Predictive in vitro models of the sterilizing activity of anti-tuberculosis drugs

Sterilizing drugs kill Mycobacterium tuberculosis that persists during chemotherapy. Predictive models should mimic the conditions causing persistence in the lesions of cavitary disease, and should grade current anti-tuberculosis drugs according to their sterilizing activity determined in clinical trials. Models should start with old, stationary cultures grown micro-aerophilically. In these, persistent bacilli occur in different populations in which there is no appreciable cell division. Population 1. Grows in liquid culture medium but not on solid medium. Killed by rifampicin. Population 2. Grows on solid culture medium. Killed by rifampicin. Population 3. Grows in liquid medium but not on solid medium. Tolerant of rifampicin. Population 4. Bacilli from Cornell model mice, after treatment with pyrazinamide and isoniazid, cannot grow in liquid or on solid culture medium. Some of these populations are incorporated in models which start with 100-day liquid medium cultures. In model 1 (population 2) the new drug is added and colony counted after 7 days incubation. In models 2 and 3, 100 mg/L rifampicin is added to the 100-day culture when the bacilli lose their ability to grow on solid culture medium (population 3). After re-suspension in rifampicin-free liquid medium for 7 days, the bacilli recover growth on solid medium, when a colony count is done. The new drug is added during incubation with rifampicin in model 3 and at the start of recovery in drug-free medium in model 2. Models 1 and 3 grade isoniazid, rifampicin and pyrazinamide according to their sterilizing activity determined by clinical trials.     

Management of pituitary apoplexy

Pituitary apoplexy is a rare clinical syndrome caused by sudden haemorrhaging or infarction of the pituitary gland, generally within a pituitary adenoma. Headache of sudden and severe onset is the main symptom, associated with visual disturbances or ocular palsy. Signs of meningeal irritation or altered consciousness may complicate the diagnosis. Corticotropic deficiency (secondary adrenal failure) may be life-threatening if untreated. Computed tomography (CT) or magnetic resonance imaging (MRI) confirm the diagnosis by revealing a pituitary tumour with haemorrhagic and/or necrotic components: CT is most useful in the acute setting (24 - 48 h), MRI is useful for identifying blood components in the subacute setting (4 days to 1 month). Owing to the highly variable course of this syndrome and the limited individual experience, the optimal management of acute pituitary apoplexy is controversial. Some authors advocate early transphenoidal surgical decompression for all patients, whereas others adopt a more conservative approach for selected patients (those without visual acuity or field defects and with normal consciousness). Glucocorticoid treatment must always be initiated immediately, at a dose of hydrocortisone 50 mg every 6 h.     

Isoprenoid biosynthesis as a novel target for antibacterial and antiparasitic drugs

The mevalonate-independent methylerythritol phosphate pathway is a long overlooked metabolic pathway for isoprenoid biosynthesis. It is present in most bacteria, including pathogens and opportunistic pathogens, in some unicellular eukaryotes, including the parasite responsible for malaria, and in the chloroplasts of all phototrophic organisms. It represents an alternative to the mevalonate pathway, which is only present in animals, fungi, the plant cytoplasm, archaebacteria and some eubacteria. This biosynthetic pathway is thus a potential target for antibacterial and antiparasitic drugs. An isopentenyl diphosphate isomerase that differs from the previously known isopentenyl diphosphate isomerase found in all other organisms, including animals, was discovered in several Gram-positive bacteria possessing the mevalonate pathway, adding another target related to isoprenoid biosynthesis.     

Estrogenic and anticarcinogenic properties of kurarinone, a lavandulyl flavanone from the roots of Sophora flavescens

Kurarinone, a lavandulyl flavanone, was isolated from a polyphenolic extract of the roots of Sophora flavescens using fractionation guided by estrogenic activity, which was determined by recombinant yeast and Ishikawa Var-I bioassays. Kurarinone showed weak estrogenic activity both in the yeast screen and in the Ishikawa Var-I assay with EC(50) values of 4.6 and 1.66 microM, respectively. Furthermore, kurarinone was found to have potent cytotoxic activity (IC(50) value = 22.2 microM) against human MCF-7/6 breast cancer cells in the sulforhodamine-B assay.     

