Photolytic manipulation of [Ca2+](i) reveals slow kinetics of potassium channels underlying the afterhyperpolarization in hipppocampal pyramidal neurons

The identity of the potassium channel underlying the slow, apamin-insensitive component of the afterhyperpolarization current (sl(AHP)) remains unknown. We studied sl(AHP) in CA1 pyramidal neurons using simultaneous whole-cell recording, calcium fluorescence imaging, and flash photolysis of caged compounds. Intracellular calcium concentration ([Ca2+](i)) peaked earlier and decayed more rapidly than sl(AHP). Loading cells with low concentrations of the calcium chelator EGTA slowed the activation and decay of sl(AHP). In the presence of EGTA, intracellular calcium decayed with two time constants. When [Ca2+](i) was increased rapidly after photolysis of DM-Nitrophen, both apamin-sensitive and apamin-insensitive outward currents were activated. The apamin-sensitive current activated rapidly (<20 msec), whereas the apamin-insensitive current activated more slowly (180 msec). The apamin-insensitive current was reduced by application of serotonin and carbachol, confirming that it was caused by sl(AHP) channels. When [Ca2+](i) was decreased rapidly via photolysis of diazo-2, the decay of sl(AHP) was similar to control (1.7 sec). All results could be reproduced by a model potassium channel gated by calcium, suggesting that the channels underlying sl(AHP) have intrinsically slow kinetics because of their high affinity for calcium.

Twice-weekly, directly observed treatment for HIV-infected and uninfected tuberculosis patients: cohort study in rural South Africa

Objective: To determine the effectiveness of twice-weekly directly observed therapy (DOT) for tuberculosis (TB) in HIV-infected and uninfected patients, irrespective of their previous treatment history. Also to determine the predictive value of 2-3 month smears on treatment outcome. Methods: Four hundred and sixteen new and 113 previously treated adults with culture positive pulmonary TB (58% HIV infected, 9% combined drug resistance) in Hlabisa, South Africa. Daily isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) given in hospital (median 17 days), followed by HRZE twice a week to 2 months and HR twice a week to 6 months in the community. Results: Outcomes at 6 months among the 416 new patients were: transferred out 2%; interrupted treatment 17%; completed treatment 3%; failure 2%; and cured 71%. Outcomes were similar among HIV-infected and uninfected patients except for death (6 versus 2%; P = 0.03). Cure was frequent among adherent HIV-infected (97%; 95% CI 94-99%) and uninfected (96%; 95% CI 92-99%) new patients. Outcomes were similar among previously treated and new patients, except for death (11 versus 4%; P = 0.01), and cure among adherent previously treated patients 97% (95% CI 92-99%) was high. Smear results at 2 months did not predict the final outcome. Conclusion: A twice-weekly rifampicin-containing drug regimen given under DOT cures most adherent patients irrespective of HIV status and previous treatment history. The 2 month smear may be safely omitted. Relapse rates need to be determined, and an improved system of keeping treatment interrupters on therapy is needed. Simplified TB treatment may aid implementation of the DOTS strategy in settings with high TB caseloads secondary to the HIV epidemic. (C) 1999 Lippincott Williams & Wilkins.

Frequency stabilised grating feedback laser diode for atom cooling applications

The free running linewidth of an external cavity grating feedback diode laser is on the order of a few megahertz and is limited by the mechanical and acoustic vibrations of the external cavity. Such frequency fluctuations can be removed by electronic feedback. We present a hybrid stabilisation technique that uses both a Fabry-Perot confocal cavity and an atomic resonance to achieve excellent short and long term frequency stability. The system has been shown to reduce the laser linewidth of an external cavity diode laser by an order of magnitude to 140 kHz, while limiting frequency excursions to 60 kHz relative to an absolute reference over periods of several hours. The scheme also presents a simple way to frequency offset two lasers many gigahertz apart which should find a use in atom cooling experiments, where hyperfine ground-state frequency separations are often required.

GIS/GPS to document increased access to community-based treatment for tuberculosis in Africa

Application of geographic information system (GIS) and global positioning system (GPS) technology in the Hlabisa community-based tuberculosis treatment programme documents the increase in accessibility to treatment after the expansion of the service from health facilities to include community workers and volunteers.

Emergence of multidrug-resistant tuberculosis in a community-based directly observed treatment programme in rural South Africa

OBJECTIVE: Although little studied in developing countries, multidrug-resistant tuberculosis (MDR-TB) is considered a major threat. We report the molecular epidemiology, clinical features and outcome of an emerging MDR-TB epidemic. METHODS: In 1996 all tuberculosis suspects in the rural Hlabisa district, South Africa, had sputum cultured, and drug susceptibility patterns of mycobacterial isolates were determined. Isolates with MDR-TB (resistant to both isoniazid and rifampicin) were DNA fingerprinted by restriction fragment length polymorphism (RFLP) using IS6110 and polymorphic guanine-cytosine-rich sequence-based (PGRS) probes. Patients with MDR-TB were traced to determine outcome. Data were compared with results from a survey of drug susceptibility done in 1994. RESULTS: The rate of MDR-TB among smear-positive patients increased six-fold from 0.36% (1/275) in 1994 to 2.3% (13/561) in 1996 (P = 0.04). A further eight smear-negative cases were identified in 1996 from culture, six of whom had not been diagnosed with tuberculosis. MDR disease was clinically suspected in only five of the 21 cases (24%). Prevalence of primary and acquired MDR-TB was 1.8% and 4.1%, respectively. Twelve MDR-TB cases (67%) were in five RFLP-defined clusters. Among 20 traced patients, 10 (50%) had died, five had active disease (25%) and five (25%) were apparently cured. CONCLUSIONS: The rate of MDR-TB has risen rapidly in Hlabisa, apparently due to both reactivation disease and recent transmission. Many patients were not diagnosed with tuberculosis and many were not suspected of drug-resistant disease, and outcome was poor.

