Impairment of the GABAergic system in the anterior insular cortex of heroin-addicted males.

Opioid addiction is a global problem, causing the greatest health burden among drug use disorders, with opioid overdose deaths topping the statistics of fatal overdoses. The multifunctional anterior insular cortex (AIC) is involved in inhibitory control, which is severely impaired in opioid addiction. GABAergic interneurons shape the output of the AIC, where abnormalities have been reported in individuals addicted to opioids. In these neurons, glutamate decarboxylase (GAD) with its isoforms GAD 65 and 67 is a key enzyme in the synthesis of GABA, and research data point to a dysregulation of GABAergic activity in the AIC in opioid addiction. Our study, which was performed on paraffin-embedded brains from the Magdeburg Brain Bank, aimed to investigate abnormalities in the GABAergic function of the AIC in opioid addiction by densitometric evaluation of GAD 65/67-immunostained neuropil. The study showed bilaterally increased neuropil density in layers III and V in 13 male heroin-addicted males compared to 12 healthy controls, with significant U-test P values for layer V bilaterally. Analysis of confounding variables showed that age, brain volume and duration of formalin fixation did not confound the results. Our findings suggest a dysregulation of GABAergic activity in the AIC in opioid addiction, which is consistent with experimental data from animal models and human neuroimaging studies.

Frequency of C-peptide and antibody levels (anti GAD, Islet cell antibodies, insulin auto antibodies) in children of Pakistan with Type-1 diabetes.

Background and Objective: The autoimmune mechanism in T1DM causes gradual loss of pancreatic ß-cell, which progresses to hyperglycemia and ultimate reliance on consistent insulin therapy. T1DM has been the commonest type of diabetes in children and this study will help in refining indulgent towards the problem and its pathophysiology in our people. The objective was to find out the prevalence of C-peptide and antibody levels (anti GAD, ICA, IAA and IA2) in children and adolescents of Pakistan with T1DM. Methods: We conducted this cross-sectional study at Department of Pediatric Endocrinology, National Institute of Child Health, Karachi between August 2019 to February 2020 and included 98 children who had T1DM for more than one month. Subjects whose GFR was <30ml/min were omitted from the study. Among those registered subjects, C-peptide, human islet cell antibody (ICA), insulin auto antibodies (IAA) and anti-glutamic acid decarboxylase were assessed. Demographical and laboratorial facts were noted on a pre-constructed proforma. Results: There were 77(78.3%) cases who had level of C-peptide <0.8 and anti-GAD was found in 47(48%) subjects. 35(35.7%) cases found positive for IA2 .and 7(7.1%) patients had insulin auto antibodies positive while ICA was negative in total 98(100%) subjects. Conclusion: Children with T1 DM possessed increased levels of anti-GAD antibodies, insulin autoantibodies and anti (IA2) but islet cells antibodies were negligible in our population when checked at a point of time. C-peptide may be normal in some, but its level declines with long duration of diabetes in children.

Prevalence of Generalized Anxiety Disorder in Japan: A General Population Survey.

Purpose: Generalized anxiety disorder (GAD) is among the most prevalent and highly disabling mental health conditions that negatively impacts patient's quality of life (QOL) and disrupts activities of daily living. However, the recognition of GAD is difficult due to substantial overlap with other mental disorders. The purpose of this study was to estimate the prevalence of GAD, assess QOL of probable GAD patients in Japan, and gain insights on the status of visiting medical institutions as well as their recognition/awareness of the disorder. Patients and Methods: We conducted a web-based cross-sectional survey of 20,009 participants using a questionnaire with approximately 30 single/multiple choice or open-ended questions in Japanese. Results: Overall prevalence of GAD based on Generalized Anxiety Disorder 7-item (GAD-7) cutoff score of ≥10 and questionnaires developed with reference to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria was 7.6% (n=1530) and 6.0% (n=1197), respectively. The degree of coincidence between GAD diagnosis by DSM-5 criteria and GAD-7 scores was moderate (Cohen's Kappa=0.47, p<0.01). Younger people reported a substantially higher prevalence of GAD compared to older. QOL scores assessed using EuroQol 5 dimensions 5-level and EuroQol Visual Analog Scale were substantially lower in probable GAD patients than those with GAD-7<10. Anxiety/depression and pain/discomfort were the most prevalent issues and depression was the most reported comorbidity for the probable GAD patients. Probable GAD patients "currently visiting medical institutions" for anxiety or other mental issues were 27.6% (422/1530); a majority had seen specialists. Most of the probable GAD patients had never heard of the disease. Conclusion: We found higher prevalence of GAD and lower QOL of probable GAD patients in Japan. There is a need for creating awareness about GAD among the general population and developing clinical guidelines on GAD in Japan so that physicians can educate their patients.

