Anti-thrombotic therapy in infective endocarditis

Despite advances in medical and surgical treatment, infective endocarditis (IE) still carries a high risk of morbidity and mortality. One of the determinants of an adverse outcome is the presence of systemic embolization and in particular, of CNS embolization. IE vegetations consist of bacteria, platelets and inflammatory cells in a fibrin mesh. The interactions between pathogens, platelets and the coagulation system are critical to vegetation initiation and growth. This understanding has led to the study of the effect of anti-thrombotic treatment on IE vegetation formation and embolization. Although it has been demonstrated that antiplatelet and anticoagulant strategies have an impact on in vitro and animal models of IE, results from the available clinical studies are conflicting. In this article, we provide an overview of the available experimental and clinical data on anti-thrombotic treatment in IE and summarize the current guidelines. An early diagnosis, prompt empiric antibiotic treatment and a careful selection of patients who benefit from early surgical intervention remain essential in the prevention of embolic complications. In patients who have other indications for antiplatelet or anticoagulant treatment, the continuation of this treatment is deemed safe in the absence of hemorrhagic complications.     

Human colon microbiota transform polycyclic aromatic hydrocarbons to estrogenic metabolites

Ingestion is an important exposure route for polycyclic aromatic hydrocarbons (PAHs) to enter the human body. Although the formation of hazardous PAH metabolites by human biotransformation enzymes is well documented, nothing is known about the PAH transformation potency of human intestinal microbiota. Using a gastrointestinal simulator, we show that human intestinal microbiota can also bioactivate PAHs, more in particular to estrogenic metabolites. PAH compounds are not estrogenic, and indeed, stomach and small intestine digestions of 62.5 nmol naphthalene, phenanthrene, pyrene, and benzo(a)pyrene showed no estrogenic effects in the human estrogen receptor bioassay. In contrast, colon digests of these PAH compounds displayed estrogenicity, equivalent to 0.31, 2.14, 2.70, and 1.48 nmol 17alpha-ethynylestradiol (EE2), respectively. Inactivating the colon microbiota eliminated these estrogenic effects. Liquid chromatography-mass spectrometry analysis confirmed the microbial PAH transformation by the detection of PAH metabolites 1-hydroxypyrene and 7-hydroxybenzo(a)pyrene in colon digests of pyrene and benzo(a)pyrene. Furthermore, we show that colon digests of a PAH-contaminated soil (simulated ingestion dose of 5 g/day) displayed estrogenic activity equivalent to 0.58 nmol EE2, whereas stomach or small intestine digests did not. Although the matrix in which PAHs are ingested may result in lower exposure concentrations in the gut, our results imply that the PAH bioactivation potency of colon microbiota is not eliminated by the presence of soil. Moreover, because PAH toxicity is also linked to estrogenicity of the compounds, the PAH bioactivation potency of colon microbiota suggests that current risk assessment may underestimate the risk from ingested PAHs.     

Sexual Satisfaction and Sexual Self Images of People with Physical Disabilities in the Netherlands

The current study investigated the association between sexual well-being, and age-of-onset, relationship status, care dependency and age among people with a physical impairment. Sexual well-being was assessed in five areas: sexual satisfaction, sexual anxiety, sexual esteem, body esteem and perceived attractiveness to others. Ninety-five men and 65 women participated. Multiple regression indicated that as age-of-onset of disability in men increased, sexual satisfaction decreased. Men with late-onset disabilities showed lower levels of sexual satisfaction and body esteem than the congenital group. In women, only having a partner was a predictor of sexual well-being. Care dependency only had a minor effect in the male group. Furthermore, mental health and feelings of helplessness correlated significantly with sexual self images in men but not in women. The results suggest that especially men with late-onset disabilities experience more adjustment problems than women and women place more emphasis on interpersonal aspects of sexuality than men.     

