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The RAF/MEK/ERK1/2 signaling cascade has been implicated in pathological cardiac hy-pertrophy downstream of some Gq-coupled receptors. The RAF family of kinases consists of three isoforms (ARAF, BRAF, and CRAF) and until recently most studies on this signaling pathway in the heart have focused on RAF1 (CRAF). In a recent issue of Clinical Science, Alharbi et al. utilized an inducible cardiac myocyte targeted knockout mouse model to de-fine the role of BRAF in pathological versus physiological hypertrophy using angiotensin II and phenylephrine (PE) infusion, respectively. They reported that loss of BRAF attenuated both pathological cardiac hypertrophy and interstitial fibrosis. BRAF knockout decreased cardiac function with PE in male mice and enhanced both interstitial and perivascular car-diac fibrosis but had no effect on hypertrophy. In contrast, loss of BRAF attenuated phys-iological hypertrophy in female mice but had no effect on fibrosis or contractility. These observations extend those previously made by this group assessing the consequences of expressing an inducible activating mutant of BRAF in the heart and the benefit of enhancing RAF/MEK/ERK1/2 signaling by exploiting the ' RAF paradox ' Additional studies are needed to better define the role of BRAF under conditions reflective of chronic stress on the heart due to the biomechanical stimulation exerted by hypertension. In addition, the role of BRAF and its activation in overt heart failure remains to be established. Nevertheless, the new findings highlight the potential importance of additional signaling events, perhaps related to RAF1 or ERK1/2 activation, in shaping BRAF signaling in a sex-and context-dependent manner.

Methylglyoxal (MGO) is a reactive glucose metabolite linked to diabetic cardiovascular disease (CVD). MGO levels surge during intermittent hyperglycemia. We hypothesize that these MGO spikes contribute to athero-sclerosis, and that pyridoxamine as a MGO quencher prevents this injury. To study this, we intravenously injected normoglycemic 8-week old male C57Bl6 ApoE-/-mice with normal saline (NS, n = 10) or 25 mu g MGO for 10 consecutive weeks (MGOiv, n = 11) with or without 1 g/L pyridoxamine (MGOiv+PD, n = 11) in the drinking water. We measured circulating immune cells by flow cytometry. We quantified aortic arch lesion area in aortic roots after Sudan-black staining. We quantified the expression of inflammatory genes in the aorta by qPCR. Intermittent MGO spikes weekly increased atherosclerotic burden in the arch 1.8-fold (NS: 0.9 +/- 0.1 vs 1.6 +/- 0.2 %), and this was prevented by pyridoxamine (0.8 +/- 0.1 %). MGOiv spikes increased circulating neutrophils and monocytes (2-fold relative to NS) and the expression of ICAM (3-fold), RAGE (5-fold), S100A9 (2-fold) and MCP1 (2-fold). All these changes were attenuated by pyridoxamine. This study suggests that MGO spikes damages the vasculature independently of plasma glucose levels. Pyridoxamine and potentially other approaches to reduce MGO may prevent excess cardiovascular risk in diabetes

BACKGROUND: Time in range (TIR) goals are rarely met in children with type 1 diabetes, except at the cost of increased hypoglycaemia episodes. Our objective was to evaluate the safety and efficiency of the Diabeloop DBL4K (Diabeloop, Grenoble, France) hybrid closed-loop system in prepubescent children. METHODS: We did a multicentre, open-label, randomised, controlled, non-inferiority, two-session crossover study in the paediatric endocrinology departments of three university hospitals in France and Belgium. Eligible participants were aged 6-12 years with type 1 diabetes for at least 1 year, glycated haemoglobin A1C 9% (75 mmol/mol) or less, and insulin pump treatment for at least 3 months. Participants were randomly assigned (1:1) to a closed-loop device or sensor-augmented pump (open loop) therapy. Randomisation was by a permuted block randomisation scheme, using an interactive web-based response system, and was stratified on centre (block size 6). The assessed closed-loop device, the Diabeloop for Kids DBL4K hybrid closed-loop system, is an automated blood glucose regulation system composed of a handset, insulin pump, and continuous glucose monitor. The open-loop system is defined as a sensor-augmented pump therapy composed of the usual insulin pump used by the patient and a continuous glucose monitor. A 72-h in-patient period was followed by a 6-week home phase. After a 1-week washout period, the participants crossed over to the other device. The primary outcome, assessed in the intention-to-treat population, was the mean proportion of time spent in hypoglycaemia (3·9 mmol/L [

Summary Background Diabetes leads to a wide range of established vascular and metabolic complications that has resulted in the implementation of diverse prevention programmes across high-income countries. Diabetes has also been associated with an increased risk of a broader set of conditions including cancers, liver disease, and common infections. We aimed to examine the trends in a broad set of cause-specific hospitalisations in individuals with diabetes in England from 2003 to 2018. Methods In this epidemiological analysis, we identified 309 874 individuals 18 years or older with diabetes (type 1 or 2) in England from the Clinical Practice Research Datalink linked to Hospital Episode Statistics inpatient data from 2003 to 2018. We generated a mixed prevalent and incident diabetes study population through serial cross sections and follow-up over time. We used a discretised Poisson regression model to estimate annual cause-specific hospitalisation rates in men and women with diabetes across 17 cause groupings. We generated a 1:1 age-matched and sex-matched population of individuals without diabetes to compare cause-specific hospitalisation rates in those with and without diabetes. Findings Hospitalisation rates were higher for all causes in persons with diabetes than in those without diabetes throughout the study period. Diabetes itself and ischaemic heart disease were the leading causes of excess (defined as absolute difference in the rate in the populations with and without diabetes) hospitalisation in 2003. By 2018, non-infectious and non-cancerous respiratory conditions, non-diabetes-related cancers, and ischaemic heart disease were the most common causes of excess hospitalisation across men and women. Hospitalisation rates of people with diabetes declined and causes of hospitalisation changed. Almost all traditional diabetes complication groups (vascular diseases, amputations, and diabetes) decreased, while conditions non-specific to diabetes (cancers, infections, non-infectious and non-cancerous respiratory conditions) increased. These differing trends represented a change in the cause of hospitalisation, such that the traditional diabetes complications accounted for more than 50% of hospitalisation in 2003, but only approximately 30% in 2018. In contrast, the proportion of hospitalisations due to respiratory infections between the same time period increased from 3% to 10% in men and from 4% to 12% in women. Interpretations Changes in the composition of excess risk and hospitalisation burden in those with diabetes means that preventative and clinical measures should evolve to reflect the diverse set of causes that are driving persistent excess hospitalisation in those with diabetes. Funding Wellcome Trust.