Antibodies against glutamic acid decarboxylase in intravenous immunoglobulin preparations can affect the diagnosis of type 1 diabetes mellitus.

BACKGROUND AND OBJECTIVES: Intravenous immunoglobulins (IVIgs) contain various autoantibodies, including those against glutamic acid decarboxylase (GADAb), a valuable biomarker of type 1 diabetes mellitus. Passive transfer of GADAb from IVIgs to patients poses a risk of misdiagnosis, and information on the specific titres of GADAb and their impact on diagnostic accuracy remains limited. This study aimed to provide further insights into the origin of GADAb detected in patient serum following IVIg infusion. MATERIALS AND METHODS: GADAb titres in IVIg products from Japan and the United States were measured using enzyme-linked immunosorbent assay-based assays. For reliable quantification, GADAb titres in pooled plasma were quantified and compared with those in the IVIg products. The determined titres were used to estimate the likelihood of passively detecting acquired GADAb in individuals receiving IVIgs. RESULTS: GADAbs were prevalent in IVIg products; however, the titres varied significantly among different lots and products. Importantly, IVIg-derived GADAb was estimated to remain detectable in patient serum for up to 100 days following a dosage of 2000 mg/kg. CONCLUSION: Clinicians should consider that IVIg preparations may contain GADAb, which can lead to false-positive results in serological assays. Careful interpretation of the assay results is key to the definitive diagnosis of type 1 diabetes mellitus.

The Impact of COVID on Adolescent Anxiety: Trends, Clinical Considerations, and Treatment Recommendations.

Rates of clinical anxiety have increased during COVID and post-quarantine in youth, with older adolescent girls and youth with minorized racial, gender, and sexuality identities most vulnerable. Given that increased anxiety to a threatening/uncertain environment is adaptive, it is important to conceptualize anxiety from a balanced perspective, evaluating its functionality. For adolescents continuing to struggle with re-integration into their social environments and school avoidance, an exposure framework is necessary to encourage approach behaviors to recalibrate the social environment as safe. Disproportion between demand for services and available providers increased greatly due to the pandemic. Evidence-based treatments for anxiety can be delivered via telehealth, in school, or in primary care settings.

Steroidogenic Factor-1 Regulation of Dorsomedial Ventromedial Hypothalamic Nucleus Ghrh Neuron Transmitter Marker and Estrogen Receptor Gene Expression in Male Rat.

