Hospitalisation costs associated with heart failure with preserved ejection fraction (HFpEF): a systematic review

Heart Failure Reviews - Heart failure with preserved ejection fraction (HFpEF) is problematic to treat, with guidelines for HFpEF management concentrated on treating prevalent comorbidities. The...     

Vitamin E-based therapy is effective in ameliorating transaminasemia in nonalcoholic fatty liver disease.

BACKGROUND: Comparative trials of ursodeoxycholic acid (UDCA), vitamin E and weight management programs among patients with nonalcoholic fatty liver disease (NAFLD) are lacking. AIM: To find an effective single agent or combination of agents for management of NAFLD. METHODS: In this retrospective study, consecutive patient with histologically confirmed NAFLD with raised ALT were included. The patients received either weight management (exercise and therapeutic lifestyle changes [TLC] diet with a target to reduce body weight 10% in 6 months) (group I) ; weight management + UDCA (300 mg BID) (group II); or weight management + UDCA + vitamin E (400 mg OD) (group III). Outcome measure was normalization of ALT. RESULTS: 42 patients (18, 12 and 12 in groups I, II and III, respectively) were included between 1996 and 2004. All patients in group III normalized their ALT levels, which was significantly higher than numbers in group I (8/18) and group II (5/12); (p=0.003). Post treatment ALT was significantly lower in group III (28.6 [9.3]) as compared to group I (59.3 [32.2]) and group II (49.0[31.8]); (p=0.01). Type of therapy received was the only factor predictive of ALT normalization. CONCLUSION: Combination regimen containing vitamin E appears to be effective in normalizing ALT among NAFLD patients.     

Soluble and membranous endothelial protein C receptor in systemic lupus erythematosus patients: Relation to nephritis

Aim of the work

To investigate the role of endothelial protein C receptor (EPCR) (membrane and soluble forms) as a biomarker of lupus nephritis (LN) in systemic lupus erythematosus (SLE) patients and to study its relation to the prognosis and response to treatment.

Spectrum of microscopic colitis in a tertiary care centre in India

INTRODUCTION: The incidence of microscopic colitis has recently increased. Although collagenous colitis and lymphocytic colitis are the two main subtypes of microscopic colitis, many patients may not fit into either category and are thus included under the header nonspecific colitis. Of late, the spectrum of microscopic colitis has widened to include minimal change colitis, microscopic colitis not otherwise specified and microscopic colitis with giant cells. There is a lack of information concerning the spectrum of microscopic colitis in Asia. METHOD: In a retrospective analysis, case records of 29 patients diagnosed with microscopic colitis between 1999-2005 were analysed. Drug use parasitic infection and common bacterial infections were excluded. Colonoscopic/ sigmoidoscopic examination was done and multiple colonic mucosal biopsies were stained serially with haematoxylin and eosin for detailed histological examination and Masson trichrome for sub-epithelial collagen band. Based on histological criteria, patients were categorised into five subtypes: collagenous colitis (presence of collagenous thickening of surface epithelium basement membrane > 10 microm), lymphocytic colitis (intra-epithelial lymphocytes more than 20 per 100 colonocytes), minimal change colitis (crypt architectural abnormality in the form of cryptitis and crypt dilatation in the absence of increase in intraepithelial lymphocytes and subepithelial collagenous band), microscopic colitis not otherwise specified (increased inflammatory cell infiltrates in the lamina propria in the absence of other abnormalities) and microscopic colitis with giant cells. RESULTS: Mean age of patients was 38.59 years (range 12-62). Of 29 patients with microscopic colitis, 7 (24.1%), 4 (13.8%), 7 (24.1%) and 11 (37.9%) were classified as collagenous colitis, lymphocytic colitis, minimal change colitis and microscopic colitis not otherwise specified, respectively. None of these patients had giant cells. There was no significant correlation between disease type and clinical manifestations. CONCLUSION: Microscopic colitis has a wide histological spectrum. Cases reported as non-specific colitis, may be categorised into definite subtypes of microscopic colitis.     

