Impaired Regulation Research Articles

The impact of impaired insulin regulation on severity of SARS-CoV-2 infection: a 2-year retrospective single-center analysis

Background: The COVID-19 pandemic has caused an international healthcare crisis and produced a large healthcare burden. Diabetes mellitus (DM) is a common disease that can be controlled via pharmacologic agents; however, many patients have poor glycemic control, leading to disease-related complications. DM has been reported in the literature to be associated with increasing morbidity and mortality in COVID-19 patients. The authors aim to assess the associations between glucose homoeostasis and COVID-19 disease severity and mortality. Methods: A retrospective chart review of patients ages 18–100 years of age admitted with COVID-19 between January 2020 and December 2021 was performed. The primary outcome was COVID-19 mortality with respect to haemoglobin A1C levels of less than 5.7%, 5.7–6.4%, and 6.5% and greater. Disease severity was determined by degree of supplemental oxygen requirements (ambient air, low-flow nasal cannula, high-flow nasal cannula, non-invasive mechanical ventilation, and invasive mechanical ventilation). COVID-19 mortality and severity were also compared to blood glucose levels on admission as grouped by less than 200 mg/dl and greater than or equal to 200 mg/dl. Results: A total of 1156 patients were included in the final analysis. There was a statistically significant association between diabetic status and mortality (P=0.0002). Statistical significance was also noted between admission blood glucose ≥200 mg/dl and mortality (P=0.0058) and respiratory disease severity (P=0.0381). A multivariate logistic regression for predicting mortality showed increasing haemoglobin A1C was associated with increased mortality (odds ratio 1.72 with 95% CI of 1.122–2.635). Conclusions: In our 2-year retrospective analysis, there was an association between a diagnosis of DM and COVID-19-related mortality. Hyperglycaemia on admission was found to be statistically significant with mortality in patients diagnosed with COVID-19. Glucose homoeostasis and insulin dysregulation likely play a contributing factor to COVID-19 disease severity and mortality.

Heart Rate Variability, Autonomic Reactivity, and Emotion Regulation during Sadness Induction in Somatic Symptom Disorder.

Preliminary evidence suggests altered heart rate variability (HRV) and impaired emotion regulation (ER) in somatic symptom disorder (SSD). Moreover, HRV can be considered an index of ER. Yet, to date, research on HRV and emotional reactivity in SSD is scarce and findings are inconsistent. Thus, this study aimed to examine ER differences, HRV at rest, and in response to emotion induction in persons with SSD compared to controls. The sample comprised 44 persons with SSD (DSM-5; 79.5% female, Mage = 45.7, SD = 14.7) and 41 persons without SSD (non-SSD; 78% female, Mage = 44.2, SD = 14.7). We assessed the participants' somatic symptom severity, ER, and control variables (e.g., depressive symptoms). Frequency and time domain HRV by ECG and subjective emotional states were measured at rest, under sadness induction, and during recovery periods. We evaluated baseline between-group differences with t-tests, and HRV and emotional reactivity and recovery with repeated measures ANOVAs. We found no significant differences in resting state HRV between persons with and without SSD. Regarding reactivity and recovery, SSD group showed lower reactivity in SDNN (standard deviation of NN interval) than non-SSD group. Moreover, SSD group reported more maladaptive ER techniques (e.g. rumination) and a higher effort to regulate their emotions during the experiment than non-SSD group. The study indicated impaired ER in persons with SSD. This finding showed more clearly in self-report than in HRV. Further research on HRV reactivity including tasks evoking other negative emotions in persons with SSD is required.

