Sulphasalazine induced hepatitis in juvenile rheumatoid arthritis.

Two 19 year old patients with juvenile chronic arthritis developed liver toxicity during treatment with sulphasalazine. A significant increase in the levels of liver enzymes in serum samples was noticed in relation to the initiation of treatment in one patient and to the increase in dose in the second. The enzymes returned to normal levels 14 days after the drug had been stopped. A rechallenge in one of the patients caused re-exacerbation. This is the first report of liver toxicity induced by sulphasalazine in juvenile chronic arthritis. As spontaneous liver involvement in juvenile chronic arthritis is not rare, the possibility of drug induced hepatitis should be recognised in these patients.     

Cognition- and Dementia-Related Adverse Effects With Sacubitril-Valsartan: Analysis of the FDA Adverse Event Report System Database

Background

Because neprilysin is involved in the degradation of amyloid-beta, there is concern that the angiotensin-neprilysin inhibitor sacubitril-valsartan could increase the risk for dementia.

Evolution of Thermal Response Properties in a Cold-Activated TRP Channel

Animals sense changes in ambient temperature irrespective of whether core body temperature is internally maintained (homeotherms) or subject to environmental variation (poikilotherms). Here we show that a cold-sensitive ion channel, TRPM8, displays dramatically different thermal activation ranges in frogs versus mammals or birds, consistent with variations in these species' cutaneous and core body temperatures. Thus, somatosensory receptors are not static through evolution, but show functional diversity reflecting the characteristics of an organism's ecological niche.     

Upregulation of GAD65 mRNA in the medulla of the rat model of metabolic syndrome

Metabolic syndrome is characterized by obesity, elevated blood pressure (BP), insulin resistance, and hypercholesterolemia. Recently an animal model of this disorder has been proposed in rats selectively bred based on their performance on a treadmill-running task. Accordingly, low capacity runner (LCR) rats exhibited all of the diagnostic criteria for metabolic syndrome, including elevated BP, as compared to their high capacity runner (HCR) counterparts [U. Wisløff, S.M. Najjar, O. Ellingsen, P.M. Haram, S. Swoap, Q. Al-Share, M. Fernstrom, K. Rezaei, S.J. Lee, L.G. Koch, S.L. Britton, Cardiovascular risk factors emerge after artificial selection for low aerobic capacity, Science 307 (2005) 418–420]. Previous studies have highlighted the importance of GABAergic neurotransmission in the medullary cardiovascular-regulatory areas in the central control of BP. Thus, we hypothesized a dysregulation in GABAergic transmission in the medullary cardiovascular-regulatory nuclei of LCR rats. To begin testing this hypothesis we carried out experiments examining expression of the GABA synthetic enzymes, GAD65 and GAD67, mRNAs in the two rat strains via radioactive in situ hybridization. Our results showed GAD65 and GAD67 mRNAs were widely expressed throughout the brainstem; quantification revealed increased GAD65 mRNA expression in LCR animals in the caudal nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (VLM) as compared to HCR rats. Conversely, no differences in the expression of GAD67 were detected in these regions. These data are consistent with the notion of altered GABAergic neurotransmission in the NTS and VLM in metabolic syndrome, and point to the importance of these regions in cardiovascular regulation.     

Comprehensive analysis of loss of heterozygosity events in glioblastoma using the 100K SNP mapping arrays and comparison with copy number abnormalities defined by BAC array comparative genomic hybridization