The novel coronavirus disease (COVID-19) has emerged as a global pandemic. This was a prospective, case-control study conducted in Izmir, Turkey. The aim of this study was to assess the relationship between COVID-19 and new-onset T1DM. We included pediatric patients (aged 6 mo–18 yr) with new-onset type-1 diabetes mellitus (T1DM) diagnosed during the COVID-19 pandemic, between April 2020 and January 2021. Polymerase chain reaction was used to diagnose COVID-19 after hospital admission. An enzyme-linked immunoassay for IgM and IgG against SARS-CoV-2 was performed after the diagnosis was confirmed. In the control group, the blood antibody test was conducted as close as possible to the time of the T1DM patient referral. A total of 118 participants were included in the study, comprising 57 (48%) patients with new-onset T1DM and 61 (52%) healthy controls. Of the 57 patients, 36 (63.2%) presented with DKA, 17 (29.7%) with diabetic ketosis, and four (7%) incidentally. The SARS-CoV-2 antibody test was positive in five (8.7%) patients with T1DM and six (10%) controls. The rate of positivity did not differ between the two groups (p = 0.901). It was not possible to demonstrate a clear association between SARS-CoV-2 infection and new-onset T1DM. Whether SARS-CoV-2 increases susceptibility to diabetes by triggering islet cell autoimmunity and affects the timing of overt diabetes in patients with existing autoimmunity should be studied in large cohorts.

The RAF/MEK/ERK1/2 signaling cascade has been implicated in pathological cardiac hy-pertrophy downstream of some Gq-coupled receptors. The RAF family of kinases consists of three isoforms (ARAF, BRAF, and CRAF) and until recently most studies on this signaling pathway in the heart have focused on RAF1 (CRAF). In a recent issue of Clinical Science, Alharbi et al. utilized an inducible cardiac myocyte targeted knockout mouse model to de-fine the role of BRAF in pathological versus physiological hypertrophy using angiotensin II and phenylephrine (PE) infusion, respectively. They reported that loss of BRAF attenuated both pathological cardiac hypertrophy and interstitial fibrosis. BRAF knockout decreased cardiac function with PE in male mice and enhanced both interstitial and perivascular car-diac fibrosis but had no effect on hypertrophy. In contrast, loss of BRAF attenuated phys-iological hypertrophy in female mice but had no effect on fibrosis or contractility. These observations extend those previously made by this group assessing the consequences of expressing an inducible activating mutant of BRAF in the heart and the benefit of enhancing RAF/MEK/ERK1/2 signaling by exploiting the ' RAF paradox ' Additional studies are needed to better define the role of BRAF under conditions reflective of chronic stress on the heart due to the biomechanical stimulation exerted by hypertension. In addition, the role of BRAF and its activation in overt heart failure remains to be established. Nevertheless, the new findings highlight the potential importance of additional signaling events, perhaps related to RAF1 or ERK1/2 activation, in shaping BRAF signaling in a sex-and context-dependent manner.

https://doi.org/10.1111/apa.16233 ABSTRACT Aim We assessed psychosocial burdens in children who developed narcolepsy after receiving the Pandemrix H1N1 vaccine during the 2009-2010 pandemic. Parental quality of life was also assessed. Methods This multicentre study covered four of the five Finnish University Hospital Districts, which dealt with about 90% of the paediatric narcolepsy cases after the Pandemrix vaccination. The medical records of children diagnosed from 2010-2014 were reviewed. The questionnaires included the Youth Self Report (YSR), Children?s Depression Inventory (CDI), the Child Behaviour Checklist (CBCL) and questions on parental resources, stress and quality of life. Results We obtained the medical records of 94 children who were aged 5-17 years at the time of their narcolepsy diagnosis and questionnaire data for 73 of those children. Most children had strong narcolepsy symptoms 25% had CDI scores that suggested depression. In addition, 41% had total CBCL problem scores above the clinically significant limit and 48% were anxious, withdrawn and had somatic complaints. Sleep latency was weakly associated with the CBCL total problem score. Half of the children needed psychiatric interventions and parental stress was common. Conclusion Depression and behavioural problems were common in children with narcolepsy after the Pandemrix vaccination and their parents frequently reported feeling stressed.