Setd2 deficiency promotes gastric tumorigenesis through inhibiting the SIRT1/FOXO pathway

Gastric cancer (GC) is the fifth most common cancer and the second leading cause of cancer death globally. SETD2 is a histone methyltransferase catalyzing tri-methylation of H3K36 (H3K36me3) and has been shown to participate in diverse biological processes and human tumors. However, the mechanism of SETD2 in GC remains unclear. Here, we reported that Setd2 deficiency predicts poor prognosis of gastric cancer. SETD2 loss facilitated H. felis/MNU and c-Myc-induced gastric tumorigenesis, respectively. The mouse model of stomach-specific Setd2 depletion together with c-MYC overexpression (AMS) developed high-grade epithelial defects, intestinal metaplasia and dysplasia at only 10–12 weeks of age. Mechanistically, Setd2 depletion resulted in impaired epigenetic regulation of Sirt1, thus inhibiting the SIRT1/FOXO pathway. Moreover, the agonists of FOXO signaling or overexpression of SIRT1 significantly rescued the enhanced cell proliferation and migration caused by Setd2 deficiency in SGC7901 cells. Together, our findings highlight an epigenetic mechanism by which SETD2 regulates gastric tumorigenesis through SIRT1/FOXO pathway. It may also pave the way for the development of targeted, patient-tailored therapies for GC patients with Setd2 deficiency.

Temporal dynamics of isolation calls emitted by pups in environmental and genetic mouse models of autism spectrum disorder

IntroductionEnvironmental and genetic factors contribute to the increased risk for neurodevelopmental disorders, including deficits in the development of social communication. In the mouse, ultrasonic vocalizations emitted by the pup stimulate maternal retrieval and potentiate maternal care. Therefore, isolation induced ultrasonic vocalization emitted by pups provides a means to evaluate deficits in communication during early development, before other ways of communication are apparent. Previous studies in our labs showed that gestational exposure to the pesticide chlorpyrifos (CPF) and the Methylenetetrahydrofolate (Mthfr)-knock-out mice are associated with impaired social preference, restricted or repetitive behavior and altered spectral properties of pups’ ultrasonic vocalization. In this study, we explore the temporal dynamics of pups’ vocalization in these Autism spectrum disorder (ASD) models.MethodsWe utilized the maternal potentiation protocol and analyzed the time course of pup vocalizations following isolation from the nest. Two models of ASD were studied: gestational exposure to the pesticide CPF and the Mthfr-knock-out mice.ResultsVocalization emitted by pups of both ASD models were dynamically modified in quantity and spectral structure within each session and between the two isolation sessions. The first isolation session was characterized by a buildup of call quantity and significant effects of USV spectral structure variables, and the second isolation session was characterized by enhanced calls and vocalization time, but minute effect on USV properties. Moreover, in both models we described an increased usage of harmonic calls with time during the isolation sessions.DiscussionCommunication between two or more individuals requires an interplay between the two sides and depends on the response and the time since the stimulus. As such, the presence of dynamic changes in vocalization structure in the control pups, and the alteration observed in the pups of the ASD models, suggest impaired regulation of vocalization associated with the environmental and genetic factors. Last, we propose that temporal dynamics of ultrasonic vocalization communication should be considered in future analysis in rodent models of ASD to maximize the sensitivity of the study of vocalizations.

PM2.5 induced neurotoxicity through unbalancing vitamin B12 metabolism by gut microbiota disturbance

ABSTRACT Fine particulate matter (PM2.5) in the atmosphere is easily accompanied by toxic and harmful substances, causing serious harm to human health, including cognitive impairment. Vitamin B12 (VitB12) is an essential micronutrient that is synthesized by bacteria and contributes to neurotransmitter synthesis as a nutrition and signaling molecule. However, the relationship between VitB12 attenuation of cognitive impairment and intestinal microbiota regulation in PM2.5 exposure has not been elucidated. In this study, we demonstrated that PM2.5 caused behavioral defects and neuronal damage in Caenorhabditis elegans (C. elegans), along with significant gene expression changes in neurotransmitter receptors and a decrease in VitB12 content, causing behavioral defects and neuronal damage in C. elegans. Methylcobalamin (MeCbl), a VitB12 analog, alleviated PM2.5-induced neurotoxicity in C. elegans. Moreover, using in vivo and in vitro models, we discovered that long-term exposure to PM2.5 led to changes in the structure of the gut microbiota, resulting in an imbalance of the VitB12-associated metabolic pathway followed by cognitive impairment. MeCbl supplementation could increase the diversity of the bacteria, reduce harmful substance contents, and restore the concentration of short-chain fatty acids (SCFAs) and neurotransmitters to the level of the control group to some degree. Here, a new target to mitigate the harm caused by PM2.5 was discovered, supplying MeCbl for relieving intestinal and intracellular neurotransmitter disorders. Our results also provide a reference for the use of VitB12 to target the adjustment of the human intestinal microbiota to improve metabolic disorders in people exposed to PM2.5.

