Bioenergetic Consequences of PINK1 Mutations in Parkinson Disease

BACKGROUND: Mutations of the gene for PTEN-induced kinase 1 (PINK1) are a cause of familial Parkinson's disease (PD). PINK1 protein has been localised to mitochondria and PINK1 gene knockout models exhibit abnormal mitochondrial function. The purpose of this study was to determine whether cells derived from PD patients with a range of PINK1 mutations demonstrate similar defects of mitochondrial function, whether the nature and severity of the abnormalities vary between mutations and correlate with clinical features. METHODOLOGY: We investigated mitochondrial bioenergetics in live fibroblasts from PINK1 mutation patients using single cell techniques. We found that fibroblasts from PINK1 mutation patients had significant defects of bioenergetics including reduced mitochondrial membrane potential, altered redox state, a respiratory deficiency that was determined by substrate availability, and enhanced sensitivity to calcium stimulation and associated mitochondrial permeability pore opening. There was an increase in the basal rate of free radical production in the mutant cells. The pattern and severity of abnormality varied between different mutations, and the less severe defects in these cells were associated with later age of onset of PD. CONCLUSIONS: The results provide insight into the molecular pathology of PINK1 mutations in PD and also confirm the critical role of substrate availability in determining the biochemical phenotype--thereby offering the potential for novel therapeutic strategies to circumvent these abnormalities

Reasons for accepting or declining to participate in randomized clinical trials for cancer therapy

This paper reports on the reasons why patients agreed to or declined entry into randomized trials of cancer following discussions conducted by clinicians in both District General and University Hospitals. Two hundred and four patients completed a 16-item questionnaire following the consultation, of these 112 (55%) were women with breast cancer. Overall results showed that 147 (72.1%) patients accepted entry to a randomized clinical trial (RCT). The main reasons nominated for participating in a trial were that ‘others will benefit’ (23.1%) and ‘trust in the doctor’ (21.1%). One of the main reasons for declining trial entry was that patients were ‘worried about randomization’ (19.6%). There was a significantly higher acceptance rate for trials providing active treatment in every arm 98 (80.6%) compared with those trials with a no treatment arm 46 (60.5%), χ2test P = 0.003. The study outlines a number of factors that appear to influence a patient’s decision to accept or decline entry into an RCT of cancer therapy. An important factor is whether or not the trial offers active treatment in all arms of the study. Communication that promotes trust and confidence in the doctor is also a powerful motivating influence. © 2000 Cancer Research Campaig

Are alcoholism treatments effective? The Project MATCH data

BACKGROUND: Project MATCH was the largest and most expensive alcoholism treatment trial ever conducted. The results were disappointing. There were essentially no patient-treatment matches, and three very different treatments produced nearly identical outcomes. These results were interpreted post hoc as evidence that all three treatments were quite effective. We re-analyzed the data in order to estimate effectiveness in relation to quantity of treatment. METHODS: This was a secondary analysis of data from a multisite clinical trial of alcohol dependent volunteers (N = 1726) who received outpatient psychosocial therapy. Analyses were confined to the primary outcome variables, percent days abstinent (PDA) and drinks per drinking day (DDD). Overall tests between treatment outcome and treatment quantity were conducted. Next, three specific groups were highlighted. One group consisted of those who dropped out immediately; the second were those who dropped out after receiving only one therapy session, and the third were those who attended 12 therapy sessions. RESULTS: Overall, a median of only 3% of the drinking outcome at follow-up could be attributed to treatment. However this effect appeared to be present at week one before most of the treatment had been delivered. The zero treatment dropout group showed great improvement, achieving a mean of 72 percent days abstinent at follow-up. Effect size estimates showed that two-thirds to three-fourths of the improvement in the full treatment group was duplicated in the zero treatment group. Outcomes for the one session treatment group were worse than for the zero treatment group, suggesting a patient self selection effect. Nearly all the improvement in all groups had occurred by week one. The full treatment group had improved in PDA by 62% at week one, and the additional 11 therapy sessions added only another 4% improvement. CONCLUSION: The results suggest that current psychosocial treatments for alcoholism are not particularly effective. Untreated alcoholics in clinical trials show significant improvement. Most of the improvement which is interpreted as treatment effect is not due to treatment. Part of the remainder appears to be due to selection effects

Management Impacts on Forest Floor and Soil Organic Carbon in Northern Temperate Forests of the US