Endometrial cancer (EC) is the most common gynaecological tumor in developed countries and its incidence is increasing. Approximately 80% of newly diagnosed EC cases are estrogen-dependent. Type 1 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD-1) is the enzyme that catalyzes the final step in estrogen biosynthesis by reducing the weak estrogen estrone (E1) to the potent estrogen 17 beta-estradiol (E2), and previous studies showed that this enzyme is implicated in the intratumoral E2 generation in EC. In the present study we employed a recently developed orthotopic and estrogen-dependent xenograft mouse model of EC to show that pharmacological inhibition of the 17 beta-HSD-1 enzyme inhibits disease development. Tumors were induced in one uterine horn of athymic nude mice by intrauterine injection of the well-differentiated human endometrial adenocarcinoma Ishikawa cell line, modified to express human 17 beta-HSD-1 in levels comparable to EC, and the luciferase and green fluorescent protein reporter genes. Controlled estrogen exposure in ovariectomized mice was achieved using subcutaneous MedRod implants that released either the low active estrone (E1) precursor or vehicle. A subgroup of E1 supplemented mice received daily oral gavage of FP4643, a well-characterized 17 beta-HSD-1 inhibitor. Bioluminescence imaging (BLI) was used to measure tumor growth non-invasively. At sacrifice, mice receiving E1 and treated with the FP4643 inhibitor showed a significant reduction in tumor growth by approximately 65% compared to mice receiving E1. Tumors exhibited metastatic spread to the peritoneum, to the lymphovascular space (LVI), and to the thoracic cavity. Metastatic spread and LVI invasion were both significantly reduced in the inhibitor-treated group. Transcriptional profiling of tumors indicated that FP4643 treatment reduced the oncogenic potential at the mRNA level. In conclusion, we show that 17 beta-HSD-1 inhibition represents a promising novel endocrine treatment for EC.

Author Correction: Identifcation of CRF89_BF, a new member of an HIV‑1 circulating BF intersubtype recombinant form family widely spread in South America. Sci Rep. 2021 Aug 3;11(1):16115. DOI: 10.1038/s41598-021-95679-z. Circulating recombinant forms (CRFs) contribute substantially to the HIV-1 pandemic. Among 105 CRFs described in the literature, 16 are BF intersubtype recombinants, most of South American origin, of which CRF12_BF is the most widely spread. A BF recombinant cluster identified in Bolivia was suggested to represent a new CRF_BF. Here we find that it belongs to a larger cluster incorporating 39 viruses collected in 7 countries from 3 continents, 22 of them in Spain, most from Bolivian or Peruvian individuals, and 12 in South America (Bolivia, Argentina, and Peru). This BF cluster comprises three major subclusters, two associated with Bolivian and one with Peruvian individuals. Near full-length genome sequence analyses of nine viruses, collected in Spain, Bolivia, and Peru, revealed coincident BF mosaic structures, with 13 breakpoints, 6 and 7 of which coincided with CRF12_BF and CRF17_BF, respectively. In a phylogenetic tree, they grouped in a clade closely related to these CRFs, and more distantly to CRF38_BF and CRF44_BF, all circulating in South America. These results allowed to identify a new HIV-1 CRF, designated CRF89_BF. Through phylodynamic analyses, CRF89_BF emergence was estimated in Bolivia around 1986. CRF89_BF is the fifth CRF member of the HIV-1 recombinant family related to CRF12_BF. This work was funded through Acción Estratégica en Salud Intramural (AESI), Instituto de Salud Carlos III, projects “Estudios sobre vigilancia epidemiológica molecular del VIH-1 en España”, PI16CIII/00033, and “Epidemiología molecular del VIH en España y su utilidad para investigaciones biológicas y en vacunas”, PI19CIII/00042; Red de Investigación en SIDA (RIS), Instituto de Salud Carlos III, Subdirección General de Evaluación y Fondo Europeo de Desarrollo Regional (FEDER), Plan Nacional I+D+I, project RD16ISCIII/0002/0004; and scientific agreement with Osakidetza-Servicio Vasco de Salud, Government of Basque Country, MVI 1001/16. Sí

Aims/hypothesis Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. Methods We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. Results The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR2) and DKD (microalbuminuria or worse) phenotype (p=9.8×10−9; although not withstanding correction for multiple testing, p>9.3×10−9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN–RESP18, GPR158, INIP–SNX30, LSM14A and MFF; p−6). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in individuals with vs without DKD (p=1.1×10−6). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys (p−11). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [p=1.6×10−8] and negatively with tubulointerstitial fibrosis [p=2.0×10−9], tubular DCLK1 expression correlated positively with fibrosis [p=7.4×10−16], and SNX30 expression correlated positively with eGFR [p=5.8×10−14] and negatively with fibrosis [p−16]). Conclusions/interpretation Altogether, the results point to novel genes contributing to the pathogenesis of DKD. Data availability The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages (https://t1d.hugeamp.org/downloads.html; https://t2d.hugeamp.org/downloads.html; https://hugeamp.org/downloads.html). Graphical abstract

BackgroundWe aimed to characterize the relationships of the changes in impaired fasting glucose (IFG) and borderline high low-density lipoprotein-cholesterol (LDL-C) status with cardiovascular disease (CVD).MethodsA total of 36,537 participants who did not have previous CVD, diabetes mellitus, or high LDL-C (≥ 4.1 mmol/L), nor were taking lipid-lowering drugs were recruited from the Kailuan study. The participants were allocated to six groups according to their baseline and follow-up fasting blood glucose (FBG) and LDL-C concentrations: (1) both were normal; (2) both normal at baseline, one abnormality subsequently; (3) both normal at baseline, both abnormal subsequently; (4) at least one abnormality that became normal; (5) at least one abnormality at baseline, a single abnormality subsequently; and (6) at least one abnormality, two abnormalities subsequently. The outcomes were CVD and subtypes of CVD (myocardial infarction and stroke). Multiple Cox regression models were used to calculate adjusted hazard ratio (HR) and confidence interval (95% CI).ResultsDuring a median follow-up period of 9.00 years, 1,753 participants experienced a CVD event. After adjustment for covariates, participants with IFG in combination with a borderline high LDL-C status at baseline and follow-up had higher risks of CVD (HR: 1.52; 95% CI: 1.04–2.23 and HR: 1.38, 95% CI: 1.13–1.70, respectively) compared with those with normal fasting blood glucose and LDL-C. Compared with participants that remained normal, those who changed from normality to having two abnormalities were at a higher risk of CVD (HR: 1.26; 95% CI: 0.98–1.61), as were those who changed from at least one abnormality to two abnormalities (HR: 1.48, 95% CI: 1.02–2.15).ConclusionChanges in IFG and borderline high LDL-C status alter the risk of CVD and its subtype, implying that it is important to focus on such individuals for the prevention and control of CVD.

