Targeting a Conserved Lysine in the Hydrophobic Pocket of HIV-1 gp41 Improves Small Molecule Antiviral Activity.

Human Immunodeficiency virus (HIV-1) fusion is mediated by glycoprotein-41, a protein that has not been widely exploited as a drug target. Small molecules directed at the gp41 ectodomain have proved to be poorly drug-like, having moderate efficacy, high hydrophobicity and/or high molecular weight. We recently investigated conversion of a fairly potent hydrophobic inhibitor into a covalent binder, by modifying it to react with a lysine residue on the protein. We demonstrated a 10-fold improvement in antiviral efficacy. Here, we continue this study, utilizing instead molecules with better inherent drug-like properties. Molecules possessing low to no antiviral activity as equilibrium binders were converted into µM inhibitors upon addition of an electrophilic warhead in the form of a sulfotetrafluorophenyl (STP) activated ester. We confirmed specificity for gp41 and for entry. The small size of the inhibitors described here offers an opportunity to expand their reach into neighboring pockets while retaining drug-likeness. STP esterification of equilibrium binders is a promising avenue to explore for inhibiting HIV-1 entry. Many gp41 targeting molecules studied over the years possess carboxylic acid groups which can be easily converted into the corresponding STP ester. It may be worth the effort to evaluate a library of such inhibitors as a way forward to small molecule inhibition of fusion of HIV and possibly other enveloped viruses.

Arsenic Toxicity From the Ingestion of Terracotta Pottery.

BACKGROUND: Symptomatic arsenic toxicity has not been associated with terracotta pottery despite thousands of years of use in food storage and preparation. We describe a case of chronic arsenic toxicity from undiagnosed pica involving the ingestion of terracotta pots. CASE REPORT: A 49-year-old woman with a history of anemia and abnormal uterine bleeding presented to the Emergency Department complaining of lower extremity pain. She was also noted to have chronic lower extremity paresthesia, constipation, and fatigue. She admitted to ingesting glazed and unglazed terracotta pots for the past 5 years. This unusual craving was thought to be a manifestation of pica in the setting of chronic anemia. The patient was found to have an elevated urinary arsenic concentration of 116 µg/24 h. An abdominal radiograph showed opacifications throughout her bowel, and she received whole bowel irrigation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Pica is a common behavior in certain populations. Practicing clinicians should be familiar with the complications of pica, including chronic arsenic toxicity and its associated array of nonspecific symptoms.

Real-time comprehensive toxicology testing in the clinical management of accidental pediatric capecitabine ingestion.

INTRODUCTION: Capecitabine is an orally bioavailable prodrug of the chemotherapeutic agent, fluorouracil. Fluorouracil is converted to several active metabolites that induce a cytotoxic effect. Capecitabine toxicity can be life-threatening with a delayed presentation from ingestion. An oral antidote, uridine triacetate, exists but requires the administration of 20 total doses over a course of five days. CASE REPORT: In this report, we describe a case where timely coordination with a clinical toxicology laboratory was utilized to drive clinical decision making and management. Two children were brought to the emergency department shortly after suspected capecitabine ingestion. MANAGEMENT AND OUTCOME: Patients were admitted to the hospital and started on uridine triacetate. Real-time comprehensive toxicology testing of the children's blood was used to rule out capecitabine toxicity and prevent several unnecessary days of hospitalization and doses of antidote. Patients were discharged safely. DISCUSSION: Real-time comprehensive toxicology testing on a patient's blood may be a valuable resource in ruling out or confirming toxic exposure in accidental pediatric ingestion of chemotherapeutic agents like capecitabine when performed in a timely manner.

Shot by a Gun Missed by a Provider.

BACKGROUND: Botulism is a paralytic disease caused by the neurotoxin produced by Clostridium botulinum. The majority of cases are due to ingestion or injection drug use. Wound botulism from traumatic injury is exceedingly rare, with only one to two cases reported each year in the United States. CASE REPORT: A 27-year-old man presented to the Emergency Department with diplopia, dysphagia, and progressive weakness 10 days after sustaining a gunshot wound to his right lower leg. He had been evaluated for the same complaints at a different facility the day prior and was discharged. His wound appeared well-healing, but a high suspicion for wound botulism led to rapid consultation with the state Poison Control Center and the Centers for Disease Control and Prevention. The patient developed worsening respiratory insufficiency and required mechanical ventilation. Expeditious treatment with equine heptavalent botulinum antitoxin resulted in significant recovery of strength in 4 days. Serum toxin bioassay tested positive for botulinum neurotoxin type A. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Wound botulism now accounts for the majority of adult botulism in the United States. It should be considered in any patient with signs of neuromuscular disease and a recent injury, even if the wound appears uninfected.

