Characterization of clioquinol and analogues as novel inhibitors of methionine aminopeptidases from Mycobacterium tuberculosis

Mycobacterium tuberculosis, the causative agent of tuberculosis claims about five thousand lives daily world-wide, while one-third of the world is infected with dormant tuberculosis. The increased emergence of multi- and extensively drug-resistant strains of M.?tuberculosis (Mtb) has heightened the need for novel antimycobacterial agents. Here, we report the discovery of 7-bromo-5-chloroquinolin-8-ol (CLBQ14)-a congener of clioquinol (CQ) as a potent and selective inhibitor of two methionine aminopeptidases (MetAP) from M.?tuberculosis: MtMetAP1a and MtMetAP1c. MetAP is a metalloprotease that removes the N-terminal methionine during protein synthesis. N-terminal methionine excision (NME) is a universally conserved process required for the post-translational modification of a significant part of the proteome. The essential role of MetAP in microbes makes it a promising target for the development of new therapeutics. Using a target-based approach in a high-throughput screen, we identified CLBQ14 as a novel MtMetAP inhibitor with higher specificity for both MtMetAP1s relative to their human counterparts. We also found that CLBQ14 is potent against replicating and aged non-growing Mtb at low micro molar concentrations. Furthermore, we observed that the antimycobacterial activity of this pharmacophore correlates well with in?vitro enzymatic inhibitory activity. Together, these results revealed a new mode of action of clioquinol and its congeners and validated the therapeutic potential of this pharmacophore for TB chemotherapy.     

Assessment of pain quality in chronic neuropathic and nociceptive pain clinical trials with the Neuropathic Pain Scale.

Although a number of measures of pain qualities exist, little research has examined the potential for these measures to identify the unique effects of pain treatments on different pain qualities. We examined the utility of the Neuropathic Pain Scale (NPS) for assessing changes in pain qualities after open label lidocaine patch 5% in 3 samples of patients: patients with peripheral neuropathic pain, low back pain, and osteoarthritis. With one exception ("cold" pain in subjects with low back pain), each of the NPS items showed significant change after open label lidocaine patch. In addition, significantly larger changes were observed for the NPS items reflecting global pain intensity and pain unpleasantness and for items assessing sharp and deep pain than for items assessing cold, sensitive, and itchy pain. The pattern of changes in pain qualities did not differ across the 3 diagnostic groups, but it did differ from the patterns of changes in pain qualities associated with other analgesic treatments. The results support the potential utility of the NPS for assessing the patterns of changes in pain qualities that can be observed after pain treatment. PERSPECTIVE: Pain clinical trials that include measures of pain qualities, such as the NPS, might identify distinct patterns of treatment effects on those pain qualities. This research might be used to help clinicians target analgesics to match the specific qualities associated with a patient's pain and to better understand the mechanisms of analgesic effects in drug development programs.     

Vaginal delivery after one caesarean section in Nigerian women.

A total of 120 Nigerian women at term pregnancy with one previous caesarean delivery were studied between June 1988 and May 1993. Elective caesarean section was performed in 3 (2.5%). Vaginal delivery was achieved in 101 (86.5%) of those allowed a trial of labour. Intrapartum caesarean section was done in 16 (13.7%) cases. Rupture of the uterus occurred in 3 cases (2.6%) with perinatal loss of 2 babies. There was no maternal mortality. There was no significant correlation between vaginal delivery and birth weight, gestational age or initial indication for the primary caesarean section. It is concluded that trial of labour is safe after a previous caesarean section in selected patients.     

The impact of charging for insecticide on the Gambian National Impregnated Bednet Programme

During the second year of the Gambian National Impregnated Bednet Programme (NIBP) charges for insecticide ($0.50 per net) were introduced into the half of the primary health care villages in the country where insecticide have been provided free of charge the previous year. Free insecticide was provided in the remaining villages that had acted as controls during the previous year. In villages where insecticide was provided free, 77% of nets were treated with insecticide. In contrast, in villages where charges were made coverage was only 14%. During the first year of the NIBP, mortality in children was significantly lower in villages where insecticide was provided free than in the control villages. Introduction of a charge for insecticide into the first group of villages and the provision of free insecticide in the latter abolished this difference. The cash income of rural Gambians is very limited and payment of even $2-3 for insecticide treatment for all the bednets in a household represents a substantial outlay. Further education on the benefits of treatment of nets and/or the provision of cheaper insecticide will be required before the full benefits of this powerful new malaria control measure can be fully realised in the Gambia.     

Validation of the Edinburgh Postnatal Depression Scale as a screening tool for depression in late pregnancy among Nigerian women

This study aimed to examine the validity of the Edinburgh Postnatal Depression Scale (EPDS) as a screening tool for depression in late pregnancy among Nigerian women. A total of 182 women in late pregnancy (32-36 weeks) completed either the English or the translated Yoruba language version of the EPDS and a proportion of them were then assessed for the presence of DSM-IV major and minor depressive disorders using the MINI International Neuropsychiatric Interview. A cut-off score of 10 on the EPDS was found to be the best for screening for both major and minor depression (sensitivity = 0.867, specificity = 0.915, Diagnostic Likelihood Ratio for a positive result = 10.200). When screening for major depression only, a cut-off of 12 was found to the most appropriate (sensitivity = 1.000, specificity = 0.961, Diagnostic Likelihood Ratio for a positive result = 25.641). The EPDS is a valid and useful instrument in screening for depression in late pregnancy among Nigerian women.     

Assessing the level of preparedness of private health providers for clinical management of HIV/AIDS epidemic in Nassarawa State, Nigeria

Very little information is available on the extent to which the private health sector is involved in clinical management of HIV/AIDS in Nigeria. This study assessed the potentials and existing capacity of 15 private health facilities in Nassarawa state for clinical management of HIV/AIDS. Information was obtained from 25 staff (15 proprietors and 10 professionals) of the randomly selected health facilities in the state using structured questionnaire. Of the 15 health facilities, three provided voluntary counselling and testing (VCT), seven had never admitted persons living with HIV/AIDS (PLWHA), two provided laboratory services, none provided home-based care for PLWHAs, two had anti-retro-viral drugs in stock, two had rooms for counselling, three had full-time doctors, and six had registered nurses. Of the 25 health workers, 5 had skills/training in conducting VCT, 15 had skills in the treatment of opportunistic infections, 14 were aware of anti-retro-viral drugs and 13 did not feel comfortable attending to PLWHAs. The study recommended capacity building on HIV/AIDS related services for the private health-workers.