Background No specific or curative therapy exists for hereditary palmoplantar keratoderma (hPPK), which can profoundly alter patient quality of life, leading sometimes to severe functional impairment and pain. The rarity and the aetiological diversity of this group of disorders can explain the difficulty in comparing the efficacy of available treatments. Objectives To review the different treatments tried in patients withhPPKsince 2008, their efficacy and safety, with an evaluation of the various therapeutic modalities that can be used to treathPPK. Methods We undertook a comprehensive review of the literature data published since 2008. Results Only a few case series and individual case reports were identified. Topical (emollients, keratolytics, retinoids, steroids) and systemic treatments (mostly different retinoids), often combined, are used to relieve symptoms. Oral retinoids appear to be the most efficient treatment, but not in allPPKforms, and with variable tolerance. New targeted treatments, according to the specific mechanisms ofhPPK, appear promising for the future. Conclusions More studies using robust methodology and involving larger cohorts of well-characterized patients (phenotype-genotype) are necessary and should be prioritized by structured networks, such as the European Network for Rare Skin Diseases (ERN-Skin), with the aim of better management of patients with rare skin diseases.

Gastroenteropathy is a common complication in diabetes associated with damages to the enteric nervous system. Systemic low-grade inflammation facilitates neurotoxicity, and associations with peripheral and autonomic neuropathy have been reported. However, less is known of associations with gastroenteropathy. To explore the area cross-sectionally, we included individuals with diabetes (type 1: 56, type 2: 100) and 21 healthy controls. Serum levels of interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by multiplex technology. Segmental gastrointestinal transit times were assessed by wireless motility capsule investigations. Symptoms of gastroparesis were rated on Gastroparesis Cardinal Symptom Index questionnaires. Compared to healthy, levels of TNF-α were decreased in type 1 diabetes and increased in type 2 diabetes, while colonic transit time was increased (all p < 0.05). In diabetes, associations between IL-8 and prolonged gastric emptying (odds ratio (OR) 1.07, p = 0.027) and between IL-10 and prolonged colonic transit (OR 29.99, p = 0.013) were seen. Inverse correlations between IL-6 and nausea/vomiting (rho = −0.19, p = 0.026) and bloating (rho = −0.29; p < 0.001) were found. These findings indicate a plausible interaction between inflammation and the enteric nervous system in diabetes, which raises the question of whether anti-inflammatory strategies could be applied in management of diabetic gastroenteropathy. Gastroenteropathy is a common complication in diabetes associated with damages to the enteric nervous system. Systemic low-grade inflammation facilitates neurotoxicity, and associations with peripheral and autonomic neuropathy have been reported. However, less is known of associations with gastroenteropathy. To explore the area cross-sectionally, we included individuals with diabetes (type 1: 56, type 2: 100) and 21 healthy controls. Serum levels of interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by multiplex technology. Segmental gastrointestinal transit times were assessed by wireless motility capsule investigations. Symptoms of gastroparesis were rated on Gastroparesis Cardinal Symptom Index questionnaires. Compared to healthy, levels of TNF-α were decreased in type 1 diabetes and increased in type 2 diabetes, while colonic transit time was increased (all p < 0.05). In diabetes, associations between IL-8 and prolonged gastric emptying (odds ratio (OR) 1.07, p = 0.027) and between IL-10 and prolonged colonic transit (OR 29.99, p = 0.013) were seen. Inverse correlations between IL-6 and nausea/vomiting (rho = −0.19, p = 0.026) and bloating (rho = −0.29; p < 0.001) were found. These findings indicate a plausible interaction between inflammation and the enteric nervous system in diabetes, which raises the question of whether anti-inflammatory strategies could be applied in management of diabetic gastroenteropathy.

Reproductive disorders caused by porcine reproductive and respiratory syndrome virus-1 are not yet fully characterized. We report QuPath-based digital image analysis to count inflammatory cells in 141 routinely, and 35 CD163 immunohistochemically stained endometrial slides of vaccinated or unvaccinated pregnant gilts inoculated with a high or low virulent PRRSV-1 strain. To illustrate the superior statistical feasibility of the numerical data determined by digital cell counting, we defined the association between the number of these cells and endometrial, placental, and fetal features. There was strong concordance between the two manual scorers. Distributions of total cell counts and endometrial and placental qPCR results differed significantly between examiner1’s endometritis grades. Total counts’ distribution differed significantly between groups, except for the two unvaccinated. Higher vasculitis scores were associated with higher endometritis scores, and higher total cell counts were expected with high vasculitis/endometritis scores. Cell number thresholds of endometritis grades were determined. A significant correlation between fetal weights and total counts was shown in unvaccinated groups, and a significant positive correlation was found between these counts and endometrial qPCR results. We revealed significant negative correlations between CD163+ counts and qPCR results of the unvaccinated group infected with the highly virulent strain. Digital image analysis was efficiently applied to assess endometrial inflammation objectively.

