Relapsing diabetes can result from moderately activating mutations in KCNJ11

Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM). Mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium channel (K(ATP)), are the commonest cause of permanent neonatal diabetes (PNDM). In addition to diabetes, some KCNJ11 mutations also result in marked developmental delay and epilepsy. These mutations are more severe on functional characterization. We investigated whether mutations in KCNJ11 could also give rise to TNDM. We identified the three novel heterozygous mutations (G53S, G53R, I182V) in three of 11 probands with clinically defined TNDM, who did not have chromosome 6q24 abnormalities. The mutations co-segregated with diabetes within families and were not found in 100 controls. All probands had insulin-treated diabetes diagnosed in the first 4 months and went into remission by 7-14 months. Functional characterization of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes. All three heterozygous mutations resulted in a reduction in the sensitivity to ATP when compared with wild-type (IC(50) approximately 30 versus approximately 7 microM, P-value for is all <0.01); however, this was less profoundly reduced than with the PNDM associated mutations. In conclusion, mutations in KCNJ11 are the first genetic cause for remitting as well as permanent diabetes. This suggests that a fixed ion channel abnormality can result in a fluctuating glycaemic phenotype. The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro.     

Cognitive and behavioural correlates of non‐adherence to HIV anti‐retroviral therapy: Theoretical and practical insight for clinical psychology and health psychology

This cross‐sectional study identified variables associated with protease inhibitor (PI) non‐adherence in 179 patients taking anti‐retroviral therapy. Univariate analyses identified 11 variables associated with PI non‐adherence. Multiple logistic regression modelling identified three predictors of PI non‐adherence: low adherence self‐efficacy and seriousness of non‐adherence and HIV (p < .001), perceived absence of HIV associated illness (p < .01), and use of more than one type of recreational drug (p = .001). The model correctly classified 83.9% of the sample, offers psychologists insight into psychological barriers to treatment adherence to guide interventions for improving adherence, and supports a modified version of the reformulated health belief model.     

Relationships among sexual behavior,hot flashes,and hormone levels in perimenopausal women

Forty-three perimenopausal women kept daily records of menstrual cycles and sexual activity. Data on hot flashes and plasma estradiol and testosterone levels were obtained at two points during the menopausal transition. The prospective data yielded a significant negative association between hot flash ratings and regularity of sexual intercourse at both time points. A significant negative correlation was found between estradiol (in the early part of the cycle) and hot flashes ratings at the first data point only, and positive correlations were found between hot flashes and ratio of testosterone to estradiol (T/E) at both. Frequency of sexual intercourse and level of plasma estradiol were higher, and T/E and hot flash ratings were lower in early perimenopausal women who were still having cycles at least once every 30 days, as compared with late perimenopausal women who were cycling less often. It was concluded that a close association exists between increasing irregularity of menstrual cycles, hot flashes, declining estradiol levels, and declining frequency of intercourse during the perimenopause. Causal relationships remain to be established.Supported by NIH Grant AG1437.     

Immune changes associated with insulin dependent diabetes may remit without causing the disease: a study in identical twins

Activation of T lymphocytes and islet cell antibodies were studied in two groups of insulin dependent diabetics and their non-diabetic identical cotwins. Group 1 comprised 12 "short term" twin pairs (diabetic twin diagnosed less than five years previously) in whom only a third of the cotwins were likely to develop diabetes; 10 of the 12 non-diabetic cotwins showed increased values of activated T lymphocytes, islet cell antibodies, or both. Group 2 comprised 10 "long term" twin pairs (diabetic twin diagnosed more than 11 years previously) in whom none of the non-diabetic cotwins was likely to develop diabetes; these pairs were selected because all the non-diabetic cotwins had shown islet cell antibodies at some time in the past, but only two still did so (one with an increased value of activated T cells). There was relative glucose intolerance in the cotwins of the short term group but not in those of the long term group. Non-diabetic cotwins of diabetics may show the immune changes associated with insulin dependent diabetes and relative glucose intolerance, but these changes may remit without leading to diabetes.     

Emergence of SARS-CoV-2 B.1.1.7 Lineage at Outpatient Testing Site,Berlin, Germany,January–March 2021

Within 5 weeks in 2021, B.1.1.7 became the dominant severe acute respiratory syndrome coronavirus 2 lineage at an outpatient testing site in Berlin, Germany. Compared with outpatients with wild-type virus infection, patients with B.1.1.7 had similar cycle threshold values, more frequent sore throat and travel history, and less frequent anosmia/ageusia.     

