Apoptosis in neurodegenerative diseases: to be or not to be? Absence of proof is not proof of absence

Apoptosis (from Greek falling off) is a term coined by Kerr, Wyllie and Currie in 1972 to describe a form of cell death associated with peculiar morphological changes. They contrasted apoptosis with necrosis, in which large numbers of cells undergo destruction and elicit a regional inflammatory response. In contrast, in apoptosis individual cells die and are being removed quickly, without inflammation, making their demise often difficult to detect. The initial concept of apoptosis was exclusively related to a morphological phenomenon.Biomedical Reviews 1995; 4: 103-108

Embrace,: a model for integrated elderly care

Introduction: Societies worldwide are challenged by the ongoing growth in health care expenditures and changing patterns in demand for health care, especially regarding long-term care. Integrated care models promise to provide a solution to control these challenges. The Chronic Care Model (CCM) offers an evidence-based framework for this. To arrange a suitable level of care, the CCM can be combined with the Kaiser Permanente Triangle, a population management model. Embrace was based on these two models and is a population-based integrated care model for all community-living elderly people of 75 years and older. Practice: Based on the results of the annual screening, elderly people will be assigned to one of three risk profiles with corresponding care intensity levels (Robust, Frail and Complex care needs). Next, a multi-disciplinary Elderly Care Team (ECT) provides personalized, pro-active and preventive care and support. All elderly people are offered a self-management support and prevention program. Regarding elderly people in the Robust profile, attention is paid to participation in society, combined with education programs on preserving one’s health. Frail elderly people and elderly people with complex care needs are regularly visited by their case manager, a social worker and a district nurse, respectively. During the first home visit, the case manager administers a history questionnaire to identify (potential) problems. Next, a care and support plan is formulated in accordance with the clients’ needs and wishes. The plan is put into practice after consultation with the ECT. During subsequent visits, the case manager and the client discuss the situation and the progress of the care and support plan. The progress and effectiveness of the interventions is monthly discussed by the ECT. Research methods: The effectiveness of Embrace is being studied by means of a stratified randomized controlled trial (RCT) with balanced allocation of elderly participants to care as usual or Embrace. Patients from participating general practitioners, aged 75 years and older, and living at home or in a home for the elderly, were eligible for inclusion. The intervention lasts twelve months. Health outcomes for elderly people and their caregivers, as well as effects on quality of care, service use, and costs will be examined. Qualitative research will be conducted to determine patient and professional experiences with Embrace. Results and conclusion: Since January 2012, Embrace is put into practice in fifteen general practitioner practices in the province of Groningen, the Netherlands. In total,1,474 elderly people are participating. The qualitative study among elderly participants indicated that, due to regular attention, participants feel safe and secure and have the confidence to remain living at home. The qualitative study among case managers indicated that, due to the structural and continuous contacts with their clients, case managers identify problems early, take preventive actions and are more competent to meet the needs of their clients. Based on the business case, including all care and support costs related to the target population, it is expected that Embrace reduces service use and costs. Preliminary results of the RCT are expected in the beginning of 2014

No evidence for decreased D2/3 receptor availability and frontal hypoperfusion in subjects with compulsive pornography use

Pornographic addiction refers to an addiction model associated with compulsive and repeated use of pornographic material. Whether the use of pornography may indeed become addictive remains a matter of debate. The current study investigated whether compulsive pornography use (CPU) is accompanied by reduced D2/3 receptor availability in the striatum and frontal hypofunctionality. Male subjects between 18 and 50 years of age with and without CPU were recruited using online and newspaper advertisements. Questionnaires were used to the assess the severity of compulsive pornography use (CIUS) and symptoms of depression, impulsivity and sensation seeking. Dopaminergic imaging was performed using [11C]-raclopride PET. Striatal binding potentials (BPND) and regional frontal cerebral influx values (R1) of [11C]-raclopride were calculated. Arterial Spin Labeling (ASL) MRI was performed to assess regional cerebral blood flow. No group differences between striatal BPND's of [11C]-raclopride in subjects with (n = 15) and without (n = 10) CPU were detected. In CPU subjects, no correlation was found between the CIUS score and striatal BPND's. Cerebral R1 values in frontal brain regions and cerebral blood flow measurements did not differ between groups. The current study fails to provide imaging support for sharing similar neurobiological alterations as previously has been reported in other addictive modalities