Epidemiology of musculoskeletal injury in the California film and motion picture industry.

INTRODUCTION: Musculoskeletal injury exerts a significant burden on US industry. The purpose of this study was to investigate the frequency and characteristics of musculoskeletal injuries in the California (CA) film and motion picture (FMP) industry which may result in unforeseen morbidity and mortality. METHODS: We reviewed the workers' compensation (WC) claims database of the Workers' Compensation Insurance Rating Bureau of California (WCIRB) and employment statistics through the US Bureau of Labor Statistics (BLS). We analyzed the frequency, type, body part affected, and cause of musculoskeletal injuries. RESULTS: From 2003 to 2009, there were 3505 WC claims of which 94.4% were musculoskeletal. In the CA FMP industry, the most common injuries were strains (38.4%), sprains (12.2%), and fractures (11.7%). The most common sites of isolated injury were the knee (18.9%), lower back (15.0%), and ankle (8.6%). Isolated musculoskeletal spine injuries represented 19.3% of all injuries. The most common causes of injury were work-directed activity (36.0%) and falls (25.5%). CONCLUSION: We present the first report on the unique profile of musculoskeletal injury claims in the FMP industry. This data provides direction for improvement of workplace safety.

Cognitive deficits in a mouse model of pre-manifest Parkinson's disease.

Early cognitive deficits are increasingly recognized in patients with Parkinson's disease (PD), and represent an unmet need for the treatment of PD. These early deficits have been difficult to model in mice, and their mechanisms are poorly understood. α-Synuclein is linked to both familial and sporadic forms of PD, and is believed to accumulate in brains of patients with PD before cell loss. Mice expressing human wild-type α-synuclein under the Thy1 promoter (Thy1-aSyn mice) exhibit broad overexpression of α-synuclein throughout the brain and dynamic alterations in dopamine release several months before striatal dopamine loss. We now show that these mice exhibit deficits in cholinergic systems involved in cognition, and cognitive deficits in domains affected in early PD. Together with an increase in extracellular dopamine and a decrease in cortical acetylcholine at 4-6 months of age, Thy1-aSyn mice made fewer spontaneous alternations in the Y-maze and showed deficits in tests of novel object recognition (NOR), object-place recognition, and operant reversal learning, as compared with age-matched wild-type littermates. These data indicate that cognitive impairments that resemble early PD manifestations are reproduced by α-synuclein overexpression in a murine genetic model of PD. With high power to detect drug effects, these anomalies provide a novel platform for testing improved treatments for these pervasive cognitive deficits.

In their words: connecting on-line weblogs to developmental processes.

This paper seeks to connect adolescents' communication within on-line weblogs or blogs to developmental processes. A total of 195 English language blogs written by self-identified 14- to 18-year-olds were selected; three entries from each blog were analysed, resulting in a sample of 585 entries. Blogger demographics, self-presentation, and blog entries (format, style, content, and tone) were coded. The blog authors in our sample were overwhelmingly female and lived within the US; the majority were between 15- and 16-years of age. Bloggers utilized usernames and userpictures for self-presentation and in addition to gender, frequently presented information about their age and location. The majority of the entries used text, were narrative and reflective in style, and contained themes related to their authors' peers and everyday life. Emotional tone was present and entries with romantic, identity, and future-related themes often contained emotional tone. Blog authors seemed to be using blogs to create narratives and to reflect about the people and events in their lives. Our results show that adolescent bloggers project off-line themes to their blogs, suggesting that their on-line and off-line contexts are psychologically connected.

Marketing novel therapies.

This article discusses how to help veterinarians to (1) understand how consumers think and why they buy or do not buy something and (2) enhance their selling and marketing skills. Specific supplements and nutraceuticals are recommended, and suggestions for marketing them provided. The article emphasizes the importance of the role that veterinarians have in providing advice on the use and efficacy of supplements in their clinics when based on actual experience.