CACNA1C-Related Channelopathies.

The CACNA1C gene encodes the pore-forming subunit of the CaV1.2 L-type Ca2+ channel, a critical component of membrane physiology in multiple tissues, including the heart, brain, and immune system. As such, mutations altering the function of these channels have the potential to impact a wide array of cellular functions. The first mutations identified within CACNA1C were shown to cause a severe, multisystem disorder known as Timothy syndrome (TS), which is characterized by neurodevelopmental deficits, long-QT syndrome, life-threatening cardiac arrhythmias, craniofacial abnormalities, and immune deficits. Since this initial description, the number and variety of disease-associated mutations identified in CACNA1C have grown tremendously, expanding the range of phenotypes observed in affected patients. CACNA1C channelopathies are now known to encompass multisystem phenotypes as described in TS, as well as more selective phenotypes where patients may exhibit predominantly cardiac or neurological symptoms. Here, we review the impact of genetic mutations on CaV1.2 function and the resultant physiological consequences.

Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis.

Pathological and clinical studies implicate antibody-dependent mechanisms in the immunopathogenesis of multiple sclerosis. We tested this hypothesis directly by investigating the ability of patient-derived immunoglobulins to mediate demyelination and axonal injury in vitro. Using a myelinating culture system, we developed a sensitive and reproducible bioassay to detect and quantify these effects and applied this to investigate the pathogenic potential of immunoglobulin G preparations obtained from patients with multiple sclerosis (n = 37), other neurological diseases (n = 10) and healthy control donors (n = 13). This identified complement-dependent demyelinating immunoglobulin G responses in approximately 30% of patients with multiple sclerosis, which in two cases was accompanied by significant complement-dependent antibody mediated axonal loss. No pathogenic immunoglobulin G responses were detected in patients with other neurological disease or healthy controls, indicating that the presence of these demyelinating/axopathic autoantibodies is specific for a subset of patients with multiple sclerosis. Immunofluorescence microscopy revealed immunoglobulin G preparations with demyelinating activity contained antibodies that specifically decorated the surface of myelinating oligodendrocytes and their contiguous myelin sheaths. No other binding was observed indicating that the response is restricted to autoantigens expressed by terminally differentiated myelinating oligodendrocytes. In conclusion, our study identifies axopathic and/or demyelinating autoantibody responses in a subset of patients with multiple sclerosis. This observation underlines the mechanistic heterogeneity of multiple sclerosis and provides a rational explanation why some patients benefit from antibody depleting treatments.

Human and cattle ergotism since 1900: symptoms, outbreaks, and regulations.

Ergotism in humans and cattle are caused by several species of Claviceps that infect rye and other cereal grains. Symptoms in humans vary greatly and are generally classified as convulsive, gangrenous, or gastrointestinal (enteric). Cattle are particularly susceptible to both gangrenous and hyperthermic ergotism (also called summer syndrome). The prevalence of ergotism has decreased as knowledge of the fungus has increased, mainly through implementation of regulations and advances in milling procedures. However, outbreaks in humans have recently occurred in lower socioeconomic populations of Ethiopia (1977 and 2001) and India (1975) with devastating results. Prominent outbreaks in cattle have occurred in Australia (1987), the United States (1996), South Africa (1996-1997), and Brazil (1999) and, as opposed to human cases, they do not appear to be bound by economic development. This review provides a detailed summary of all major ergot epidemics since 1900 in both humans and cattle. Special attention is devoted to the ergotism symptoms and to the regulations surrounding the control of ergot in the food supply.

Calmodulin Mutations in Human Disease.

Calcium ions (Ca2+) are the basis of a unique and potent array of cellular responses. Calmodulin (CaM) is a small but vital protein that is able to rapidly transmit information about changes in Ca2+ concentrations to its regulatory targets. CaM plays a critical role in cellular Ca2+ signaling, and interacts with a myriad of target proteins. Ca2+-dependent modulation by CaM is a major component of a diverse array of processes, ranging from gene expression in neurons to the shaping of the cardiac action potential in heart cells. Furthermore, the protein sequence of CaM is highly evolutionarily conserved, and identical CaM proteins are encoded by three independent genes (CALM1-3) in humans. Mutations within any of these three genes may lead to severe cardiac deficits including severe long QT syndrome (LQTS) and/or catecholaminergic polymorphic ventricular tachycardia (CPVT). Research into disease-associated CaM variants has identified several proteins modulated by CaM that are likely to underlie the pathogenesis of these calmodulinopathies, including the cardiac L-type Ca2+ channel (LTCC) CaV1.2, and the sarcoplasmic reticulum Ca2+ release channel, ryanodine receptor 2 (RyR2). Here, we review the research that has been done to identify calmodulinopathic CaM mutations and evaluate the mechanisms underlying their role in disease.

How integrating primary care and public health could improve population health outcomes: a view from Liverpool, UK.

Although primary care is at the forefront of delivering healthcare to the population, its role in preventing poor health has varied throughout history. Faced with growing demand on healthcare services and a rise in noncommunicable diseases, some health systems are attempting to integrate healthcare delivery with broader population health and wellbeing interventions. Liverpool has a rich history of taking action to improve population health; this paper discusses a range of interventions that have taken place across the city. There is a renewed opportunity to systematise approaches to primary and secondary prevention, strengthened by the lead that general practitioners now have in commissioning health services and their accountability for improved population health outcomes through clinical commissioning groups. This is strongly articulated in the Healthy Liverpool program, a city-wide plan for health and care services. This paper suggests that four key enablers strengthen delivery of public health priorities through primary care: maximising opportunities to identify risk factors for preventable disease, fully exploiting the data collected in primary care to plan and design services, responding to community needs and assets through community engagement, and addressing wider determinants of health through strong partnerships.