Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations.

WHIM syndrome is typically caused by C-terminal gain-of-function variants in , yet clinical heterogeneity suggests additional genetic modifiers. We investigated a family in which the 22-year-old proband harbored two heterozygous variants: a novel missense variant, c.1022C>A (p.

Sequence-Dependent Repolarization Is Modulated by Endogenous Action Potential Duration Gradients Rather Than Electrical Coupling in Ventricular Myocardium.

Background: Previous studies suggest the relationship between activation time (AT) and action potential duration (APD) in the heart is dependent on electrotonic coupling, but this has not been directly tested. This study assessed whether acute changes in electrical coupling, or other determinants of conduction or repolarization, modulate APD heterogeneity.

Methods And Results: Langendorff-perfused guinea pig hearts were epicardially paced and optically mapped after treatment with the gap junction uncoupler carbenoxolone, ephaptic uncoupler mannitol, ephaptic enhancer dextran 2MDa, sodium channel inhibitor flecainide, or rapid component of the delayed rectifier potassium channel inhibitor E4031.

Expanding CXCR4 variant landscape in WHIM syndrome: integrating clinical and functional data for variant interpretation.

Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is a rare, combined immunodeficiency disease predominantly caused by gain-of-function variants in the gene that typically results in truncation of the carboxyl terminus of C-X-C chemokine receptor type 4 (CXCR4) leading to impaired leukocyte egress from bone marrow to peripheral blood. Diagnosis of WHIM syndrome continues to be challenging and is often made through clinical observations and/or genetic testing. Detection of a pathogenic variant in an affected individual supports the diagnosis of WHIM syndrome but relies on an appropriate annotation of disease-causing variants.

Mental health profiles and academic achievement in Australian school students.

This study explored mental health profiles in Australian school students using indicators of well-being (i.e., optimism, life satisfaction, and happiness) and psychological distress (i.

Mannitol and hyponatremia regulate cardiac ventricular conduction in the context of sodium channel loss of function.

Scn5a heterozygous null () mice have historically been used to investigate arrhythmogenic mechanisms of diseases such as Brugada syndrome (BrS) and Lev's disease. Previously, we demonstrated that reducing ephaptic coupling (EpC) in ex vivo hearts exacerbates pharmacological voltage-gated sodium channel (Na)1.5 loss of function (LOF).

Extracellular Perinexal Separation Is a Principal Determinant of Cardiac Conduction.

Background: Cardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in the heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular resistance.

Ephaptic Coupling Is a Mechanism of Conduction Reserve During Reduced Gap Junction Coupling.

Many cardiac pathologies are associated with reduced gap junction (GJ) coupling, an important modulator of cardiac conduction velocity (CV). However, the relationship between phenotype and functional expression of the connexin GJ family of proteins is controversial. For example, a 50% reduction of GJ coupling has been shown to have little impact on myocardial CV due to a concept known as conduction reserve.

Hypernatremia and intercalated disc edema synergistically exacerbate long-QT syndrome type 3 phenotype.

Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the long-QT syndrome type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function.

Basic epidemiology of wellbeing among children and adolescents: A cross-sectional population level study.

Wellbeing and mental health are fundamental rights of children and adolescents essential for sustainable development. Understanding the epidemiology of child and adolescent wellbeing is essential to informing population health approaches to improving wellbeing and preventing mental illness. The present study estimated the prevalence of wellbeing and how wellbeing indicators were distributed across social and economic groups.

The conduction velocity-potassium relationship in the heart is modulated by sodium and calcium.

The relationship between cardiac conduction velocity (CV) and extracellular potassium (K) is biphasic, with modest hyperkalemia increasing CV and severe hyperkalemia slowing CV. Recent studies from our group suggest that elevating extracellular sodium (Na) and calcium (Ca) can enhance CV by an extracellular pathway parallel to gap junctional coupling (GJC) called ephaptic coupling that can occur in the gap junction adjacent perinexus. However, it remains unknown whether these same interventions modulate CV as a function of K.

Childhood determinants of past-year anxiety and depression in recently transitioned military personnel.

Background: Anxiety and depression may hamper a smooth transition from military to civilian life and may be important predictors of longer-term health and functioning. However, it is as yet unclear to what extent they are determined by childhood factors in a recently transitioned population.

Methods: We utilised logistic regression and Generalised Structural Equation Modelling to analyse associations of ICD-10 past-year anxiety and depression with childhood trauma and disorder in a recently transitioned population using detailed interview data from the ADF (Australian Defence Force) Transition and Wellbeing Research Programme.

Childhood Trauma and Childhood Mental Disorder in Military and Employed Civilian Men.