Ventromedial hypothalamic nucleus (VMN) growth hormone-releasing hormone (Ghrh) neurotransmission shapes counterregulatory hormone secretion. Dorsomedial VMN Ghrh neurons express the metabolic-sensitive transcription factor steroidogenic factor-1/NR5A1 (SF-1). In vivo SF-1 gene knockdown tools were used here to address the premise that in male rats, SF-1 may regulate basal and/or hypoglycemic patterns of Ghrh, co-transmitter biosynthetic enzyme, and estrogen receptor (ER) gene expression in these neurons. Single-cell multiplex qPCR analyses showed that SF-1 regulates basal profiles of mRNAs that encode Ghrh and protein markers for neurochemicals that suppress (γ-aminobutyric acid) or enhance (nitric oxide; glutamate) counterregulation. SF-1 siRNA pretreatment respectively exacerbated or blunted hypoglycemia-associated inhibition of glutamate decarboxylase67 (GAD67/GAD1) and -65 (GAD65/GAD2) transcripts. Hypoglycemia augmented or reduced nitric oxide synthase and glutaminase mRNAs, responses that were attenuated by SF-1 gene silencing. Ghrh and Ghrh receptor transcripts were correspondingly refractory to or increased by hypoglycemia, yet SF-1 knockdown decreased both gene profiles. Hypoglycemic inhibition of ER-alpha and G protein-coupled-ER gene expression was amplified by SF-1 siRNA pretreatment, whereas as ER-beta mRNA was amplified. SF-1 knockdown decreased (corticosterone) or elevated [glucagon, growth hormone (GH)] basal counterregulatory hormone profiles, but amplified hypoglycemic hypercorticosteronemia and -glucagonemia or prevented elevated GH release. Outcomes document SF-1 control of VMN Ghrh neuron counterregulatory neurotransmitter and ER gene transcription. SF-1 likely regulates Ghrh nerve cell receptivity to estradiol and release of distinctive neurochemicals during glucose homeostasis and systemic imbalance. VMN Ghrh neurons emerge as a likely substrate for SF-1 control of glucose counterregulation in the male rat.

Ligands of the trace amine-associated receptors (TAARs): A new class of anxiolytics.

Most cases of anxiety are currently treated with either benzodiazepines or serotonin reuptake inhibitors. These drugs carry with them risks for a multitude of side effects, and patient compliance suffers for this reason. There is thus a need for novel anxiolytics, and among the most compelling prospects in this vein is the study of the TAARs. The anxiolytic potential of ulotaront, a full agonist at the human TAAR1, is currently being investigated in patients with generalized anxiety disorder. Irrespective of whether this compound succeeds in clinical trials, a growing body of preclinical literature underscores the relevance of modulating the TAARs in anxiety. Multiple behavioral paradigms show anxiolytic-like effects in rodents, possibly due to increased neurogenesis and plasticity, in addition to a panoply of interactions between the TAARs and other systems. Crucially, multiple lines of evidence suggest that the TAARs, particularly TAAR1, TAAR2, and TAAR5, are expressed in the extended amygdala and hippocampus. These regions are central in the actuation of anxiety, and are particularly susceptible to neurogenic and neuroplastic effects which the TAARs are now known to regulate. The TAARs also regulate the dopamine and serotonin systems, both of which are implicated in anxiety. Ligands of the TAARs may thus constitute a new class of anxiolytics.

Glucose transporter-2 regulation of VMN GABA neuron metabolic sensor and transmitter gene expression.

Glucose transporter-2 (GLUT2) monitors cellular glucose uptake. Astrocyte GLUT2 controls glucose counterregulatory hormone secretion. In vivo gene silencing and laser-catapult-microdissection tools were used here to investigate whether ventromedial hypothalamic nucleus (VMN) GLUT2 may regulate dorsomedial (VMNdm) and/or ventrolateral (VMNvl) γ-aminobutyric acid (GABA) neurotransmission to control this endocrine outflow in female rats. VMN GLUT2 gene knockdown suppressed or stimulated hypoglycemia-associated glutamate decarboxylase (GAD)1 and GAD2 mRNA expression in VMNdm versus VMNvl GABAergic neurons, respectively. GLUT2 siRNA pretreatment also modified co-expressed transmitter marker gene profiles in each cell population. VMNdm GABA neurons exhibited GLUT2 knockdown-sensitive up-regulated 5'-AMP-activated protein kinase-alpha1 (AMPKα1) and -alpha2 (AMPKα2) transcripts during hypoglycemia. Hypoglycemic augmentation of VMNvl GABA neuron AMPKα2 was refractory to GLUT2 siRNA. GLUT2 siRNA blunted (VMNdm) or exacerbated (VMNvl) hypoglycemic stimulation of GABAergic neuron steroidogenic factor-1 (SF-1) mRNA. Results infer that VMNdm and VMNvl GABA neurons may exhibit divergent, GLUT2-dependent GABA neurotransmission patterns in the hypoglycemic female rat. Data also document differential GLUT2 regulation of VMNdm versus VMNvl GABA nerve cell SF-1 gene expression. Evidence for intensification of hypoglycemic hypercorticosteronemia and -glucagonemia by GLUT2 siRNA infers that VMN GLUT2 function imposes an inhibitory tone on these hormone profiles in this sex.

