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Obesity and nonalcoholic fatty liver disease (NAFLD) are an increasing health care burden worldwide. Weight loss is currently the best option to alleviate NAFLD and is efficiently achieved by bariatric surgery. Presence of NAFLD seems to be predictive for postoperative weight loss. To date, only few predictive factors for postbariatric weight loss (age, diabetes, psychiatric disorders) are established. Since liver fibrosis is the pathogenic driver for the progression of liver disease, we investigated its role in predicting postoperative weight loss. This study focuses on the correlation between fibrosis stage and weight loss. University and university-affiliated cooperation, Germany. We used a prospective, single-center cohort study including 164 patients who underwent bariatric surgery with simultaneous liver biopsies. Liver fibrosis was determined histologically according to Kleiner score and noninvasively by APRI and FIB-4 score. Percentage of total body weight loss was calculated at 1-year follow up visit. Thirty-two patients were found without fibrosis, whereas 91 patients showed mild fibrosis (F1), 37 significant fibrosis (F2), and only 4 patients presented advanced fibrosis (F3) at the time of bariatric surgery. Weight loss was similar across different degrees of fibrosis stage. Accordingly, linear regression analysis did not identify predictors of weight loss among fibrosis scores. In multivariable analysis, age and presence of diabetes showed the strongest predictive value. Baseline presence of fibrosis was not associated with postoperative weight loss, while age and diabetes were independent predictors of weight loss. Bariatric surgery should be applied independently of the fibrosis stage. • Stage of hepatic fibrosis does not predict postbariatric weight-loss results. • Therefore, stage of hepatic fibrosis should not influence the indication for metabolic surgery. • Age and presence of Type 2 diabetes mellitus have negative impact on postbariatric weight-loss. [ABSTRACT FROM AUTHOR]

Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSCs), the main profibrotic hepatic cells. Yet, little is known about the interplay of neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer of contraction, in liver fibrosis. We demonstrate that HSCs are the source of NEP. Importantly, NPY originates majorly from the splanchnic region and is cleaved by NEP in order to terminate contraction. Interestingly, NEP deficiency (Nep −/−) showed less fibrosis but portal hypertension upon liver injury in two different fibrosis models in mice. We demonstrate the incremental benefit of Nep −/− in addition to AT1R blocker (ARB) or ACE inhibitors for fibrosis and portal hypertension. Finally, oral administration of Entresto, a combination of ARB and NEP inhibitor, decreased hepatic fibrosis and portal pressure in mice. These results provide a mechanistic rationale for translation of NEP-AT1R-blockade in human liver fibrosis and portal hypertension. [Display omitted] • Proteolysis of NPY by NEP promotes liver fibrosis via NPY 1 receptor blockade in HSCs • In the liver, NPY enhances contraction induced by AT1R stimulation • Administration of Entresto decreases liver fibrosis and portal pressure Neprilysin is upregulated in fibrosis and activated hepatic stellate cells (HSCs). Nep −/− reduced fibrosis due to increased levels of neuropeptide Y. Ortiz et al. describe a new player in fibrosis and deliver the molecular rationale for combined neprilysin and angiotensin inhibition as treatment of human liver fibrosis with portal hypertension. [ABSTRACT FROM AUTHOR]

Pharmacoresistance to antiepileptic drugs (AEDs) is a major challenge in epilepsy therapy, affecting at least 30% of patients. Thus, there is considerable interest in the mechanisms responsible for such pharmacoresistance, with particular attention on the specific cellular and molecular factors that lead to reduced drug sensitivity. Current hypotheses of refractory epilepsy include the multidrug transporter hypothesis, which posits that increased expression or function of drug efflux transporters, such as P-glycoprotein (Pgp), in brain capillaries reduces the local concentration of AEDs in epileptic brain regions to subtherapeutic levels. In the present study, this hypothesis was addressed by evaluating the efficacy of six AEDs in wildtype and Pgp deficient Mdr1a/b −/− mice in the intrahippocampal kainate model of mesial temporal lobe epilepsy. In this model, frequent focal electrographic seizures develop after an initial kainate-induced status epilepticus. These seizures are resistant to major AEDs, but the mechanisms of this resistance are unknown. In the present experiments, the focal nonconvulsive seizures were resistant to carbamazepine and phenytoin, whereas high doses of valproate and levetiracetam exerted moderate and phenobarbital and diazepam marked anti-seizure effects. All AEDs suppressed generalized convulsive seizures. No significant differences between wildtype and Pgp-deficient mice were observed in anti-seizure drug efficacies. Also, the individual responder and nonresponder rates in each experiment did not differ between mouse genotypes. This does not argue against the multidrug transporter hypothesis in general, but indicates that Pgp is not involved in the mechanisms explaining that focal electrographic seizures are resistant to some AEDs in the intrahippocampal mouse model of partial epilepsy. This was substantiated by the finding that epileptic wildtype mice do not exhibit increased Pgp expression in this model. [ABSTRACT FROM AUTHOR]