BACKGROUND: With the growing incidence of diabetes mellitus (DM), an increasing number of organ donors with DM can be expected. We sought to investigate the association between donor DM with early post-transplant outcomes.METHODS: From a national cohort of adult liver transplant recipients (1996-2016), all recipients transplanted with a liver from a DM donor (n=69) were matched 1:2 with recipients of livers from non-DM donors (n=138). The primary end-point included early post-transplant outcome, such as the incidence of primary non-function (PNF), hepatic artery thrombosis (HAT), and 90-day graft survival. Cox regression analysis was used to analyze the impact of donor DM on graft failure.RESULTS: PNF was observed in 5.8% of grafts from DM donors versus 2.9% of non-DM donor grafts (p=0.31). Recipients of grafts derived from DM donors had a higher incidence of HAT (8.7% vs. 2.2%, p=0.03) and decreased 90-day graft survival (88.4% [70.9-91.1] vs. 96.4% [89.6-97.8], p=0.03) compared to recipients of grafts from non-DM donors. The adjusted hazard ratio for donor DM on graft survival was 2.21 (1.08-4.53, p=0.03).CONCLUSION: Donor DM is associated with diminished outcome early after liver transplantation. The increased incidence of HAT after transplantation of livers from DM donors requires further research.

Inositol 1,4,5-trisphosphate receptor 1 (ITPR1) is an intracellular Ca2+ release channel critical for numerous cellular processes. Despite its ubiquitous physiological significance, ITPR1 mutations have thus far been linked to primarily movement disorders. Surprisingly, most disease-associated ITPR1 mutations generate a loss of function. This leaves our understanding of ITPR1-associated pathology oddly one-sided, as little is known about the pathological consequences of ITPR1 gain of function (GOF). To this end, we generated an ITPR1 gating domain mutation (D2594K) that substantially enhanced the inositol trisphosphate (IP3)-sensitivity of ITPR1, and a mouse model expressing this ITPR1-D2594K+/− GOF mutation. We found that heterozygous ITPR1-D2594K+/− mutant mice exhibited male infertility, azoospermia, and acrosome loss. Furthermore, we functionally characterized a human ITPR1 variant V494I identified in the UK Biobank database as potentially associated with disorders of the testis. We found that the ITPR1-V494I variant significantly enhanced IP3-induced Ca2+ release in HEK293 cells. Thus, ITPR1 hyperactivity may increase the risk of testicular dysfunction.

Summary: Higher incidences of fractures are seen in people with type 1 diabetes (T1D), but knowledge on different fracture sites is sparse. We found a higher incidence mainly for distal fracture sites in people with T1D compared to controls. It must be further studied which fractures attributed to the higher incidence rates (IRs) at specific sites. Introduction: People with T1D have a higher incidence of fractures compared to the general population. However, sparse knowledge exists on the incidence rates of individual fracture sites. Therefore, we examined the incidence of various fracture sites in people with newly treated T1D compared to matched controls. Methods: All people from the UK Clinical Practice Research Datalink GOLD (1987–2017), of all ages with a T1D diagnosis code (n = 6381), were included. People with T1D were matched by year of birth, sex, and practice to controls (n = 6381). Fracture IRs and incidence rate ratios (IRRs) were calculated. Analyses were stratified by fracture site and sex. Results: The IR of all fractures was significantly higher in people with T1D compared to controls (IRR: 1.39 (CI95%: 1.24–1.55)). Compared to controls, the IRR for people with T1D was higher for several fracture sites including carpal (IRR: 1.41 (CI95%: 1.14–1.75)), clavicle (IRR: 2.10 (CI95%: 1.18–3.74)), foot (IRR: 1.70 (CI95%: 1.23–2.36)), humerus (IRR: 1.46 (CI95%: 1.04–2.05)), and tibia/fibula (IRR: 1.67 CI95%: 1.08–2.59)). In women with T1D, higher IRs were seen at the ankle (IRR: 2.25 (CI95%: 1.10–4.56)) and foot (IRR: 2.11 (CI95%: 1.27–3.50)), whereas in men with T1D, higher IRs were seen for carpal (IRR: 1.45 (CI95%: 1.14–1.86)), clavicle (IRR: 2.13 (CI95%: 1.13–4.02)), and humerus (IRR: 1.77 (CI95%: 1.10–2.83)) fractures. Conclusion: The incidence of carpal, clavicle, foot, humerus, and tibia/fibula fractures was higher in newly treated T1D, but there was no difference at other fracture sites compared to controls. Therefore, the higher incidence of fractures in newly treated people with T1D has been found mainly for distal fracture sites.

Introduction:Anaemia parameters in children with type- 1 diabetes and their relationship with metabolic control has received little attention in the literature. We aimed to determine the incidence of anaemia and to investigate anaemia parameters and their relationship with metabolic control in paediatric type-1 diabetes mellitus (DM) patients.Methods:A retrospective case control study was conducted using the medical records of 33 patients with type-1 diabetes and 33 healthy children. In both groups, anaemia parameters including haemogram parameters and iron, total iron-binding capacity (TIBC), ferritin, vitamin B12 and folate were noted. In the case group, HbA1c levels, duration of diabetes and insulin treatment dose were also noted.Results:Mean diabetes duration was 8.4±11.4 months, mean HbA1c level was 10.6±2.9 and mean insulin treatment dose was 0.7±0.2 u/kg/day. Comparison of haemogram parameters between the case and control groups were non-significant. TIBC was lower in the patients than in controls. Folate and ferritin were higher in patients than in controls.Conclusion:According to this study, type-1 DM did not increase the risk for anaemia in children. Ferritin was higher in patients than in controls, which suggests that inflammation was present in the patients with type-1 DM.

