37781778
[Free radicals and ailing proteins--the culprits behind Parkinson disease?].
Parkinson's disease is one of the most common neurodegenerative diseases, and affects approximately 1% of the population over 65 years of age. Many different insults appear to be involved in the etiology of the disease, among them environmental toxins and mitochondrial dysfunction. During the past five years, mutations in five different genes have been linked to rare, familial forms of Parkinson's disease. One of the mutated proteins, alpha-synuclein is normally implicated in synaptic plasticity and vesicle function. Dysfunction of this protein might lead to increased cytoplasmic dopamine levels. Since cytoplasmic dopamine is readily prone to autooxidation and enzymatic degradation--processes which generate reactive oxygen species--failure to properly store dopamine into vesicles might lead to oxidative stress. Indeed, nigral tissue from idiopathic Parkinson's disease patients shows signs of oxidative damage. In this article we propose that dopamine-induced oxidative stress might be a common final pathway in the pathogenesis of the disease.
17250985
Loss of SNAP-25 and rabphilin 3a in sensory-motor cortex in Huntington's disease.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG-expansion in the gene encoding the protein huntingtin. The disease is characterized by progressive motor disturbances, cognitive defects, dementia, and weight loss. Using western blotting and immunohistochemistry we have assessed the expression levels and patterns of a number of proteins involved in neurotransmitter release in post-mortem frontal cortex samples from 10 HD cases with different disease grades. We report a loss of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, synaptosome-associated protein 25 (SNAP 25) in HD brains of grades I-IV. Moreover, in brains of grade III and IV we found a reduction in rabphilin 3a, a protein involved in vesicle docking and recycling. These losses appear to be specific and not due to a general loss of synapses in the HD cortex. Thus, levels of synaptobrevin II, syntaxin 1, rab3a or synaptophysin are unaltered in the same patient samples. SNAP 25 and rabphilin 3a are crucial for neurotransmitter release. Therefore, we suggest that a deficient pre-synaptic transmitter release may underlie some of the symptoms of HD.
23578107
Synaptic dysfunction in Huntington’s disease: a new perspective
Abstract.Huntington’s disease (HD) is caused by a polyglutamine expansion in the protein huntingtin and is characterized by intraneuronal inclusions and widespread neuronal death at the late stage of the disease. In research, most of the emphasis has been on understanding the cell death and its mechanisms. Until recently, it was believed that the vast majority, if not all, of the symptoms in HD are a direct consequence of neurodegeneration. However, increasing evidence shows that subtle alterations in synaptic function could underlie the early symptoms. It is of particular interest to understand the nature of this neuronal dysfunction. Normal huntingtin interacts with various cytoskeletal and synaptic vesicle proteins that are essential for exocytosis and endocytosis. Altered interactions of mutant huntingtin with its associated partners could contribute to abnormal synaptic transmission in HD. This review describes recent advances in understanding synaptic dysfunction in HD.
660912
Cholinergic neuronal defect without cell loss in Huntington's disease.
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (IT15) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium-sized spiny neurons. Traditionally, the large cholinergic striatal interneurons are believed to be spared. Recent studies demonstrate that neuronal dysfunction without cell death also plays an important role in early and mid-stages of the disease. Here, we report that cholinergic transmission is affected in a HD transgenic mouse model (R6/1) and in tissues from HD patients. Stereological analysis shows no loss of cholinergic neurons in the striatum or septum in R6/1 mice. In contrast, the levels of mRNA and protein for vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) are decreased in the striatum and cortex, and acetylcholine esterase activity is lowered in the striatum of R6/1 mice already at young ages. Accordingly, VAChT is also reduced in striatal tissue from patients with HD. The decrease of VAChT in the patient samples studied is restricted to the striatum and does not occur in the hippocampus or the spinal cord. The expression and localization of REST/NRSF, a transcriptional regulator for the VAChT and ChAT genes, are not altered in cholinergic neurons. We show that the R6/1 mice exhibit severe deficits in learning and reference memory. Taken together, our data show that the cholinergic system is dysfunctional in R6/1 and HD patients. Consequently, they provide a rationale for testing of pro-cholinergic drugs in this disease.