Sleep Health and Anxiety Symptoms in Midlife Women: The Study of Women's Health Across the Nation (SWAN).

Purpose: To investigate the associations between anxiety symptoms in midlife women and sleep features later in life, the aim is to test the hypothesis that poor sleep, as measured by each of six individual dimensions (4 objective actigraphy measures, 2 self-reports) of sleep health, is associated with higher levels of anxiety symptoms in midlife women. Participants and Methods: The participants in this longitudinal analysis included women from the SWAN Sleep I Study, a subcohort of the community-dwelling midlife women participating in the core Study of Women's Health Across the Nation (SWAN), which was initiated in 1996. Of the 370 participants enrolled in the Sleep Study, 270 were included in the analytic sample, and 100 who did not meet the inclusion criteria were excluded. Baseline measures of six dimensions of multidimensional sleep health (actigraphy measures: efficiency, duration, mid-sleep timing, regularity; self-report measures: alertness, satisfaction) were obtained between 2003 and 2005, corresponding to SWAN core annual/biennial assessments 5-8. Associations of each dimension with self-reported anxiety symptoms (Generalized Anxiety Disorder - 7-item scale; GAD-7), collected during visits 12 (2009-2011), 13 (2011-2013), and 15 (2015-2017), were examined using mixed models. The GAD-7 outcome was measured both continuously and as a categorical variable due to its skewed distribution. Results: No statistically significant associations were found between any of the six baseline sleep health dimensions and the GAD-7 score after adjustment for covariates. Conclusion: The reasons for the lack of support for our hypothesis, despite previous evidence supporting an association between sleep and anxiety, are unclear. There is considerable overlap between anxiety and sleep symptoms, which may complicate the interpretation of our the findings. Thus, the failure to identify associations is likely multifactorial, and more studies with shorter follow-up intervals are warranted to better understand these relationships.

Integrating EEG and Ensemble Learning for Accurate Grading and Quantification of Generalized Anxiety Disorder: A Novel Diagnostic Approach.

Current assessments for generalized anxiety disorder (GAD) are often subjective and do not rely on a standardized measure to evaluate the GAD across its severity levels. The lack of objective and multi-level quantitative diagnostic criteria poses as a significant challenge for individualized treatment strategies. To address this need, this study aims to establish a GAD grading and quantification diagnostic model by integrating an electroencephalogram (EEG) and ensemble learning. In this context, a total of 39 normal subjects and 80 GAD patients were recruited and divided into four groups: normal control, mild GAD, moderate GAD, and severe GAD. Ten minutes resting state EEG data were collected for every subject. Functional connectivity features were extracted from each EEG segment with different time windows. Then, ensemble learning was employed for GAD classification studies and brain mechanism analysis. Hence, the results showed that the Catboost model with a 10 s time window achieved an impressive 98.1% accuracy for four-level classification. Particularly, it was found that those functional connections situated between the frontal and temporal lobes were significantly more abundant than in other regions, with the beta rhythm being the most prominent. The analysis framework and findings of this study provide substantial evidence for the applications of artificial intelligence in the clinical diagnosis of GAD.

Comparative Analysis of High-Frequency and Low-Frequency Transcutaneous Electrical Stimulation of the Right Median Nerve in the Regression of Clinical and Neurophysiological Manifestations of Generalized Anxiety Disorder.