Obesity is the main cause of type 2 diabetes mellitus (T2DM). Roux-en-Y gastric bypass (RYGB) surgery is an effective treatment for this obesity-related health problem. However, the adverse effects of T2DM on bone tissue persist or even aggravate after this surgical procedure. As studies on the mandibular condyle bone are scarce, the aim of the present study was to assess its compositional characteristics in T2DM and RYGB conditions. Thirty-two male C57BL/6 mice at 8 weeks of age were randomly assigned to receive either a high-fat or low-fat diet. After 14 weeks of high-fat diet intake, seven obese mice were subjected to RYGB surgery. All animals were euthanized at the age of 30 weeks. Mandibular bones were removed and the trabecular condyle region was assessed using Raman spectroscopy. A decreased mineralization was observed for both T2DM and RYGB condyle bones when compared to controls, with elevated carbonate substitutions for the RYGB group. No compositional differences in crystallinity and presence of advanced glycation end products were found between the groups, with the exception of an increased presence of N-carboxymethyl-lysine in RYGB bone compared to their T2DM counterpart. Site-specific measurements revealed a non-uniform bone composition, with increasing mineralization and carbonate substitutions towards the centre of the mandibular condyle. T2DM and RYGB surgery affect the mandibular condyle bone quality, as investigated at compositional level. Assessment of bone structural properties and remodelling should be carried out to further explore the effects of T2DM and RYGB surgery on this skeleton area. Electronic supplementary material The online version of this article (10.1007/s00223-020-00732-0) contains supplementary material, which is available to authorized users.

The aim of this study was to explore how prepregnancy glycosylated hemoglobin (HbA1c) affects the course of HbA1c and insulin requirements during pregnancy, the gestational length, and birthweight.An observational cohort study was conducted consisting of 380 women with type 1 diabetes who gave birth 530 times from 2004 to 2014. The participants were divided into four groups according to prepregnancy HbA1c.HbA1c was significantly different between the groups at all time intervals from week 5 to 10 to week 33 to 36 (P ≤ .01). In group 1, with the lowest prepregnancy HbA1c (6.5% [48 mmol/mol]), HbA1c stayed at the same level throughout pregnancy. In the other groups (group 2: 6.5% [48 mmol/mol]-7.9% [63 mmol/mol], group 3: 8% [64 mmol/mol]-9.9% [86 mmol/mol], and group 4: 10% [86 mmol/mol]) a decrease in HbA1c was seen in early pregnancy but stabilized from midpregnancy onward. Group 1 had the lowest daily insulin requirements throughout pregnancy among the four groups (P = .001). The relationship between birthweight and prepregnancy HbA1c was found to be inversely U-shaped. Mean gestational length in group 4 was significantly shorter than in group 1 (P = .001).In this very large cohort, we found that a poor prepregnancy HbA1c is a predictor for poor glycemic control during pregnancy and that HbA1c decreases until midpregnancy and then plateaus. A very poor prepregnancy HbA1c is associated with shorter gestational length and lower birthweight, which is contrary to the common assumption that poor glycemic control leads to higher birthweight.背景: 本研究旨在探讨孕前糖化血红蛋白(HbA1c)对孕期HbA1c进程和胰岛素需求、孕周和出生体重的影响。 方法: 对2004年至2014年间总计生育530次的380例1型糖尿病妇女进行观察性队列研究。受试者根据孕前HbA1c水平分为四组。 结果: HbA1c在5~10周、33~36周各时间点组间差异均有统计学意义(P0.01); 第1组孕前HbA1c最低(6.5%[48 mmol/mol]), 整个孕期HbA1c维持在同一水平。其他各组(第2组:6.5%[48 mmol/mol]~7.9%[63 mmol/mol], 第3组:8%[64 mmol/mol]~9.9%[86 mmol/mol], 第4组:10%[86 mmol/mol]), 早孕时HbA1c下降, 但中期以后稳定。在四组中, 第一组在整个妊娠期间的每日胰岛素需求量最低(P=0.001)。出生体重与孕前HbA1c呈倒U型关系。第4组的平均孕长明显短于第1组(P=0.001)。 结论: 在这个较大的队列中, 我们发现孕前HbA1c较高是妊娠期血糖控制较差的预测因子, 而HbA1c在妊娠中期下降, 然后进入平台期。极高的孕前HbA1c与较短的孕长和较低的出生体重有关, 这与血糖控制不佳会导致较高出生体重的普遍假设相反。.

Individuals with neurofibromatosis 1 (NF1) may have problems in managing the transition between childhood and adulthood, such as forming a relationship or finding a partner. We aimed to determine the association between NF1 and forming and ending marital or cohabiting relationships by comparing a large Danish population of adults with NF1 with population comparisons. In this population-based cohort study, we compared a population of Danish adults who were hospitalized for or with complications to prior diagnosed NF1 (n = 787) with population comparisons matched on gender and birth year (n = 7787) through nationwide registries with annually updated information on marriage and cohabitation. Discrete-time survival models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the formation and termination of relationships, with adjustment for birth year, gender, and somatic and psychiatric comorbidities at entry. Individuals with NF1 were significantly less likely to form a relationship (HR = 0.65; 95% CI: 0.58–0.73), with the lowest association for individuals ≥33 years (HR 0.40; 95% CI: 0.25–0.63) and the highest for those aged 18–20 years (HR 0.82; 95% CI: 0.70–0.96). No significant difference was found for ending relationships (HR 1.00; 95% CI: 0.86–1.16). In conclusion, individuals who were hospitalized for NF1 are less likely to engage in marital or cohabiting relationships than population comparisons and are older when they form their first relationship. Once a relationship has been established, however, couples with a NF1-individual are not at greater risk of ending the relationship.

Contains fulltext : 218710.pdf (Publisher’s version ) (Closed access) The aim of this review was to provide an overview of developments, clinical implications and gaps in knowledge regarding the relationship between diabetes and sleep over the past 25 years, with special focus on contributions from the behavioural sciences. Multiple prospective observational and experimental studies have shown a link between suboptimal sleep and impaired glucose tolerance, decreased insulin sensitivity and the development of type 2 diabetes. While prevalence rates of suboptimal sleep vary widely according to definition, assessment and sample, suboptimal subjective sleep quality appears to be a common reality for one-third of people with type 1 diabetes and over half of people with type 2 diabetes. Both physiological and psychosocial factors may impair sleep in these groups. In turn, suboptimal sleep can negatively affect glycaemic outcomes directly or indirectly via suboptimal daytime functioning (energy, mood, cognition) and self-care behaviours. Technological devices supporting diabetes self-care may have both negative and positive effects. Diabetes and its treatment also affect the sleep of significant others. Research on the merits of interventions aimed at improving sleep for people with diabetes is in its infancy. Diabetes and sleep appear to be reciprocally related. Discussion of sleep deserves a central place in regular diabetes care. Multi-day, multi-method studies may shed more light on the complex relationship between sleep and diabetes at an individual level. Intervention studies are warranted to examine the potential of sleep interventions in improving outcomes for people with diabetes. 9 p.