Heart rate variability and risk of agitation in Alzheimer's disease: the Atherosclerosis Risk in Communities Study.

Agitation in Alzheimer's disease is common and may be related to impaired emotion regulation capacity. Heart rate variability, a proposed index of autonomic and emotion regulation neural network integrity, could be associated with agitation propensity in Alzheimer's disease. We used the Atherosclerosis Risk in Communities Study cohort data, collected over seven visits spanning over two decades, to investigate whether heart rate variability (change) was associated with agitation risk in individuals clinically diagnosed with dementia due to Alzheimer's disease. Agitation (absence/presence) at Visit 5, the primary outcome, was based on the Neuropsychiatric Inventory agitation/aggression subscale, or a composite score comprising the total number of agitation/aggression, irritability, disinhibition and aberrant motor behaviour subscales present. Visit 1-5 heart rate variability measures were the log-transformed root mean square of successive differences in R-R intervals and standard deviation of normal-to-normal R-R intervals obtained from resting, supine, standard 12-lead ECGs. To aid interpretability, heart rate variability data were scaled such that model outputs were expressed for each 0.05 log-unit change in heart rate variability (which approximated to the observed difference in heart rate variability with every 5 years of age). Among 456 participants who had dementia, 120 were clinically classified to have dementia solely attributable to Alzheimer's disease. This group showed a positive relationship between heart rate variability and agitation risk in regression models, which was strongest for measures of (potentially vagally mediated) heart rate variability change over the preceding two decades. Here, a 0.05 log-unit of heart rate variability change was associated with an up to 10-fold increase in the odds of agitation and around a half-unit increase in the composite agitation score. Associations persisted after controlling for participants' cognitive status, heart rate (change), sociodemographic factors, co-morbidities and medications with autonomic effects. Further confirmatory studies, incorporating measures of emotion regulation, are needed to support heart rate variability indices as potential agitation propensity markers in Alzheimer's disease and to explore underlying mechanisms as targets for treatment development.

FRI046 Clinical Phenotyping Of Adults With Genetic Obesity

Abstract Disclosure: M.S. Welling: None. M. Mohseni: None. R.E. Meeusen: None. M.R. Boon: None. C.J. de Groot: None. M.M. van Haelst: None. J.A. Visser: None. E.L. van den Akker: None. E.F. van Rossum: None. Introduction: In rare cases of obesity, genetic defects lead to hyperphagia and severe early-onset obesity. Genetic testing in patients with a suspected genetic obesity phenotype is important, as it can lead to patient-tailored treatment advice. For children, the Endocrine Society (ES) recommends genetic testing in children with early-onset of obesity (<5 years) and hyperphagia. It is unclear whether these recommendations can also be used in adult obesity care. Therefore, we aimed to phenotype adult patients with genetic obesity disorders. In addition, we assessed the suitability of the pediatric ES recommendations in these patients. Methods: We analyzed clinical data of patients with non-syndromic genetic obesity (NSO) and syndromic genetic obesity (SO), who visited our academic obesity center (Erasmus Medical Center, Rotterdam, the Netherlands). A standardized medical questionnaire, including topics concerning e.g. age of onset of obesity, hunger and satiation, was assessed. Anthropometrics, body composition (bio-impedance analysis), and resting energy expenditure (REE, indirect calorimetry) were measured. Differences between the NSO and SO groups were studied. Results: Sixty-six patients, of which n=26 with NSO and n=40 with SO, were included: median BMI and age at intake were 41.2 vs 39.2 kg/m2 and 25.7 vs 24.8 yrs, respectively (ns). The median age of onset of obesity was 2.5 [1-5] yrs in NSO and 9.5 [4-14] yrs in SO (p<0.001). Impaired appetite regulation was present in both groups: increased feelings of hunger in 64.0 vs 51.3% and impaired satiation in 47.1 vs 32.0% in NSO vs SO (ns). Binge eating was reported in 63.2% of SO, compared to 40.0% in NSO (p=0.071). The pediatric ES recommendations were fulfilled in 57.5% of NSO and 27.5% of SO (p=0.014). Compared to NSO, SO had a higher prevalence of intellectual deficit (3.8 vs 55.0%, p<0.001), autism (7.7 vs 26.3%, p=0.061) and retinal problems (0 vs 20.0%, p=0.015). There were no differences in body composition or REE. Conclusion: We report distinct phenotypic features concerning the age of onset of obesity, appetite regulation, and the presence of intellectual deficit, autism and retinal problems in adults with non-syndromic genetic obesity or syndromic genetic obesity. Additionally, this study demonstrates that the Endocrine Society’s recommendations for genetic testing in children with obesity, do not suit well for adults with obesity. Recommendations for genetic testing in adults with obesity are needed. Presentation: Friday, June 16, 2023

