Mechanism of thioamide drug action against tuberculosis and leprosy

Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target–drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar K_is against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.     

Chronic heavy ethanol consumption is associated with decreased platelet aggregation in rats

Although moderate alcohol consumption seems to be protective against atherosclerosis, coronary artery disease rate increases with its higher doses. Platelet aggregation is an important process which contributes to the atherosclerosis. The aim of this study was to determine whether heavy ethanol consumption stimulates or inhibits platelet aggregation. Fourteen adult male Wistar rats were used. Ethanol (7.2%, v/v) in a modified liquid diet was given to eight rats for 21 days, which mimicked characteristics similar to human chronic alcoholism. Six rats constituted the control group. Adenosine diphophate (ADP) and collagen-induced platelet aggregation was measured in whole blood. We found reduced ADP-induced mean maximal aggregation in the alcoholic rat group compared to the control group at dose of 5 microM (p < 0.005). We also found decreased platelet aggregation responses to collagen in the alcoholic group (p < 0.006 for 2 microg/ml collagen, and p < 0.05 for 5 microg/ml collagen). In conclusion, chronic heavy ethanol consumption results in the decreased platelet aggregation in a rat model of alcoholism. Therefore, increased mortality from coronary artery disease in chronic alcoholism may be explained by other factors such as dietary imbalances and coexisting conditions, which include hypertension and depression.     

Left ventricular function in male patients with secondary hypogonadism

BACKGROUND: In addition to the effects on ventricular repolarization, testosterone could also affect left ventricular performance. The enhancement of left ventricular contractility in testosterone-deficient rats following testosterone replacement implies to the possible testosterone effect. OBJECTIVES: The aim of the current study is to reveal the alterations of left ventricular functions, if any, in secondary hypogonadal male patients. METHODS: Thirty-four males with secondary hypogonadism comprised the study group. The control group consisted of 30 healthy subjects. Echocardiographic measurements including left ventricular dimensions, ejection fraction, mitral inflow, and left ventricular outflow parameters were obtained from all subjects. Tissue Doppler parameters were also measured from left ventricular lateral wall and interventricular septum. RESULTS: Left ventricular diameters, wall thicknesses, and performance parameters were similar in both groups. Mitral inflow parameters showed a statistically insignificant difference. Pulse-wave tissue Doppler interpretation of hypogonadal and healthy subjects were similar in terms of lateral and septal basal segment Sm, Em, and Am wave velocities. CONCLUSIONS: Regarding the findings of previous studies that showed impaired myocardial contractility and lusitropy in testosterone deficient rats and our study results, further studies are needed for better understanding of testosterone's effects on human myocardium.     

A malignant mass in the breast is not always breast cancer

A 37-year-old woman presented to the Internal Medicine Clinic with complaints of abdominal pain and constipation which had begun 3 months earlier. A colonoscopy was performed, and wall thickening of the sigmoid colon was detected. A biopsy of the sigmoid colon revealed a poorly differentiated, mucin-producing adenocarcinoma with a signet-ring pattern. No distant metastasis was detected. The patient was treated with chemotherapy consisting of 5-fluorouracil, leucovorin, and oxaliplatin. One and a half years later, a painless mass, which was not fixed to the skin, measuring 1 cm in diameter, was found in the lower outer quadrant of the left breast. A core biopsy of the mass was performed, and a histopathological report confirmed metastasis to the breast from mucinous adenocarcinoma of an intestinal primary.