205100912
Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.
Huntington's disease is a severe progressive neurodegenerative disorder caused by a CAG expansion in the IT15 gene, which encodes huntingtin. The disease primarily affects the neostriatum and cerebral cortex and also associates with increased incidence of diabetes. Here, we show that mutant huntingtin disrupts intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin. We demonstrate that mutant huntingtin impairs glucose-stimulated insulin secretion in insulin-producing beta-cells, without altering stored levels of insulin. Using VSVG-YFP, we show that mutant huntingtin retards post-Golgi transport. Moreover, we demonstrate that the speed of insulin vesicle trafficking is reduced. Using immunoprecipitation of mutant and wild-type huntingtin in combination with mass spectrometry, we reveal an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. Thus, our findings have revealed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta-cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.
41256785
It's not just what you do, it's the way that you do it: the effect of different payment card formats and survey administration on willingness to pay for health gain.
A general population sample of 314 Australian respondents were randomly allocated to complete a contingent valuation survey administered by face-to-face or telephone ('phone-mail-phone') interview. Although the telephone interview was quicker to complete, no significant difference was found in values obtained through either method. Within each sub-sample, respondents were also randomly allocated to the three different versions of the payment card (PC) questionnaire format: values listed from high-to-low, values listed from low-to-high and values randomly shuffled. The high-to-low version resulted in significantly higher values than the other versions. Further analyses indicate that the randomly shuffled PC version may produce the most 'valid' values.
29684839
Responding to global infectious disease outbreaks: Lessons from SARS on the role of risk perception, communication and management

 Abstract
 
 With increased globalisation comes the likelihood that infectious disease appearing in one country will spread rapidly to another, severe acute respiratory syndrome (SARS) being a recent example. However, although SARS infected some 10,000 individuals, killing around 1000, it did not lead to the devastating health impact that many feared, but a rather disproportionate economic impact. The disproportionate scale and nature of this impact has caused concern that outbreaks of more serious disease could cause catastrophic impacts on the global economy. Understanding factors that led to the impact of SARS might help to deal with the possible impact and management of such other infectious disease outbreaks. In this respect, the role of risk—its perception, communication and management—is critical.
 This paper looks at the role that risk, and especially the perception of risk, its communication and management, played in driving the economic impact of SARS. It considers the public and public health response to SARS, the role of the media and official organisations, and proposes policy and research priorities for establishing a system to better deal with the next global infectious disease outbreak. It is concluded that the potential for the rapid spread of infectious disease is not necessarily a greater threat than it has always been, but the effect that an outbreak can have on the economy is, which requires further research and policy development.
 

18389993
Global public goods and the global health agenda: problems, priorities and potential
The 'global public good' (GPG) concept has gained increasing attention, in health as well as development circles. However, it has suffered in finding currency as a general tool for global resource mobilisation, and is at risk of being attached to almost anything promoting development. This overstretches and devalues the validity and usefulness of the concept. This paper first defines GPGs and describes the policy challenge that they pose. Second, it identifies two key areas, health R&D and communicable disease control, in which the GPG concept is clearly relevant and considers the extent to which it has been applied. We point out that that, while there have been many new initiatives, it is not clear that additional resources from non-traditional sources have been forthcoming. Yet achieving this is, in effect, the entire purpose of applying the GPG concept in global health. Moreover, the proliferation of disease-specific programs associated with GPG reasoning has tended to promote vertical interventions at the expense of more general health sector strengthening. Third, we examine two major global health policy initiatives, the Global Fund against AIDS, Tuberculosis and Malaria (GFATM) and the bundling of long-standing international health goals in the form of Millennium Development Goals (MDG), asking how the GPG perspective has contributed to defining objectives and strategies. We conclude that both initiatives are best interpreted in the context of traditional development assistance and, one-world rhetoric aside, have little to do with the challenge posed by GPGs for health. The paper concludes by considering how the GPG concept can be more effectively used to promote global health.
7050862
The placenta, a transducer linking maternal nutrition to adult disease in the offspring?