Delayed Surgical Treatment of Cervical Spine Injury in an Adolescent Patient

Introduction. Cervical spine injury is recognised as one of the most disabling types of vertebral column and spinal cord injuries. With a high level of disability, this type of injury remains quite rare among children. The main types of complications in this kind of injury include impaired regulations of the respiratory and cardiovascular systems, tetra- and paraparesis, and pelvic organ disorders. The analysis of recent publications indicated early surgery (in less than 24 hours) as the main condition for reducing post-traumatic complications.Materials and methods. The paper presents a clinical case of delayed surgery (in more than 24 hours) performed in a 17-year-old patient who was admitted to hospital after a traffic accident. After diagnostic measures, according to indications, a delayed surgery was performed on day 3: anterior spine fusion at the level of C5-Th1 with the installation of a vertebral body endoprosthesis and fixation with a bone plate.Results and discussion. The present case confirms the need for patients with combined spinal cord injury and mild traumatic brain injury to undergo a full range of diagnostic examinations including: brain and spine imaging, and, in the presence of compression and signs of spinal cord injury, MRI of the spinal cord (if necessary, the brain) at the level of injury. In the absence of gross structural damage to the brain, urgent decompression of the spinal cord and spine stabilization are indicated to eliminate the traumatic and spinal shock.Conclusion. Mild traumatic brain injury cannot be considered a contraindication for delayed cervical spine surgery. The present case is indicative of early surgical treatment of spinal injury, especially of the cervical spine, without neurological onset. All diagnostic measures were performed in full. Despite the surgical treatment and rehabilitation measures, the neurological deficit in the patient was not completely eliminated and persisted after 1 year.

Impaired cAMP processivity by phosphodiesterase-protein kinase A complexes in acrodysostosis.

Acrodysostosis represents a group of rare genetic disorders characterized by defective skeletal development and is often accompanied by intellectual disabilities. Mutations in the 3'5'cyclic AMP (cAMP)-dependent protein kinase (PKA) type I regulatory subunit isoform α (RIα) and phosphodiesterase (PDE) PDE4D have both been implicated in impaired PKA regulation in acrodysostosis. How mutations on PDEs and RIα interfere with the regulation of cAMP-PKA signaling is not understood. cAMP-PKA signaling can be described in two phases. In the activation phase, cAMP binding to RIα dissociates the free C-subunit (Catalytic subunit). PDEs hydrolyze cAMP bound to RIα, priming the cAMP-free RIα for reassociation with the C-subunit, thereby completing one PKA activation cycle. Signal termination is thus critical for resetting PKA to its basal state and promoting adaptation to hormonal hyperstimulation. This proceeds through formation of a transient signal termination RIα: PDE complex that facilitates cAMP channeling from the cAMP-binding domain of RIα to the catalytic site of PDE. Signal termination of cAMP-PKA proceeds in three steps: Step 1) Channeling: translocation of cAMP from the CNB of RIα to the PDE catalytic site for hydrolysis. Step 2) Processivity: binding of free cAMP from the cytosol at both CNBs of RIα. Step 3) Product (5'AMP) release from the PDE hydrolysis site through competitive displacement by a new molecule of cAMP that triggers subsequent activation cycles of PKA. We have identified the molecular basis for two acrodysostosis mutants, PDE (PDE8 T690P) and RIα (T207A), that both allosterically impair cAMP-PKA signal termination. A combination of amide hydrogen/deuterium exchange mass spectrometry (HDXMS) and fluorescence polarization (FP) reveals that PDE8 T690P and RIα T207A both blocked processive hydrolysis of cAMP by interfering with competitive displacement of product 5'AMP release from the nucleotide channel at the end of each round of cAMP hydrolysis. While T690P blocked product 5'AMP release from the PDE, T207A greatly slowed the release of the substrate from RIα. These results highlight the role of processivity in cAMP hydrolysis by RIα: PDE termination complexes for adaptation to cAMP from GPCR hyperstimulation. Impairment of the signal termination process provides an alternate molecular basis for acrodysostosis.