We aimed to retrospectively investigate childhood trauma and childhood mental disorder in military and employed civilian men aged 18 to 54 years. Data, derived from the 2010 Australian Defence Force (ADF) Mental Health Prevalence and Wellbeing Study and the 2007 Australian Bureau of Statistics National Survey of Mental Health and Wellbeing Study, were analyzed and compared using direct age standardization and logistic regression. A greater proportion of ADF reported childhood trauma, multiple trauma types, trauma onset below 12 years of age, and interpersonal trauma than civilian employed men.

Associations Among Childhood Trauma, Childhood Mental Disorders, and Past-Year Posttraumatic Stress Disorder in Military and Civilian Men.

To identify early life factors associated with posttraumatic stress disorder (PTSD), we investigated the association between childhood trauma and mental disorders with International Classification of Diseases (ICD)-diagnosed past-year PTSD in employed military and civilian men. Data were derived from the 2010 Australian Defence Force (ADF) Mental Health Prevalence and Wellbeing Study (N = 1,356) and the 2007 Australian Bureau of Statistics (ABS) National Survey of Mental Health and Wellbeing Study (N = 2,120) and analyzed using logistic regression and generalized structural equation modeling. After controlling for demographics, PTSD was associated with childhood anxiety, adjusted odds ratio (AOR) = 3.

Associations of childhood trauma and childhood mental disorder with past-year mental disorder in military and civilian employed men.

Childhood factors are pivotal to understanding mental health over the lifespan. However, there is a dearth of research exploring childhood trauma and childhood disorder simultaneously in determining adult mental disorder. We aimed to analyze childhood trauma and childhood disorder in determining past-year disorder in military and civilian employed men aged 18-60 years.

Childhood trauma and the impact of deployment on the development of mental disorder in military males.

Background: Childhood adversity is associated with mental disorder following military deployment. However, it is unclear how different childhood trauma profiles relate to developing a post-deployment disorder. We investigated childhood trauma prospectively in determining new post-deployment probable disorder.

Aged rats with preserved memory dynamically recruit hippocampal inhibition in a local/global cue mismatch environment.

Similar to elderly humans, aged outbred Long-Evans rats exhibit individual differences in memory abilities, including a subset of aged rats that maintain memory function on par with young adults. Such individuals provide a basis for investigating mechanisms of resilience to age-related decline. The present study examined hippocampal gene expression in young adults and aged rats with preserved memory function under behavioral task conditions well established for assessing information processing central to the formation of episodic memory.

Social disparities in the prevalence of diabetes in Australia and in the development of end stage renal disease due to diabetes for Aboriginal and Torres Strait Islanders in Australia and Maori and Pacific Islanders in New Zealand.

Background: Disparities in health status occur between people with differing socioeconomic status and disadvantaged groups usually have the highest risk exposure and the worst health outcome. We sought to examine the social disparities in the population prevalence of diabetes and in the development of treated end stage renal disease due to type 1 diabetes which has not previously been studied in Australia and New Zealand in isolation from type 2 diabetes.

Methods: This observational study examined the population prevalence of diabetes in a sample of the Australian population (7,434,492) using data from the National Diabetes Services Scheme and of treated end stage renal disease due to diabetes using data from the Australian and New Zealand Dialysis and Transplant Registry.

The impact of antecedent trauma exposure and mental health symptoms on the post-deployment mental health of Afghanistan-deployed Australian troops.

Background: Both traumatic deployment experiences and antecedent traumas increase personnel's risk of developing PTSD and depression. However, only cross-sectional studies have assessed whether antecedent trauma moderates stress reactions to deployment experiences. This study prospectively examines whether antecedent trauma moderates the association between deployment trauma and post-deployment PTSD and depressive symptoms after accounting for antecedent mental health problems, in a large Australian Defence Force (ADF) sample.

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward.

Unlabelled: The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity.

Residential Location and Kidney Transplant Outcomes in Indigenous Compared With Nonindigenous Australians.

Background: Indigenous Australians experience significantly worse graft and patient outcomes after kidney transplantation compared with nonindigenous Australians. It is unclear whether rural versus urban residential location might contribute to this.

Methods: All adult patients from the Australia and New Zealand Dialysis and Transplant Registry who received a kidney transplant in Australia between January 1, 2000, and December 31, 2012, were investigated.

Racial disparities in pediatric kidney transplantation in New Zealand.

Racial disparities in transplantation rates and outcomes have not been investigated in detail for NZ, a country with unique demographics. We studied a retrospective cohort of 215 patients <18 yr who started renal replacement therapy in NZ 1990-2012, using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). Primary outcomes were time to first kidney transplant, death-censored graft survival, and retransplantation after loss of primary graft.