Background/Objectives: The anxiolytic effect of transcutaneous electrical nerve stimulation (TENS) is associated with the activation of endogenous inhibitory mechanisms in the central nervous system. Both low-frequency, high-amplitude TENS (LF-TENS) and high-frequency, low-amplitude TENS (HF-TENS) are capable of activating opioid, GABA, serotonin, muscarinic, and cannabinoid receptors. However, there has been no comparative analysis of the effectiveness of HF-TENS and LF-TENS in the treatment of GAD. The purpose of our research was to study the effectiveness of direct HF-TENS and LF-TENS of the right median nerve in the treatment of patients with GAD compared with sham TENS. Methods: The effectiveness of direct HF-TENS and LF-TENS of the right median nerve in the treatment of GAD was studied using Generalized Anxiety Disorder 7-item scale (GAD-7) and the Hamilton Anxiety Rating Scale (HAM-A). 40 patients underwent sham TENS, 40 patients passed HF-TENS (50 Hz-50 µs-sensory response) and 41 patients completed LF -TENS (1 Hz-200 µs-motor response) for 30 days daily. After completion of treatment, half of the patients received weekly maintenance therapy for 6 months. Electroencephalography was performed before and after treatment. Results: Our study showed that a significant reduction in the clinical symptoms of GAD as assessed by GAD-7 and HAM-A was observed after HF-TENS and LF-TENS by an average of 42.4%, and after sham stimulation only by 13.5% for at least 2 months after the end of treatment. However, LF-TENS turned out to be superior in effectiveness to HF-TENS by 51% and only on electroencephalography leads to an increase in PSD for the alpha rhythm in the occipital regions by 24% and a decrease in PSD for the beta I rhythm in the temporal and frontal regions by 28%. The prolonged effect of HF-TENS and LF-TENS was maintained without negative dynamics when TENS treatment was continued weekly throughout the entire six-month observation period. Conclusions: A prolonged anxiolytic effect of direct TENS of the right median nerve has been proven with greater regression of clinical and neurophysiological manifestations of GAD after LF-TENS compared to HF-TENS. Minimal side effects, low cost, safety, and simplicity of TENS procedures are appropriate as a home treatment modality.

Psychological status of pregnant women during the omicron pandemic outbreak in China.

BACKGROUND: Pregnant women faced great challenges and psychological and physiological changes of varying degrees during the omicron epidemic outbreak. It is important to recognize the potential impact of these challenges on the mental health of pregnant women and to provide appropriate resources and support to mitigate their effects. METHOD: By using the convenience sampling approach, a total of 401 pregnant women from two hospitals of different grades in two cities were included in the survey. The cross-sectional survey was conducted by basic characteristics, Generalized Anxiety Disorder (GAD-7), Patient Health Questionnaire (PHQ-9), Insomnia Severity Index (ISI) and self-made questionnaire. RESULTS: Insomnia affected 207 participants (51.6%), depression affected 160 participants (39.9%) and anxiety affected 151 participants (37.7%). Moreover, pregnant women in provincial capital city were more likely to experience anxiety, depression and insomnia than those in county-level city (P < 0.01). Pregnant women's anxiety, depression and insomnia were positively correlated with the severity of COVID-19 infection (P < 0.05). However, COVID-19 infection had no appreciable impact on maternal demand for termination of pregnancy and cesarean section (P > 0.05). CONCLUSION: Pregnant women frequently suffer from anxiety disorder, depression and insomnia as a result of the omicron pandemic in China. During this period, the community and medical professionals should provide more psychological counseling, conduct health education and offer virtual prenatal care to pregnant women (particularly in the provincial capital city).

Comparison of first-year nursing students' GAD-7 scores: a pilot study focusing on Generation Z.

BACKGROUND: In a post-pandemic landscape, Generation Z (Gen Z) nursing students are increasingly facing mental health challenges, notably anxiety. This study investigated these challenges among first-year nursing students. AIMS: The primary objective was to assess self-reported anxiety levels in first-year undergraduate nursing students, focusing on Gen Z, before or at the onset of their initial clinical placement post-pandemic. METHODS: Employing a cross-sectional design, this study used the Generalized Anxiety Disorder-7 (GAD-7) questionnaire to evaluate anxiety levels. It encompassed first-year nursing students from various fields at a university in North East England, considering generational differences, field of nursing, and demographic variables. FINDINGS: Results indicated anxiety levels among generational groups, with Gen Z students exhibiting extreme variations. Notably, students in Mental Health Nursing reported less anxiety than their counterparts in other nursing fields. The study also sheds light on the ramifications of the COVID-19 pandemic on student mental health. CONCLUSIONS: The study underscores the necessity for bespoke support systems in educational and clinical environments, particularly for Gen Z students. It advocates for comprehensive strategies in universities and clinical settings to nurture nursing students' emotional health, thereby enhancing their resilience and long-term career prospects.

