The metabolism and disposition of GSK2140944 in healthy human subjects

1.?GSK2140944 is a novel bacterial topoisomerase inhibitor in development for the treatment of bacterial infections. The metabolism and disposition in healthy human subjects was investigated.

2.?Six male subjects received [¹⁴C] GSK2140944 orally (2000?mg) and as a single 2-hour i.v. infusion (1000?mg). Urinary elimination (59%) was major by the i.v. route, whereas fecal elimination (53%) pre-dominated via the oral route. Accelerator mass spectrometry (AMS) was used for the analysis of plasma and bile samples due to the low level of radioactivity in samples (low specific activity of the doses). Unchanged GSK2140944 was the predominant circulating component (>60% DRM), with the main circulating metabolite M4 formed by oxidation of the triazaacenaphthylene moiety representing 10.8% (considered major) and 8.6% drug-related material by the oral and i.v. route, respectively. Approximately 50% of the oral dose was absorbed and eliminated mainly as unchanged GSK2140944 in urine (～20% of dose). Elimination via metabolism (～13% of dose) was relatively minor. The facile oxidation of GSK2140944 to metabolite M4 was believed to be a result of activation by adjacent electron withdrawing groups.

3.?This study demonstrates the use of AMS to overcome radioprofiling challenges presented by low specific activity resulted from high doses administration.     

Osteosarcoma of limb bones: a clinical,radiological and histopathological diagnostic agreement at Black Lion Teaching Hospital,Ethiopia

Objectives

To measure the strength of agreement in clinical, radiological and histopathological diagnosis of osteosarcoma in a 5 year study period.

Setting

Addis Ababa University, Black-Lion (‘Tikur Anbessa’) Hospital-BLH, is the country''s highest tertiary level referral and teaching hospital. The departments involved in this study (Radiology, Pathology and Orthopedics) receive referred patients from all over the country.

Methods

All bone tumor patients, presenting to the three departments at BLH between the study period, December, 2003 – March, 2008 were recruited for the study. 51 patients with radiological diagnosis of osteosarcoma of the extremities were identified and their clinical and histopathological diagnoses reviewed in detail. All patients had a clinical examination, plain radiographs and biopsies of the affected part of the extremity. Radiographs of selected difficult cases were discussed at joint orthopedic & radiologic sessions every week. The radiological and histopathological diagnoses made were categorized separately using WHO classification of bone tumors. Strength of agreement between radiological and histopathological diagnoses was measured using Cohen''s Kappa test.

Results

Of the total of 216 bone tumor patients presented and biopsied in the five year period, fifty one (51) had osteosarcoma of extremity bones. Commonest age affected by osteosarcoma was 16 (7–55years) and sex ratio was 1:1. Osteosarcoma was also the single most common clinical, radiological and histological diagnosis made. Considering all bone tumors presented together, the study indicated that radiological diagnosis was confirmed by similar histological diagnosis in 172 out 205 cases (84 %) and the corresponding Cohen''s Kappa value (0.82) showed excellent level of agreement between radiological and histological diagnoses of all bone tumors. The agreement between radiological and histopathological diagnoses of osteosarcoma of the limbs was 84.5%.

Conclusion

There is an excellent agreement between clinical, radiological and histopathological diagnoses of bone tumors in general and osteosarcoma in particular. In setups where there is limited or no histopathological service, joint clinical and radiological decision could lead to a higher degree of accuracy in diagnosis of bone tumors, especially osteosarcoma. Radiological diagnosis of bone tumors at Black Lion Hospital, Addis Ababa is excellent.     

