Spontaneous onset of TNFα-triggered colonic inflammation depends on functional T lymphocytes,S100A8/A9 alarmins,and MHC H-2 haplotype

Recently, we established a doxycycline-inducible human tumor necrosis factor alpha (TNFα)-transgenic mouse line, ihTNFtg. Non-induced young and elderly mice showed low but constitutive expression of hTNFα due to promoter leakiness. The persistently present hTNFα stimulated endogenous pro-inflammatory mouse mS100A8/A9 alarmins. Secreted mS100A8/A9 in turn induced the expression and release of mouse mTNFα. The continuous upregulation of pro-inflammatory mTNFα and mS100A8/A9 proteins, due to their mutual expression dependency, gradually led to increased levels in colon tissue and blood. This finally exceeded the threshold levels tolerated by the healthy organism, leading to the onset of intestinal inflammation. Here, recombinant hTNFα functioned as an initial trigger for the development of chronic inflammation. Crossing ihTNFtg mice with S100A9^KO mice lacking active S100A8/A9 alarmins or with Rag1^KO mice lacking T and B lymphocytes completely abrogated the development of colonic inflammation, despite the still leaky hTNFα promoter. Furthermore, both the intensity of the immune response and the strength of immunosuppressive Treg induction was found to depend on the major histocompatibility complex (MHC) genetic composition. In summary, the onset of intestinal inflammation in elderly mice depends on at least four factors that have to be present simultaneously: TNFα upregulation, S100A8/A9 protein expression, functional T lymphocytes and genetic composition, with the MHC haplotype being of central importance. Only joint action of these factors leads to chronic intestinal inflammation, while absence of any of these determinants abrogates the development of the autoimmune disorder. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Albino mice as an animal model for infantile nystagmus syndrome

Purpose. Individuals with oculocutaneous albinism are predisposed to visual system abnormalities affecting the retina and retinofugal projections, which may lead to reduced visual acuity and Infantile Nystagmus Syndrome (INS). Due to absence of an established mammalian animal model, mechanisms underlying INS remain elusive. In this study, we screened wild-type mice of varying pigmentation for ocular motor abnormalities in order to identify a possible mouse model for INS. Methods. Three albino mouse strains (CD1, BALB/c, DBA/1), and two normally pigmented strains (129S6, C57BL/6) were screened using infrared oculography. Varying visual stimuli (black or white background, stationary pattern, optokinetic, i.e., horizontally rotating pattern) were displayed to the full (fVF) or anterior visual field (aVF) of the restrained mouse. Results. We found spontaneous nystagmus, specifically jerks and oscillations, in albino mice under all experimental conditions. Median eye velocity was between 0.8 and 3.4 deg/s, depending on the strain. In contrast, the eyes in pigmented mice were nearly stable with a median absolute eye velocity of below 0.4 deg/s. In albino mice, fVF optokinetic stimuli elicited an optokinetic response (OKR) in the correct direction, albeit with superimposed oscillations. However, aVF optokinetic stimuli evoked reversed OKR in these strains, a well known feature of INS. Conclusions. Based on our results, we endorse the investigated albino mouse strains as new animal models for INS.     

What drives the costs of heart failure care in Germany? A health services cost analysis

Aims

Heart failure (HF) represents an increasing burden on health-care systems because of the aging population. The aim of this study was to explore its costs of care in Germany from the payer perspective and to identify the main drivers.

Subjects and methods

As part of a trial, primary care physicians (PCPs) enrolled eligible patients and documented actual clinical and 12-month retrospective ambulatory health-care utilisation data related to HF [PCP and cardiologist contacts, and cardiovascular (CV) medication] and provided the doctors’ reports of hospitalisations during 2004 and 2005, enabling the collection and calculation of costs. Furthermore, each hospitalisation was classified according to the cause of admission into HF, CV or other hospitalisation.

Results

Thirty-seven physicians enrolled 168 patients with complete data of 159 patients (95?%). Patients (mean age 68?±?10?years, 73?% male, 47?% ischaemic aetiology) had ascertained systolic HF (mean ejection fraction 33?±?7?%) with NYHA class II/III in 53/45?%. Mean (SD; median) annual costs of 96 hospitalisations, CV medication, and 337 cardiologist and 3,037 PCP practice contacts were 3,545 (8,065; 0), 854 (835; 638), 117 (105; 106) and 269 (190; 233) euros, respectively, totalling 4,792 (8249;1341) euros. Fourteen per cent of all patients incurred 50?% of total costs. Twenty-five HF, 49 CV and 22 other hospitalisations incurred 13, 73 and 14?% of hospital care costs, respectively.

Conclusions

These secondary outcome data might indicate a trend that neither HF ambulatory care nor hospitalisation but rather interventional cardiology is the main cost driver. Planning interventions aimed at reduced hospitalisation and costs should include further clarification of the mechanisms of CV hospitalisation and reimbursement.     