The universality of anxiety experiences between Germany, Indonesia, and the US: A measurement invariance analysis.

BACKGROUND: Generalized Anxiety Disorder-7 (GAD-7) is a widely used self-report that assesses generalized anxiety disorder symptomatology. Whilst previous studies have reported good-to-excellent psychometric properties across different languages, it remains unclear whether GAD-7 measures the same construct across Western and non-Western countries. Here, we tested the hypothesis that the GAD-7 is measurement invariant across Western and non-Western countries and the hypothesis that a less severe GAD symptomatology can be found in non-Western countries. METHODS: The present study employed an online survey to examine the GAD-7's measurement invariance (MI) across community samples from Indonesia, Germany, and the USA (N = 2350). MI was computed using multiple-group confirmatory factor analyses with a general factor model of the GAD-7. RESULTS: The general factor of the GAD-7 had good model fit and configural, metric, scalar, and residual MI across the three countries. No significant differences were found in mean scores (Indonesia, M = 1.78, SD = 0.64, Germany, M = 1.84, SD = 0.69, USA, M = 1.87, SD = 0.79; F (2, 1514) = 3.079, p = 0.046; Games-Howell post-hoc analysis, tGermany-Indonesia = 1.720, p = 0.199; tGermany-USA = 0.750, p = 0.734; tIndonesia-USA = 2.330, p = 0.053). LIMITATIONS: This study's online nature may have inflated cross-country similarities and reduced data generalizability. CONCLUSION: The full MI demonstrates the GAD-7 captures the same GAD construct across Western and non-Western countries. Inconsistent with the previous findings GAD severity levels were similar across countries. Despite some possible reservations, the GAD-7 appears to be a culturally fair GAD measure.

Genome-wide identification and expression analysis of the GAD family reveal their involved in embryogenesis and hormones responses in Dimocarpus longan Lour.

Glutamate decarboxylase (GAD) is involved in GABA metabolism and plays an essential regulatory role in plant growth, abiotic stresses, and hormone response. This study investigated the expression mechanism of the GAD family during longan early somatic embryogenesis (SE) and identified 6 GAD genes based on the longan genome. Homology analysis indicated that DlGAD genes had a closer relationship with dicotyledonous plants. The analysis of cis-acting elements in the promoter region suggests that the GAD genes were associated with various stress responses and hormones. RNA sequencing (RNA-Seq) and the qRT-PCR data indicated that most DlGAD genes were highly expressed in the incomplete compact pro-embryogenic cultures (ICpEC) and upregulated in longan embryogenic callus (EC) after treatments with 2,4-D, high temperature (35 °C), IAA, and ABA. Moreover, the RNA-Seq analysis also revealed that DlGADs exhibit different expression patterns in various tissues and organs. The subcellular localization results showed that DlGAD5 was localized in the cytoplasm, suggesting that it played a role in the cytoplasm. Transient overexpression of DlGAD5 enhanced the expression levels of DlGADs and increased the activity of glutamate decarboxylase in longan embryogenic callus (EC), while the content of glutamic acid decreased. Thus, the DlGAD gene can play an important role in the early somatic embryogenesis of longan by responding to hormones such as IAA and ABA. DlGAD5 can affect the growth and development of longan by stimulating the expression of the DlGAD gene family, thereby increasing the GAD activity in the early SE of longan, participating in hormone synthesis and signaling pathways.

GHSR in a Subset of GABA Neurons Controls Food Deprivation-Induced Hyperphagia in Male Mice.

The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)-producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2-expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)-expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2-expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation-induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice.

