Mycobacterium tuberculosis Gyrase Inhibitors as a New Class of Antitubercular Drugs

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.     

Evaluation of antiretroviral treatment in two private medical centers in Addis, Ethiopia

Ethiopia is one of the countries affected severely by the HIV/AIDS epidemic in sub-Saharan Africa. The disease is gradually fatal without antiretroviral therapy (ARV). The experience with antiretroviral therapy is limited in this country. This study is the first of its kind that has evaluated the status and implication of the clinical use of ARV drugs in Ethiopia. The guidelines for the initiation of treatment, the strengths and weaknesses of such treatment and the implications of similar intervention in a wider scale were assessed. Clinical records of 33 patients under follow-up and treatment with ARV in Hayat Hospital and Bethezatha Medical Center were identified. Data were collected from the medical records using a tool designed for the purpose. All 33 patients were receiving ARV for a mean duration of about 4 months. Twenty- three (69.7%) were males and 10 (30.3%) were females and the mean age was 38 years. Fifteen (45.5%) were married, fourteen (40.7%) were single, one (3%) divorced and there was no record for three (9.1%). Fifteen (45.5%) were businessmen, seven (21.2%) were private employees, four (12.1%) civil servants and in the remaining seven (21.2%) their occupation was not recorded. The decision to initiate ARV therapy was entirely based on the presence of symptomatic HIV disease. CD4+ lymphocyte count was done in 24 (72.7%) and basic hematological tests were done for all. However, biochemical investigations were incomplete in all of them. Triple therapy was started for all patients and the cost of the drugs was covered by their family in eleven (33.3%), by the patients in twenty-two (66.7%). Side effects of the drugs were noted in ten (30.3%) that resulted in change of the regimen in two and drug interruption in one. Response to treatment was entirely based on clinical parameters only. Twenty-three patients (69.7%) were noted to improve while nine (27.3%) remained the same and death occurred in one (3%). Standard triple therapy was used in all patients in this study and symptomatic HIV disease was the reason for the initiation of treatment. The improvement observed was not substantiated by immunological or virological parameters. Thus, the impacts of ARVs cannot be measured and the response documented in this study can be due to the effective treatment of opportunistic infections. Hence a standard protocol should be developed based on the minimum set-up required for the initiation of ARV therapy.     

Barriers to Creutzfeldt-Jakob disease autopsies, California

Creutzfeldt-Jakob disease (CJD) surveillance relies on autopsy and neuropathologic evaluation. The 1990-2000 CJD autopsy rate in California was 21%. Most neurologists were comfortable diagnosing CJD (83%), but few pathologists felt comfortable diagnosing CJD (35%) or performing autopsy (29%). Addressing obstacles to autopsy is necessary to improve CJD surveillance.     

Musculoskeletal sarcoidosis in an Ethiopian

We report a patient with osseous lesions of his fingers and thumbs that eventually were proved to be a manifestation of systemic sarcoidosis. This had been mis-diagnosed as tuberculosis and the patient had previously been treated without effect with two full courses of anti-tuberculosis chemotherapy. Eventually the clinical and radiological suspicions were confirmed by biopsy.     

Investigation of a possible iatrogenic case of Creutzfeldt-Jakob disease after a neurosurgical procedure.

OBJECTIVE: To investigate a case of Creutzfeldt-Jakob disease (CJD) possibly acquired from contaminated neurosurgical instruments. DESIGN: Retrospective review of medical records, hospital databases, service log books, and state vital statistics. SETTING: A tertiary care hospital (hospital A) in Missouri. PATIENTS: The case patient was a 38-year-old African American woman with a 9-month history of progressive memory loss, visual disturbances, and dementia. She underwent neurosurgery in November 1996. CJD was confirmed in April 2004 by immunodiagnostic testing of brain biopsy samples. All patients who underwent neurosurgery at the same hospital within 6 months before or after the case patient's procedure were identified and investigated for preoperative or postoperative evidence of CJD. RESULTS: We reviewed data on 268 neurosurgical procedures, 84 pathology log entries, and 60 death certificates for neurosurgical patients at hospital A and identified 2 suspected cases of CJD. Clinical features and definitive prion testing of stored brain biopsy samples excluded a diagnosis of CJD. Standard operating room procedures were in place, but specific protocols for handling instruments potentially contaminated with prions were not used. CONCLUSIONS: Neurosurgical instruments were not implicated as the source exposure for CJD in the case patient. The 2 patients with suspected CJD were identified from different data sources, suggesting good internal consistency in data collection. The key elements of this investigation are suggested for use in future investigations into potential cases of iatrogenic CJD.     

