Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction.

Connective tissue growth factor (CTGF) is reported to be a target gene of transforming growth factor beta (TGFbeta) and bone morphogenetic protein (BMP) in vitro. Its physiological role in angiogenesis and skeletogenesis during mouse development has been described recently. Here, we have mapped expression of CTGF mRNA during mouse heart development, postnatal adult life, and after experimental myocardial infarction. Furthermore, we investigated the relationship between CTGF and the BMP/TGFbeta signaling pathway in particular during heart development in mutant mice. Postnatally, CTGF expression in the heart became restricted to the atrium. Strikingly, 1 week after myocardial infarction, when myocytes have disappeared from the infarct zone, CTGF and TGFbeta expression as well as activated forms of TGFbeta but not BMP, Smad effector proteins are colocalized exclusively in the fibroblasts of the scar tissue, suggesting possible cooperation between CTGF and TGFbeta during the pathological fibrotic response.     

Neutrophil cytoplasmic antibodies (p-ANCA) in ulcerative colitis.

AIMS--To study ulcerative colitis associated neutrophil cytoplasmic antibodies (p-ANCA) in respect of class and subclass distribution, antigen specificity, and (sub)cellular localisation of the antigen(s) to which these antibodies are directed. METHODS--p-ANCA positivity was determined using the standard indirect immunofluorescence test (IIFT). The immunoglobulin (Ig) subclass distribution of p-ANCA was investigated using monoclonal antibodies directed against IgG1, IgG2, IgG3, and IgG4. Intracellular antigen localisation studies were performed on (fractionated) neutrophils using antigen-specific antibodies. RESULTS--In contrast to vasculitis associated ANCA, ulcerative colitis p-ANCA are mainly of IgG1 and IgG3 subclass and lack IgG4. Ulcerative colitis p-ANCA are myeloid specific. IIFT data indicate that the related antigen(s) seem(s) to be located not in the cytosol, but in the granules (most likely the azurophil granules) of the neutrophil. CONCLUSIONS--p-ANCA in ulcerative colitis have a different immunoglobulin subclass distribution than the ANCA of systemic necrotising vasculitis and necrotising and crescentic glomerulonephritis. This may point to differences in immune regulation between these diseases. Both cathepsin G and lactoferrin are recognised by a subpopulation of ulcerative colitis p-ANCA. In our series, eight out of 36 (22%) of ulcerative colitis associated p-ANCA react with lactoferrin and seven (19.5%) other sera with cathepsin G. None of them recognised both antigens. The main target antigen(s) of ulcerative colitis p-ANCA still remain(s) to be identified.     

The Impact of Pre-exposure Prophylaxis on Sexual Well-Being Among Men Who Have Sex with Men

Archives of Sexual Behavior - Pre-exposure prophylaxis (PrEP) is a promising strategy to reduce HIV incidence among men who have sex with men (MSM). How and when PrEP is used could in part be...     

COVID-19 mortality in the UK Biobank cohort: revisiting and evaluating risk factors

European Journal of Epidemiology - Most studies of severe/fatal COVID-19 risk have used routine/hospitalisation data without detailed pre-morbid characterisation. Using the community-based UK...     

Evaluation of serum type III procollagen peptide as an exposure marker in retired coal workers

Serum type III procollagen peptide (PIIIP), a degradation product of the type III collagen precursor, has been put forward as an exposure marker for mineral dust. We evaluated PIIIP levels as a marker of exposure to and effects of coal dust in retired coal miners (n = 104). To this end: (a) the individual cumulative dust exposure was calculated from job-exposure matrices, and (b) in addition to routine chest radiography (CR) of all miners according to the criteria of the International Labour Organisation (ILO), a subgroup (n = 46) was screened by high-resolution computed tomography (HRCT). Profusion score (CR and HRCT) tended to increase with cumulative dust exposure, even in the absence of CR evidence for pneumoconiosis (i.e. CR , 0/1, n = 35). In contrast to our previous findings in active miners, PIIIP levels were not increased in miners as compared with non-dust-exposed controls (n = 29), and no differences were observed between miners without (ILO = 0/0) and miners with coal workers' pneumoconiosis (CWP; ILO 0/1). No trend in PIIIP versus pneumoconiosis stage was present, either by CR or by the more sensitive HRCT score. PIIIP was also unrelated to any lung function parameter (FEV₁, FVC, impedance, diffusion capacity). Age, medication, medical history and smoking habits had no significant effect on PIIIP levels. In the miners with CWP (i.e. ILO > 0/0, n = 28) a significant negative correlation was present between PIIIP values and (log) cumulative dust exposure. This decrease in serum PIIIP levels with increasing cumulative exposure may be due to chronic adaptive changes in type III collagen deposition and/or breakdown. Other relations between exposure and PIIIP were not observed. In conclusion, the present findings do not support the use of serum type III procollagen peptide as a marker of exposure to and (early) interstitial or respiratory effects of coal dust.     