Macronutrient intake and malabsorption in HIV infection: a comparison with other malabsorptive states

Background—Wasting is a major complication of HIVinfection. The role of malabsorption in wasting is controversial.
Aims—To assess oral intake and malabsorption in acohort of weight losing HIV infected patients, with or without chronic diarrhoea.
Methods—A prospective study using a predefinedprotocol for HIV infected patients was performed in a gastroenterologyand nutrition unit in a university hospital. A retrospective comparison was made with HIV negative patients with malabsorption due either tosmall bowel disease or resection. Body weight and height, serum albumin, oral intake of macronutrients, faecal weight, and faecal fatwere measured.
Results—Seventy nine weight losing HIV infectedpatients were studied. Among the 66 patients with more than 5% lipidmalabsorption, wasting was significantly greater in patients withcryptosporidiosis (n=22) than in patients with microsporidiosis (n=18)who exhibited significantly more wasting than patients with noidentified enteropathogen (n=26) (body mass index 16.8 (14.0-20.7),18.9 (16.5-21.3), 19.7(15.9-23), respectively). When controlling forthe level of lipid malabsorption, HIV infected patients had asignificantly lower energy intake than HIV negative patients withchronic malabsorption. In HIV infected patients, but not in othercategories of malabsorbers, body mass index correlated significantlywith energy intake (r=0.33, 95% confidence intervals 0.12 to 0.51).
Conclusion—In weight losing HIV infectedpatients, reduced energy intake is superimposed on malabsorption andsignificantly contributes to wasting.

     

Fine-tuning the ubiquitin-proteasome system to treat pulmonary fibrosis

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an extremely aggressive lung disease that develops almost exclusively in older individuals, carries a very poor prognosis, and lacks any truly effective therapies. The current conceptual model is that IPF develops because of an age-related decline in the ability of the lung epithelium to regenerate after injury, largely due to death or senescence of epithelial progenitor cells in the distal airways. This loss of regenerative capacity is thought to initiate a chronic and ineffective wound-healing response, characterized by persistent, low-grade lung inflammation and sustained production of collagen and other extracellular matrix materials. Despite recent advances in our understanding of IPF pathobiology, there remains a pressing need to further delineate underlying mechanisms to develop more effective therapies for this disease. In this review, we build the case that many of the manifestations of IPF result from a failure of cells to effectively manage their proteome. We propose that epithelial progenitor cells, as well as immune cells and fibroblasts, become functionally impaired, at least in part, because of an accumulation or a loss in the expression of various crucial proteins. Further, we propose that central to this defect is the dysregulation of the ubiquitin-proteasome system (UPS), which is the major protein-degradation system in eukaryotic cells. Lastly, borrowing concepts from other fields, we discuss how targeting the UPS system could be employed as a novel treatment for IPF and perhaps for other fibrotic lung diseases as well.     

Ca2+ channels in the apical membrane of the toad urinary bladder

Previously (Van Driessche et al. 1987) we showed that small inward (mucosa towards serosa) oriented shortcircuit currents (I _sc) were recorded through the toad urinary bladder when the mucosal side was exposed to Ca²⁺ free solutions containing K⁺, Na⁺ (+amiloride), Cs⁺ or Rb⁺ as main cation. This current component is inhibitable by micromolar concentrations of mucosal La³⁺ and divalent cations (Ca²⁺, Cd²⁺) and is considerably elevated by oxytocin (0.1 U/ml). The present study demonstrates that the addition of 50 nmol/l Ag⁺ to the mucosal medium during oxytocin treatment caused an additional large increase of the La³⁺-sensitiveI _sc component. The power density spectrum of the fluctuation in current contained a Lorentzian component which was enhanced by oxytocin treatment. The Lorentzian component disappeared as a consequence of the administration of mucosal Ag⁺. In experiments with Ca²⁺, Ba²⁺ or Mg²⁺ as principal mucosal cation, the La³⁺-sensitiveI _sc component was negligible under control conditions and during oxytocin treatment. Mucosal Ag⁺ (40 nmol/l) elicited a large inward oriented current which was blockable by the calcium channel blockers, La³⁺ and Cd²⁺. Also the organic calcium entry blockers, nicardipine and verapamil (10 mol/l) depressed the inward current considerably. Noise analysis of the currents carried by divalent cations showed a La³⁺-sensitive noise component. Oxytocin-Ag⁺ activated currents could not be recorded in the absence of the divalent cations or small inorganic cations, e.g. with solutions which contained N-methyld-glucamine (NMDG) as main mucosal cation.