfu of virus. Only 4 mutations that result in amino acid changes were identified, 1 in viral matrix protein VP40 and 3 in L, the RNA-dependent RNA polymerase. In addition, 6 differences were identified in noncoding regions of transcribed mRNA, and 1 silent codon change was identified in the L gene. Interestingly, the amino acid mutation identified in VP40 occurs in a nonconserved loop structure between 2 domains that are homologues only among MARV species. The L gene mutations were equally intriguing, clustering near a highly conserved motif in viral RNA-dependent RNA polymerases.     

Circadian phase delay induced by phototherapeutic devices

INTRODUCTION: The Canadian Forces has initiated a multiple study project to optimize circadian phase changes using appropriately timed phototherapy and/or ingestion of melatonin for those personnel on long-range deployments and shift workers. The work reported here compared four phototherapeutic devices for efficacy in effecting circadian phase delays. METHODS: In a partially counterbalanced treatment order, 14 subjects (7 men and 7 women), ages 18-51 yr, participated in 5 weekly experimental sessions of phototherapy with 4 different phototherapy devices (light tower, light visor, Litebook, LED spectacles) and a no-phototherapy control. Phototherapy was applied from 24:00 to 02:00 on night. (1) Dim light melatonin onset (DLMO) was assessed on night 1 and night. (2) Subjects were tested for psychomotor performance (serial reaction time, logical reasoning, and serial subtraction tasks) and completed the Stanford Sleepiness Scale on night 1 at 19:00, 23:00, 01:00, 02:00, and 03:00. After phototherapy, subjects completed a phototherapy side-effects questionnaire. RESULTS: All phototherapy devices produced melatonin suppression and significant phase delays. Sleepiness was significantly decreased with the light tower, the light visor, and the Litebook. Task performance was only slightly improved with phototherapy. The LED spectacles and light visor caused greater subjective performance impairment, more difficulty viewing the computer monitor and reading printed text than the light tower or the Litebook. The light visor, the Litebook, and the LED spectacles caused more eye discomfort than the light tower. CONCLUSIONS: The light tower was the best device, producing melatonin suppression and circadian phase change while relatively free of side effects.     

Cotard's syndrome and delayed diagnosis in Kashmir,India

Cotard's syndrome is a rare syndrome, characterized by the presence of nihilistic delusions. The syndrome is typically related to depression and is mostly found in middle-aged or older people. A few cases have been reported in young people with 90% of these being females. We present a case of a young pregnant woman suffering from Cotard's syndrome. This is the first report of this syndrome in a pregnant woman. The case was diagnosed late, due to lack of awareness of psychiatric problems in primary care physicians resulting in undue suffering, loss of precious time and resources for the patient. Besides highlighting the rare combination of pregnancy and Cotard's syndrome this report delineates the difficulties faced by patients with such symptoms in a low resource setting.     

Clinical and epidemiological observations of cutaneous tuberculosis in Larkana,Pakistan

BACKGROUND: Cutaneous tuberculosis is widespread in Pakistan but has not been fully documented. This study was conducted to determine the clinical pattern, nature and existence of the disease in Larkana, Sindh province, Pakistan. METHODS: We are reporting 153 cases of patients with cutaneous tuberculosis who visited our department from 1996 to 1999. All cases were diagnosed at the clinic, and the biopsies were examined for histopathological evidence. The patients received three antituberculous treatments during a 9 month course. RESULTS: Clinically, 63 (41.2%) cases of lupus vulgaris, 54 (35.3%) of scrofuloderma, 29 (19.59%) of lupus verrucosa cutis, six (3.92%) of tuberculosis cutis orificialis and one (0.64%) case of disseminated cutaneous tuberculosis were observed in our department from 1996 to 1999. All patients were aged between 3 and 50 years and had experienced the present complaints for 1 to 12 years. Sixty-nine (45.1%) cases were children aged under 10 years, 50 cases (37.25%) were aged between 10 and 20 years, and 27 cases (17.65%) were aged over 20 years. There was no considerable ratio difference of the disease between male and female patients. Histopathologically, all the specimens showed chronic granulomatous changes; the majority was infiltrated with epitheloid cells, langhans giant cells, plasma cells and other inflammatory cells, such as lymphocytes, eosinophils and neutrophils in ulcerated lesions. Increased numbers of mast cells were seen in upper and lower dermis in two-thirds of the specimens. Caseating necrosis was visible in half of the specimens while Ziehl-Neelsen stain was negative in all the sections. CONCLUSIONS: The observed number of patients was moderately large, thus indicating a high incidence of cutaneous tuberculosis in Larkana. Lupus vulgaris, a form of cutaneous tuberculosis, was widespread in this area and prevalent in adults, while scrofuloderma was prevalent in children. Moreover, the existing rate of the disease was higher in children aged under 10 years and lower in adults. This indicates that children are more prone to this disease than adults.     

Evaluation of negative emotional care experiences in burn care

Aim and objective. To assess recollection of negative emotional experiences during burn care. Background. Patients in intensive care frequently report negative emotional experiences. Patients with severe burns who are treated in intensive care units undergo painful care procedures, but there have been no recent evaluations of their care experiences. Design. Former burn patients (n = 42) were randomly assigned to three groups: postal questionnaire, telephone interview and face‐to‐face interview. Methods. Assessments included negative care experiences (feelings of uncertainty, powerlessness, being afraid, insecure, being a nuisance, or neglected), severity of injury, patient satisfaction, personality traits and psychological symptoms. Results. Overall, the degree of recalled negative experiences was low and associated with greater severity of injury, more symptoms of post‐traumatic stress disorder and lower satisfaction with care. The feeling of powerlessness was the most common, as 67% of participants had such feelings to some extent. Conclusions. Overall, negative care experiences were uncommon and most prevalent among the severely injured. Such experiences were also associated with psychological symptoms and lower patient satisfaction. Relevance to clinical practice. Although relatively uncommon, negative emotional care experiences should be monitored more closely during care.     

Obesity and the need for bariatric surgery in Pakistan

After establishing a foothold in the West, the pandemic of obesity now threatens to spin out of control in the developing nations of Asia and the Indian subcontinent. Like many of its neighbors, Pakistan has witnessed an unprecedented growth in the number of overweight and obese individuals in its population, and obesity is proving to be an issue of considerable public health concern. Conventional medical therapies for obesity and related complications have proven to be less than effective, especially in the population of the southeast, which appears to be inherently predisposed to developing obesity‐related complications. Bariatric surgery is fast emerging as a definitive therapeutic alternative for obesity and has proven to be highly successful and cost‐effective at producing remission of complications of the same. In this article, we expound the need for introducing and incorporating bariatric surgery as part of the therapeutic protocols for obese individuals of South Asian descent suffering from the chronic and debilitating complications of obesity.