Bone Morphogenetic Protein-7 and Connective Tissue Growth Factor: Novel Targets for Treatment of Renal Fibrosis?

Renal fibrosis is the major determinant in progression of kidney disease and results from an inappropriate response to acute and chronic kidney injury. Transforming growth factor (TGF)-β1 is the driving force behind renal fibrosis and has since long been regarded as the key factor to be targeted in prevention and treatment of renal fibrosis. Despite the impressive results obtained in experimental renal fibrosis, TGF-β1 blockade has not yet translated into an effective and safe therapeutic in human patients. Therefore, it remains important to explore the role of additional growth factors which are involved in renal regeneration and fibrosis. Recently, bone morphogenetic protein (BMP)-7 and connective tissue growth factor (CTGF) have both emerged as novel modulators of profibrotic TGF-β1 activity. The expression of BMP-7 is decreased in various models of renal disease, while CTGF is strongly upregulated in experimental and human renal fibrosis. In experimental kidney injury, administration of BMP-7 or inhibition of CTGF have been sufficient to result in striking improvement of renal function and structure. This review summarizes the current knowledge of BMP-7 and CTGF in the kidney, and discusses their therapeutic potential in renal fibrosis.     

Inhibition of rat brain and liver protein synthesis by amphetamine

Dose-dependent, amphetamine-induced reductions in protein synthesis were determined in vivo by measuring [3H]lysine incorporation into trichloroacetic acid precipitated protein in homogenates prepared from different regions of the brain or liver. Low-to-moderate doses of amphetamine (1-5 mg/kg) decreased striatal protein synthesis whereas higher doses (10 mg/kg) reduced it in the cerebral cortices, cerebellum, and remaining portions of the cerebrum, as well as in the striatum and liver. Reductions in regional brain protein synthesis occur following amphetamine treatment in relatively low doses known to change various aspects of physiology and behavior.     

A summary-statistics-based approach to examine the role of serotonin transporter promoter tandem repeat polymorphism in psychiatric phenotypes

In genetic studies of psychiatric disorders in the pre-genome-wide association study (GWAS) era, one of the most commonly studied loci is the serotonin transporter (SLC6A4) promoter polymorphism, a 43-base-pair insertion/deletion polymorphism in the promoter region (5-HTTLPR). The genetic association signals between 5-HTTLPR and psychiatric phenotypes, however, have been inconsistent across many studies. Since the polymorphism cannot be tested via available SNP arrays, we had previously proposed an efficient machine learning algorithm to predict the genotypes of 5-HTTLPR based on the genotypes of eight nearby SNPs, which requires access to individual-level genotype and phenotype data. To utilize the advantage of publicly available GWAS summary statistics obtained from studies with very large sample sizes, we develop a GWAS summary-statistics-based approach for testing the variable number of tandem repeat (VNTR) associations with various phenotypes. We first cross-verify the accuracy of the summary-statistics-based approach for 61 phenotypes in the UK Biobank. Since we observed a strong similarity between the predicted individual-level 5-HTTLPR genotype-based approach and the summary-statistics-based approach, we applied our method to the available neurobehavioral GWAS summary statistics data obtained from large-scale GWAS. We found no genome-wide significant evidence for association between 5-HTTLPR and any of the neurobehavioral traits. We did observe, however, genome-wide significant evidence for association between this locus and human adult height, BMI, and total cholesterol. Our summary-statistics-based approach provides a systematic way to examine the role of VNTRs and related types of genetic polymorphisms in disease risk and trait susceptibility of phenotypes for which large-scale GWAS summary statistics data are available.Subject terms: Behavioural genetics, Genetic association study