Purpose This study describes swallow-related quality of life (SWAL-QOL) in patients with myotonic dystrophy type 1 (DM1) and investigates its association with swallowing function and disease severity. Methods A SWAL-QOL questionnaire was completed by 75 DM1 patients and 25 healthy control subjects. The severity of the disease was evaluated using the muscular impairment rating scale (MIRS). Twenty-eight DM1 patients underwent a videofluroscopic swallowing examination (VFS). Spearman’s correlation coefficient was used to measure the direction and strength of associations. Results The SWAL-QOL median scores were significantly lower for the DM1 group than for the healthy control group. The scores for the majority of the SWAL-QOL domains were lower in patients with proximal muscular weakness (MIRS 4 and 5). Postswallow vallecular pooling and piecemeal deglutition were the most impaired VFS outcome variables. Conclusion Our results suggest that a multidimensional swallowing assessment is recommended for DM1 patients as SWAL-QOL and VFS measure different aspects of the swallowing function, thus providing complementary information.

AimsAltered immune functions as well as fatty acid intake and status have been associated with the development of type 1 diabetes. We aimed to study the relationship between fatty acids and immunological markers in young children with increased genetic risk for type 1 diabetes in order to define putative mechanisms related to development of islet autoimmunity.MethodsSerum samples for fatty acid and immunological marker measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children born between 2002 and 2007 in 15 countries. Case children (n = 95) were defined as having repeated positivity for at least two out of four diabetes-associated autoantibodies. For each case child, control children were selected matched for country and date of birth (n = 173). Serum fatty acids and immunological markers were measured from cord serum and at the age of 6 and 12 months. Spearman correlation coefficients were calculated between fatty acids and immunological markers.ResultsCorrelations between circulating fatty acids and immunological markers were different in case children who developed islet autoimmunity than in control children already at birth continuing across the first year of life. In case children, saturated fatty acids (SFAs) showed stronger correlations with immunological markers, while in controls, polyunsaturated fatty acids (PUFAs) showed stronger correlations.ConclusionsIn cases, SFAs were associated with several immunological markers (CXCL10, IL-6, IL-9, IL-17, and CM-CSF) previously linked to the type 1 diabetes disease process. Findings indicate that fatty acids could have immunomodulatory potential in the early phase of the disease development, although causality between fatty acids and the immunological pathways remains to be explored.Trial registry numberNCT00179777

CCR5 is the main HIV co-receptor. We aimed to (1) compare CCR5 expression on immune cells between people living with HIV (PLHIV) using combination antiretroviral therapy (cART) and HIV-uninfected controls, (2) relate CCR5 expression to viral reservoir size and (3) assess determinants of CCR5 expression. This cross-sectional study included 209 PLHIV and 323 controls. Percentages of CCR5+ cells (%) and CCR5 mean fluorescence intensity assessed by flow cytometry in monocytes and lymphocyte subsets were correlated to host factors, HIV-1 cell-associated (CA)-RNA and CA-DNA, plasma inflammation markers and metabolites. Metabolic pathways were identified. PLHIV displayed higher percentages of CCR5+ monocytes and several CD8+ T cell subsets, but lower percentages of CCR5+ naive CD4+ T cells and regulatory T cells (Tregs). HIV-1 CA-DNA and CA-RNA correlated positively with percentages of CCR5+ lymphocytes. Metabolome analysis revealed three pathways involved in energy metabolism associated with percentage of CCR5+ CD8+ T cells in PLHIV. Our results indicate that CCR5 is differently expressed on various circulating immune cells in PLHIV. Hence, cell-trafficking of CD8+ T cells and Tregs may be altered in PLHIV. Associations between energy pathways and percentage of CCR5+ CD8+ T cells in PLHIV suggest higher energy demand of these cells in PLHIV.

Single nucleotide polymorphisms (SNPs) in insulin and insulin receptor genes may influence the interaction between the two molecules, as may anti-insulin antibodies (IAs), commonly found in patients with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) treated with exogenous insulin. We examined the impact of two SNPs in the human insulin gene (INS), rs3842752 and rs689, and two in the insulin receptor gene (INSR) rs2245649 and rs2229429, on disease susceptibility, glycaemic control, and IAs formation in 100 T1D patients and 101 T2D patients treated with insulin. 79 individuals without diabetes were typed as healthy controls. The minor alleles of rs3842752 and rs689 in INS protected against T1D (OR: 0.50, p = 0.01 and OR: 0.44; p = 0.002, respectively). The minor alleles of both rs2245649 and rs2229429 in INSR were risk factors for poor glycaemic control (HbA1c ≥ 80 mmol/mol) in T1D (OR: 5.35, p = 0.009 and OR: 3.10, p = 0.01, respectively). Surprisingly, the minor alleles of rs2245649 and rs2229429 in INSR associated strongly with the absence of IAs in T1D (OR = 0.28, p = 0.008 and OR = 0.30, p = 0.002, respectively). In conclusion, the minor alleles of the investigated INS SNPs protect against T1D, and the minor alleles of the investigated INSR SNPs are associated with poor glycaemic control and the absence of IAs in T1D.

