Neutrophil-to-lymphocyte ratio at diagnosis predicts colonoscopic activity in pediatric inflammatory bowel diseases (pIBD).

Background: Neutrophil-to-lymphocyte ratio (NLR) is a novel biomarker studied in several autoimmune diseases including inflammatory bowel diseases (IBD) in adults, but poorly characterized in pediatric IBD (pIBD). We aimed to primarily investigate the relationship between NLR and pIBD endoscopic disease severity. We also examined whether NLR predicted hospitalization, surgery, and therapy response by 52 weeks.

Development of novel GI-centric prostaglandin E receptor type 4 (EP4) agonist prodrugs as treatment for ulcerative colitis and other intestinal inflammatory diseases.

Prostaglandin E receptor type 4 (EP4) agonists have been shown to be effective in treating experimental ulcerative colitis (UC) in animals and in human clinical trials, but their development has been impeded by unacceptable systemic side effects. In this study, a series of methylene phosphate prodrugs of a highly potent and selective prostaglandin EP4 receptor agonist were designed to target and remain localized in the gastrointestinal (GI) tract after either oral or rectal instillation. The prodrugs were designed to be converted to liberate active EP4 agonist by intestinal alkaline phosphate (IAP), a ubiquitous enzyme found at the luminal of the intestinal wall thus exposing the colon epithelial barrier while reducing systemic exposure to the active agonist.

Bolstering connectedness through peer support: Randomized-controlled trial of a web-based peer support program for adolescents with inflammatory bowel disease.

Background: Inflammatory bowel disease (IBD) is a chronic autoimmune disease often diagnosed during adolescence. IBD negatively impacts all aspects of health-related quality of life, resulting in physical, emotional, social, school, and work functioning challenges. Adolescents have identified the need for peer support in managing their disease and promoting positive health outcomes.

A2B adenosine receptor-triggered intracellular calcium mobilization: Cell type-dependent involvement of Gi, Gq, Gs proteins and protein kinase C.

Activation of PLCβ enzymes by G and G proteins is a common mechanism to trigger cytosolic Ca increase. We and others reported that G inhibitor FR900358 (FR) can inhibit both and G- and, surprisingly, G-mediated intracellular Ca mobilization. Thus, the G-G-PLCβ-Ca signaling axis depends entirely on the presence of active G, which reasonably explained FR-inhibited G-induced Ca release.

Pregnancy and age differentially affect stiffness, injury susceptibility, and composition of murine uterosacral ligaments.

Pelvic organ prolapse is a debilitating condition that diminishes quality of life, and it has been linked to pregnancy and aging. Injury of the uterosacral ligaments (USLs), which provide apical support to the pelvic organs, is a major cause of uterine prolapse. In this study, we examined the effect of pregnancy and age on the apparent elastic modulus, susceptibility to collagen damage, and extracellular matrix (ECM) composition of the murine USL.

Photoswitchable Diazocine Derivative for Adenosine A Receptor Activation in Psoriasis.

Incorporating photoisomerizable moieties within drugs offers the possibility of rapid and reversible light-dependent switching between active and inactive configurations. Here, we developed a photoswitchable adenosine A receptor (AR) agonist that confers optical control on this G protein-coupled receptor through noninvasive topical skin irradiation in an animal model of psoriasis. This was achieved by covalently bonding an adenosine-5'-methyluronamide moiety to a diazocine photochrome, whose singular photoswitching properties facilitated repeated interconversion between a thermally stable, biologically inactive agonist form and a photoinduced, pharmacologically active configuration.

Systematic review and meta-analysis of protocols and yield of direct from sputum sequencing of .

Direct sputum whole genome sequencing (dsWGS) can revolutionize () diagnosis by enabling rapid detection of drug resistance and strain diversity without the biohazard of culture. We searched PubMed, Web of Science and Google scholar, and identified 8 studies that met inclusion criteria for testing protocols for dsWGS. Utilising meta-regression we identify several key factors positively associated with dsWGS success, including higher bacillary load, mechanical disruption, and enzymatic/chemical lysis.

Third-Generation CD73 Inhibitors Based on a 4,6-Disubstituted-2-Thiopyridine Scaffold.

Various series of 4,6-disubstituted-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5'-nucleotidase (CD73) inhibitors. Altogether, about ninety compounds were prepared using a general synthetic pathway involving one or two steps (eventually one-pot) procedures. Variation of the nature of the substituents in positions 4 and 6 (methyl, trifluoromethyl or phenyl) of the thiopurine ring, as well as on the thiol function, was examined and led to marked differences both in term of reactivity and ability to interfere with the putative target protein.

Mitochondrial A Adenosine Receptor as a Mechanism for the Protective Effects of AAR Agonists on Chemotherapy-Induced Neuropathic Pain.