<p>Abstract</p> <p>Background</p> <p>The role of forests in the global carbon cycle has been the subject of a great deal of research recently, but the impact of management practices on forest soil dynamics at the stand level has received less attention. This study used six forest management experimental sites in five northern states of the US to investigate the effects of silvicultural treatments (light thinning, heavy thinning, and clearcutting) on forest floor and soil carbon pools.</p> <p>Results</p> <p>No overall trend was found between forest floor carbon stocks in stands subjected to partial or complete harvest treatments. A few sites had larger stocks in control plots, although estimates were often highly variable. Forest floor carbon pools did show a trend of increasing values from southern to northern sites. Surface soil (0-5 cm) organic carbon content and concentration were similar between treated and untreated plots. Overall soil carbon (0-20 cm) pool size was not significantly different from control values in sites treated with partial or complete harvests. No geographic trends were evident for any of the soil properties examined.</p> <p>Conclusions</p> <p>Results indicate that it is unlikely that mineral soil carbon stocks are adversely affected by typical management practices as applied in northern hardwood forests in the US; however, the findings suggest that the forest floor carbon pool may be susceptible to loss.</p

NMDA Receptor Stimulation Induces Reversible Fission of the Neuronal Endoplasmic Reticulum

With few exceptions the endoplasmic reticulum (ER) is considered a continuous system of endomembranes within which proteins and ions can move. We have studied dynamic structural changes of the ER in hippocampal neurons in primary culture and organotypic slices. Fluorescence recovery after photobleaching (FRAP) was used to quantify and model ER structural dynamics. Ultrastructure was assessed by electron microscopy. In live cell imaging experiments we found that, under basal conditions, the ER of neuronal soma and dendrites was continuous. The smooth and uninterrupted appearance of the ER changed dramatically after glutamate stimulation. The ER fragmented into isolated vesicles in a rapid fission reaction that occurred prior to overt signs of neuronal damage. ER fission was found to be independent of ER calcium levels. Apart from glutamate, the calcium ionophore ionomycin was able to induce ER fission. The N-methyl, D-aspartate (NMDA) receptor antagonist MK-801 inhibited ER fission induced by glutamate as well as by ionomycin. Fission was not blocked by either ifenprodil or kinase inhibitors. Interestingly, sub-lethal NMDA receptor stimulation caused rapid ER fission followed by fusion. Hence, ER fission is not strictly associated with cellular damage or death. Our results thus demonstrate that neuronal ER structure is dynamically regulated with important consequences for protein mobility and ER luminal calcium tunneling

Soil warming accelerates decomposition of fine woody debris

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Plant and Soil 356 (2012): 405-417, doi:10.1007/s11104-012-1130-x.Soil warming from global climate change could increase decomposition of fine woody debris (FWD), but debris size and quality may mitigate this effect. The goal of this study was to investigate the effect of soil warming on decomposition of fine woody debris of differing size and quality. We placed FWD of two size classes (2 × 20 cm and 4 × 40 cm) and four species (Acer saccharum, Betula lenta, Quercus rubra and Tsuga canadensis) in a soil warming and ambient area at Harvard Forest in central Massachusetts. We collected the debris from each area over two years and measured mass loss and lignin concentration. Warming increased mass loss for all species and size classes (by as much as 30%), but larger debris and debris with higher initial lignin content decomposed slower than smaller debris and debris with lower initial lignin content. Lignin degradation did not follow the same trends as mass loss. Lignin loss from the most lignin-rich species, T. canadensis, was the highest despite the fact that it lost mass the slowest. Our results suggest that soil warming will increase decomposition of FWD in temperate forests. It is imperative that future models and policy efforts account for this potential shift in the carbon storage pool

Combined effects of cigarette smoking, gene polymorphisms and methylations of tumor suppressor genes on non small cell lung cancer: a hospital-based case-control study in China

<p>Abstract</p> <p>Background</p> <p>Cigarette smoking is the most established risk factor, and genetic variants and/or gene promoter methylations are also considered to play an essential role in development of lung cancer, but the pathogenesis of lung cancer is still unclear.</p> <p>Methods</p> <p>We collected the data of 150 cases and 150 age-matched and sex-matched controls on a Hospital-Based Case-Control Study in China. Face to face interviews were conducted using a standardized questionnaire. Gene polymorphism and methylation status were measured by RFLP-PCR and MSP, respectively. Logistic regressive model was used to estimate the odds ratios (OR) for different levels of exposure.</p> <p>Results</p> <p>After adjusted age and other potential confounding factors, smoking was still main risk factor and significantly increased 3.70-fold greater risk of NSCLC as compared with nonsmokers, and the ORs across increasing levels of pack years were 1, 3.54, 3.65 and 7.76, which the general dose-response trend was confirmed. Our striking findings were that the risk increased 5.16, 8.28 and 4.10-fold, respectively, for NSCLC with promoter hypermethylation of the <it>p16</it>, <it>DAPK </it>or <it>RARβ </it>gene in smokers with <it>CYP1A1 </it>variants, and the higher risk significantly increased in smokers with null <it>GSTM1 </it>and the OR was 17.84 for NSCLC with <it>p16 </it>promoter hypermethylation, 17.41 for <it>DAPK</it>, and 8.18 for <it>RARβ </it>in smokers with null <it>GSTM1 </it>compared with controls (all p < 0.01).</p> <p>Conclusion</p> <p>Our study suggests the strong combined effects of cigarette smoke, <it>CYP1A1 </it>and <it>GSTM1 </it>Polymorphisms, hypermethylations of <it>p16</it>, <it>DAPK </it>and <it>RARβ </it>promoters in NSCLC, implying complex pathogenesis of NSCLC should be given top priority in future research.</p