Background Aldosterone synthase deficiency (ASD) caused by mutations in the CYP11B2 gene is characterized by isolated mineralocorticoid deficiency. Data are scarce regarding clinical and biochemical outcomes of the disease in the follow-up. Objective Assessment of the growth and steroid profiles of patients with ASD at the time of diagnosis and after discontinuation of treatment. Design and method Children with clinical diagnosis of ASD were included in a multicenter study. Growth and treatment characteristics were recorded. Plasma adrenal steroids were measured using liquid chromatography-mass spectrometry. Genetic diagnosis was confirmed by CYP11B2 gene sequencing and in silico analyses. Results Sixteen patients from 12 families were included (8 females; median age at presentation: 3.1 months, range: 0.4 to 8.1). The most common symptom was poor weight gain (56.3%). Median age of onset of fludrocortisone treatment was 3.6 months (range: 0.9 to 8.3). Catch-up growth was achieved at median 2 months (range: 0.5 to 14.5) after treatment. Fludrocortisone could be stopped in 5 patients at a median age of 6.0 years (range: 2.2 to 7.6). Plasma steroid profiles revealed reduced aldosterone synthase activity both at diagnosis and after discontinuation of treatment compared to age-matched controls. We identified 6 novel (p.Y195H, c.1200 + 1G > A, p.F130L, p.E198del, c.1122-18G > A, p.I339_E343del) and 4 previously described CYP11B2 variants. The most common variant (40%) was p.T185I. Conclusions Fludrocortisone treatment is associated with a rapid catch-up growth and control of electrolyte imbalances in ASD. Decreased mineralocorticoid requirement over time can be explained by the development of physiological adaptation mechanisms rather than improved aldosterone synthase activity. As complete biochemical remission cannot be achieved, a long-term surveillance of these patients is required.

Due to prolonged hyperglycemia many of the diabetic patients suffer from complications such as liver damage. Diabetic patients are known to have the need for liver surgeries more than non-diabetic do. The ischemia reperfusion injuries (IRI) are one of the main complications of these surgeries and the IRI-related increase in oxidative stress has been known to be higher in diabetic patients. Metformin and aerobic exercise are important tools being used especially in type-2 diabetes. However, their effects and roles in liver IRI in type-1 diabetic patients are not known. This study aimed to investigate the effects of metformin and exercise on hepatic IRI in diabetes in streptozotocin induced type-1 diabetic mice. Diabetes was induced by streptozotocin and two weeks after the disease developed, mice were started to treat with metformin and/or aerobic exercise during four-weeks. Blood glucose levels of the mice were measured again and the glucose tolerance test (OGTT) was performed for each mouse. The day after OGTT, ischemia was performed for 45 minutes in the liver and then reperfusion was provided for 5 hours. The liver of the mice was isolated at the end of the experiments. The malondialdehyde, superoxide dismutase and nitrite levels were measured with colorimetric analysis. Metformin reduced the insulin resistance alone and together with aerobic exercise. Oxidative stress in the liver after IRI was diminished both with metformin and/or aerobic exercise in diabetic mice. Our study indicated that metformin accompanied with aerobic exercise might be an important treatment strategy for preventing the IRI in the liver of type-1 diabetic patients.

In Kenya, HIV-1 key populations including men having sex with men (MSM), people who inject drugs (PWID) and female sex workers (FSW) are thought to significantly contribute to HIV-1 transmission in the wider, mostly heterosexual (HET) HIV-1 transmission network. However, clear data on HIV-1 transmission dynamics within and between these groups are limited. We aimed to empirically quantify rates of HIV-1 flow between key populations and the HET population, as well as between different geographic regions to determine HIV-1 'hotspots' and their contribution to HIV-1 transmission in Kenya. We used maximum-likelihood phylogenetic and Bayesian inference to analyse 4058 HIV-1 pol sequences (representing 0.3 per cent of the epidemic in Kenya) sampled 1986-2019 from individuals of different risk groups and regions in Kenya. We found 89 per cent within-risk group transmission and 11 per cent mixing between risk groups, cyclic HIV-1 exchange between adjoining geographic provinces and strong evidence of HIV-1 dissemination from (i) West-to-East (i.e. higher-to-lower HIV-1 prevalence regions), and (ii) heterosexual-to-key populations. Low HIV-1 prevalence regions and key populations are sinks rather than major sources of HIV-1 transmission in Kenya. Targeting key populations in Kenya needs to occur concurrently with strengthening interventions in the general epidemic. ispartof: VIRUS EVOLUTION vol:8 issue:1 ispartof: location:England status: published

ispartof: REVIEWS IN CARDIOVASCULAR MEDICINE vol:24 issue:1 status: published

The rising prevalence of type 1 diabetes (T1D) over the past decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In nonobese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes development in TLR4-deficient (TLR4−/−) NOD mice. In 70–90-day-old normoglycemic (prediabetic) female NOD TLR4+/+ and NOD TLR4−/− mice, gut morphology and microbiome composition were analyzed. Parameters of lipid metabolism, glucose homeostasis, and mitochondrial respiratory activity were measured in vivo and ex vivo. Compared with NOD TLR4+/+ mice, NOD TLR4−/− animals showed lower muscle mass of the small intestine, higher abundance of Bacteroidetes, and lower Firmicutes in the large intestine, along with lower levels of circulating short-chain fatty acids (SCFA). These changes are associated with higher body weight, hyperlipidemia, and severe insulin and glucose intolerance, all occurring before the onset of diabetes. These mice also exhibited insulin resistance–related abnormalities of energy metabolism, such as lower total respiratory exchange rates and higher hepatic oxidative capacity. Distinct alterations of gut morphology and microbiota composition associated with reduction of circulating SCFA may contribute to metabolic disorders promoting the progression of insulin-deficient diabetes/T1D development.

Aims/hypothesis Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.