Childhood screening for type 1 diabetes comparing automated multiplex Antibody Detection by Agglutination-PCR (ADAP) with single plex islet autoantibody radiobinding assays.

BACKGROUND: Two or more autoantibodies against either insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A) or zinc transporter 8 (ZnT8A) denote stage 1 (normoglycemia) or stage 2 (dysglycemia) type 1 diabetes prior to stage 3 type 1 diabetes. Automated multiplex Antibody Detection by Agglutination-PCR (ADAP) assays in two laboratories were compared to single plex radiobinding assays (RBA) to define threshold levels for diagnostic specificity and sensitivity. METHODS: IAA, GADA, IA-2A and ZnT8A were analysed in 1504 (54% females) population based controls (PBC), 456 (55% females) doctor's office controls (DOC) and 535 (41% females) blood donor controls (BDC) as well as in 2300 (48% females) patients newly diagnosed (1-10 years of age) with stage 3 type 1 diabetes. The thresholds for autoantibody positivity were computed in 100 10-fold cross-validations to separate patients from controls either by maximizing the χ2-statistics (chisq) or using the 98th percentile of specificity (Spec98). Mean and 95% CI for threshold, sensitivity and specificity are presented. FINDINGS: The ADAP ROC curves of the four autoantibodies showed comparable AUC in the two ADAP laboratories and were higher than RBA. Detection of two or more autoantibodies using chisq showed 0.97 (0.95, 0.99) sensitivity and 0.94 (0.91, 0.97) specificity in ADAP compared to 0.90 (0.88, 0.95) sensitivity and 0.97 (0.94, 0.98) specificity in RBA. Using Spec98, ADAP showed 0.92 (0.89, 0.95) sensitivity and 0.99 (0.98, 1.00) specificity compared to 0.89 (0.77, 0.86) sensitivity and 1.00 (0.99, 1.00) specificity in the RBA. The diagnostic sensitivity and specificity were higher in PBC compared to DOC and BDC. INTERPRETATION: ADAP was comparable in two laboratories, both comparable to or better than RBA, to define threshold levels for two or more autoantibodies to stage type 1 diabetes. FUNDING: Supported by The Leona M. and Harry B. Helmsley Charitable Trust (grant number 2009-04078), the Swedish Foundation for Strategic Research (Dnr IRC15-0067) and the Swedish Research Council, Strategic Research Area (Dnr 2009-1039). AL was supported by the DiaUnion collaborative study, co-financed by EU Interreg ÖKS, Capital Region of Denmark, Region Skåne and the Novo Nordisk Foundation.

Subjective and objective cognitive functioning in untreated late-life depression: An exploration centered on comorbid generalized anxiety disorder.

BACKGROUND: Late-Life Depression (LLD) is a prevalent mental health disorder that is often accompanied by cognitive impairments. The objective of this study is to investigate the influence of coexisting Generalized Anxiety Disorder (GAD) on both subjective and objective cognitive abilities in untreated LLD individuals. METHODS: A total of 77 participants aged 60 years and above were recruited for this study, comprising 31 individuals with Major Depressive Disorder (LLD group), 46 with MDD and coexisting Generalized Anxiety Disorder (LLDA group), and 54 healthy controls (HC). Prior to the study, all patients had abstained from psychotropic medication for a minimum of two weeks. Comprehensive neuropsychological assessments were administered to all participants. RESULTS: The LLDA group exhibited substantial disparities in memory, attention, processing speed,executive function,overall cognitive functioning, and subjective cognitive functioning when compared to the HC group. The LLD group displayed deficits in memory, SCWT-W in attention, SCWT-C in processing speed,overall cognitive functioning, and subjective cognitive functioning in comparison to the healthy controls. Although the LLD group achieved lower average scores in executive function, TMTA in processing speed, and DSST in attention than the HC group, no significant distinctions were identified between these groups in these domains. Linear regression analysis unveiled that anxiety symptoms had a significant impact on subjective cognitive deficits among MDD patients, but exhibited a milder influence on objective cognitive performance. After adjusting for the severity of depression, anxiety symptoms were found to affect TMTA in processing speed and subjective cognitive functioning in LLD patients. CONCLUSION: Late-Life Depression (LLD) exhibits pervasive cognitive impairments, particularly in individuals with generalized anxiety disorder, presenting a crucial target for future therapeutic interventions. Among elderly individuals with depression, anxiety symptoms significantly impact subjective cognitive functioning, suggesting its potential utility in distinguishing between depression-associated cognitive decline and pre-dementia conditions.

