The Schistosoma mansoni Cytochrome P450 (CYP3050A1) Is Essential for Worm Survival and Egg Development.

Schistosomiasis affects millions of people in developing countries and is responsible for more than 200,000 deaths annually. Because of toxicity and limited spectrum of activity of alternatives, there is effectively only one drug, praziquantel, available for its treatment. Recent data suggest that drug resistance could soon be a problem. There is therefore the need to identify new drug targets and develop drugs for the treatment of schistosomiasis. Analysis of the Schistosoma mansoni genome sequence for proteins involved in detoxification processes found that it encodes a single cytochrome P450 (CYP450) gene. Here we report that the 1452 bp open reading frame has a characteristic heme-binding region in its catalytic domain with a conserved heme ligating cysteine, a hydrophobic leader sequence present as the membrane interacting region, and overall structural conservation. The highest sequence identity to human CYP450s is 22%. Double stranded RNA (dsRNA) silencing of S. mansoni (Sm)CYP450 in schistosomula results in worm death. Treating larval or adult worms with antifungal azole CYP450 inhibitors results in worm death at low micromolar concentrations. In addition, combinations of SmCYP450-specific dsRNA and miconazole show additive schistosomicidal effects supporting the hypothesis that SmCYP450 is the target of miconazole. Treatment of developing S. mansoni eggs with miconazole results in a dose dependent arrest in embryonic development. Our results indicate that SmCYP450 is essential for worm survival and egg development and validates it as a novel drug target. Preliminary structure-activity relationship suggests that the 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol moiety of miconazole is necessary for activity and that miconazole activity and selectivity could be improved by rational drug design

Demographics and baseline disease characteristics of Black and Hispanic patients with multiple sclerosis in the open-label, single-arm, multicenter, phase IV CHIMES trial

BACKGROUND: Black/African American patients with multiple sclerosis (BpwMS) and Hispanic/Latino patients with multiple sclerosis (HpwMS), who historically have been underrepresented in multiple sclerosis (MS) clinical trials, exhibit greater disease severity and more rapid disease progression than White patients with MS (WpwMS). The lack of diversity and inclusion in clinical trials, which may be due to barriers at the system, patient and study levels, impacts the ability to effectively assess risks, benefits and treatment responses in a generalized patient population. METHODS: CHIMES (Characterization of Ocrelizumab in Minorities With Multiple Sclerosis), an open-label, single-arm, multicenter, phase IV study of self-identified BpwMS and HpwMS aged 18-65 years with relapsing MS and an Expanded Disability Status Score (EDSS) of ≤5.5, was developed in collaboration with patients with MS, national advocacy groups and clinical researchers. Patients were enrolled at study centers across the US, including Puerto Rico, and 1 site in Kenya. RESULTS: A total of 182 patients enrolled in CHIMES: 113 (62.1%) were BpwMS, and 69 (37.9%) were HpwMS; the mean (SD) baseline EDSS score was 2.4 (1.4), and 62.6% of patients were treatment naive. Using the pooled non-BpwMS/HpwMS group in the OPERA ocrelizumab trials as a reference population, patients enrolled in CHIMES were younger, had a higher mean body mass and had a greater T2 lesion volume but similar T2 lesion number on MRI. CONCLUSION: BpwMS and HpwMS have been consistently underrepresented in clinical trials, limiting the understanding of disease biology and response to treatment in this population. Data from the CHIMES study revealed differences in demographics and some baseline disease characteristics and disease burden between BpwMS and HpwMS vs WpwMS. These differences could have an impact when assessing clinical outcomes in BpwMS and HpwMS. GOV IDENTIFIER: NCT04377555

Non-invasive neurosensory testing used to diagnose and confirm successful surgical management of lower extremity deep distal posterior compartment syndrome

<p>Abstract</p> <p>Background</p> <p>Chronic exertional compartment syndrome (CECS) is characterized by elevated pressures within a closed space of an extremity muscular compartment, causing pain and/or disability by impairing the neuromuscular function of the involved compartment. The diagnosis of CECS is primarily made on careful history and physical exam. The gold standard test to confirm the diagnosis of CECS is invasive intra-compartmental pressure measurements. Sensory nerve function is often diminished during symptomatic periods of CECS. Sensory nerve function can be documented with the use of non-painful, non-invasive neurosensory testing.</p> <p>Methods</p> <p>Non-painful neurosensory testing of the myelinated large sensory nerve fibers of the lower extremity were obtained with the Pressure Specified Sensory Device™ in a 25 year old male with history and invasive compartment pressures consistent with CECS both before and after running on a tread mill. After the patient's first operation to release the deep distal posterior compartment, the patient failed to improve. Repeat sensory testing revealed continued change in his function with exercise. He was returned to the operating room where a repeat procedure revealed that the deep posterior compartment was not completely released due to an unusual anatomic variant, and therefore complete release was accomplished.</p> <p>Results</p> <p>The patient's symptoms numbness in the plantar foot and pain in the distal calf improved after this procedure and his repeat sensory testing performed before and after running on the treadmill documented this improvement.</p> <p>Conclusion</p> <p>This case report illustrates the principal that non-invasive neurosensory testing can detect reversible changes in sensory nerve function after a provocative test and may be a helpful non-invasive technique to managing difficult cases of persistent lower extremity symptoms after failed decompressive fasciotomies for CECS. It can easily be performed before and after exercise and be repeated at multiple intervals without patient dissatisfaction. It is especially helpful when other traditional testing has failed.</p

Method for remotely powering a device such as a lunar rover

A method of supplying power to a device such as a lunar rover located on a planetary surface is provided. At least one, and preferably three, laser satellites are set in orbit around the planet. Each satellite contains a nuclear reactor for generating electrical power. This electrical power is converted into a laser beam which is passed through an amplifying array and directed toward the device such as a lunar rover. The received laser beam is then converted into electrical power for use by the device