This month’s Journal carries an article from Shanghai on the regulation of glucose transporters (GLUT) in humanplacenta(1).Thestudiesbringapossiblenewplayer into the ongoing drama of nutritional regulation of fetal growth and development. The in vitro studies by Gao et al. (1) examined the effects of CRH on mRNA and protein concentrations of GLUT1 and GLUT3. Using a variety of techniques, including small interfering RNA for the corticotrophin releasing hormone receptor type 1 (CRH-R1) receptor, antibodies to the receptor, and receptor blockers, the studies convincingly show that CRH stimulates trophoblast production of GLUT1 and inhibits the expression of GLUT3 via the CRH-R1 receptor. The area is of increasing interest as data accumulate that fetal growth is an important determinant of adult health. The Barker hypothesis posits that restricted intrauterine growth associated with the birth of a small infant leads to early onset diabetes, hypertension, and ischemic heart disease (2). This hypothesis is linked to the concept of phenotypic plasticity, a widespread phenomenon in nature whereby the environment interacts with the genome to determine an organism’s phenotype (3). In the setting of intrauterine growth restriction, it is proposed that impaired nutrient transfer to the fetus leads to the development of a metabolic phenotype that is adapted to an environment low in nutrients. The fetus adapted to low nutrients that is then born into a Western society with high-energy diets is maladapted, develops obesity, diabetes, hypertension, and early heart disease. There are strong animal data for this scenario; however, human data are more limited (4). Given the importance of optimizing fetal growth, the pathway to optimal fetal growth becomes of great interest. Unfortunately, this pathway is very poorly characterized. Worldwide, low birth weight is very common, leading to a recent Gates Foundation call for studies on the underlying mechanisms leading to impaired fetal growth (http://www. grandchallenges.org/GCGHDocs/Healthy_Growth_Rules_ and_Guidelines.pdf). Althoughconditions suchaspreeclampsia are well-known associates of impaired growth, there is little knowledge on the etiology of most cases. Major deficiencies in knowledge extend to even what might be the ideal diet for a pregnant woman to produce a healthy baby with an optimum metabolic phenotype for the 21st century. National guidelines for maternal intakes exist, but these are not founded on a sound evidence base of longitudinal studies of infant outcomes (5). Recent research on comparative nutritional intakes of protein, fat, and carbohydrate suggest that all animals have a genetically determined target intake of macronutrients (6). This work strongly suggests that an ideal target intake would exist for pregnant women, but this has not yet been defined. With an ideal maternal intake, the placenta is the port via which this nutrition is transported to the fetus. How exactly this occurs and how it is regulated again remains unclear. Nutrient sensing by the fetus may involve the IGF axis within the fetal liver (7). How is nutrient sensing performed by the placenta on behalf of the fetus? Syncytiotrophoblast expression of GLUT1 is stimulated by placental variant growth hormone, which increases across gestation as does GLUT1; so perhaps again the IGF axis is central (8). How does the placenta determine how much nutrient will be invested in placental growth and how much transferred to the fetus for fetal growth? How does the placenta regulate the nutrient mix it provides to the fetus and is the ideal nutrient mix for the mother the same for the fetus?
23247928
Unexplained antepartum stillbirth: a consequence of placental aging?
Unexplained antepartum stillbirth is a major obstetric health problem. Data demonstrate a rapid rise in risk per 1000 continuing pregnancies as gestation advances beyond 40 weeks. We review the evidence that such stillbirths are a consequence of aging related changes in the late gestation placenta. We suggest that the relatively small number of continuing pregnancies after 40 completed weeks means that negative effects of genes that produce aging affect so few pregnancies that polymorphisms in genes that produce these effects are retained in the population. Aging related changes likely represent a consequence of the damaging effects of oxidative stress, increased by cigarette smoking counteracted by the mitigating effects of oxidative defence pathways. The aging related changes are likely downstream from nutrient sensing units such as mTOR and include effects on production of telomerase and consequent shortening of telomere length. The late gestation changes occur in the context of increasing fetal growth and nutrient supply demands that can produce the rapid development of a mismatch between placental supply and fetal need resulting in fetal demise. Premature aging may also play an important role in antepartum stillbirth occurring earlier in pregnancy, especially in the context of growth restriction.