Identification of Inhibitors of Fungal Fatty Acid Biosynthesis.

Fungal fatty acid (FA) synthase and desaturase enzymes are essential for the growth and virulence of human fungal pathogens. These enzymes are structurally distinct from their mammalian counterparts, making them attractive targets for antifungal development. However, there has been little progress in identifying chemotypes that target fungal FA biosynthesis.

An Unbiased Drug Screen for Seizure Suppressors in Duplication 15q Syndrome Reveals 5-HT and Dopamine Pathway Activation as Potential Therapies.

Background: Duplication 15q (Dup15q) syndrome is a rare neurogenetic disorder characterized by autism and pharmacoresistant epilepsy. Most individuals with isodicentric duplications have been on multiple medications to control seizures. We recently developed a model of Dup15q in Drosophila by elevating levels of fly Dube3a in glial cells using repo-GAL4, not neurons.

Efficacy of Primary Repair in Professional Athletes with Chronic Radial Collateral Ligament Injuries of Thumb Metacarpophalangeal Joint.

Management of grade III injuries of the radial collateral ligament (RCL) of the thumb is controversial. These injuries are often treated with early surgery. However, early surgery may not be practical for the professional athlete.

A Systematic Screen Reveals a Diverse Collection of Medications That Induce Antifungal Resistance in Species.

The increasing incidence of and high mortality rates associated with invasive fungal infections (IFIs) impose an enormous clinical, social, and economic burden on humankind. In addition to microbiological resistance to existing antifungal drugs, the large number of unexplained treatment failures is a serious concern. Due to the extremely limited therapeutic options available, it is critical to identify and understand the various causes of treatment failure if patient outcomes are to improve.

Prevalence of Amyotrophic Lateral Sclerosis - United States, 2014.

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive and fatal neuromuscular disease; the majority of ALS patients die within 2-5 years of receiving a diagnosis (1). Familial ALS, a hereditary form of the disease, accounts for 5%-10% of cases, whereas the remaining sporadic cases have no clearly defined etiology (1). ALS affects persons of all races and ethnicities; however, whites, males, non-Hispanics, persons aged >60 years, and those with a family history of ALS are more likely to develop the disease (1-3).

Blood Lead, Bone Turnover, and Survival in Amyotrophic Lateral Sclerosis.

Blood lead and bone turnover may be associated with the risk of amyotrophic lateral sclerosis (ALS). We aimed to assess whether these factors were also associated with time from ALS diagnosis to death through a survival analysis of 145 ALS patients enrolled during 2007 in the National Registry of Veterans with ALS. Associations of survival time with blood lead and plasma biomarkers of bone resorption (C-terminal telopeptides of type I collagen (CTX)) and bone formation (procollagen type I amino-terminal peptide (PINP)) were estimated using Cox models adjusted for age at diagnosis, diagnostic certainty, diagnostic delay, site of onset, and score on the Revised ALS Functional Rating Scale.

Target Abundance-Based Fitness Screening (TAFiS) Facilitates Rapid Identification of Target-Specific and Physiologically Active Chemical Probes.

Traditional approaches to drug discovery are frustratingly inefficient and have several key limitations that severely constrain our capacity to rapidly identify and develop novel experimental therapeutics. To address this, we have devised a second-generation target-based whole-cell screening assay based on the principles of competitive fitness, which can rapidly identify target-specific and physiologically active compounds. Briefly, strains expressing high, intermediate, and low levels of a preselected target protein are constructed, tagged with spectrally distinct fluorescent proteins (FPs), and pooled.

Association of fractures with the incidence of amyotrophic lateral sclerosis.

Objective: Elevated bone turnover observed in ALS patients suggests poor bone health and increased fracture risk. We therefore evaluated the relationship of fracture to subsequent ALS risk.

Methods: We followed 4,529,460 Swedes from 1987 to 2010 and identified ALS and fractures from the Swedish National Patient Register.

Body Mass Index and Amyotrophic Lateral Sclerosis: A Study of US Military Veterans.

Amyotrophic lateral sclerosis (ALS) may be associated with low body mass index (BMI) at the time of diagnosis. However, the role of premorbid BMI in the development of ALS and survival after diagnosis remains unclear. In 2005-2010, we interviewed 467 patients with ALS from the US National Registry of Veterans with ALS and 975 frequency-matched veteran controls.