Seizing the Connection: Exploring the Interplay Between Epilepsy and Glycemic Control in Diabetes Management.

Epilepsy, a neurological disorder characterized by recurrent seizures, and diabetes, a metabolic disorder characterized by impaired regulation of glucose levels, are two distinct conditions that may appear unrelated at first glance. Nevertheless, recent scholarly investigations have revealed these entities' intricate and ever-evolving interplay. This review initially delves into the intricate interplay between epilepsy and its potential ramifications on glycemic control. Seizures, particularly those accompanied by convulsive manifestations, have the potential to induce acute perturbations in blood glucose levels via diverse mechanisms, encompassing the liberation of stress hormones, the emergence of insulin resistance, and the dysregulation of the autonomic nervous system. Comprehending these intricate mechanisms is paramount in customizing productive strategies for managing diabetes in individuals with epilepsy. On the contrary, it is worth noting that diabetes can substantially impact the trajectory and control of epilepsy. The correlation between hyperglycemia and an elevated susceptibility to seizures, as well as the potential for exacerbating the intensity of epilepsy, has been established. This narrative review offers a concise exposition of the intricate interplay between epilepsy and glycemic control within diabetes management. The objective of exploring reciprocal influences, underlying mechanisms, and common risk factors is to augment the clinical comprehension of this intricate interconnection. In essence, this acquired knowledge possesses the potential to serve as a guiding compass for healthcare professionals, enabling them to craft bespoke therapeutic approaches that enhance the holistic welfare of individuals grappling with the coexistence of epilepsy and diabetes.

Development of an integrated program of sensory rehabilitation based on vibroacoustic and virtual reality and its effectiveness on the emotional profile in children with autism spectrum disorder: A Case study

Introduction: Impaired emotion regulation in children with autism spectrum disorder (ASD) significantly affects their interactions. Aim: The aim of this study was to develop a rehabilitation program based on vibroacoustic and virtual reality techniques and evaluate its effectiveness on the emotional profile of children with ASD. Method: The research employed a single-subject ABA design. The population included all children with ASD attending the Zehn ara Rehabilitation Clinic in Tehran in the second half of 2021, from which 5 participants were purposively selected. Initially, the combined program was implemented for 10 sessions of 30 minutes each on two randomly chosen participants from the sample, and after validating the program, three additional participants were included in the study. The Sensory Profile 2 questionnaire (2014) was used in this research. During the baseline phase, at the end of each intervention session, and during a one-month follow-up period, the questionnaires were completed. Data analysis involved visual analysis, percentage of improvement, and percentage of overlapping and non-overlapping data. Results: The results indicated that based on the obtained effect sizes, the intervention had a significant impact on emotional regulation in participants 1 to 5, with 90%, 80%, 80%, 100%, and 90% certainty, respectively. Furthermore, the percentage of improvement resulting from the interventions for participants 1 to 5 was 20.08%, 28.75%, 28.24%, 27.24%, and 21.02%, respectively. Conclusion: Based on the findings, the combined rehabilitation program was effective in improving the emotional profile of children with autism. Therefore; this approach can be recommended as an appropriate intervention for individuals with ASD.

Increased brain microvascular hemoglobin concentrations in children with cerebral malaria.