We have undertaken an extensive high-resolution analysis of loss of heterozygosity (LOH) in 30 high grade gliomas using the Affymetrix 100K SNP mapping array. Only 70% of LOH events were accompanied by a copy number loss (CNA(loss)), and of the other 30%, the distal region of 17p preferentially showed copy number neutral (CNN)-associated LOH. Combined analysis of CNA(loss) and LOH using MergeLevels analysis software predicts whether the observed losses occurred on a diploid or tetraploid background. In a side-by-side comparison between SNP and bacterial artificial chromosome (BAC) arrays, the overall identification of CNAs was similar on both platforms. The resolution provided by the SNP arrays, however, allowed a considerably more accurate definition of breakpoints as well as defining small events within the cancer genomes, which could not be detected on BAC arrays. CNN LOH was only detected by the SNP arrays, as was ploidy prediction. From our analysis, therefore, it is clear that simultaneously defining CNAs and CNN-LOH using the SNP platform provides a higher resolution and more complete analysis of the genetic events that have occurred within tumor cells. Our extensive analysis of SNP array data has also allowed an objective assessment of threshold LOH scores that can accurately predict LOH. This capability has important implications for interpretation of LOH events since they have consistently been used to localize potential tumor suppressor genes within the cancer genome.     

The contribution of immune regulatory and thyroid specific genes to the etiology of Graves' and Hashimoto's diseases

The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) are believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely these loci interact and their interactions may influence disease phenotype and severity.     

The genetic and clinical outcome of isolated fetal muscular ventricular septal defect (VSD)

Introduction: Our objective was to evaluate the incidence of chromosomal aberration (both microscopic and submicroscopic) and the clinical outcome of fetuses with isolated muscular ventricular septal defect (VSD).

Material and methods: The study included 40 pregnant women whose fetuses were diagnosed with isolated muscular ventricular septal defect (mVSD). Of these, 30 patients underwent amniocentesis and 10 declined. All samples were tested by chromosomal microarray analysis (CMA). Of the 40 women in the study, 32 gave birth and the clinical outcome of the children was retrieved from the patients’ medical records.

Results: Of the 30 patients who underwent amniocentesis, one was detected with mosaic Klinefelter syndrome and one was detected with a pathogenic copy number variant unrelated to the VSD. Clinical follow-up was performed on 26 children after birth. The first postnatal echocardiography did not detect a VSD in 13 (50%) of the followed-up children. Spontaneous closure occurred in another eight (30.8%) children during the postnatal follow-up period. In only five children (19.2%) VSD was still detected by echocardiography after the first year of life.

Discussion: Isolated muscular VSD diagnosed prenatally does not appear to be a significant risk factor for chromosomal abnormalities and has a favorable clinical outcome.     

A fourth dimension in decision making in hepatology

Today, the assessment of liver function in patients suffering from acute or chronic liver disease is based on liver biopsy and blood tests including synthetic function, liver enzymes and viral load, most of which provide only circumstantial evidence as to the degree of hepatic impairment. Most of these tests lack the degree of sensitivity to be useful for follow‐up of these patients at the frequency that is needed for decision making in clinical hepatology. Accurate assessment of liver function is essential to determine both short‐ and long‐term prognosis, and for making decisions about liver and non‐liver surgery, TIPS, chemoembolization or radiofrequency ablation in patients with chronic liver disease. Liver function tests can serve as the basis for accurate decision‐making regarding the need for liver transplantation in the setting of acute failure or in patients with chronic liver disease. The liver metabolic breath test relies on measuring exhaled ¹³C tagged methacetin, which is metabolized only by the liver. Measuring this liver‐specific substrate by means of molecular correlation spectroscopy is a rapid, non‐invasive method for assessing liver function at the point‐of‐care. The ¹³C methacetin breath test (MBT) is a powerful tool to aid clinical hepatologists in bedside decision‐making. Our recent findings regarding the ability of point‐of‐care ¹³C MBT to assess the hepatic functional reserve in patients with acute and chronic liver disease are reviewed along with suggested treatment algorithms for common liver disorders.     

JC Virus T-Antigen DNA in Gastrointestinal Mucosa of Immunosuppressed Patients: A Prospective,Controlled Study

Background  

JC virus (JCV), a polyoma virus, is the etiological agent of progressive multifocal leukoencephalopathy in immunosuppressed patients. JCV T-Ag has proven oncogenic potential and is expressed in colonic polyps and carcinomas. We proposed that the prevalence of JCV T-Ag DNA is higher in the normal gastrointestinal (GI) mucosa of immunosuppressed patients compared with their immunocompetent counterparts.