Interrelationships Between Pituitary Hormones as Assessed From 24-hour Serum Concentrations in Healthy Older Subjects

Context: Hormones of the hypothalamic-pituitary-target gland axes are mostly investigated separately, whereas the interplay between hormones might be as important as each separate hormonal axis.Objective: Our aim is to determine the interrelationships between GH, TSH, ACTH, and cortisol in healthy older individuals.Design: We made use of 24-hour hormone serum concentrations assessed with intervals of 10 minutes from 38 healthy older individuals with a mean age (SD) of 65.1 (5.1) years from the Leiden Longevity Study. Cross-correlation analyses were performed to assess the relative strength between 2 24-hour hormone serum concentration series for all possible time shifts. Cross-approximate entropy was used to assess pattern synchronicity between 2 24-hour hormone serum concentration series.Results: Within an interlinked hormonal axis, ACTH and cortisol were positively correlated with a mean (95% confidence interval) correlation coefficient of 0.78 (0.74-0.81) with cortisol following ACTH concentrations with a delay of 10 minutes. Between different hormonal axes, we observed a negative correlation coefficient between cortisol and TSH of -0.30 (-0.36 to -0.25) with TSH following cortisol concentrations with a delay of 170 minutes. Furthermore, a positive mean (95% confidence interval) correlation coefficient of 0.29 (0.22-0.37) was found between TSH and GH concentrations without any delay. Moreover, cross-approximate entropy analyses showed that GH and cortisol exhibit synchronous serum concentration patterns.Conclusions: This study demonstrates that interrelations between hormones from interlinked as well as different hypothalamic-pituitary-target gland axes are observed in healthy older individuals. More research is needed to determine the biological meaning and clinical consequences of these observations.Pathophysiology, epidemiology and therapy of agein

V-ATPase-Mediated Granular Acidification Is Regulated by the V-ATPase Accessory Subunit Ac45 in POMC-Producing Cells

The regulation of the V-ATPase, the proton pump mediating intraorganellar acidification, is still elusive. We find that excess of the neuroendocrine V-ATPase accessory subunit Ac45 reduces the intragranular pH and consequently disturbs prohormone convertase activation and prohormone processing. Thus, Ac45 represents the first V-ATPase regulator

Mucosal microbiota modulate host intestinal immune signatures in Inflammatory Bowel Disease

BackgroundHost intestinal immune gene signatures and microbial dysregulations expose potential mechanisms in the pathogenesis of inflammatory bowel diseases (IBD). Profiling of mucosa-attached microbiota allows the understanding of locally present microbial communities and their immediate impact on the host. This study evaluated interactions between host mucosal gene expression and intestinal mucosa-attached microbiota in IBD.MethodsIntestinal mucosal bulk RNA-sequencing data was combined with mucosal 16S rRNA gene sequencing data from 696 intestinal biopsies derived from 337 patients with IBD (181 with Crohn’s disease [CD] and 156 with ulcerative colitis [UC]) and 16 non-IBD controls. Hierarchical all-against-all associations testing (HAllA) was used to assess factors affecting host gene expressions and microbiota. Mucosal cell enrichments were predicted by deconvolution. Linear mixed interaction models were used to investigate host-microbiota interactions, adjusting for age, sex, BMI and batch effects. Variation explanation analysis was performed by Lasso regression.ResultsIn total, 15,934 intestinal genes and 113 microbial taxa were identified and included in subsequent analyses. Host intestinal gene expressions were characterized by tissue- and inflammation-specificity, whereas intraindividual variability of the mucosal microbiota dominated over disease location and inflammation effects. We observed forty associations between the mucosal expression of genes and the abundance of specific microbes independent of dysbiosis (FDR<0.05). Examples include a positive association between aryl hydrocarbon receptor (AHR) and Bifidobacterium, and a negative association between interleukin 18 receptor 1 (IL18R1) and Lachnoclostridium. Furthermore, 112 gene-microbiota interactions changed in patients with microbial dysbiosis compared to non-dysbiosis (FDR<0.05). These interactions were enriched in immune-related and extracellular matrix organization pathways. For example, the IL1R1 gene was positively associated with Collinsella abundance in non-dysbiotic patients, whereas an inverse association was observed in high dysbiosis. Finally, the presence of mucosal microbial taxa explained up to 10% of the variation in cell type enrichment, affecting epithelial cells, macrophages and regulatory T-cells.ConclusionInteractions between host intestinal gene expressions and mucosa-attached microbiota are disrupted in patients with IBD. Furthermore, mucosal microbiota are highly personalized and potentially contribute to intestinal cell type alterations. Our study unravels key immune-mediated molecular pathways and relevant bacteria in intestinal tissue, which may guide drug development and precision medicine in IBD

Human Prion Diseases in The Netherlands (1998–2009): Clinical, Genetic and Molecular Aspects

Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998–2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively over-represented (22,4%). Combined PrPSc and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a “pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation

Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease

Several molecular subtypes of sporadic Creutzfeldt-Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt-Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt-Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Patients with sporadic Creutzfeldt-Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as ‘suspected sporadic Creutzfeldt-Jakob disease' but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt-Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt-Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt-Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease to include findings from magnetic resonance imaging scan

Comorbidity, not patient age, is associated with impaired safety outcomes in vedolizumab- and ustekinumab-treated patients with inflammatory bowel disease-a prospective multicentre cohort study

Background: Few data are available on the effects of age and comorbidity on treatment outcomes of vedolizumab and ustekinumab in inflammatory bowel disease (IBD). Aims: To evaluate the association between age and comorbidity with safety and effectiveness outcomes of vedolizumab and ustekinumab in IBD. Methods: IBD patients initiating vedolizumab or ustekinumab in regular care were enrolled prospectively. Comorbidity prevalence was assessed using the Charlson Comorbidity Index (CCI). Association between age and CCI, both continuously assessed, with safety outcomes (any infection, hospitalisation, adverse events) during treatment, and effectiveness outcomes (clinical response and remission, corticosteroid-free remission, clinical remission combined with biochemical remission) after 52 weeks of treatment were evaluated. Multivariable logistic regression was used to adjust for confounders. Results: We included 203 vedolizumab- and 207 ustekinumab-treated IBD patients, mean age 42.2 (SD 16.0) and 41.6 (SD 14.4). Median treatment duration 54.0 (IQR 19.9-104.0) and 48.4 (IQR 24.4-55.1) weeks, median follow-up time 104.0 (IQR 103.1-104.0) and 52.0 weeks (IQR 49.3-100.4). On vedolizumab, CCI associated independently with any infection (OR 1.387, 95% CI 1.022-1.883, P = 0.036) and hospitalisation (OR 1.586, 95% CI 1.127-2.231, P = 0.008). On ustekinumab, CCI associated independently with hospitalisation (OR 1.621, 95% CI 1.034-2.541, P = 0.035). CCI was not associated with effectiveness, and age was not associated with any outcomes. Conclusions: Comorbidity - but not age - is associated with an increased risk of hospitalisations on either treatment, and with any infection on vedolizumab. This underlines the importance of comorbidity assessment and safety monitoring of IBD patients

Well being of obstetric patients on minimal blood transfusions (WOMB trial)

Background: Primary postpartum haemorrhage is an obstetrical emergency often causing acute anaemia that may require immediate red blood cell (RBC) transfusion. This anaemia results in symptoms such as fatigue, whic