Obstructive Sleep Apnea Syndrome Is Less Frequent in Patients With Well-Controlled Acromegaly Treated With Somatostatin Analogues, Pegvisomant or in Combination

Background: Obstructive sleep apnea (OSA) often occurs in patients with active acromegaly and improves after treatment. Less is known about the development of OSA in patients after a longer period of control treated with somatostatin analogues (SSA) and pegvisomant. Methods: Seventy-nine patients (12 females, 17 males; age 49 +/- 14 years; body mass index 29.9 +/- 5.4 kg/m(2); IGF-1 184 +/- 73 mu g/L; disease duration 13 +/- 8 years (mean +/- standard deviation)) with wellcontrolled acromegaly treated with SSA (38%), pegvisomant (38%) or in combination (24%) who underwent ambulatory polygraphy were included in a prospective multicenter cross-sectional study. Results: Fourteen percent had OSA (range of apnea-hypopnea index (AHI) 5 -15). Patients with OSA (AHI >= 5 vs. < 5) had a longer disease duration (16 +/- 1 vs. 12 +/- 8 years; P = 0.01) and were older (61 +/- 9 vs. 47 +/- 13 years; P = 0.037). The AHI of all patients correlated with age (P = 0.01; r = 0.44). No differences were seen in terms of BMI and Epworth sleepiness scale score. Previous transsphenoidal surgery and radiation had no impact of the detection of OSA. The duration of well-controlled acromegaly was 7 +/- 3 years. Conclusion: OSA in patients with well-controlled acromegaly treated with SSA, pegvisomant or in combination is less frequent (14%) than previously described. Early treatment to reduce the active disease period should be aimed to prevent OSA

Case series: convalescent plasma therapy for patients with COVID-19 and primary antibody deficiency

Patients with primary antibody deficiency are at risk for severe and in many cases for prolonged COVID-19. Convalescent plasma treatment of immunocompromised individuals could be an option especially in countries with limited access to monoclonal antibody therapies. While studies in immunocompetent COVID19 patients have demonstrated only a limited benefit, evidence for the safety, timing, and effectiveness of this treatment in antibody-deficient patients is lacking. Here, we describe 16 cases with primary antibody deficiency treated with convalescent plasma in four medical centers. In our cohort, treatment was associated with a reduction in viral load and improvement of clinical symptoms, even when applied over a week after onset of infection. There were no relevant side effects besides a short-term fever reaction in one patient. Longitudinal full-genome sequencing revealed the emergence of mutations in the viral genome, potentially conferring an antibody escape in one patient with persistent viral RNA shedding upon plasma treatment. However, he resolved the infection after a second course of plasma treatment. Thus, our data suggest a therapeutic benefit of convalescent plasma treatment in patients with primary antibody deficiency even months after infection. While it appears to be safe, PCR follow-up for SARS-CoV-2 is advisable and early re-treatment might be considered in patients with persistent viral shedding

Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1

Screening of a carefully selected library of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic nucleotide-binding domain (CNB) of the cAMP sensor, EPAC1. Two of these hits (I942 and I178) were selected for their robust and reproducible inhibitory effects within the primary screening assay. Follow-up characterisation by ligand observed nuclear magnetic resonance (NMR) revealed direct interaction of I942 and I178 with EPAC1 and EPAC2-CNBs in vitro. Moreover, in vitro guanine nucleotide exchange factor (GEF) assays revealed that I942 and, to a lesser extent, I178 had partial agonist properties towards EPAC1, leading to activation of EPAC1, in the absence of cAMP, and inhibition of GEF activity in the presence of cAMP. In contrast, there was very little agonist action of I942 towards EPAC2 or protein kinase A (PKA). To our knowledge, this is the first observation of non-cyclic-nucleotide small molecules with agonist properties towards EPAC1. Furthermore, the isoform selective agonist nature of these compounds highlights the potential for the development of small molecule tools that selectively up-regulate EPAC1 activity

Isopentenyl-Diphosphate Isomerases in Human and Mouse: Evolutionary Analysis of a Mammalian Gene Duplication