Objective: Homeopathic globules are commonly used in clinical practice, while research focuses on liquid potencies. Sequential dilution and succussion in their production process has been proposed to change the physico-chemical properties of the solvent(s). It has been reported that aqueous potencies of various starting materials showed significant differences in ultraviolet light transmission compared to controls and between different dilution levels. The aim of the present study was to repeat and expand these experiments to homeopathic globules.Methods: Globules were specially produced for this study by Spagyros AG (Gümligen, Switzerland) from 6 starting materials (Aconitum napellus, Atropa belladonna, phosphorus, sulfur, Apis mellifica, quartz) and for 6 dilution levels (6x, 12x, 30c, 200c, 200CF (centesimal discontinuous fluxion), 10,000CF). Native globules and globules impregnated with solvents were used as controls. Globules were dissolved in ultrapure water, and absorbance in the ultraviolet range was measured. The average absorbance from 200 to 340nm was calculated and corrected for differences between measurement days and instrumental drift.Results: Statistically significant differences were found for A. napellus, sulfur, and A. mellifica when normalized average absorbance of the various dilution levels from the same starting material (including control and solvent control globules) was compared. Additionally, absorbance within dilution levels was compared among the various starting materials. Statistically significant differences were found among 30c, 200c and 200CF dilutions.Conclusion: This study has expanded previous findings from aqueous potencies to globules and may indicate that characteristics of aqueous high dilutions may be preserved and detectable in dissolved globules. [ABSTRACT FROM AUTHOR]

Despite more than 20 clinically approved antiepileptic drugs (AEDs), there remains a substantial unmet clinical need for patients with refractory (AED-resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we previously evaluated whether epileptic rats respond differently to AEDs and discovered AED responsive and resistant animals in the same models. In the present study, we used the same approach for the widely used intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. In a first step, we examined anti-seizure effects of 6 AEDs on spontaneous recurrent focal electrographic seizures and secondarily generalized convulsive seizures in epileptic mice, showing that the focal nonconvulsive seizures were resistant to carbamazepine and phenytoin, whereas valproate and levetiracetam exerted moderate and phenobarbital and diazepam marked anti-seizure effects. All AEDs seemed to suppress generalized convulsive seizures. Next we investigated the inter-individual variation in the anti-seizure effects of these AEDs and, in case of focal seizures, found responders and nonresponders to all AEDs except carbamazepine. Most nonresponders were resistant to more than one AED. Our data further validate the intrahippocampal kainate mouse model as a model of difficult-to-treat focal seizures that can be used to investigate the determinants of AED efficacy. [ABSTRACT FROM AUTHOR]

BACKGROUND & AIMS: It is not clear how nitric oxide (NO) released from enteric neurons relaxes gastrointestinal (GI) smooth muscle. In analogy to the vascular system, NO might directly induce relaxation of smooth muscle cells (SMCs) by acting on its receptor, NO-sensitive guanylyl cyclase (NO-GC). Alternatively, intermediate cells, such as the interstitial cells of Cajal (ICCs), might detect nitrergic signals to indirectly regulate smooth muscle tone, and thereby regulate the motor function of the GI tract. We investigated the role of ICCs and SMCs in nitrergic relaxation using mice with cell-specific disruption of the gene encoding the β1 subunit of NO-GC (GUCY1B3). METHODS: We created mice that lack NO-GC specifically in SMCs (SM-guanylyl cyclase knockout [GCKO]), ICCs (ICC-GCKO), or both (SM/ICC-GCKO). We investigated the effects of" exogenous and endogenous NO on murine fundus using isometric force studies. Total gut transit time was measured to monitor the functional consequences of NO-GC deletion on GI motility in vivo. RESULTS: NO-GC is expressed in ICC and SMC. Deletion of the NO receptor from SMCs incompletely reduced NO-induced fundus relaxation, which was hardly affected after ICC-specific deletion. Gut transit time did not change in SM-GCKO or ICC-GCKO mice compared with control mice. However, nitrergic relaxation was not observed in SM/ICC-GCKO mice, which had increased gut transit time compared with controls. CONCLUSIONS: In mice, NO-GC is the only NO receptor to relax the fundus; deletion of NO-GC from the combination of SMCs and ICCs blocks nitrergic signaling. Therefore, ICCs and SMCs jointly mediate the relaxant effect of enteric NO. [ABSTRACT FROM AUTHOR]

Abstract: Growth hormone (GH) has been shown to be released by immune cells in vitro. Thus, the intracellular confinement of GH immunoreactivity was investigated in cultured bovine lymphocytes using con-focal microscopy. Peripheral blood lymphocytes from cows in early pregnancy (10–20days post insemination; pi) or during mid-pregnancy (day 110–140 pi) were harvested and cultured for 48h in presence of phytohemagglutinin-M (PHA-M) or served as controls. Thereafter, immunocytochemistry was conducted using a homologous GH-antibody. Double staining (GH-antibody and directly DYE 549 labeled CD3-antibody) was performed to classify the cells. Con-focal laser scanning was applied verifying the immunofluorescence labeling. Interestingly, the presence of GH immunoreactivity in the cytoplasm, which indicates GH synthesis, was restricted to small cells. Whereas, few T-like cells revealed surface bound GH. Lowest immunoreactivity, concerning the number of the total labeled cells as well as the intensity of labeling was recorded in early pregnancy. Stimulation with PHA-M enhanced total labeled cells in early pregnancy. In contrast, PHA-M had no such effects in mid-pregnancy. The results confirm the specific regulation of synthesis of lymphocytic GH during pregnancy in the cow. The identification of cells producing GH and the elucidation of the mechanisms underlying the expression of GH in larger number of cells during mid-pregnancy than in the early pregnancy need further investigations. [Copyright &y& Elsevier]