Alterations in mitochondrial function are the linchpin in numerous disease states including in the development of chemotherapy-induced neuropathic pain (CIPN), a major dose-limiting toxicity of widely used chemotherapeutic cytotoxins. In CIPN, mitochondrial dysfunction is characterized by deficits in mitochondrial bioenergetics (e.g.

Potent and Selective Human 5-HT Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity.

Rigidified nucleoside derivatives with (N)-methanocarba replacement of ribose have been repurposed as peripheral subtype-selective 5-HT serotonin receptor antagonists for heart and lung fibrosis and intestinal/vascular conditions. 4'-Cyano derivative (MRS8209; , 4.27 nM) was 47-fold (human binding, but not rat and mouse) and 724-fold (functionally) selective at 5-HTR, compared to antitarget 5-HTR, and predicted to form a stable receptor complex using docking and molecular dynamics.

Cardiopulmonary Exercise Testing, Rehabilitation, and Exercise Training in Postpulmonary Embolism.

Long-term exercise intolerance and functional limitations are common after an episode of acute pulmonary embolism (PE), despite 3 to 6 months of anticoagulation. These persistent symptoms are reported in more than half of the patients with acute PE and are referred as "post-PE syndrome." Although these functional limitations can occur from persistent pulmonary vascular occlusion or pulmonary vascular remodeling, significant deconditioning can be a major contributing factor.

MRS3997, a dual adenosine A/A receptor agonist, reduces brain ischemic damage and alleviates neuroinflammation in rats.

The endogenous neuromodulator adenosine is massively released during hypoxic/ischemic insults and differentially modulates post-ischemic damage depending on the expression and recruitment of its four metabotropic receptor subtypes, namely A, A, A and A receptors (ARs, ARs, ARs and ARs). We previously demonstrated, by using a model of transient middle cerebral artery occlusion (tMCAo) in rats, that selective activation of ARs, as well as ARs, ameliorates post-ischemic brain damage in contrast to neuroinflammation. In the present study, we investigated whether the multitarget nucleoside MRS3997, a full agonist at both ARs and ARs, would afford higher neuroprotection in post-ischemic damage.

Using Phosphatidylethanol as an Adjunct to Self-Reported Alcohol Use Improves Identification of Liver Fibrosis Risk.

Introduction: Accurate assessment of alcohol use informs prevention and management of liver disease. We examined whether phosphatidylethanol (PEth, an alcohol metabolite) blood concentrations are associated with liver fibrosis risk independently of self-reported alcohol use, among persons with and without HIV.

Methods: We pooled individual-level data from 12 studies from the United States, Russia, Uganda, and South Africa with PEth, Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), and fibrosis-4 (FIB-4) measurements.

Selective bioorthogonal probe for N-glycan hybrid structures.

Metabolic incorporation of chemically tagged monosaccharides is a facile means of tagging cellular glycoproteins and glycolipids. However, since the monosaccharide precursors are often shared by several pathways, selectivity has been difficult to attain. For example, N-linked glycosylation is a chemically complex and ubiquitous posttranslational modification, with three distinct classes of GlcNAc-containing N-glycan structures: oligomannose, hybrid and complex.

Chimeras Derived from a P2Y Receptor Antagonist and UDP-Sugar Agonists for Potential Treatment of Inflammation.

Tethered glycoconjugates of a naphthalene- and piperidine-containing antagonist of the P2Y receptor (PPTN) were synthesized, and their nM receptor binding affinity was determined using a fluorescent tracer in hP2YR-expressing whole CHO cells. The rationale for preparing mono- and disaccharide conjugates of the antagonists was to explore the receptor binding site, which we know recognizes a glucose moiety on the native agonist (UDP-glucose), as well as enhance aqueous solubility and pharmacokinetics, including kidney excretion to potentially counteract sterile inflammation. Glycoconjugates with varied linker length, including PEG chains, were compared in hP2YR binding, suggesting that an optimal affinity (IC, nM) in the piperidine series was achieved for triazolyl -linked glucose conjugates having one (, MRS4872, 3.

Structure-Activity Relationship of Truncated 4'-Selenonucleosides: A Adenosine Receptor Activity and Binding Selectivity.

This study explored the impact of structural modifications on truncated 4'-selenonucleosides as ligands for the A adenosine receptor (AR). We synthesized and evaluated a series of these compounds for their binding affinities, functional activities, and structural interactions by using computational modeling. The SAR study revealed that all compounds exhibited selective and notable hAAR binding, among which ( = 5.

Evaluation of the Tuberculosis Infection Care Cascade Among Pregnant Individuals in a Low-Tuberculosis-Burden Setting.

In the United States, tuberculosis (TB) screening is recommended for pregnant individuals with TB risk factors. We conducted a retrospective study of perinatal TB infection testing and treatment in a tertiary health system. Of 165 pregnant individuals with positive TB infection tests, only 9% completed treatment within 4.