Triangle Counting in Dynamic Graph Streams

Estimating the number of triangles in graph streams using a limited amount of memory has become a popular topic in the last decade. Different variations of the problem have been studied, depending on whether the graph edges are provided in an arbitrary order or as incidence lists. However, with a few exceptions, the algorithms have considered {\em insert-only} streams. We present a new algorithm estimating the number of triangles in {\em dynamic} graph streams where edges can be both inserted and deleted. We show that our algorithm achieves better time and space complexity than previous solutions for various graph classes, for example sparse graphs with a relatively small number of triangles. Also, for graphs with constant transitivity coefficient, a common situation in real graphs, this is the first algorithm achieving constant processing time per edge. The result is achieved by a novel approach combining sampling of vertex triples and sparsification of the input graph. In the course of the analysis of the algorithm we present a lower bound on the number of pairwise independent 2-paths in general graphs which might be of independent interest. At the end of the paper we discuss lower bounds on the space complexity of triangle counting algorithms that make no assumptions on the structure of the graph.Comment: New version of a SWAT 2014 paper with improved result

The Cyclic AMP Cascade Is Altered in the Fragile X Nervous System

Fragile X syndrome (FX), the most common heritable cause of mental retardation and autism, is a developmental disorder characterized by physical, cognitive, and behavioral deficits. FX results from a trinucleotide expansion mutation in the fmr1 gene that reduces levels of fragile X mental retardation protein (FMRP). Although research efforts have focused on FMRP's impact on mGluR signaling, how the loss of FMRP leads to the individual symptoms of FX is not known. Previous studies on human FX blood cells revealed alterations in the cyclic adenosine 3′, 5′-monophosphate (cAMP) cascade. We tested the hypothesis that cAMP signaling is altered in the FX nervous system using three different model systems. Induced levels of cAMP in platelets and in brains of fmr1 knockout mice are substantially reduced. Cyclic AMP induction is also significantly reduced in human FX neural cells. Furthermore, cAMP production is decreased in the heads of FX Drosophila and this defect can be rescued by reintroduction of the dfmr gene. Our results indicate that a robust defect in cAMP production in FX is conserved across species and suggest that cAMP metabolism may serve as a useful biomarker in the human disease population. Reduced cAMP induction has implications for the underlying causes of FX and autism spectrum disorders. Pharmacological agents known to modulate the cAMP cascade may be therapeutic in FX patients and can be tested in these models, thus supplementing current efforts centered on mGluR signaling

Mutations in Potassium Channel KCND3 Cause Spinocerebellar Ataxia Type 19

OBJECTIVE: To identify the causative gene for the neurodegenerative disorder spinocerebellar ataxia type 19 (SCA19) located on chromosomal region 1p21-q21. METHODS: Exome sequencing was used to identify the causal mutation in a large SCA19 family. We then screened 230 ataxia families for mutations located in the same gene (KCND3, also known as Kv4.3) using high-resolution melting. SCA19 brain autopsy material was evaluated, and in vitro experiments using ectopic expression of wild-type and mutant Kv4.3 were used to study protein localization, stability, and channel activity by patch-clamping. RESULTS: We detected a T352P mutation in the third extracellular loop of the voltage-gated potassium channel KCND3 that cosegregated with the disease phenotype in our original family. We identified 2 more novel missense mutations in the channel pore (M373I) and the S6 transmembrane domain (S390N) in 2 other ataxia families. T352P cerebellar autopsy material showed severe Purkinje cell degeneration, with abnormal intracellular accumulation and reduced protein levels of Kv4.3 in their soma. Ectopic expression of all mutant proteins in HeLa cells revealed retention in the endoplasmic reticulum and enhanced protein instability, in contrast to wild-type Kv4.3 that was localized on the plasma membrane. The regulatory β subunit Kv channel interacting protein 2 was able to rescue the membrane localization and the stability of 2 of the 3 mutant Kv4.3 complexes. However, this either did not restore the channel function of the membrane-located mutant Kv4.3 complexes or restored it only partially. INTERPRETATION: KCND3 mutations cause SCA19 by impaired protein maturation and/or reduced channel function

Physical Links: Defining and detecting inter-chain entanglement

Fluctuating filaments, from densely-packed biopolymers to defect lines in structured fluids, are prone to become interlaced and form intricate architectures. Understanding the ensuing mechanical and relaxation properties depends critically on being able to capture such entanglement in quantitative terms. So far, this has been an elusive challenge. Here we introduce the first general characterization of non-ephemeral forms of entanglement in linear curves by introducing novel descriptors that extend topological measures of linking from close to open curves. We thus establish the concept of physical links. This general method is applied to diverse contexts: equilibrated ring polymers, mechanically-stretched links and concentrated solutions of linear chains. The abundance, complexity and space distribution of their physical links gives access to a whole new layer of understanding of such systems and open new perspectives for others, such as reconnection events and topological simplification in dissipative fields and defect lines

Reaction rates and transport in neutron stars

Understanding signals from neutron stars requires knowledge about the transport inside the star. We review the transport properties and the underlying reaction rates of dense hadronic and quark matter in the crust and the core of neutron stars and point out open problems and future directions.Comment: 74 pages; commissioned for the book "Physics and Astrophysics of Neutron Stars", NewCompStar COST Action MP1304; version 3: minor changes, references updated, overview graphic added in the introduction, improvements in Sec IV.A.

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

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