Lemmingborg0817

Stress is a known trigger for the symptoms of irritable bowel syndrome (IBS), a gastrointestinal (GI) disorder that presents with abnormal bowel habits and abdominal pain due to visceral hypersensitivity. While behavioral therapies have been used to attenuate IBS symptoms, the underlying mechanisms by which these therapies interact with stress-induced pathology remains to be delineated. Here we use a rat model to test the hypothesis that exposure to environmental enrichment (EE) inhibits stress-induced changes within the brain-gut axis to prevent visceral and somatic hypersensitivity and colonic hyperpermeability.

Female rats (n=8/group) were housed in EE one week before and one week during exposure to water avoidance stress (WAS) while controls were housed in standard cages (SH). One day after the final WAS exposure, colonic and somatic sensitivity were assessed by the visceromotor response (VMR) to colorectal distension (CRD) and withdrawal threshold elicited by an electronic von Frey on the hind paw ofal therapies may ameliorate visceral pain associated stress-related pathologies such as the irritable bowel syndrome.The leptin receptor (Lepr) pathway is important for food intake regulation, energy expenditure, and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chromosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-LeprL536Hfs*6-1NKB), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, LeprL536Hfs*6 develop early onset obesity and their body weight exceeds that of Leprdb/db mice at an age of 30 weeks. Similar to Leprdb/db mice, the LeprL536Hfs*6 model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Leprdb/wt with LeprL536Hfs*6/wt mice results in compound heterozygous LeprL536Hfs*6/db mice, which develop even higher body weight and fat mass than both homozygous Leprdb/db and LeprL536Hfs*6 mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.

Cardiovascular outcomes are worse among individuals from areas with limited socioeconomic resources. This study evaluated the relationship between high socioeconomic deprivation and isolated coronary artery bypass grafting (CABG) outcomes.

We linked statewide Society of Thoracic Surgeons Adult Cardiac Surgery Database data to Medicare fee-for-service records for 10,423 Michigan residents undergoing isolated CABG between 01/2012-12/2018. High socioeconomic deprivation was defined as residing in the highest decile of zip code-level area deprivation index (ADI). Multivariable logistic regression estimated the relationship between top ADI decile and major morbidity, in-hospital mortality, and operative mortality. Panobinostat mw Survival analyses evaluated long-term survival comparing patients in the top versus not in the top ADI decile.

A total of 1,036 patients were in the top decile of ADI (ADI>82.4), and were more likely to be female, black, and have a higher predicted risk of mortality. Patients in the top ADI decile had significantly higher rates of major morbidity (17.4% versus 11.4%, adjusted odds ratio =1.26, 95% CI 1.04-1.54, p=0.021) and in-hospital mortality (3.2% versus 1.3%, adjusted odds ratio=1.84, 95% CI 1.18-2.86, p=0.007), but not operative mortality. The adjusted hazard of mortality was 16% higher for patients residing in the top ADI decile (95% CI 1.01-1.33, p=0.032).

Isolated CABG patients residing in the highest areas of socioeconomic deprivation differed with respect to demographic and clinical characteristics, and experienced worse short and long-term outcomes compared with those not in the top ADI decile.

Isolated CABG patients residing in the highest areas of socioeconomic deprivation differed with respect to demographic and clinical characteristics, and experienced worse short and long-term outcomes compared with those not in the top ADI decile.

To evaluate whether children with neurofibromatosis type 1 (NF1) and tuberous sclerosis have different birth characteristics compared with the general population.

We identified all individuals born in Sweden between 1973 and 2014 from the nationwide Medical Birth Register for whom information on both biological parents was available (n=4 242 122). Individuals with NF1 and individuals with tuberous sclerosis were identified using data from Swedish population-based health data registers. Using logistic regression models, we assessed the associations between these 2 neurocutaneous syndromes and birth characteristics in a cohort that included 1804 subjects with NF1 and 450 with tuberous sclerosis.

Children with NF1 and tuberous sclerosis were significantly more likely to be born preterm and via cesarean delivery. In addition, children with NF1 were also more likely to be born with other birth characteristics, such as short length, a large head circumference, and a low Apgar score. Moreover, children with NF1 had an increased odds of being born with a high birth weight or large for gestational age (OR, 1.61; 95% CI, 1.42-1.82 and OR, 1.82; 95% CI, 1.60-2.06, respectively).

Children with NF1 and tuberous sclerosis differ from the general population in terms of several birth characteristics, with the strongest associations observed for high birth weight and large for gestational age in individuals with NF1.