Impact of antiangiogenic treatment on the erectile function in patients with advanced renal cell carcinoma

We longitudinally assessed erectile function as well as the willingness to use pro-erectile treatment in a cohort on AAT for advanced RCC. Thirty-seven patients with advanced RCC completed the five-item version of the International Index of Erectile Function (IIEF-5) and other interview items before (T0) and 12 weeks into therapy (T12) with AAT. Patients were further asked if they were willing to use and pay out-of-pocket for on-demand treatment with phosphodiesterase-5-inhibitors (PDE-5i). Statistical analysis was performed using nonparametric hypothesis testing. The IIEF-5 score at T12 was significantly decreased compared with T0 (p < .001). Subjective patient satisfaction regarding their sexual lives was associated with higher IIEF-5 scores at both time points (p = .006 and p = .03, respectively). At T12, subjective sexual contentment showed a nonsignificant trend towards decline (p = .074). Patients who opted for medical treatment of ED showed significantly better IIEF-5 scores at both time points compared with the rest of the cohort (p < .001 and p = .005, respectively). In summary, AAT seems to have a negative effect on erectile function in RCC patients, however, the role of psychosocial issues warrants further elucidation. Affected patients may benefit from a proactive approach promoting medical treatment of erectile dysfunction during AAT.     

Clinical Phenotype and Relevance of LRP5 and LRP6 Variants in Patients With Early-Onset Osteoporosis (EOOP)

Reduced bone mineral density (BMD; ie, Z-score ≤−2.0) occurring at a young age (ie, premenopausal women and men <50 years) in the absence of secondary osteoporosis is considered early-onset osteoporosis (EOOP). Mutations affecting the WNT signaling pathway are of special interest because of their key role in bone mass regulation. Here, we analyzed the effects of relevant LRP5 and LRP6 variants on the clinical phenotype, bone turnover, BMD, and bone microarchitecture. After exclusion of secondary osteoporosis, EOOP patients (n = 372) were genotyped by gene panel sequencing, and segregation analysis of variants in LRP5/LRP6 was performed. The clinical assessment included the evaluation of bone turnover parameters, BMD by dual-energy X-ray absorptiometry, and microarchitecture via high-resolution peripheral quantitative computed tomography (HR-pQCT). In 50 individuals (31 EOOP index patients, 19 family members), relevant variants affecting LRP5 or LRP6 were detected (42 LRP5 and 8 LRP6 variants), including 10 novel variants. Seventeen variants were classified as disease causing, 14 were variants of unknown significance, and 19 were BMD-associated single-nucleotide polymorphisms (SNPs). One patient harbored compound heterozygous LRP5 mutations causing osteoporosis-pseudoglioma syndrome. Fractures were reported in 37 of 50 individuals, consisting of vertebral (18 of 50) and peripheral (29 of 50) fractures. Low bone formation was revealed in all individuals. A Z-score ≤−2.0 was detected in 31 of 50 individuals, and values at the spine were significantly lower than those at the hip (−2.1 ± 1.3 versus −1.6 ± 0.8; p = .003). HR-pQCT analysis (n = 34) showed impaired microarchitecture in trabecular and cortical compartments. Significant differences regarding the clinical phenotype were detectable between index patients and family members but not between different variant classes. Relevant variants in LRP5 and LRP6 contribute to EOOP in a substantial number of individuals, leading to a high number of fractures, low bone formation, reduced Z-scores, and impaired microarchitecture. This detailed skeletal characterization improves the interpretation of known and novel LRP5 and LRP6 variants. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Migraine-like headaches associated with nickel allergy requiring removal of atrial septal defect closure device

There is a deficit of literature regarding the association between nickel allergy–induced symptoms and implanted devices. This report describes a case of nickel allergy causing debilitating migraine-like symptoms, failing to resolve with medical therapy, requiring surgical removal of the device and repair of the defect.     

Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1^asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1^asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1^asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1^asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Radiologische Interventionen bei Schlaganfall

Notfall + Rettungsmedizin - In den letzten Jahren hat sich die mechanische Thrombektomie mit Stent-Retrievern als wichtiger Bestandteil der Behandlung des ischämischen Schlaganfalls etabliert....