David K. Simon

Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators

PPARgamma coactivator 1alpha (PGC-1alpha) is a potent stimulator of mitochondrial biogenesis and respiration. Since the mitochondrial electron transport chain is the main producer of reactive oxygen species (ROS) in most cells, we examined the effect of PGC-1alpha on the metabolism of ROS. PGC-1alpha is coinduced with several key ROS-detoxifying enzymes upon treatment of cells with an oxidative stressor; studies with RNAi or null cells indicate that PGC-1alpha is required for the induction of many ROS-detoxifying enzymes, including GPx1 and SOD2. PGC-1alpha null mice are much more sensitive to the neurodegenerative effects of MPTP and kainic acid, oxidative stressors affecting the substantia nigra and hippocampus, respectively. Increasing PGC-1alpha levels dramatically protects neural cells in culture from oxidative-stressor-mediated death. These studies reveal that PGC-1alpha is a broad and powerful regulator of ROS metabolism, providing a potential target for the therapeutic manipulation of these important endogenous toxins.

Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.

OBJECTIVE Our goal was to determine the impact of the initiation of inappropriate antimicrobial therapy on survival to hospital discharge of patients with septic shock. METHODS The appropriateness of initial antimicrobial therapy, the clinical infection site, and relevant pathogens were retrospectively determined for 5,715 patients with septic shock in three countries. RESULTS Therapy with appropriate antimicrobial agents was initiated in 80.1% of cases. Overall, the survival rate was 43.7%. There were marked differences in the distribution of comorbidities, clinical infections, and pathogens in patients who received appropriate and inappropriate initial antimicrobial therapy (p < 0.0001 for each). The survival rates after appropriate and inappropriate initial therapy were 52.0% and 10.3%, respectively (odds ratio [OR], 9.45; 95% CI, 7.74 to 11.54; p < 0.0001). Similar differences in survival were seen in all major epidemiologic, clinical, and organism subgroups. The decrease in survival with inappropriate initial therapy ranged from 2.3-fold for pneumococcal infection to 17.6-fold with primary bacteremia. After adjustment for acute physiology and chronic health evaluation II score, comorbidities, hospital site, and other potential risk factors, the inappropriateness of initial antimicrobial therapy remained most highly associated with risk of death (OR, 8.99; 95% CI, 6.60 to 12.23). CONCLUSIONS Inappropriate initial antimicrobial therapy for septic shock occurs in about 20% of patients and is associated with a fivefold reduction in survival. Efforts to increase the frequency of the appropriateness of initial antimicrobial therapy must be central to efforts to reduce the mortality of patients with septic shock.

Medical Consultation for Migraine: Results From the American Migraine Study

Background.—Migraine headaches are often disabling but usually responsive to treatment. Nonetheless, many people with migraine never consult a doctor for headaches. In a sample of the US population, we sought to determine the proportion of active migaineurs who ever consulted a doctor for headache and to identify the headache characteristics and sociodemographic factors associated with consulting.

Outcomes of Kidney Transplantation in HIV-Infected Recipients

BACKGROUND The outcomes of kidney transplantation and immunosuppression in people infected with human immunodeficiency virus (HIV) are incompletely understood. METHODS We undertook a prospective, nonrandomized trial of kidney transplantation in HIV-infected candidates who had CD4+ T-cell counts of at least 200 per cubic millimeter and undetectable plasma HIV type 1 (HIV-1) RNA levels while being treated with a stable antiretroviral regimen. Post-transplantation management was provided in accordance with study protocols that defined prophylaxis against opportunistic infection, indications for biopsy, and acceptable approaches to immunosuppression, management of rejection, and antiretroviral therapy. RESULTS Between November 2003 and June 2009, a total of 150 patients underwent kidney transplantation; survivors were followed for a median period of 1.7 years. Patient survival rates (±SD) at 1 year and 3 years were 94.6±2.0% and 88.2±3.8%, respectively, and the corresponding mean graft-survival rates were 90.4% and 73.7%. In general, these rates fall somewhere between those reported in the national database for older kidney-transplant recipients (≥65 years) and those reported for all kidney-transplant recipients. A multivariate proportional-hazards analysis showed that the risk of graft loss was increased among patients treated for rejection (hazard ratio, 2.8; 95% confidence interval [CI], 1.2 to 6.6; P=0.02) and those receiving antithymocyte globulin induction therapy (hazard ratio, 2.5; 95% CI, 1.1 to 5.6; P=0.03); living-donor transplants were protective (hazard ratio, 0.2; 95% CI, 0.04 to 0.8; P=0.02). A higher-than-expected rejection rate was observed, with 1-year and 3-year estimates of 31% (95% CI, 24 to 40) and 41% (95% CI, 32 to 52), respectively. HIV infection remained well controlled, with stable CD4+ T-cell counts and few HIV-associated complications. CONCLUSIONS In this cohort of carefully selected HIV-infected patients, both patient- and graft-survival rates were high at 1 and 3 years, with no increases in complications associated with HIV infection. The unexpectedly high rejection rates are of serious concern and indicate the need for better immunotherapy. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00074386.).