Traditional healers as tuberculosis treatment supervisors: precedent and potential

SETTING: Hlabisa, South Africa. OBJECTIVE: To determine precedent and potential for traditional healers to act as tuberculosis (TB) treatment supervisors. METHODS: Literature review to describe precedent for the involvement of traditional healers in TB treatment supervision. Interviews with 100 TB patients to determine use of healers and their acceptability as supervisors. Interviews with 24 healers in the project sub-district to determine willingness to act as supervisors. RESULTS: Despite extensive literature on the interaction between traditional healers and conventional health services, including descriptions of traditional understandings of TB, no published work was identified that reported supervision of TB patients by traditional healers. Of 100 patients interviewed, only 10% had used a healer as the first health provider for their illness, but 40% had attended a healer at some time prior to diagnosis. Although only 4% believe healers can cure TB, 84% would consider choosing a healer as a treatment supervisor. Of the 24 healers, 15 (63%) distinguished between two types of diagnosis made among patients with. symptoms suggestive of TB: TB and idliso. Idliso is poisoning or bewitching, and is said to be best cured by healers, while TB is infectious and cannot be cured by healers. Most healers (88%) reported having referred patients with possible TB to hospital in the past; all were keen to negotiate collaboration with health services, and 92% were willing to act as treatment supervisors. CONCLUSIONS: While there is little reported precedent for traditional healers to interact formally with tuberculosis treatment services, the potential for collaboration seems to be high, at least in our setting.

Treatment of schizophrenia

This selective review on the treatment of schizophrenia provides an update on two important issues. Firstly, new antipsychotic drugs have improved the quality of life for people with schizophrenia. This review outlines some practical issues surrounding the use of these drugs. Secondly, evidence suggests that the prompt identification and treatment of people with psychoses (including schizophrenia and affective psychoses) results in improved clinical outcomes.1 The important role that general practitioners can play in reducing the duration of untreated psychosis is also discussed.

Who fails to complete tuberculosis treatment? Temporal trends and risk factors for treatment interruption in a community-based directly observed therapy programme in a rural district of South Africa

SETTING: Hlabisa Tuberculosis Programme, Hlabisa, South Africa. OBJECTIVE: To determine trends in and risk factors for interruption of tuberculosis treatment. METHODS: Data were extracted from the control programme database starting in 1991. Temporal trends in treatment interruption are described; independent risk factors for treatment interruption were determined with a multiple logistic regression model, and Kaplan-Meier survival curves for treatment interruption were constructed for patients treated in 1994-1995. RESULTS: Overall 629 of 3610 surviving patients (17%) failed to complete treatment; this proportion increased from 11% (n = 79) in 1991/1992 to 22% (n = 201) in 1996. Independent risk factors for treatment interruption were diagnosis between 1994-1996 compared with 1991-1393 (odds ratio [OR] 1.9, 95% confidence interval [CT] 1.6-2.4); human immunodeficiency virus (HIV) positivity compared with HIV negativity (OR 1.8, 95% CI 1.4-2.4); supervised by village clinic compared with community health worker (OR 1.9, 95% CI 1.4-2.6); and male versus female sex (OR 1.3, 95% CI 1.1-1.6). Few patients interrupted treatment during the first 2 weeks, and the treatment interruption rate thereafter was constant at 1% per 14 days. CONCLUSIONS: Frequency of treatment interruption from this programme has increased recently. The strongest risk factor was year of diagnosis, perhaps reflecting the impact of an increased caseload on programme performance. Ensuring adherence to therapy in communities with a high level of migration remains a challenge even within community-based directly observed therapy programmes.