Associations between respiratory illnesses and secondhand smoke exposure in flight attendants: A cross-sectional analysis of the Flight Attendant Medical Research Institute Survey

Abstract Background Secondhand tobacco smoke (SHS) is associated with increased risk of respiratory illness, cancer, and cardiovascular disease. Prior to smoking bans on airlines in the late 1980s, flight attendants were exposed to a significant amount of SHS. In the present study, we examine associations between flight attendant SHS exposure and development of respiratory illnesses and cardiovascular disease. Methods Between December 2006 and October 2010, three hundred sixty-two flight attendants completed an online questionnaire with information regarding experience as a flight attendant, medical history, smoking history, and SHS exposure. Rates of illnesses in flight attendants were compared with an age and smoking history matched population sample from NHANES 2005-2006. Logistic regression analysis was used to examine the association of reported medical conditions and pre-ban years of exposure. Results Compared with the sample from NHANES 2005-2006, flight attendants had increased prevalence of chronic bronchitis (11.7% vs. 7.2%, p &lt; 0.05), emphysema/COPD (3.2% vs. 0.9%, p &lt; 0.03), and sinus problems (31.5% vs. 20.9%, p &lt; 0.002), despite a lower prevalence of medical illnesses including high blood pressure, diabetes, high cholesterol, heart failure, cancer, and thyroid disease. Amongst flight attendants who reported never smoking over their lifetimes, there was not a significant association between years of service as a flight attendant in the pre-smoking ban era and illnesses. However, in this same group, there was a significantly increased risk of daily symptoms (vs. no symptoms) of nasal congestion, throat, or eye irritation per 10-year increase of years of service as a flight attendant prior to the smoking ban (OR 2.14, 95% CI 1.41 - 3.24). Conclusions Flight attendants experience increased rates of respiratory illnesses compared to a population sample. The frequency of symptoms of nasal congestion, throat or eye irritation is associated with occupational SHS exposure in the pre-smoking ban era

Cocaine Is Low on the Value Ladder of Rats: Possible Evidence for Resilience to Addiction

International audienceBACKGROUND:Assessing the relative value of cocaine and how it changes with chronic drug use represents a long-standing goal in addiction research. Surprisingly, recent experiments in rats--by far the most frequently used animal model in this field--suggest that the value of cocaine is lower than previously thought.METHODOLOGY/PRINCIPAL FINDINGS:Here we report a series of choice experiments that better define the relative position of cocaine on the value ladder of rats (i.e., preference rank-ordering of different rewards). Rats were allowed to choose either taking cocaine or drinking water sweetened with saccharin--a nondrug alternative that is not biologically essential. By systematically varying the cost and concentration of sweet water, we found that cocaine is low on the value ladder of the large majority of rats, near the lowest concentrations of sweet water. In addition, a retrospective analysis of all experiments over the past 5 years revealed that no matter how heavy was past cocaine use most rats readily give up cocaine use in favor of the nondrug alternative. Only a minority, fewer than 15% at the heaviest level of past cocaine use, continued to take cocaine, even when hungry and offered a natural sugar that could relieve their need of calories.CONCLUSIONS/SIGNIFICANCE:This pattern of results (cocaine abstinence in most rats; cocaine preference in few rats) maps well onto the epidemiology of human cocaine addiction and suggests that only a minority of rats would be vulnerable to cocaine addiction while the large majority would be resilient despite extensive drug use. Resilience to drug addiction has long been suspected in humans but could not be firmly established, mostly because it is difficult to control retrospectively for differences in drug self-exposure and/or availability in human drug users. This conclusion has important implications for preclinical research on the neurobiology of cocaine addiction and for future medication development