Brain swelling is associated with death from cerebral malaria, but it is unclear whether brain swelling is caused by cerebral edema or vascular congestion-two pathological conditions with distinct effects on tissue hemoglobin concentrations. We used near-infrared spectroscopy (NIRS) to noninvasively study cerebral microvascular hemoglobin concentrations in 46 Malawian children with cerebral malaria. Cerebral malaria was defined by the presence of the malaria parasite Plasmodium falciparum on a blood smear, a Blantyre coma score of 2 or less, and retinopathy. Children with uncomplicated malaria (n = 33) and healthy children (n = 29) were enrolled as comparators. Cerebral microvascular hemoglobin concentrations were higher among children with cerebral malaria compared with those with uncomplicated malaria [median (25th, 75th): 145.2 (95.2, 190.0) μM versus 82.9 (65.7, 105.4) μM, P = 0.008]. Cerebral microvascular hemoglobin concentrations correlated with brain swelling score determined by MRI (r = 0.37, P = 0.03). Fluctuations in cerebral microvascular hemoglobin concentrations over a 30-min time period were characterized using detrended fluctuation analysis (DFA). DFA determined self-similarity of the cerebral microvascular hemoglobin concentration signal to be lower among children with cerebral malaria compared with those with uncomplicated malaria [0.63 (0.54, 0.70) versus 0.91 (0.82, 0.94), P < 0.0001]. The lower self-similarity of the hemoglobin concentration signal in children with cerebral malaria suggested impaired regulation of cerebral blood flow. The elevated cerebral tissue hemoglobin concentration and its correlation with brain swelling suggested that excess blood volume, potentially due to vascular congestion, may contribute to brain swelling in cerebral malaria.

Testosterone deficiency in patients with chronic kidney disease: prevalence and clinical significance (literature review)

There is an increase in the prevalence of chronic kidney disease in the world. This is primarily due to the increase in the incidence of diabetes mellitus and arterial hypertension as the main etiological factors. A progressive decline in the excretory function of the kidneys is associated with metabolic disorders such as metabolic acidosis, hyperuricemia, hyperparathyroidism, oxidative and inflammatory stress, etc. This leads, in turn, to a decrease in the body weight of patients, primarily due to the loss of muscle mass. Such changes have an adverse effect, including on the synthesis of sex hormones, in particular, on the level of testosterone, the production of which decreases in the cohort of patients under discussion. Hormonal imbalance in the form of hypogonadism can play a significant role in increasing cardiovascular risk. Renal replacement therapy may be an independent risk factor for the development and progression of hypogonadism. At the same time, the problems of impaired regulation, synthesis and balance of sex hormones, as well as the issues of correction of secondary hypogonadism in patients with chronic kidney disease remain poorly understood and are of scientific interest.

Primary weight loss failure after Roux-en-Y gastric bypass is characterized by impaired gut-hormone mediated regulation of food intake

Background/ObjectivesAfter Roux-en-Y gastric bypass (RYGB) a subset of patients never obtain excess BMI loss (EBMIL) > 50% and are categorized as having primary weight loss (WL) failure. We hypothesized that postprandial concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) would be lower in patients with primary WL failure compared with patients with successfully maintained WL. Furthermore, that inhibition of gut hormone secretions would increase ad libitum food intake less in patients with primary WL failure.Subjects/MethodsTwenty women with primary WL failure (LowEBMIL < 50%) were individually matched to twenty women with successful WL (HighEBMIL > 60%) on age, preoperative BMI and time from RYGB. On separate days performed in a random order, patient-blinded subcutaneous injections of octreotide or saline (placebo) were followed by a fixed breakfast and an ad libitum lunch with blood sampling for appetite regulating hormones and Visual-Analogue-Scale (VAS)-scoring of hunger/satiety. Furthermore, participants underwent gene variant analysis for GLP-1, PYY and their receptors, indirect calorimetry, dual-energy X-ray absorptiometry (DXA)-scans, 4-days at-home food registration and 14-days step counting.ResultsOn placebo days, postprandial GLP-1, PYY and cholecystokinin (CCK) concentrations were similar between groups after breakfast. Fasting ghrelin was lower in LowEBMIL, but the postprandial suppression was similar. LowEBMIL had lower satiety VAS-scores and less suppression of hunger VAS-scores. Gene variants did not differ between groups. Octreotide diminished GLP-1, PYY, CCK and ghrelin concentrations in both groups. Octreotide did not affect ad libitum food intake in LowEBMIL (−1% [−13, 12], mean [95%CI]), while food intake increased in HighEBMIL (+23% [2,44]).ConclusionsPrimary WL failure after RYGB was not characterized by impaired secretions of appetite regulating gut hormones. Interestingly, inhibition of gut hormone secretions with octreotide only increased food intake in patients with successful WL post-RYGB. Thus, an impaired central anorectic response to gut hormones may contribute to primary WL failure after RYGB.

