Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis

Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome–encoded, transfer RNA (tRNA^[Ser]Sec). Here, we have identified a human tRNA^[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2′-O-methylribosylation at uridine 34 in mutant tRNA^[Ser]Sec. Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA^[Ser]Sec. This study identifies a tRNA mutation that selectively impairs synthesis of stress-related selenoproteins and demonstrates the importance of tRNA modification for normal selenoprotein synthesis.     

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.     

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.     

Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees

OBJECTIVE— Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown.RESEARCH DESIGN AND METHODS— We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations.RESULTS— Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P = 6.9 × 10⁻¹⁰). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60% in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at >40 years).CONCLUSIONS— We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an “obesogenic” environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.The leptin-melanocortin axis controls human energy homeostasis, and the melanocortin-4 receptor (MC4R) is a key player in its central regulation (1). Loss-of-function mutations in MC4R cause severe familial forms of obesity (2,3), and infrequent gain-of-function polymorphisms have been associated with protection against obesity (4,5). At least 72 nonsynonymous mutations have been discovered so far, but some have no obvious functional consequences (6,7), highlighting the importance of functional characterization of MC4R mutations in the determination of potential pathogenicity. MC4R is a membrane-bound G-protein–coupled receptor that activates adenylate cyclase. Loss-of-function mutations result in a partial or complete loss of function as measured by cAMP production. The majority of missense mutations in MC4R result in intracellular retention of the mutated protein, whereas some primarily affect ligand binding or ligand/receptor activation (8,9). In some cases, the alteration of the basal activity of the receptor (8,10) has been reported.The prevalence of loss-of-function MC4R mutations ranges from 0.5 to 5.8% in childhood-onset obesity (11–14). The contribution of MC4R mutations to late-onset obesity is still debated (13,15–18). Obesity due to MC4R mutations has been extensively studied, and although heterozygous loss-of-function mutations can clearly cause familial obesity, they can be found in individuals who are not obese (19). There is a need for reliable estimates of penetrance. Furthermore, no study has thoroughly assessed the effect of loss-of-function MC4R mutations in elderly subjects. Previous studies using part of our French cohort evidenced the first mutation in MC4R and demonstrated that most of them lead to an intracellular retention of the receptor (2,13,18).Although hyperphagia is a key feature of MC4R deficiency, with increased food intake at an ad libitum test meal reported in severely obese MC4R-deficient children (10), an apparent amelioration of obesity and food intake disturbances has been suggested in adulthood in some studies (6,11). Obesity is a complex trait, and MC4R mutations offer a unique opportunity to analyze the effects of both aging and shared environment on the evolution of body mass in this paradigm. In this extensive study of 2,257 unrelated obese subjects, 2,677 control subjects of European descent, and 25 multigenerational pedigrees with several MC4R mutations carriers, we provide a comprehensive picture of the prevalence of this condition and of factors that determine the expression of the obesity phenotype and support previous observations reported in a German familial study (20).     

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.     

Melanocortin receptors as targets in the treatment of obesity

The central melanocortin system plays a critical role in energy homeostasis. It is well established that melanocortin-containing neurons are nutritionally regulated and that genetic alterations in the melanocortin system produce profound effects on food intake, energy expenditure, and body weight. Within the brain, melanocortin-producing neurons originate in the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract (NTS) in the brainstem and project to various nuclei modulating energy balance. A large body of pharmacological and genetic evidence implicates the central melanocortin 4 receptors (MC4Rs) in the effects of melanocortin peptides on ingestive behaviour, energy expenditure, and body weight. Preclinical studies with endogenous and synthetic melanocortin ligands demonstrate that they produce potent effects on food intake and energy expenditure. Clinical studies thus far have been somewhat less successful and have been hampered by the induction of side effects, which present obstacles to the development of successful therapeutic agents. However, various promising strategies are being pursued to overcome these limitations, including the synthesis of more selective and potent melanocortin analogs.     

Trends in mortality of liver cancer before and during the COVID-19 pandemic, 2017–2021

We studied the trends in liver cancer-related mortality before and during the COVID-19 pandemic. Quarterly age-standardized mortality and quarterly percentage change (QPC) for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) were estimated using the US national mortality database 2017–2021. Quarterly age-standardized mortality from HCC decreased steadily with an average QPC of −0.4% (95% confidence interval [CI]: −0.6% to −0.2%). A decrease in hepatitis C virus and hepatitis B virus-related HCC mortality of −2.2% (95% CI: −2.4% to −1.9%) and −1.1% (95% CI: −2.0% to −0.3%) was noted. In contrast, mortality for HCC from nonalcoholic fatty liver disease (3.0%, 95% CI: 2.0%–4.0%) and alcohol-related liver disease (1.3%, 95% CI: 0.8%–1.9%) demonstrated a linear increase. There was a linear increase in the quarterly age-standardized ICC-related mortality (0.8%, 95% CI: 0.5%–1.0%). While ICC-related mortality continued to increase, HCC-related mortality tended to decline mainly due to a decline in mortality due to viral hepatitis.     

Efficacy and safety of,and patient satisfaction with,colonoscopic-administered fecal microbiota transplantation in relapsing and refractory community- and hospital-acquired Clostridium difficile infection

OBJECTIVE:

To report the efficacy and safety of, and patient satisfaction with, colonoscopic fecal microbiota transplantation (FMT) for community- and hospital-acquired Clostridium difficile infection (CDI).

METHODS:

A retrospective medical records review of patients who underwent FMT between July 1, 2012 and August 31, 2013 was conducted. A total of 22 FMTs were performed on 20 patients via colonoscopy. The patients were divided into ‘community-acquired’ and ‘hospital-acquired’ CDI. Telephone surveys were conducted to determine procedure outcome and patient satisfaction. Primary cure rate was defined as resolution of diarrhea without recurrence within three months of FMT, whereas secondary cure rate described patients who experienced resolution of diarrhea and return of normal bowel function after a second course of FMT.

RESULTS:

Nine patients met the criteria for community-acquired CDI whereas 11 were categorized as hospital-acquired CDI. A female predominance in the community-acquired group (88.89% [eight of nine]) was found (P=0.048). The primary cure rate was 100% (nine of nine) and 81.8% (nine of 11 patients) in community- and hospital-acquired CDI groups, respectively (P=0.189). Two patients in the hospital-acquired group had to undergo a repeat FMT for persistent symptomatic infection; the secondary cure rate was 100%. During the six-month follow-up, all patients were extremely satisfied with the procedure and no complications or adverse events were reported.

CONCLUSION:

FMT was a highly successful and very acceptable treatment modality for treating both community- and hospital-acquired CDI.     

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.     

Focal dystonia after removal of a parietal meningioma.

A patient presented at the age of 50 years with a right-sided, writing-specific dystonia which settled without treatment. Ten years later she developed focal seizures affecting the right leg and occasionally spreading to the right arm. A left parietal meningioma was removed and 2 years later she developed dystonic movements of her right hand. Gliotic changes were seen on magnetic resonance imaging in the superficial left parietal lobe. Mechanisms involved in the generation of dystonia associated with cortical injury are discussed.