WORK-RELATED DISABILITY : RESULTS FROM THE AMERICAN MIGRAINE STUDY

Migraine headache is a highly prevalent, often severely painful and frequently disabling disorder. The indirect costs related to disability greatly exceed the direct cost of medical care. The objective of this paper is to describe work-related disability associated with migraine headache and predictors of disability. In a two-stage survey of the US population, we estimate missed workdays and impairment at work in a sample of 1663 migraine sufferers, age 18 years and older. Lost workday equivalents (LWDE) was derived as the sum of actual missed workdays and the product of percentage effectiveness at work and days at work with the most severe headache. Overall, reported actual lost workdays and reduced effectiveness at work contributed approximately equally to total LWDE. A total of 51.1% of females and 38.1% of male migraineurs experienced six or more LWDE per year. This subgroup of migraine sufferers accounted for about 90% of the total LWDE experienced by all respondents. Among women, headache duration was the strongest predictor of LWDE followed by less significant associations with number of symptoms and pain level. Among men, only pain level was significantly associated with LWDE. Among sociodemographic factors, disability was more likely among older (40+) subjects and less likely among individuals with higher education and higher income (females only), even after adjusting for headache features. Health-care interventions may yield the greatest individual benefit (by reducing pain and disability) and the greatest societal benefit (by reducing indirect costs) if they are directed to those who account for the greatest proportion of disability.

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

Past adult lead exposure is associated with longitudinal decline in cognitive function

Objective: To determine whether adults with past exposure to neurotoxicants have progressive declines in cognitive function years after exposure has ceased, and whether tibia lead is a predictor of the magnitude of change. Methods: A total of 535 former organolead manufacturing workers with a mean age of 55.6 years, a mean duration of 16 years since last occupational lead exposure, and low blood lead levels at the first study visit and 118 controls were evaluated with neurobehavioral tests two to four times over 4 years. “Peak” tibia lead levels, estimated from current levels measured by X-ray fluorescence, were used to predict changes in cognitive function over time. Results: In former lead workers, peak tibia lead ranged from −2.2 to 98.7 μg Pb/g bone mineral. Compared to controls, former lead workers performed worse over time for three tests of visuo-constructive ability and verbal memory and learning (p < 0.05). In former lead workers, peak tibia lead predicted declines for six tests of verbal memory and learning, visual memory, executive ability, and manual dexterity (p < 0.05 for four tests and < 0.10 for two additional tests). On average, for these six tests, an increase of 15.7 μg/g of peak tibia lead was equivalent in its effects on annual test decline to 5 more years of age at baseline. Conclusions: These are the first data to suggest that cognitive function can progressively decline due to past occupational exposures to a neurotoxicant.

Non-invasive brain stimulation for Parkinson's disease: a systematic review and meta-analysis of the literature

A systematic review and meta-analysis were conducted to quantify the efficacy of transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) for the treatment of motor dysfunction in patients with Parkinson’s disease (PD). Prospective studies which evaluated the effects of either TMS (12 studies) or ECT (five studies) on motor function in PD using the motor subscale of the Unified Parkinson’s Disease Rating Scale (UPDRS) for TMS studies and any continuous measures of motor function in PD for ECT studies were included. The pooled effect size (standardised mean difference between pre-treatment versus post-treatment means) from a random effects model was 0.62 (95% confidence interval: 0.38, 0.85) for TMS treatment and 1.68 (0.79, 2.56) for ECT treatment, and from a fixed effects model was 0.59 (0.39, 0.78) for TMS treatment and 1.55 (1.07, 2.03) for ECT treatment. TMS, across applied stimulation sites and parameters, can exert a significant, albeit modest, positive effect on the motor function of patients with PD. ECT also may exert a significant effect on motor function in PD patients.

Population variation in migraine prevalence: a meta-analysis.

A meta-analysis of published studies was conducted to identify factors which explained variation in estimates of migraine prevalence. Twenty-four population based studies contributed a total of 168 gender and age specific estimates of migraine prevalence. In linear regression analysis, 70.6% of the variation in these prevalence estimates was explained by gender, age (AGE+AGE2), a binary variable for case definition, and an interaction term between age and the case definition. Initially, we identified five groups of case definitions among the 24 studies. Only the definition of Waters (any 2 of warning, nausea, or unilateral pain) was associated with statistically significant differences in prevalence estimates among studies; accordingly the other 4 groups were combined. Several other factors were examined as predictors of migraine prevalence including the method of selecting the study population, the source of the population, the response rate and whether diagnoses were confirmed by a clinical assessment. None of these factors substantially increased explained variance. We conclude that after taking sociodemographic factors and case definition into account, estimates of migraine prevalence are remarkably stable among studies.

Meta‐analysis of Parkinson's Disease: Identification of a novel locus, RIT2

Genome‐wide association (GWAS) methods have identified genes contributing to Parkinsons disease (PD); we sought to identify additional genes associated with PD susceptibility.