Macmillantange4088

Considering these results, we propose new mechanisms for modulation of the immune response by HCN.

Neuropsychiatric symptoms (NPSs) in early dementia have been suggested to predict a higher risk of dementia progression. However, the literature is not yet clear whether the risk is similar across Alzheimer's dementia (AD) and non-Alzheimer's dementia (non-AD), as well as across different NPSs. This study examined the association between NPSs in early dementia and the risk of progression to severe dementia, specifically in AD and non-AD, as well as across various NPSs.

This cohort study included 7,594 participants who were ≥65years and had early dementia (global Clinical Dementia Rating [CDR] = 1). Participants completed Neuropsychiatric-Inventory-Questionnaire at baseline and were followed-up almost annually for progression to severe dementia (global CDR = 3) (median follow-up = 3.5years; interquartile range = 2.1-5.9years). Cox regression was used to examine progression risk, stratified by AD and non-AD.

The presence of NPSs was associated with risk of progression to severe dementia, but primarily in AD (HR 1.4, 95% confidence interval [CI] 1.1-1.6) and not in non-AD (HR 0.9, 95% CI 0.5-1.5). When comparing across various NPSs, seven NPSs in AD were associated with disease progression, and they were depression, anxiety, apathy, delusions, hallucinations, irritability and motor disturbance (HR 1.2-1.6). In contrast, only hallucinations and delusions were associated with disease progression in non-AD (HR 1.7-1.9).

NPSs in early dementia-especially among individuals with AD-can be useful prognostic markers of disease progression. They may inform discussion on advanced care planning and prompt clinical review to incorporate evidence-based interventions that may address disease progression.

NPSs in early dementia-especially among individuals with AD-can be useful prognostic markers of disease progression. They may inform discussion on advanced care planning and prompt clinical review to incorporate evidence-based interventions that may address disease progression.

Isolated prolactin deficiency is a rare disorder manifesting as absence of puerperal lactation. We identified a two-generation family with 3 women experiencing alactogenesis.

We hypothesized a heterozygous genetic mutation.

This was a family-based study.

Two generations of women (proband, sister and niece) with puerperal alactogenesis and one control were studied. Prolactin levels in the three women ranged from 0.618 to 1.4ng/mL (2.8-29.2ng/mL). All the women had regular menstrual cycles during their reproductive years. The niece required fertility treatment to become pregnant and the proband and sister underwent menopause before age 45 years.

PRL exons 1-5 were sequenced.

We sought a heterozygous, deleterious gene variant with functional consequences.

We identified a heterozygous mutation (c.658C>T) changing CGA to TGA (p.Arg220Ter) in exon 5 of the prolactin gene. Transfection of PRL containing the stop gain mutation resulted in similar intracellular prolactin levels compared to PRL wild type, but little detectable immunoactive or bioactive prolactin in conditioned medium. Prolactin secretion was also impaired by a PRL stop gain mutation deleting both of the terminal cysteine amino acids (c.652A>T; p.Lys218Ter).

This is the first report of a PRL mutation causing familial prolactin deficiency and alactogenesis. The loss of the terminal cysteine resulted in failure of prolactin secretion. Secretion was not rescued by deleting the penultimate cysteine, with which it forms a disulfide bond. These data suggest that the PRL C terminal is critical for protein secretion.

This is the first report of a PRL mutation causing familial prolactin deficiency and alactogenesis. The loss of the terminal cysteine resulted in failure of prolactin secretion. Secretion was not rescued by deleting the penultimate cysteine, with which it forms a disulfide bond. These data suggest that the PRL C terminal is critical for protein secretion.

Congenital chloride diarrhoea (CLD) is a rare autosomal recessive disease caused by mutations in the solute family carrier 26 member 3 (SLC26A3) gene. Patients suffer from life-long watery diarrhea and chloride loss. Inflammatory bowel disease (IBD) has been reported in individual patients with CLD and in scl26a3-deficient mice.

We performed an international multicentre analysis to build a CLD cohort and to identify cases with IBD. We assessed clinical and genetic characteristics of subjects and studied the cumulative incidence of CLD-associated IBD.

In a cohort of 72 patients with CLD caused by 17 different SLC26A3 mutations, we identified 12 patients (17%) diagnosed with IBD. Nine patients had Crohn's disease, two ulcerative colitis, and one IBD-unclassified (IBD-U). Prevalence of IBD in our cohort of CLD is higher than the highest prevalence of IBD in Europe (p < 0.0001). The age of onset was variable (13.5 years, IQR 8.5 - 23.5 years). Patients with CLD and IBD had lower z-score for height than those without IBD. 4/12 patients had required surgery (ileostomy formation n=2, ileocaecal resection due to ileocaecal valve stenosis n=1, and colectomy due to stage II transverse colon cancer n=1). At last follow-up, 5/12 were on biologics (adalimumab, infliximab, or vedolizumab), 5/12 on immunosuppressant (azathioprine or mercaptopurine), one on 5-ASA and one off-treatment.

A substantial proportion of patients with CLD develop IBD. This suggests potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. NK-104 calcium Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer.

A substantial proportion of patients with CLD develop IBD. This suggests potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer.

frailty measurement may identify patients at risk of decline after hospital discharge, but many measures require specialist review and/or additional testing.

to compare validated frailty tools with routine electronic health record (EHR) data at hospital discharge, for associations with readmission or death.

observational cohort study.

hospital ward.

consented cardiology inpatients ≥70years old within 24hours of discharge.

patients underwent Fried, Short Physical Performance Battery (SPPB), PRISMA-7 and Clinical Frailty Scale (CFS) assessments. An EHR risk score was derived from the proportion of 31 possible frailty markers present. Electronic follow-up was completed for a primary outcome of 90-day readmission or death. Secondary outcomes were mortality and days alive at home ('home time') at 12months.

in total, 186 patients were included (79 ± 6years old, 64% males). The primary outcome occurred in 55 (30%) patients. Fried (hazard ratio [HR] 1.47 per standard deviation [SD] increase, 95% confidence interval [CI] 1.