In schizophrenia,non-remitters and partial remitters to treatment with antipsychotics are qualitatively distinct classes with respect to neurocognitive deficits and neuro-immune biomarkers: results of soft independent modeling of class analogy

Around one third of schizophrenia patients are non-responders to antipsychotic therapy. The present study aimed to delineate the pathway-phenotypes of non-remitters (NRTT) and partial remitters (PRTT) to treatment with antipsychotics as defined using the Global Clinical Impression scales. We recruited 60 NRTT, 50 PRTT and 43 healthy controls and measured schizophrenia symptoms, neurocognitive tests, plasma CCL11, interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box-1 protein (HMGB1), κ- and μ-opioid receptors (KOR and MOR, respectively), endomorphin-2 (EM-2), and β-endorphin. Soft independent modeling of class analogy (SIMCA) showed that NRTT and PRTT are significantly discriminated with a cross-validated accuracy of 94.7% and are qualitatively distinct classes using symptomatome, and neuro-immune-opioid-cognitome (NIOC) features as modeling variables. Moreover, a NIOC pathway phenotype discriminated PRTT from healthy controls with an accuracy of 100% indicating that PRTT and controls are two qualitative distinct classes. Using NIOC features as discriminatory variables in SIMCA showed that all PRTT were rejected as belonging to the normal control class and authenticated as belonging to their target class. In conclusion, a non-response to treatment can best be profiled using a SIMCA model constructed using symptomatome and NIOC features. A partial response should be delineated using SIMCA by authenticating patients as controls or PRTT instead of using scale-derived cut-off values or a number of scale items being rated mild or better. The results show that PRTT is characterized by an active NIOC pathway phenotype and that both NRTT and PRTT should be treated by targeting neuro-immune and opioid pathways.

     

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...     

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.

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.     

Solitary rectal ulcer syndrome in children and adolescents: a descriptive clinicopathologic study

Solitary rectal ulcer syndrome (SRUS) is an uncommon disorder of the rectum. While benign, it can cause concern for patients and affect quality of life. Reported studies on SRUS worldwide are scarce. The aim of this study is to describe the clinicopathologic characteristics of SRUS in a cohort of children based in Saudi Arabia. In this study, children with a confirmed diagnosis of SRUS at King Abdulaziz University Hospital (KAUH) were included, during the period November 2003 to November 2017. Data were collected from hospital medical records. The study comprised twenty-one patients: 17 males (81%) and 4 females (19%); the median age was 11.4 years (range, 5.43-17.9 years). The most common presenting symptoms were rectal bleeding in 21 patients (100%), passage of mucus in 16 (76.1%), abdominal pain in 14 (66.6%), constipation in 13 (61.9%), straining in 9 (42.9%), and rectal prolapse in 5 (23.8%). The most common finding at initial colonoscopy was a single ulcer in 7 patients (33.3%), multiple ulcers in 6 (28.5%), polypoid lesions in 5 (23.8%), and hyperemic mucosa in 3 (14.2%). All patients received medical treatment and 14 (81%) continued to manifest one or more of the symptoms following treatment, which required subsequent modification of the treatment course. None of the patients required surgery. In conclusion, the study found rectal bleeding to be the most common presentation, with a single ulcer being the most prevalent lesion in endoscopy. Treatment response was variable, but almost half of patients reported relief of symptoms following treatment.