Quality of Care Delivered to Tuberculosis Patients among Public Hospitals in Central Northeast Ethiopia

BackgroundInappropriate Tuberculosis (TB) diagnosis and treatment contributes to unfavorable health outcome among TB patients. Improving quality of healthcare service helps to avert TB related morbidity. Despite these facts, the level of quality of service is not known in the hospitals. Hence, the present study was conducted to assess the quality of care delivered to TB patients among public hospitals.MethodsA facility-based cross-sectional study was conducted from March 15 to April 30, 2019 in North Shewa Zone, Amhara region, Ethiopia. All TB patients who had follow-up in the hospitals were included. This resulted in the involvement of 82 TB patients. Data was collected by trained data collectors using facility audit, clinical observation checklists, structured questionnaire and in-depth interview. Data was analyzed using SPSS version 20. Binary logistic regression analysis was done to identify the predictors of patients'' satisfaction.ResultsIn this study, 82 respondents with a mean age of 36.48 (±13.27) years were participated. The mean quality score for structural dimension was 59.5%, and 53.7% of participants were found to be satisfied in outcome dimension. The mean score for process dimension of quality of service were 67.9%. Having TB symptoms were significantly associated with the level of patient satisfaction towards TB care [AOR = 0.217, p = 0.015].ConclusionQuality of TB services from structural and outcome dimension were low and higher in process dimension. Thus, careful attention on the quality of services will help to reduce the burden of TB.     

Epizootiological importance of Glossina morsitans submorsitans (Diptera: Glossinidae) (Newstead) in the Ghibe River Valley, Southwest Ethiopia

The epizootiological importance of Glossina morsitans submorsitans in Ghibe River Valley was undertaken from October 2000 to September 2001. The flies were collected using baited monoconical traps. G. m. submorsitans occurred with a mean apparent density of 4.26 ± 0.49 flies/trap/day and the apparent density was characterized by an increase during the wet season and a decrease during the dry season. Among 450 G. m. submorsitans, approximately 5% were found to be infected with trypanosome. Of these infected flies, 76% were female. Nanomonas, Duttonella and Trypanozoon were the three trypanosome subgenera detected and occurred in the proportions of 57.1%, 38.1% and 4.8%, respectively. Among 139 blood meals of G. m. submorsitans collected, 54.68% were identified to group or species levels. Accordingly, 36.84%, 25%, 11.84% and 10.53% accounted for cattle, kudu, suidae (warthog and/or wild pig) and human, respectively and others such as goats (6.58%), bovidae (5.26%), baboon (2.63%) and water buck (1.32%). While 21.05% of the blood meals were found to be out of detection range.     

Hepatitis regulation by the inflammasome signaling pathway

Hepatitis is damage and inflammation of the liver. It is triggered by both environmental and endogenous insults and is a platform for developing liver cirrhosis and cancer. Both innate and adaptive immune activation contribute to hepatic inflammation and disease. Viral hepatitis is the most common form of hepatitis and is typically associated with chronic viral infection. Alcohol-induced and non-alcoholic steatohepatitis are two rising hepatic problems. The innate immune inflammasome signaling cascade mediates the production of essential proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. These cytokines regulate hepatic cell interaction and crosstalk of the various inflammatory pathways and influence disease outcome.     

Mucosal host responses to bacteriuria in colonic and ileal neobladders

OBJECTIVE: To study the local host response in patients with colonic and ileal neobladders, with or without bacteriuria. METHODS: Twenty-three patients with colonic neobladders and 19 with ileal neobladders were included. Eleven radical prostatectomy patients and seven healthy male volunteers were used as controls. Six urine samples were obtained from all patients and controls over a six-month period. The samples were cultured semiquantitatively, and the number of neutrophils and concentrations of the inflammatory mediators interleukin 6 and 8 (IL-6, IL-8) in the urine were determined. RESULTS: The prostatectomy patients and healthy volunteers had sterile urine, and concentrations of IL-6 and IL-8 were below the detection limit. Most (>70%) of the urine samples from patients with colonic and ileal neobladders showed anaerobic or aerobic bacterial growth, and uropathogens were identified in about 45% of the samples. The local host response was minimal or undetectable in the sterile urine samples. However, the host response was markedly induced by uropathogenic strains in the urine, but not by urinary carriage of nonpathogenic or anaerobic strains. IL-8, but not IL-6, was increased in colonic neobladders, which corresponds to the mucosal host responses in patients with intact lower urinary tracts and asymptomatic bacteriuria. In ileal neobladders, the IL-8 responses were higher, and levels of IL-6 were significantly increased. CONCLUSION: Neobladders exhibit a significant local host response to colonization with bacterial uropathogens. This reaction is more pronounced and includes IL-6 activation in ileal neobladders than in colonic neobladders.     