Type 2 alveolar epithelial cell-derived circulating extracellular vesicle-encapsulated surfactant protein C as a mediator of cardiac inflammation in COVID-19

Inflammation Research - Among the countless endeavours made at elucidating the pathogenesis of COVID-19, those aimed at the histopathological alterations of type 2 alveolar epithelial cells (AT2)...     

Visceral leishmaniasis

Visceral leishmaniasis (VL) is a vector-borne parasitic disease targeting tissue macrophages. It is among the most neglected infectious diseases. Classical manifestations of VL include chronic fever, hepatosplenomegaly, and pancytopenia. Most cases can be detected through serologic and molecular testing. Although therapy has historically relied on antimonials, newer therapeutic options include conventional or liposomal amphotericin B, paromomycin and miltefosine. Coinfection with human immunodeficiency virus (HIV) is increasingly reported and comes with additional diagnostic and therapeutic challenges. This article provides an up-to-date clinical review of VL focusing on clinical presentation, diagnosis, management, and issues related to HIV coinfection.     

Constant Transmission Properties of Variant Creutzfeldt-Jakob Disease in 5 Countries

Variant Creutzfeldt-Jakob disease (vCJD) has been reported in 12 countries. We hypothesized that a common strain of agent is responsible for all vCJD cases, regardless of geographic origin. To test this hypothesis, we inoculated strain-typing panels of wild-type mice with brain material from human vCJD case-patients from France, the Netherlands, Italy, and the United States. Mice were assessed for clinical disease, neuropathologic changes, and glycoform profile; results were compared with those for 2 reference vCJD cases from the United Kingdom. Transmission to mice occurred from each sample tested, and data were similar between non-UK and UK cases, with the exception of the ranking of mean clinical incubation times of mouse lines. These findings support the hypothesis that a single strain of infectious agent is responsible for all vCJD infections. However, differences in incubation times require further subpassage in mice to establish any true differences in strain properties between cases.     

Electromyographic and affective responses of episodic tension-type headache patients and headache-free controls during stressful task performance

Thirty-four subjects meeting diagnostic criteria for episodic tension-type headache and 42 who rarely experienced headaches participated in two laboratory sessions in which cephalic electromyographic (EMG) activity, electrodermal activity, heart rate, and finger temperature were recorded. Subjects performed relaxation, choice reaction time, psychomotor tracking, voluntary muscle contraction, and cold pressor tasks. Headache subjects showed significantly greater EMG activity than controls during baseline and stressful task performance. During relaxation, both groups reduced EMG activity from baseline levels, and there was no significant difference in EMG level between the groups during relaxation. Headache subjects reported higher levels of subjective anxiety, depression, anger, and stress than controls. Headache subjects also reported higher levels of pain than controls, and headache subjects reported greater pain during stressful task performance relative to baseline and recovery periods.This research was supported by NIH Grant R01-NS-25114.     

Calibration of estimated biting forces in domestic canids: comparison of post-mortem and in vivo measurements

Estimates of biting forces are widely used in paleontological and comparative studies of feeding mechanics and performance, and are usually derived from lever models based on measurements made on the skull that are relevant to the mechanics of the masticatory system. Owing to assumptions and unmeasurable errors in their estimation, such values are used comparatively rather than as absolute estimates. The purpose of this paper was to provide calibration of post-mortem calculated bite force estimates by comparing them to in vivo forces derived from a sample of 20 domestic dogs ( Canis familiaris ) during muscle stimulation under general anaesthesia. Two lever models previously described in the literature were used to estimate post-mortem values, and regression analysis was also performed to derive best-fit equations against a number of morphometric measurements on the skull. The ranges of observed forces in vivo were 147–946 N at the canine, and 524–3417 N at the second molar. The lever models substantially underestimated these forces, giving mean values between 39% and 61% of the observed means. Predictability was considerably improved by removing the linear bias and deviation of the regression slope from unity with an adjustment equation. Best-fit statistical models developed on these animals performed considerably better (calculated means within 0.54% of observed means) and included easily measureable variables such as bodyweight, dimensions of the temporalis fossa and out-lever from the jaw joint to the biting tooth. These data should lead to more accurate absolute, rather than relative, estimates of biting forces for other extant and fossil canids, and other carnivorans by extrapolation.