Diagnosis and Treatment of Generalized Anxiety Disorder in Japan: Psychiatric Specialist Survey.

Purpose: Generalized anxiety disorder (GAD) is a suboptimally managed chronic recurring psychiatric condition with a lifetime prevalence of 2.6% in Japan. We assessed the current status of GAD management in Japan. Patients and Methods: This was an observational, cross-sectional study conducted through an anonymous web-based survey in Japan from December 12-16, 2022. Psychiatrists and psychosomatic medicine physicians who agreed to participate and saw ≥10 outpatients in the previous month were eligible. Survey questionnaire comprised 37 single/multiple choice, numerical entry, or open-ended questions in Japanese. Results: Among 509 participants (493 psychiatrists and 16 psychosomatic medicine physicians), 96.9% were aware of GAD. On average, 12.4 outpatients and 1.0 inpatient were diagnosed with GAD per physician per month. Of 433 physicians having patients diagnosed with GAD, 46.9% used operational diagnostic tools; among these, DSM-5 diagnostic criteria were used by 81.5% physicians. The majority (54.7%) of participants did not use a self-administered rating scale; depression scales were used more than anxiety scales. Among these 433 physicians, 96.8% used selective serotonin reuptake inhibitors for GAD management, and 79.2% used it as the first choice; of 431 physicians who prescribed drug therapy, 54.3% gave antidepressant monotherapy as first choice. The most frequent symptom in patients diagnosed with GAD was excessive anxiety/worry (96.5%); depression was the most commonly reported comorbidity (84.3%) as per physicians aware of GAD (N=508). Conclusion: This study illustrates that although GAD awareness is high among Japanese psychiatric specialists, GAD is not frequently diagnosed using operational diagnostic approaches. Due to a lack of Japanese guidelines for GAD diagnosis and treatment, diverse international guidelines are followed, with similar treatment paradigms as that of depression. This may not be an optimal approach given cultural/geographical differences. These findings highlight the need for uniform diagnosis and treatment recommendations for GAD management in Japan. Clinical Trial Registration: UMIN-CTR: UMIN000049572.

Perturbing cortical networks: in vivo electrophysiological consequences of pan-neuronal chemogenetic manipulations using deschloroclozapine.

Introduction: Chemogenetic techniques, specifically the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have become invaluable tools in neuroscience research. Yet, the understanding of how Gq- and Gicoupled DREADDs alter local field potential (LFP) oscillations in vivo remains incomplete. Methods: This study investigates the in vivo electrophysiological effects of DREADD actuation by deschloroclozapine, on spontaneous firing rate and LFP oscillations recorded from the anterior cingulate cortex in lightly anesthetized male rats. Results: Unexpectedly, in response to the administration of deschloroclozapine, we observed inhibitory effects with pan-neuronal hM3D(Gq) stimulation, and excitatory effects with pan-neuronal hM4D(Gi) stimulation in a significant portion of neurons. These results emphasize the need to account for indirect perturbation effects at the local neuronal network level in vivo, particularly when not all neurons express the chemogenetic receptors uniformly. In the current study, for instance, the majority of cells that were transduced with both hM3D(Gq) and hM4D(Gi) were GABAergic. Moreover, we found that panneuronal cortical chemogenetic modulation can profoundly alter oscillatory neuronal activity, presenting a potential research tool or therapeutic strategy in several neuropsychiatric models and diseases. Discussion: These findings help to optimize the use of chemogenetic techniques in neuroscience research and open new possibilities for novel therapeutic strategies.