Is the Mediterranean Diet Pattern Associated with Weight Related Health Complications in Adults? A Cross-Sectional Study of Australian Health Survey

We hypothesized that unhealthy dietary pattern would be associated with weight related complications among overweight. We analysed data from the Australian Health Survey conducted from 2011 to 2013. A total of 5055 adults with at least overweight (body mass index ≥25 kg/m²) were analysed. We used logistic regression to assess the association between unhealthy dietary pattern, defined by low adherence to Mediterranean Diet Score (MDS), and weight related complications, defined by the Edmonton Obesity Staging System (EOSS). We repeated the logistic regression models by age and socio-economic disadvantage strata in sensitivity analyses. We also repeated the main analysis on a propensity score matched dataset (n = 3364). Complications by EOSS ≥2 was present in 3036 (60.1%) participants. There was no statistically significant association between unhealthy dietary pattern and weight related complication (odds ratio 0.98 (95%confidence interval: 0.85, 1.12)). The null association remained the same after repeating the analysis on three age and five socio-economic indexes for areas strata. The finding persisted after the analysis was repeated on a propensity score matched dataset. We found no evidence to support the hypothesis that unhealthy dietary pattern was associated with weight related complications in this cross-sectional study of the Australian population with overweight or obesity.     

Cognition and neuropathology in aging: multidimensional perspectives from the Rush Religious Orders Study and Rush Memory And Aging Project

It is increasingly recognized that the correlation between neuropathological lesions and cognition is modest and accounts for about a quarter of the variance of cognition among older adults. Some individuals maintain normal cognitive functioning amidst significant brain pathology, while others suffer varying degrees of cognitive and neurological deterioration that render them dependent and frail. We present data from the Religious Orders Study and the Memory and Aging Project pertaining to pathology and cognition, and propose a paradigm shift in consideration of the neurobiology of healthy aging and dementia. Factors that modify or mediate the association between neuropathology and cognition are also discussed. It is hypothesized that the concept of resilient aging can serve as a useful entity in understanding mechanisms that underlie healthy aging amidst disease-related pathology.     

Trimethoprim as Adjuvant Treatment in Schizophrenia: A Double-Blind,Randomized, Placebo-Controlled Clinical Trial

Various infectious agents, such as Toxoplasma gondii, have been hypothesized to be potentially relevant etiological factors in the onset of some cases of schizophrenia. We conducted a randomized, double-blind, placebo-controlled treatment trial in an attempt to explore the hypothesis that the symptoms of schizophrenia may be related to infection of the central nervous system with toxoplasma gondii. Systematically selected patients with ongoing and at least moderately severe schizophrenia from Butajira, in rural Ethiopia, were randomly allocated to trimethoprim or placebo, which were added on to participants'' regular antipsychotic treatments. Trial treatments were given for 6 months. The Positive and Negative Syndrome Scale (PANSS) was used to assess outcome. Ninety-one patients were included in the study, with 80 cases (87.9%) positive for T. gondii immunoglobulin G antibody. Seventy-nine subjects (87.0%) completed the trial. The mean age of subjects was 35.3 (SD = 8.0) years, with a mean duration of illness of 13.2 (SD = 6.7) years. Both treatment groups showed significant reduction in the overall PANSS score with no significant between-group difference. In this sample of patients with chronic schizophrenia, trimethoprim used as adjuvant treatment is not superior to placebo. However, it is not possible to draw firm conclusion regarding the etiological role of toxoplasmosis on schizophrenia based on this study because the timing and the postulated mechanisms through which toxoplasmosis produces schizophrenia are variable.