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.
3109318
A general model for continuous noninvasive pulmonary artery pressure estimation
Elevated pulmonary artery pressure (PAP) is a significant healthcare risk. Continuous monitoring for patients with elevated PAP is crucial for effective treatment, yet the most accurate method is invasive and expensive, and cannot be performed repeatedly. Noninvasive methods exist but are somewhat inaccurate, expensive, and cannot be used for continuous monitoring. We present a machine learning model based on heart sounds that estimates pulmonary artery pressure with enough accuracy to exclude an invasive diagnostic operation, allowing for consistent monitoring of heart condition in suspect patients without the cost and risk of invasive monitoring. We conduct a greedy search through 38 possible features using a 109-patient cross-validation to find the most predictive features. Our best general model has a standard estimate of error (SEE) of 8.3mmHg, which outperforms the previous best performance in the literature on a general set of unseen patient data.
8297391
Assessing the macroeconomic impact of a healthcare problem: the application of computable general equilibrium analysis to antimicrobial resistance.
There is a positive relationship between the health of a nation and its economic prosperity. However, in evaluating health care, economists typically concentrate on the economic impact only to the health (care) sector, which may mis-specify the social costs and benefits of a disease or intervention. This paper demonstrates the value of using a macroeconomic approach to modelling a major health problem, using the context of antimicrobial resistance and the application of the computable general equilibrium technique. This approach is described in detail and its 'added value' demonstrated in the case of AMR.
20390905
Use, option and externality values: are contingent valuation studies in health care mis-specified?
A general population sample of Australian respondents completed a contingent valuation (CV) survey that asked them to value six scenarios. These varied according to whether the scenario was seeking to elicit: (i) use value; (ii) externality value; (iii) option value; or (iv) a combination. Results indicate that use plus externality and/or option value was significantly greater than use value alone. As CV studies in health (care) overwhelmingly focus on use value alone - often implicitly through study design rather than explicitly - this raises the possibility of mis-specification in CV research in health (care). The implications for CV in health (care) are considered.
39397016
The relationship between reliability and size of willingness-to-pay values: a qualitative insight.
In a previous paper, the reliability of willingness-to-pay (WTP) values was found to be an increasing function of the size of WTP expressed. Here, the results of a qualitative exercise conducted alongside this quantitative study are presented. The results of this exercise suggest that higher WTP values may require more thought from the respondent which, in turn, gives them greater stability. At low levels of WTP, values appear to be taken from a 'discretionary account', where expenditure is more volatile. Caveats to this result, and suggestions for future research, are considered in the discussion.
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?