Current approach to diabetic polyneuropathy: current diagnosis and treatment

Diabetes mellitus and its associated neuropathy are among the leading problems affecting the quality of life negatively. Diabetic foot problems due to neuropathy cause very serious problems. Physicians may focus too much on blood sugar regulation and ignore examinations for other macro and microvascular complications of diabetes. Although it appears earlier in patients with impaired blood sugar regulation, neuropathic symptoms are seen in almost half of diabetic patients who generally exceed 10 years. With early diagnosis and treatment, the quality of life of patients increases significantly. We touched on this issue in order to raise awareness of neuropathy, which is so common.

Epigenetic Downregulation of Hsa-miR-193b-3p Increases Cyclin D1 Expression Level and Cell Proliferation in Human Meningiomas.

Meningiomas are common intracranial tumors in adults. Abnormal microRNA (miRNA) expression plays a role in their pathogenesis. Change in miRNA expression level can be caused by impaired epigenetic regulation of miRNA-encoding genes. We found the genomic region covering the MIR193B gene to be DNA hypermethylated in meningiomas based on analysis of genome-wide methylation (HumanMethylation450K Illumina arrays). Hypermethylation of MIR193B was also confirmed via bisulfite pyrosequencing. Both hsa-miR-193b-3p and hsa-miR-193b-5p are downregulated in meningiomas. Lower expression of hsa-miR-193b-3p and higher MIR193B methylation was observed in World Health Organization (WHO) grade (G) II/III tumors as compared to GI meningiomas. CCND1 mRNA was identified as a target of hsa-miR-193b-3p as further validated using luciferase reporter assay in IOMM-Lee meningioma cells. IOMM-Lee cells transfected with hsa-miR-193b-3p mimic showed a decreased cyclin D1 level and lower cell viability and proliferation, confirming the suppressive nature of this miRNA. Cyclin D1 protein expression (immunoreactivity) was higher in atypical than in benign meningiomas, accordingly to observations of lower hsa-miR-193b-3p levels in GII tumors. The commonly observed hypermethylation of MIR193B in meningiomas apparently contributes to the downregulation of hsa-miR-193b-3p. Since hsa-miR-193b-3p regulates proliferation of meningioma cells through negative regulation of cyclin D1 expression, it seems to be an important tumor suppressor in meningiomas.

Pulmonary Circulation Under Pressure: Pathophysiological and Therapeutic Implications of BK Channel.

The large-conductance Ca2+-activated K+ (BK) channel is widely expressed in the pulmonary blood vessels and plays a significant role in regulating pulmonary vascular tonus. It opens under membrane depolarization, increased intracellular Ca+2 concentration, and chronic hypoxia, resulting in massive K+ efflux, membrane hyperpolarization, decreased L-type Ca+2 channel opening, and smooth muscle relaxation. Several reports have demonstrated an association between BK channel dysfunction and pulmonary hypertension (PH) development. Decreased BK channel subunit expression and impaired regulation by paracrine hormones result in decreased BK channel opening, increased pulmonary vascular resistance, and pulmonary arterial pressure being the cornerstone of PH. The resulting right ventricular pressure overload ultimately leads to ventricular remodeling and failure. Therefore, it is unsurprising that the BK channel has arisen as a potential target for treating PH. Recently, a series of selective, synthetic BK channel agonists have proven effective in attenuating the pathophysiological progression of PH without adverse effects in animal models.

Thinking about the consequences: The detrimental role of future thinking on intrapersonal problem-solving in depression.