Assessment of inflamed synovial membrane in the knee joint by dynamic magnetic resonance imaging

Dynamic magnetic resonance imaging (dynamic MRI) was used to examine the synovial membrane in the knee joints of 15 patients with rheumatoid arthritis (RA) in order to investigate the relationship between pathological and MRI findings. Signal intensities in the regions of interest (ROI), identified as the synovial membrane of the suprapatellar pouch, were measured on MR images. Signal intensities at various times after the injection of contrast medium Gd–diethylenetriaminopentoacetic acid (Gd–DTPA) were normalized relative to the signal intensity at 80s, and designated as the normalized signal intensity (NSI). Pathological findings were quantified, and the types of inflamed synovial membrane were classified as either acute or chronic. A significant difference in NSI was observed between acute and chronic types (P 0.05). Dynamic MRI was capable of classifying acute and chronic RA by measuring NSI 20s after contrast medium injection. Dynamic MRI was therefore shown to be useful for assessing regional synovial inflammation.     

Redox Balance via Lactate Dehydrogenase Is Important for Multiple Stress Resistance and Virulence in Enterococcus faecalis

Enterococcus faecalis is a highly stress resistant opportunistic pathogen. The intrinsic ruggedness of this bacterium is supposed to be the basis of its capacity to colonize the hostile environments of hospitals and to cause several kinds of infections. We show in this work that general resistance to very different environmental stresses depends on the ability of E. faecalis to maintain redox balance via lactate dehydrogenase (LDH). Furthermore, LDH-deficient mutants are less successful than the wild type at colonizing host organs in a murine model of systemic infection. Taken together, our results, as well as those previously published for Staphylococcus aureus (A. R. Richardson, S. J. Libby, and F. C. Fang, Science 319:1672–1676, 2008), identify LDH as an attractive drug target. These drugs may have additional applications, as in the fight against glycopeptide antibiotic-resistant bacteria and even cancer.     

Lipopolysaccharide Causes an Increase in Intestinal Tight Junction Permeability in Vitro and in Vivo by Inducing Enterocyte Membrane Expression and Localization of TLR-4 and CD14

