Inflammation and endothelial function: Direct vascular effects of human C-reactive protein on nitric oxide bioavailability

Background - Circulating concentrations of the sensitive inflammatory marker C-reactive protein (CRP) predict future cardiovascular events, and CRP is elevated during sepsis and inflammation, when vascular reactivity may be modulated. We therefore investigated the direct effect of CRP on vascular reactivity. Methods and Results - The effects of isolated, pure human CRP on vasoreactivity and protein expression were studied in vascular rings and cells in vitro, and effects on blood pressure were studied in rats in vivo. The temporal relationship between changes in CRP concentration and brachial flow-mediated dilation was also studied in humans after vaccination with Salmonella typhi capsular polysaccharide, a model of inflammatory endothelial dysfunction. In contrast to some previous reports, highly purified and well-characterized human CRP specifically induced hyporeactivity to phenylephrine in rings of human internal mammary artery and rat aorta that was mediated through physiological antagonism by nitric oxide (NO). CRP did not alter endothelial NO synthase protein expression but increased protein expression of GTP cyclohydrolase-1, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, the NO synthase cofactor. In the vaccine model of inflammatory endothelial dysfunction in humans, increased CRP concentration coincided with the resolution rather than the development of endothelial dysfunction, consistent with the vitro findings; however, administration of human CRP to rats had no effect on blood pressure. Conclusions - Pure human CRP has specific, direct effects on vascular function in vitro via increased NO production; however, further clarification of the effect, if any, of CRP on vascular reactivity in humans in vivo will require clinical studies using specific inhibitors of CRP. © 2005 American Heart Association, Inc

Weak D type 2 is the most prevalent weak D type in Portugal

The weak D phenotype is the most common D variant, with a frequency of 0.2-1% in Caucasian individuals. There are several weak D types, with different frequencies in European countries, which may pose serologic problems and have the potential for alloimmunization. Samples from Portuguese individuals were tested for RhD by two or three distinct monoclonal and oligoclonal antisera, in direct agglutination tests. When discrepant results were observed, samples were tested with panels of monoclonal anti-D by LISS-indirect antigobulin test. Cases that reacted weakly with IgM but positive with IgG anti-D were analysed by PCR-sequence-specific primers and real-time PCR. Ninety-nine samples were referred after being characterized as weak D. This genotype was recognized, with a preponderance of weak D type 2 (63.6%) over type 1 (16.2%) and 3 (14.1%). The high incidence of weak D type 2 in our population is in marked contrast to studies performed in other European populations and might be due to our sample selection criteria or ethnic variation. There are advantages in genotyping serologically depressed D samples to avoid the waste of D-negative RBC units and the use of immunoglobulin in pregnant women, who have no risk of alloimmunization

SMIM1 absence is associated with reduced energy expenditure and excess weight

This is the author accepted manuscript.Data and code availability; Participants’ phenotypes and SMIM1 locus genotypes are accessible via the relevant cohort environments: UK Biobank (https://www.ukbiobank.ac.uk/) and MVP (https://www.mvp.va.gov/pwa/discover-mvp-data). Access to these cohorts requires an active project application. All the data generated for this study are available in an anonymized version in supplementary tables or in the Zenodo repository at: https://zenodo.org/records/10685501. The code used to analyze the cohorts is available at https://github.com/stefanucci-luca/vel_ko_analysis. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.Background Obesity rates have nearly tripled in the past 50 years, and by 2030, more than one billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are aetiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments. Methods We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in SMIM1 and the general population, leveraging data from 5 cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber and DEXA scan. Findings We found that individuals homozygous for a loss-of-function genetic variant in the Small Integral Membrane Protein 1 (SMIM1) gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin-adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure. Conclusion This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them.National Institute for Health and Care Research (NIHR)British Heart FoundationNHS Blood and Transplan