Identification of small molecules that disrupt vacuolar function in the pathogen Candida albicans.

The fungal vacuole is a large acidified organelle that performs a variety of cellular functions. At least a sub-set of these functions are crucial for pathogenic species of fungi, such as Candida albicans, to survive within and invade mammalian tissue as mutants with severe defects in vacuolar biogenesis are avirulent. We therefore sought to identify chemical probes that disrupt the normal function and/or integrity of the fungal vacuole to provide tools for the functional analysis of this organelle as well as potential experimental therapeutics.

Endosomal Trafficking Defects Can Induce Calcium-Dependent Azole Tolerance in Candida albicans.

The azole antifungals arrest fungal growth through inhibition of ergosterol biosynthesis. We recently reported that a Candida albicans vps21Δ/Δ mutant, deficient in membrane trafficking through the late endosome/prevacuolar compartment (PVC), continues to grow in the presence of the azoles despite the depletion of cellular ergosterol. Here, we report that the vps21Δ/Δ mutant exhibits less plasma membrane damage upon azole treatment than the wild type, as measured by the release of a cytoplasmic luciferase reporter into the culture supernatant.

Occupational exposures and the risk of amyotrophic lateral sclerosis.

Objectives: To examine the associations of specific occupations and occupational exposures with the risk of amyotrophic lateral sclerosis (ALS) in the Swedish population.

Methods: A nested case-control study was conducted in Sweden. Patients with ALS diagnosed during 1991-2010 (n=5020) were identified from the National Patient Register and 5 controls per case (n=25 100) were randomly selected from the general Swedish population, individually matched to cases by birth year and sex.

Blood levels of trace metals and amyotrophic lateral sclerosis.

Some trace metals may increase risk of amyotrophic lateral sclerosis (ALS), whereas others may be beneficial. Our goal was to examine associations of ALS with blood levels of selenium (Se), zinc (Zn), copper (Cu), and manganese (Mn). We conducted a case-control study of 163 neurologist confirmed patients from the National Registry of Veterans with ALS and 229 frequency-matched veteran controls.

Occupational Exposure to Electric Shocks and Magnetic Fields and Amyotrophic Lateral Sclerosis in Sweden.

Background: Amyotrophic lateral sclerosis (ALS) has been consistently related to "electric occupations," but associations with magnetic field levels were generally weaker than those with electrical occupations. Exposure to electric shock has been suggested as a possible explanation. Furthermore, studies were generally based on mortality or prevalence of ALS, and studies often had limited statistical power.

Imaging findings associated with cognitive performance in primary lateral sclerosis and amyotrophic lateral sclerosis.

Introduction: Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes.

Methods: The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients.

Severe head injury and amyotrophic lateral sclerosis.

Our objective was to examine whether severe head injury, subtypes of head injury, or repeated head injuries are associated with ALS risk based on the Swedish population and health registers. We conducted a case-control study, nested within a cohort of 5,764,522 individuals who were born in Sweden during 1901-1970 and followed between 1991 and 2007. The study included 4004 ALS patients identified from the Swedish Patient Register during follow-up and 20,020 randomly selected controls matched by gender and birth year.

Infection of the central nervous system, sepsis and amyotrophic lateral sclerosis.

Background: Severe infections may lead to chronic inflammation in the central nervous system (CNS) which may in turn play a role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). The relentless progression and invasive supportive treatments of ALS may on the other hand induce severe infections among ALS patients.

Methodology And Principal Findings: The present study included 4,004 ALS patients identified from the Swedish Patient Register during 1991-2007 and 20,020 age and sex matched general population controls.

Exposure to community violence and protective and risky contexts among low income urban African American adolescents: a prospective study.

This study examined protective and risky companionship and locations for exposure to community violence among African American young adolescents living in high crime, urban areas. The Experience Sampling Method (ESM), an in vivo data collection method, was employed to gather information from 233 students (62% female) over 3 years, beginning in the 6th grade. Questionnaire variables of exposure to community violence were regressed onto ESM companionship and location variables, cross-sectionally and longitudinally, separately for boys and girls.

Usage of support services in primary lateral sclerosis.

Patients with amyotrophic lateral sclerosis (ALS) rely on a variety of support services during the course of their illness. Patients with primary lateral sclerosis (PLS) have a slower progression of disease and different clinical spectrum. Their needs for allied health services and social support have not been well characterized.