N-acetyltransferase 2 (NAT2) gene polymorphisms in Parkinson's disease

BACKGROUND: Parkinson's disease (PD) is a movement disorder caused by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain. The molecular basis of this neural death is unknown, but genetic predisposition and environmental factors may cause the disease. Sequence variations in N-acetyltransferase 2 (NAT2) gene leading to slow acetylation process have been associated with PD, but results are contradictory. METHODS: We analyzed three NAT2 genetic variations, c.481C>T, c.590G>A (p.R197Q) and c.857G>A (p.G286E), which are known to result in a slow acetylator phenotype. Using validated PCR-RFLP assays, we genotyped 243 healthy unrelated Caucasian control subjects and 124 PD patients for these genetic variations. Further, we have undertaken a systematic review of NAT2 studies on PD and we incorporated our results in a meta-analysis consisting of 10 studies, 1,206 PD patients and 1,619 control subjects. RESULTS: Overall, we did not find significant differences in polymorphic acetylation genotypes in PD and control subjects. In the meta-analysis of slow acetylators from 10 studies and representing 604/1206 PD vs. 732/1619 control subjects, a marginally significant odds ratio (OR) of 1.32 (95% CI 1.12–1.54, p < 0.05) was obtained. Re-analysis of the data to exclude the only two studies showing positive association of slow acetylators to PD, resulted in a non-significant OR (1.07, 95% CI 0.9–1.28). Furthermore, meta-analysis of studies for c.590G>A, where both allele and genotype frequencies in PD vs. control subjects were analyzed, did not give significant summary odds ratios as well. CONCLUSION: We found little evidence for differences in polymorphic acetylation genotypes in PD and control subjects. Results of the meta-analyses did not also provide conclusive evidence for an overall association of NAT2 slow acetylator genotypes to PD

G Protein Subunit Dissociation and Translocation Regulate Cellular Response to Receptor Stimulation

We examined the role of G proteins in modulating the response of living cells to receptor activation. The response of an effector, phospholipase C-β to M3 muscarinic receptor activation was measured using sensors that detect the generation of inositol triphosphate or diacylglycerol. The recently discovered translocation of Gβγ from plasma membrane to endomembranes on receptor activation attenuated this response. A FRET based G protein sensor suggested that in contrast to translocating Gβγ, non-translocating Gβγ subunits do not dissociate from the αq subunit on receptor activation leading to prolonged retention of the heterotrimer state and an accentuated response. M3 receptors with tethered αq induced differential responses to receptor activation in cells with or without an endogenous translocation capable γ subunit. G protein heterotrimer dissociation and βγ translocation are thus unanticipated modulators of the intensity of a cell's response to an extracellular signal

Expanding the Grading of Recommendations Assessment, Development, and Evaluation (Ex-GRADE) for Evidence-Based Clinical Recommendations: Validation Study

Clinicians use general practice guidelines as a source of support for their intervention, but how much confidence should they place on these recommendations? How much confidence should patients place on these recommendations? Various instruments are available to assess the quality of evidence of research, such as the revised Wong scale (R-Wong) which examines the quality of research design, methodology and data analysis, and the revision of the assessment of multiple systematic reviews (R-AMSTAR), which examines the quality of systematic reviews

A cross-sectional study of self-reported chemical-related sensitivity is associated with gene variants of drug-metabolizing enzymes

BACKGROUND: N-acetyltransferases (NAT) and glutathione S-transferases (GST) are involved in the metabolism of several ubiquitous chemical substances leading to the activation and detoxification of carcinogenic heterocyclic and aromatic amines. Since polymorphisms within these genes are described to influence the metabolism of ubiquitous chemicals, we conducted the present study to determine if individuals with self-reported chemical-related sensitivity differed from controls without self-reported chemical-related sensitivity with regard to the distribution of genotype frequencies of NAT2, GSTM1, GSTT1, and GSTP1 polymorphisms. METHODS: Out of 800 subjects who answered a questionnaire of ten items with regard to their severity of chemical sensitivity 521 unrelated individuals agreed to participate in the study. Subsequently, genetic variants of the NAT2, GSTM1, GSTT1, and GSTP1 genes were analyzed. RESULTS: The results show significant differences between individuals with and without self-reported chemical-related sensitivity with regard to the distribution of NAT2, GSTM1, and GSTT1 gene variants. Cases with self-reported chemical-related sensitivity were significantly more frequently NAT2 slow acetylators (controlled OR = 1.81, 95% CI = 1.27–2.59, P = 0.001). GSTM1 and GSTT1 genes were significantly more often homozygously deleted in those individuals reporting sensitivity to chemicals compared to controls (GSTM1: controlled OR 2.08, 95% CI = 1.46–2.96, P = 0.0001; GSTT1: controlled OR = 2.80, 95% CI = 1.65–4.75, P = 0.0001). Effects for GSTP1 gene variants were observed in conjunction with GSTM1, GSTT1 and NAT2 gene. CONCLUSION: The results from our study population show that individuals being slow acetylators and/or harbouring a homozygous GSTM1 and/or GSTT1 deletion reported chemical-related hypersensitivity more frequently