Pharmacokinetics,pharmacodynamics, tolerability and prediction of clinically effective dose of ACT‐774312: A novel CRTH2 antagonist

ACT‐774312 is an antagonist of the chemoattractant receptor‐homologous molecule expressed on T helper (Th) 2 cells (CRTH2), in development for the treatment of nasal polyposis or other allergic and type‐2 inflammatory diseases. Placebo, single doses of 1‐1000 mg, or multiple doses of 30‐500 mg either once or twice daily for 4 days of ACT‐774312 were administered orally to healthy subjects. The single‐ and multiple‐dose pharmacokinetics (PK) of ACT‐774312 were dose proportional and characterized by a time to attainment of maximum plasma concentrations between 1 and 3 hours and a terminal elimination half‐life of about 12 hours In the presence of food, t_max was delayed by 1 hour and exposure to ACT‐774312 slightly decreased. Full blockade (>90% of the maximum effect, E_max) of CRTH2 as measured in a whole blood internalization assay was observed after 50 mg ACT‐774312 twice daily and lasted for at least 9 hours The relationship between ACT‐774312 concentration and CRTH2 blockade was described by a E_max model. The estimated twice‐daily dose of ACT‐774312 at which full blockade of CRTH2 is achieved at trough in at least 80% of subjects was estimated at 109 mg. Administration of ACT‐774312 was safe and well tolerated at all doses. For none of the recorded adverse events, a relationship to dose was discerned, and there were no clinically relevant findings on the measured ECG, clinical laboratory and vital signs variables. The observed PK, pharmacodynamics and safety profile warrant further development of ACT‐774312.     

Pentadecapeptide BPC 157 resolves Pringle maneuver in rats,both ischemia and reperfusion

BACKGROUND The Pringle maneuver [portal triad obstruction(PTO)] provides huge disturbances during ischemia and even more thereafter in reperfusion.Contrarily, a possible solution may be stable gastric pentadecapeptide BPC 157,with already documented beneficial effects in ischemia/reperfusion conditions.Recently, BPC 157, as a cytoprotective agent, successfully resolved vessel occlusions in rats(ischemic colitis; deep vein thrombosis, superior anterior pancreaticoduodenal vein; bile duct cirrhosis) through rapid collateral vessel recruitment to circumvent vessel occlusion. Thereby, medication BPC 157 regimens were administered as a single challenge before and during ischemia or,alternatively, at various time points during reperfusion.AIM To introduce BPC 157 therapy against pringle maneuver-damage.METHODS In deeply anesthetised rats, the portal triad was clamped up for 30 min. Rats then underwent reperfusion for either 15 min or 24 h. Medication [(10 μg, 10 ng/kg)regimens, administered as a single challenge] picked(a) ischemia, PTO period [at 5 min before(ip) or at 5 or 30 min of ligation time(as a bath to PTO)] or(b)reperfusion, post-PTO period [at 1 or 15 min(bath during surgery) or 24 h(ip)reperfusion-time]. We provided gross, microscopy, malondialdehyde, serum enzymes, electrocardiogram, portal, caval, and aortal pressure, thrombosis and venography assessments.RESULTS BPC 157 counteracts electrocardiogram disturbances(increased P wave amplitude, S1Q3T3QRS pattern and tachycardia). Rapidly presented vascular pathway(portal vein-superior mesenteric vein-inferior mesenteric vein-rectal veins-left ileal vein-inferior caval vein) as the adequate shunting immediately affected disturbed haemodynamics. Portal hypertension and severe aortal hypotension during PTO, as well as portal and caval hypertension and mild aortal hypotension in reperfusion and refractory ascites formation were markedly attenuated(during PTO) or completely abrogated(reperfusion); thrombosis in portal vein tributaries and inferior caval vein or hepatic artery was counteracted during portal triad obstruction PTO. Also, counteraction included the whole vicious injurious circle [i.e., lung pathology(severe capillary congestion), liver(dilated central veins and terminal portal venules), intestine(substantial capillary congestion, submucosal oedema, loss of villous architecture), splenomegaly, right heart(picked P wave values)] regularly perpetuated in ischemia and progressed by reperfusion in Pringle rats.CONCLUSION BPC 157 resolves pringle maneuver-damage in rats, both for ischemia and reperfusion.     

Obstructive Sleep Apnea and Atrial Arrhythmogenesis

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with relevant morbidity and mortality. Besides hypertension, valvular disease and cardiomyopathy, mainly ischemic and dilated, also other conditions like obesity, alcohol abusus, genetic factors and obstructive sleep apnea (OSA) are discussed to contribute to the progression from paroxysmal to persistent AF. The prevalence of OSA among patients with AF is 40-50%. OSA is characterized by periodic or complete cessation of effective breathing during sleep due to obstruction of the upper airways. Obstructive respiratory events result in acute intrathoracic pressure swings and profound changes in blood gases together leading to atrial stretch and acute sympatho-vagal dysbalance resulting in acute apnea related to electrophysiological and hemodynamic alterations. Additionally, repetitive obstructive events in patients with OSA may lead to sympathetic and neurohumoral activation and subsequent structural and functional changes in the atrium creating an arrhythmogenic substrate for AF in the long run. This review focuses on the acute and chronic effects of negative thoracic pressure swings, changes in blood pressure and sympatho-vagal dysbalance induced by obstructive respiratory events on atrial electrophysiology and atrial structure in patients with obstructive sleep apnea.     

Translation and validation of a tool to assess the impact of clinical pharmacists’ interventions

International Journal of Clinical Pharmacy - Background The tool CLEO in French language is designed for estimating the potential relevance of pharmacists’ interventions (PIs) in three...