Despite the fact that depressed individuals encounter a multitude of social problems in daily life, research on social problem-solving has largely been dominated by research on interpersonal problems and there is a paucity of research on intrapersonal problems. Intrapersonal problems are linked to one's subjective psychological functioning and involve managing one's own feelings and emotions pertaining to the self. Given that depressed individuals exhibit impaired emotion regulation, it is possible that their ability to solve intrapersonal problems may be impaired, especially in relation to future thinking. The aim of this study was to investigate whether future thinking, in the form of thinking about the consequences of a problem being resolved or remaining unresolved has an impact on intrapersonal problem-solving in depression. Forty-five depressed and fifty-four non-depressed participants completed a modified version of the means end problem-solving task (MEPS). In the task, participants were presented with a series of intrapersonal problems and were asked to generate consequences of the problems being resolved or remaining unresolved. Participants were then presented with a positive resolution to each of the problems and were asked to solve the problem to achieve the positive resolution. Following a delay, participants were asked to recall all of the consequences initially generated. Overall, depressed individuals generated fewer-relevant means and less effective solutions to problems than non-depressed participants. Depressed individuals also demonstrated impaired intrapersonal problem-solving following the generation of resolved and unresolved consequences, compared to a baseline condition, where no consequences were generated. These findings suggest that future thinking impairs intrapersonal problem-solving and indicates that a more nuanced approach to future thinking and social problem-solving in depression is needed across different real-life problem-solving contexts.

Putative neural mechanisms underlying release-mode-specific abnormalities in dopamine neural activity in a schizophrenia-like model: The distinct roles of glutamate and serotonin in the impaired regulation of dopamine neurons.

Abnormalities in dopamine function might be related to psychiatric disorders such as schizophrenia. Even at the same concentration, dopamine exerts opposite effects on information processing in the prefrontal cortex depending on independent dopamine release modes known as tonic and phasic releases. This duality of dopamine prevents a blanket interpretation of the implications of dopamine abnormalities for diseases on the basis of absolute dopamine levels. Moreover, the mechanisms underlying the mode-specific dopamine abnormalities are not clearly understood. Here, I show that the two modes of dopamine release in the prefrontal cortex of a schizophrenia-like model are disrupted by different mechanisms. In the schizophrenia-like model established by perinatal exposure to inflammatory cytokine, epidermal growth factor, tonic release was enhanced and phasic release was decreased in the prefrontal cortex. I examined the activity of dopamine neurons in the ventral tegmental area (VTA), which sends dopamine projections to the prefrontal cortex, under anaesthesia. The activation of VTA dopamine neurons during excitatory stimulation (local application of glutamate or N-methyl-d-aspartic acid [NMDA]), which is associated with phasic activity, was blunt in this model. Dopaminergic neuronal activity in the resting state related to tonic release was increased by disinhibition of the dopamine neurons due to the impairment of 5HT2 (5HT2A) receptor-regulated GABAergic inputs. Moreover, chronic administration of risperidone ameliorated this disinhibition of dopaminergic neurons. These results provide an idea about the mechanism of dopamine disturbance in schizophrenia and may be informative in explaining the effects of atypical antipsychotics as distinct from those of typical drugs.

Acute Deletion of the Glucocorticoid Receptor in Hepatocytes Disrupts Postprandial Lipid Metabolism in Male Mice.

Hepatic lipid metabolism is highly dynamic, and disruption of several circadian transcriptional regulators results in hepatic steatosis. This includes genetic disruption of the glucocorticoid receptor (GR) as the liver develops. To address the functional role of GR in the adult liver, we used an acute hepatocyte-specific GR knockout model to study temporal hepatic lipid metabolism governed by GR at several preprandial and postprandial circadian timepoints. Lipidomics analysis revealed significant temporal lipid metabolism, where GR disruption results in impaired regulation of specific triglycerides, nonesterified fatty acids, and sphingolipids. This correlates with increased number and size of lipid droplets and mildly reduced mitochondrial respiration, most noticeably in the postprandial phase. Proteomics and transcriptomics analyses suggest that dysregulated lipid metabolism originates from pronounced induced expression of enzymes involved in fatty acid synthesis, β-oxidation, and sphingolipid metabolism. Integration of GR cistromic data suggests that induced gene expression is a result of regulatory actions secondary to direct GR effects on gene transcription.