Bacterial-derived lipopolysaccharides (LPS) play an essential role in the inflammatory process of inflammatory bowel disease. A defective intestinal tight junction (TJ) barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut. Despite its importance in mediating intestinal inflammation, the physiological effects of LPS on the intestinal epithelial barrier remain unclear. The major aims of this study were to determine the effects of physiologically relevant concentrations of LPS (0 to 1 ng/mL) on intestinal barrier function using an in vitro (filter-grown Caco-2 monolayers) and an in vivo (mouse intestinal perfusion) intestinal epithelial model system. LPS, at physiologically relevant concentrations (0 to 1 ng/mL), in the basolateral compartment produced a time-dependent increase in Caco-2 TJ permeability without inducing cell death. Intraperitoneal injection of LPS (0.1 mg/kg), leading to clinically relevant plasma concentrations, also caused a time-dependent increase in intestinal permeability in vivo. The LPS-induced increase in intestinal TJ permeability was mediated by an increase in enterocyte membrane TLR-4 expression and a TLR-4–dependent increase in membrane colocalization of membrane-associated protein CD14. In conclusion, these studies show for the first time that LPS causes an increase in intestinal permeability via an intracellular mechanism involving TLR-4–dependent up-regulation of CD14 membrane expression.An integral function of intestinal epithelial cells is to act as a physical barrier, separating the noxious luminal environment from the underlying lamina propria and the deeper intestinal layers.^1,2 The apically located tight junctions (TJs) form a paracellular seal between the lateral membranes of adjacent intestinal epithelial cells, and act as a structural and functional barrier against paracellular flux of luminal substances. Defective intestinal epithelial TJ barrier has been shown to be an important pathogenic factor of inflammatory bowel disease (IBD) and necrotizing enterocolitis (NEC) by allowing paracellular permeation of luminal antigens that elicit and promote inflammatory response.^1,2 Both clinical and animal studies have shown the importance of a defective intestinal TJ barrier in the development and prolongation of intestinal inflammation in IBD and NEC.^1–5 These studies have shown that normalization of intestinal barrier in patients with active Crohn’s disease predicts prolonged clinical remission, whereas a persistent increase in intestinal permeability portends poor clinical outcome with rapid recurrence of the disease.^6,7 Additionally, animal studies have also shown that a primary defect in intestinal junctional complexes was sufficient to induce or aggravate intestinal inflammation in murine models of IBD,^8,9 whereas therapeutic tightening or enhancement of the intestinal TJ barrier prevented the development of intestinal inflammation.^3,10The terms endotoxin and lipopolysaccharide (LPS) are used interchangeably and refer to the major cell wall component of Gram-negative bacteria.^11,12 LPS are complex amphiphilic molecules having a hydrophobic (consisting of lipid A) and a hydrophilic (consisting of carbohydrate core and polysaccharide O-antigen) component and are released from bacterial cell wall by shedding or through bacterial lysis.^11–13 LPS concentrations are highest in the gut lumen, where many trillions of commensal bacteria reside. Normally, LPS in the gut lumen do not penetrate across the healthy intestinal epithelium^14,15; however, in intestinal permeability disorders, the defective TJ barrier allows paracellular flux of LPS and other luminal antigens.^{11–13,16–19} The intestinal tissue and circulating LPS levels are markedly elevated in IBD and NEC, and play an important role in mediating inflammatory response.^{11–13,16–18} The involvement of LPS in the initiation and propagation of intestinal inflammation in IBD and NEC has been well demonstrated.^20–23 These studies have shown LPS to be an important contributing factor of intestinal inflammation, and removal of circulating LPS accelerated the clinical improvement of IBD and NEC.^20,22,23 Despite the importance of a defective intestinal barrier in the accentuation and prolongation of intestinal inflammation in IBD and NEC,^3,6,9,20,22 the effects of circulating levels of LPS on the intestinal epithelial barrier remain unknown. Because LPS levels are markedly elevated in these diseases and play an important role in the inflammatory process, understanding the effects of LPS on intestinal barrier function has important potential clinical significance.In normal healthy individuals, plasma concentrations of LPS range from undetectable levels up to 0.2 ng/mL.^11,12,20,22 A variety of physiological factors such as prolonged physical exertion, high-fat diet, physiological stresses, or heat can lead to elevated plasma LPS levels as high as 1 to 2 ng/mL.^24–27 Patients with intestinal permeability disorders such as Crohn’s disease, NEC, acute pancreatitis, alcoholic liver disease, and critical illnesses also have elevated plasma LPS levels ranging up to 2 to 10 ng/mL.^{11–13,20,22,28} Based on these reports, we consider LPS levels of 0 to 1.0 ng/mL to be physiologically relevant and 0 to 10 ng/mL to be clinically relevant. (For reference, the concentration of LPS in the gut lumen has been reported to be 1.8 μg/mL in the rat distal ileum.^29,30) Inexplicably, in most of the published studies, extreme pharmacological concentrations of LPS ranging between 50 and 1000 μg/mL, which exceed the physiologically achievable concentrations by 10⁴- to 10⁷-fold, have been used to assess various biological responses.^30–34 At these extreme concentrations, LPS causes rapid cell death in various cell types studied, including in intestinal and immune cells,^30,33–35 and does not provide accurate depiction of biological activity of LPS. Herein, we show that LPS, at physiologically and clinically relevant concentrations (0 to 10 ng/mL), does not cause intestinal epithelial cell death, but causes a selective increase in intestinal TJ permeability in vitro and in vivo. These studies also show for the first time that pattern recognition receptors Toll-like receptor 4 (TLR-4) and CD14 play a central role in the modulation of the intestinal epithelial TJ barrier.