Farnesoid X Receptor (FXR) Activation and FXR Genetic Variation in Inflammatory Bowel Disease

Contains fulltext : 96924.pdf (publisher's version ) (Open Access)BACKGROUND: We previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD. METHODS: mRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD) and 1193 UC) and in 853 healthy controls. RESULTS: mRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD. CONCLUSIONS: FXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients

Early detection and counselling intervention of asthma symptoms in preschool children: study design of a cluster randomised controlled trial

Background. Prevention of childhood asthma is an important public health objective. This study evaluates the effectiveness of early detection of preschool children with asthma symptoms, followed by a counselling intervention at preventive child health centres. Early detection and counselling is expected to reduce the prevalence of asthma symptoms and improve health-related quality of life at age 6 years. Methods/design. This cluster randomised controlled trial was embedded within the Rotterdam population-based prospective cohort study Generation R in which 7893 children (born between April 2002 and January 2006) participated in the postnatal phase. Sixteen child health centres are involved, randomised into 8 intervention and 8 control centres. Since June 2005, an early detection tool has been applied at age 14, 24, 36 and 45 months at the intervention centres. Children who met the intervention criteria received counselling intervention (personal advice to parents to prevent smoke exposure of the child, and/or referral to the general practitioner or asthma nurse). The primary outcome was asthma diagnosis at age 6 years. Secondary outcomes included frequency and severity of asthma symptoms, health-related quality of life, fractional exhaled nitric oxide and airway resistance at age 6 years. Analysis was according to the intention-to-treat principle. Data collection will be completed end 2011. Discussion. This study among preschool children provides insight into the effectiveness of early detection of asthma symptoms followed by a counselling intervention at preventive child health centres. Trial registration. Current Controlled Trials ISRCTN15790308

Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial

BACKGROUND: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock. METHODS: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116. FINDINGS: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]). INTERPRETATION: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock. FUNDING: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation

Man and the Last Great Wilderness: Human Impact on the Deep Sea

The deep sea, the largest ecosystem on Earth and one of the least studied, harbours high biodiversity and provides a wealth of resources. Although humans have used the oceans for millennia, technological developments now allow exploitation of fisheries resources, hydrocarbons and minerals below 2000 m depth. The remoteness of the deep seafloor has promoted the disposal of residues and litter. Ocean acidification and climate change now bring a new dimension of global effects. Thus the challenges facing the deep sea are large and accelerating, providing a new imperative for the science community, industry and national and international organizations to work together to develop successful exploitation management and conservation of the deep-sea ecosystem. This paper provides scientific expert judgement and a semi-quantitative analysis of past, present and future impacts of human-related activities on global deep-sea habitats within three categories: disposal, exploitation and climate change. The analysis is the result of a Census of Marine Life – SYNDEEP workshop (September 2008). A detailed review of known impacts and their effects is provided. The analysis shows how, in recent decades, the most significant anthropogenic activities that affect the deep sea have evolved from mainly disposal (past) to exploitation (present). We predict that from now and into the future, increases in atmospheric CO2 and facets and consequences of climate change will have the most impact on deep-sea habitats and their fauna. Synergies between different anthropogenic pressures and associated effects are discussed, indicating that most synergies are related to increased atmospheric CO2 and climate change effects. We identify deep-sea ecosystems we believe are at higher risk from human impacts in the near future: benthic communities on sedimentary upper slopes, cold-water corals, canyon benthic communities and seamount pelagic and benthic communities. We finalise this review with a short discussion on protection and management methods

Myelin Proteomics: Molecular Anatomy of an Insulating Sheath

Fast-transmitting vertebrate axons are electrically insulated with multiple layers of nonconductive plasma membrane of glial cell origin, termed myelin. The myelin membrane is dominated by lipids, and its protein composition has historically been viewed to be of very low complexity. In this review, we discuss an updated reference compendium of 342 proteins associated with central nervous system myelin that represents a valuable resource for analyzing myelin biogenesis and white matter homeostasis. Cataloging the myelin proteome has been made possible by technical advances in the separation and mass spectrometric detection of proteins, also referred to as proteomics. This led to the identification of a large number of novel myelin-associated proteins, many of which represent low abundant components involved in catalytic activities, the cytoskeleton, vesicular trafficking, or cell adhesion. By mass spectrometry-based quantification, proteolipid protein and myelin basic protein constitute 17% and 8% of total myelin protein, respectively, suggesting that their abundance was previously overestimated. As the biochemical profile of myelin-associated proteins is highly reproducible, differential proteome analyses can be applied to material isolated from patients or animal models of myelin-related diseases such as multiple sclerosis and leukodystrophies