Children with NF1 and tuberous sclerosis differ from the general population in terms of several birth characteristics, with the strongest associations observed for high birth weight and large for gestational age in individuals with NF1.The Zn2+ receptor GPR39 is proposed to be involved in the pathophysiology of depression. GPR39 knockout (KO) animals show depressive- and anxiety-like behaviour, and resistance to conventional monoamine-based antidepressants. However, it is unclear as to which brain regions are involved in the pro-depressive phenotype of GPR39KO mice and the resistance to monoamine-targeting antidepressant treatment. Our current study confirmed previous results, showing that mice lacking GPR39 display enhanced passive coping-like behaviour compared with their wild-type controls. Furthermore, this study shows for the first time that GPR39KO displayed aberrant challenge-induced neuronal activity in key brain regions associated with passive coping behaviour. Imipramine induced only a marginal reduction in the enhanced passive coping behaviour in GPR39KO mice, which was associated with attenuation of the hyperactive prefrontal cortex. Similarly, the aberrant activity within the amygdalar subregions was normalized following imipramine treatment in the GPR39KO mice, indicating that imipramine mediates these effects independently of GPR39 in the prefrontal cortex and amygdala. However, imipramine failed to modulate the aberrant brain activity in other brain regions, such as the anterior CA3 and the dentate gyrus, in GPR39KO mice. Normalization of aberrant activity in these areas has been shown previously to accompany successful behavioural effects of antidepressants. Taken together, our data suggest that monoamine-based antidepressants such as imipramine exert their action via GPR39-dependent and -independent pathways. Failure to modulate passive-coping related aberrant activity in important brain areas of the depression circuitry is proposed to mediate/contribute to the greatly reduced antidepressant action of monoamine-based antidepressants in GPR39KO mice.The study of prions and the discovery of candidate therapeutics for prion disease have been facilitated by the ability of prions to replicate in cultured cells. Paradigms in which prion proteins from different species are expressed in cells with low or no expression of endogenous prion protein (PrP) have expanded the range of prion strains that can be propagated. In these systems, cells stably expressing a PrP of interest are typically generated via coexpression of a selectable marker and treatment with an antibiotic. Here, we report the unexpected discovery that the aminoglycoside G418 (Geneticin) interferes with the ability of stably transfected cultured cells to become infected with prions. In G418-resistant lines of N2a or CAD5 cells, the presence of G418 reduced levels of protease-resistant PrP following challenge with the RML or 22L strains of mouse prions. G418 also interfered with the infection of cells expressing hamster PrP with the 263K strain of hamster prions. Interestingly, G418 had minimal to no effect on protease-resistant PrP levels in cells with established prion infection, arguing that G418 selectively interferes with de novo prion infection. As G418 treatment had no discernible effect on cellular PrP levels or its localization, this suggests that G418 may specifically target prion assemblies or processes involved in the earliest stages of prion infection.FTY720 (fingolimod) is an analog of sphingosine, a ubiquitous sphingolipid. Phosphorylated FTY720 (FTY720-P) non-selectively binds to sphingosine-1-phosphate receptors (S1PRs) and regulates multiple cellular processes including cell proliferation, inflammation, and vascular remodeling. We recently demonstrated that S1PR3 expression in the medial prefrontal cortex (mPFC) of rats promotes stress resilience and that S1PR3 expression in blood may serve as a biomarker for PTSD. Here we investigate the effects of FTY720 in regulating the stress response. We found that single and repeated intraperitoneal injections of FTY720 increased baseline plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations. FTY720 reduced social anxiety- and despair-like behavior as assessed by increased social interaction time and reduced time spent immobile in the Porsolt forced swim test. In blood, FTY720 administration reduced lymphocyte and reticulocyte counts, but raised erythrocyte counts. FTY720 also reduced mRNA of angiopoietin 1, endothelin 1, plasminogen, TgfB2, Pdgfa, and Mmp2 in the medial prefrontal cortex, suggesting that FTY720 reduced vascular remodeling. The antidepressant-like and anxiolytic-like effects of FTY720 may be attributed to reduced vascular remodeling as increased stress-induced blood vessel density in the brain contributes to behavior associated with vulnerability in rats. Together, these results demonstrate that FTY720 regulates baseline HPA axis activity but reduces social anxiety and despair, providing further evidence that S1PRs are important and novel regulators of stress-related functions.

Inflammatory response plays a critical role in the initiation and progression of type 2 diabetes mellitus (T2DM). Myeloperoxidase (MPO), a leukocyte-derived protagonist, exerts its proinflammatory properties in many complications. We explored the associations between serum extracellular vesicle (EV)-derived MPO as well as serum MPO and T2DM.

We performed a cross-sectional study in 151 individuals, including 93 patients with T2DM and 58 non-T2DM controls. The concentrations of serum EV-derived MPO and serum MPO were measured by Luminex Assay.

Our data showed that serum EV-derived MPO concentrations and serum MPO concentrations were significantly higher in T2DM patients compared with non-T2DM subjects. In addition, multivariate logistic regression analysis revealed that serum EV-derived MPO as well as serum MPO was independently associated with the presence of T2DM even after adjusting for confounding factors (OR=1.836 /1 ng EV-derived MPO, 95% CI=1.395-2.417, P<0.001; OR=4.135 /10ng serum MPO, 95% CI=2.