Abstract. Isopentenyl diphosphate isomerase (IDI) activates isopentenyl diphosphate (IPP) for polymerization by converting it to its highly nucleophilic isomer dimethylallyl diphosphate (DMAPP). In plants, this central reaction of isoprenoid biosynthesis is catalyzed by various highly conserved isozymes that differ in expression pattern and subcellular localization. Here we report the identification of an IDI duplication in mammals. In contrast to the situation in plants, only one of the two isoforms (IDI1) is highly conserved, ubiquitously expressed and most likely responsible for housekeeping isomerase activity. The second isoform (IDI2) is much more divergent. We demonstrate that after the initial duplication IDI2 underwent a short phase of apparently random change, during which its active center became modified. Afterwards, IDI2 was exapted for a novel function and since then has been under strong purifying selection for at least 70 million years. Molecular modeling shows that the modified IDI2 is still likely to catalyze the isomerization of IPP to DMAPP. In humans, IDI2 is expressed at high levels only in skeletal muscle, where it may be involved in the specialized production of isoprenyl diphosphates for the posttranslational modification of proteins. The significant positive fitness effect of IDI2, revealed by the pattern of sequence conservation, as well as its Correspondence to: Skaidrite K. Krisans

Protein phosphatase 1 (PP-1)-dependent inhibition of insulin secretion by leptin in INS-1 pancreatic β-cells and human pancreatic islets

Leptin inhibits insulin secretion from pancreatic beta-cells, and in turn, insulin stimulates leptin biosynthesis and secretion from adipose tissue. Dysfunction of this adipoinsular feedback loop has been proposed to be involved in the development of hyperinsulinemia and type 2 diabetes mellitus. At the molecular level, leptin acts through various pathways, which in combination confer inhibitory effects on insulin biosynthesis and secretion. The aim of this study was to identify molecular mechanisms of leptin action on insulin secretion in pancreatic beta-cells. To identify novel leptin-regulated genes, we performed subtraction PCR in INS-1 beta-cells. Regulated expression of identified genes was confirmed by RT-PCR and Northern and Western blotting. Furthermore, functional impact on beta-cell function was characterized by insulin-secretion assays, intracellular Ca(2+) concentration measurements, and enzyme activity assays. PP-1alpha, the catalytic subunit of protein phosphatase 1 (PP-1), was identified as a novel gene down-regulated by leptin in INS-1 pancreatic beta-cells. Expression of PP-1alpha was verified in human pancreatic sections. PP-1alpha mRNA and protein expression is down-regulated by leptin, which culminates in reduction of PP-1 enzyme activity in beta-cells. In addition, glucose-induced insulin secretion was inhibited by nuclear inhibitor of PP-1 and calyculin A, which was in part mediated by a reduction of PP-1-dependent calcium influx into INS-1 beta-cells. These results identify a novel molecular pathway by which leptin confers inhibitory action on insulin secretion, and impaired PP-1 inhibition by leptin may be involved in dysfunction of the adipoinsular axis during the development of hyperinsulinemia and type 2 diabetes mellitus

Clinical impact of the TCF7L2 gene rs7903146 type 2 diabetes mellitus risk polymorphism in women with gestational diabetes mellitus: Impaired glycemic control and increased need of insulin therapy.

Background The single nucleotide polymorphism in TCF7L2 rs7903146 is associated with an increased risk of type 2 diabetes mellitus and gestational diabetes mellitus. Mechanisms by which this mutation acts, and its impact on the clinical course of the diseases remain unclear. Here we investigated the clinical impact of the T risk allele in women with gestational diabetes mellitus.Methods We genotyped the CST polymorphism in 164 Caucasian women with GDM (German n =114; Greek n =50). The impact of the T allele on the results of the 75g oral-glucose-tolerance-test, and on the required therapy (diet/lifestyle or insulin) was investigated.Results During oral-glucose-tolerance-test, women harboring the T allele displayed significantly higher glucose values at 60 min (p = 0.034) and were more likely to require insulin therapy even after adjusting for confounders, such as BMI and age.Conclusion These results provide evidence that the T risk allele in TCF7L2 rs7903146 is associated with failure in early postprandial glycemic control and requirement of insulin therapy in women with gestational diabetes mellitus, even after adjusting for confounding factors such BMI and age