Diagnosis and treatment of mental disorders: a survey of Singapore mental health professionals

Background: A series of surveys of mental health literacy have been undertaken in Australia, involving members of the general public as well as general practitioners and mental health professionals, whereby respondents consider vignettes of depression and of schizophrenia, offer a diagnosis and rate a series of possible interventions for their judged helpfulness. A similar survey was undertaken in Singapore and is reported in this paper. Methods: The survey was undertaken at a large state psychiatric hospital with staff (psychiatrists, allied health professionals, psychiatrically and generally trained nursing staff) rating a vignette of mania, in addition to the vignettes derived in Australia for depression and schizophrenia, and with the Australian intervention options extended somewhat to respect Singapore facilities. Results: Responses of those in the four professional groups were compared. The psychiatrists were highly accurate in generating diagnoses, other staff somewhat less so for diagnosing depression (with a percentage instead choosing a diagnosis of stress) and mania (with a percentage instead diagnosing a schizophrenic condition). Reported helpfulness ratings identified those interventions judged consensually as likely to be helpful or harmful, as well as establishing some differences across the four professional groups. Conclusions: The consensus decisions of helpful treatments for depression and schizophrenia revealed very similar findings to judgements made by Australian professionals. The treated outcome of schizophrenia was judged as somewhat worse than that for mania and depression. While non-medical staff differed from psychiatrists in judging the comparative utility of some drug interventions and lifestyle issues, there was clear evidence of a relatively dominant 'medical model' to recommended treatments, while traditional healing practices and services were rated as distinctly unhelpful.

Whole-body pre-cooling and heat storage during self-paced cycling performance in warm humid conditions

The aim of this study was to establish the effect that pre-cooling the skin without a concomitant reduction in core temperature has on subsequent self-paced cycling performance under warm humid (31 degrees C and 60% relative humidity) conditions. Seven moderately trained males performed a 30 min self-paced cycling trial on two separate occasions. The conditions were counterbalanced as control or whole-body pre-cooling by water immersion so that resting skin temperature was reduced by approximate to 5-6 degrees C. After pre-cooling, mean skin temperature was lower throughout exercise and rectal temperature was lower (P < 0.05) between 15 and 25 min of exercise. Consequently, heat storage increased (P < 0.003) from 84.0 +/- 8.8 W . m(-2) to 153 +/- 13.1 W . m(-2) (mean +/- s((x) over bar)) after pre-cooling, while total body sweat fell from 1.7 +/- 0.1 1 . h(-1) to 1.2 +/- 0.1 1 . h(-1) (P < 0.05). The distance cycled increased from 14.9 +/- 0.8 to 15.8 +/- 0.7 km (P < 0.05) after pre-cooling. The results indicate that skin pre-cooling in the absence of a reduced rectal temperature is effective in reducing thermal strain and increasing the distance cycled in 30 min under warm humid conditions.

Can tissue drug concentrations be monitored by microdialysis during or after isolated limb perfusion for melanoma treatment?

Isolated limb perfusion (ILP) with melphalan is used to treat recurrent melanoma. This study aimed to develop a microdialysis technique for melphalan tissue concentration measurement during ILP. The effects of melphalan concentration (50-600 mu g/ml), microdialysis flow rate (0.55-17.5 mu l/min), probe length (5-50 mm) and temperature (25-41.5 degrees C) on in vitro recovery were studied. In addition, in vivo recovery was measured in rat hindlimbs perfused with melphalan using 50 mm microdialysis probes implanted subcutaneously and into muscle. Both dialysate and tissue sample melphalan concentrations were determined by high performance liquid chromatography. The in vitro recovery of melphalan was not affected by melphalan concentration or temperature, but increased with probe length and decreased with flow rate. The melphalan concentrations in subcutaneous and muscle dialysates were not significantly different. A linear relationship was found between tissue dialysate concentrations and actual tissue concentrations of melphalan (r(2) = 0.97). Microdialysis is a potential method for tissue drug monitoring which may assist in the efficacious use of cytotoxics in human ILP. (C) 2000 Lippincott Williams & Wilkins.

Effect of coinfection with STDs and of STD treatment on HIV shedding in genital-tract secretions - Systematic review and data synthesis

Objective: To determine whether coinfection with sexually transmitted diseases (STD) increases HIV shedding in genital-tract secretions, and whether STD treatment reduces this shedding. Design: Systematic review and data synthesis of cross-sectional and cohort studies meeting. predefined quality criteria. Main Outcome Measures: Proportion of patients with and without a STD who had detectable HIV in genital secretions, HIV toad in genital secretions, or change following STD treatment. Results: Of 48 identified studies, three cross-sectional and three cohort studies were included. HIV was detected significantly more frequently in participants infected with Neisseria gonorrhoeae (125 of 309 participants, 41%) than in those without N gonorrhoeae infection (311 of 988 participants, 32%; P = 0.004). HIV was not significantly more frequently detected in persons infected with Chlamydia trachomatis (28 of 67 participants, 42%) than in those without C trachomatis infection (375 of 1149 participants, 33%; P = 0.13). Median HIV load reported in only one study was greater in men with urethritis (12.4 x 10(4) versus 1.51 x 10(4) copies/ml; P = 0.04). In the only cohort study in which this could be fully assessed, treatment of women with any STD reduced the proportion of those with detectable HIV from 39% to 29% (P = 0.05), whereas this proportion remained stable among controls (15-17%), A second cohort study reported fully on HIV load; among men with urethritis, viral load fell from 12.4 to 4.12 x 10(4) copies/ml 2 weeks posttreatment, whereas viral load remained stable in those without urethritis. Conclusion: Few high-quality studies were found. HIV is detected moderately more frequently in genital secretions of men and women with a STD, and HIV load is substantially increased among men with urethritis, Successful STD treatment reduces both of these parameters, but not to control levels. More high-quality studies are needed to explore this important relationship further.