Involvement of the PI 3-kinase signaling pathway in progression of colon adenocarcinoma

The phosphoinositide 3-kinase (PI 3-kinase) signaling pathway has been shown to play a pivotal role in intracellular signal transduction pathways involved in cell growth, cellular transformation and tumorigenesis. Analysis of several colon adenocarcinoma cell lines indicates that the PI 3-kinase signaling pathway is up-regulated in colon cancers. In particular, the protein levels and phosphorylation status of Akt and p70 S6 kinase are up-regulated in colon adenocarcinoma cell lines. More significantly, we have demonstrated for the first time that the phosphorylation of FKHR, a downstream target of Akt, is increased in these cell lines. Intriguingly, phosphorylation of three components of the PI 3-kinase signaling pathway, namely Akt, p70 S6 kinase and FKHR, are in direct correlation with the degree of tumorigenic potential of the colon cell lines tested. No differences in the protein levels of the two subunits of PI 3-kinase, p85 and p110alpha, and PTEN were noted. Real-time quantitative PCR indicated an increase in levels of Akt message only, and not of the other signaling pathway components. Inhibition of the PI 3-kinase with wortmannin decreased the anchorage-independent growth of colon cells in a soft agar assay. Hence, the components of the PI 3-kinase signaling pathway could serve as potential candidates for drug development in treatment of colon cancer.     

Thromboembolic events occur despite sinus rhythm maintenance in patients treated for atrial fibrillation: The Canadian Trial of Atrial Fibrillation experience

BACKGROUND: Anticoagulation reduces the risk of stroke in patients with atrial fibrillation. It is not clear whether patients who revert and are maintained in sinus rhythm should continue to receive warfarin. The recommendation is to anticoagulate these patients for a minimum of four weeks after cardioversion. Whether warfarin should be maintained for a longer period of time is unknown. METHODS AND RESULTS: To address this question, data from the Canadian Trial of Atrial Fibrillation were reviewed. Among the 403 patients, 81.9% had at least one risk factor for stroke, of whom only 60% were on warfarin. Nine thromboembolic events occurred in nine patients (2.2%): all had at least one risk factor for stroke. Six events occurred in patients who were either not anticoagulated (n=4) or for whom the international normalization ratio was subtherapeutic (n=2). Eight of the nine patients were in sinus rhythm at the last follow-up visit before and at the time of evaluation of the thromboembolic event. CONCLUSIONS: Anticoagulants are underused in atrial fibrillation patients at risk of stroke. Thromboembolic events are most often associated with suboptimal levels of anticoagulation and they occur despite the appearance of sinus rhythm maintenance.     

The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals

BACKGROUND: It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer. To date, however, the published results of randomized, placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect. We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population. METHODS: The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study is a randomized, double-blind, placebo-controlled primary prevention trial. A total of 13 017 French adults (7876 women aged 35-60 years and 5141 men aged 45-60 years) were included. All participants took a single daily capsule of a combination of 120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 mug of selenium, and 20 mg of zinc, or a placebo. Median follow-up time was 7.5 years. RESULTS: No major differences were detected between the groups in total cancer incidence (267 [4.1%] for the study group vs 295 [4.5%] for the placebo group), ischemic cardiovascular disease incidence (134 [2.1%] vs 137[2.1%]), or all-cause mortality (76 [1.2%] vs 98 [1.5%]). However, a significant interaction between sex and group effects on cancer incidence was found (P = .004). Sex-stratified analysis showed a protective effect of antioxidants in men (relative risk, 0.69 [95% confidence interval [CI], 0.53-0.91]) but not in women (relative risk, 1.04 [95% CI, 0.85-1.29]). A similar trend was observed for all-cause mortality (relative risk, 0.63 [95% CI, 0.42-0.93] in men vs 1.03 [95% CI, 0.64-1.63] in women; P = .11 for interaction). CONCLUSIONS: After 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants, especially of beta carotene.