Voluntary Counselling, HIV Testing and Sexual Behaviour Among Patients with Tuberculosis in a Rural District of Malawi.

OBJECTIVES: A study was conducted in new patients registered with tuberculosis (TB) in a rural district of Malawi in order to 1) verify the acceptability of voluntary counselling and testing for human immunodeficiency virus (HIV) infection; 2) describe sexual behaviour and condom use; and 3) identify socio-demographic and behavioural risk factors associated with 'no condom use'. DESIGN: Cross-sectional study. METHODS: Consecutive patients diagnosed with TB between January and December 2000 were offered voluntary counselling and HIV testing (VCT) and were subsequently interviewed. RESULTS: There were 1,049 new TB patients enrolled in the study. Of these, 1,007 (96%) were pre-test counselled, 955 (91%) underwent HIV testing and 912 (87%) were post-test counselled; 43 (4%) patients refused HIV testing. The overall HIV infection rate was 77%. Of all HIV-positive TB patients, 691 (94%) were put on cotrimoxazole. There were 479 (49%) TB patients who reported sexual encounters, of whom only 6% always used condoms. Unprotected sex was associated with having TB symptoms for over 1 month, having had less than 8 years of school education, being single, divorced or widowed or having sex with the same partner. CONCLUSIONS: Offering VCT to TB patients in this setting has a high acceptance rate and provides an opportunity to strengthen and integrate TB and HIV programmes

Cotrimoxazole prophylaxis in HIV-infected individuals after completing anti-tuberculosis treatment in Thyolo, Malawi.

SETTING: Thyolo, rural southern Malawi. OBJECTIVES: To determine 1) the proportion who continue with cotrimoxazole prophylaxis for the prevention of opportunistic infections, and 2) the reasons for continuing or stopping prophylaxis, in human immunodeficiency virus (HIV) infected individuals with tuberculosis (TB) who complete anti-tuberculosis treatment. DESIGN: A cross-sectional study. METHODS: A questionnaire study of all HIV-infected TB patients who had been registered over a 3-month period to receive anti-tuberculosis treatment and cotrimoxazole prophylaxis and who had completed antituberculosis treatment 3-6 months earlier. RESULTS: Of 82 HIV-infected individuals who were alive at the time of interview, 76 (93%) were continuing with cotrimoxazole and wished to do so indefinitely. The most common reason for continuing the drug was to prevent illness associated with HIV, while the most common reason for stopping was long distances to the health facility. Ninety-six percent of patients received cotrimoxazole free of charge from a health centre. Of those who wished to continue indefinitely, the majority (63%) could not afford to pay for the drug. CONCLUSIONS: In a rural setting, the great majority of HIV-infected individuals continued with cotrimoxazole after completing anti-tuberculosis treatment. Making the drug available and providing it free of charge is essential if it is to remain accessible for longer term prevention

Passive Versus Active Tuberculosis Case Finding and Isoniazid Preventive Therapy Among Household Contacts in a Rural District of Malawi.

SETTING: Thyolo district, rural Malawi. OBJECTIVES: To compare passive with active case finding among household contacts of smear-positive pulmonary tuberculosis (TB) patients for 1) TB case detection and 2) the proportion of child contacts aged under 6 years who are placed on isoniazid (INH) preventive therapy. DESIGN: Cross-sectional study. METHODS: Passive and active case finding was conducted among household contacts, and the uptake of INH preventive therapy in children was assessed. RESULTS: There were 189 index TB cases and 985 household contacts. Human immunodeficiency virus (HIV) prevalence among index cases was 69%. Prevalence of TB by passive case finding among 524 household contacts was 0.19% (191/100000), which was significantly lower than with active finding among 461 contacts (1.74%, 1735/100000, P = 0.01). Of 126 children in the passive cohort, 22 (17%) received INH, while in the active cohort 25 (22%) of 113 children received the drug. Transport costs associated with chest X-ray (CXR) screening were the major reason for low INH uptake. CONCLUSIONS: Where the majority of TB patients are HIV-positive, active case finding among household contacts yields nine times more TB cases and is an opportunity for reducing TB morbidity and mortality. The need for a CXR is an obstacle to the uptake of INH prophylaxis

Sexually Transmitted Infections and Sexual Behaviour Among Commercial Sex Workers in a Rural District of Malawi.

In Thyolo District, Malawi, a study was conducted among commercial sex workers (CSWs) attending mobile clinics in order to; determine the prevalence and pattern of sexually transmitted infections (STIs), describe sexual behaviour among those who have an STI and identify risk factors associated with 'no condom use'. There were 1817 CSWs, of whom 448 (25%) had an STI. Of these, the commonest infections included 237 (53%) cases of abnormal vaginal discharge, 109 (24%) cases of pelvic inflammatory disease and 95 (21%) cases of genital ulcer disease (GUD). Eighty-seven per cent had sex while symptomatic, 17% without condoms. Having unprotected sex was associated with being married, being involved with commercial sex outside a known rest-house or bar, having a GUD, having fewer than two clients/day, alcohol intake and having had no prior medication for STI. The high levels of STIs, particularly GUDs, and unprotected sex underlines the importance of developing targeted interventions for CSWs and their clients

Voluntary Counselling, HIV Testing and Adjunctive Cotrimoxazole Reduces Mortality in Tuberculosis Patients in Thyolo, Malawi.

OBJECTIVES: To assess the feasibility and effectiveness of voluntary counselling, HIV testing and adjunctive cotrimoxazole in reducing mortality in a cohort of tuberculosis (TB) patients registered under routine programme conditions in a rural district of Malawi. DESIGN: 'Before' and 'after' cohort study using historical controls. METHODS: Between 1 July 1999 and 30 June 2000 all TB patients were started on standardized anti-TB treatment, and offered voluntary counselling and HIV testing (VCT). Those found to be HIV-positive were offered cotrimoxazole at a dose of 480 mg twice daily, provided there were no contraindications. Side-effects were monitored clinically. End-of-treatment outcomes in this cohort (intervention group) were compared with a cohort registered between 1 July 1998 and 30 June 1999 in whom VCT and cotrimoxazole was not offered (control group). FINDINGS: A total of 1986 patients was registered in the study: 1061 in the intervention group and 925 in the control cohort. In the intervention group, 1019 (96%) patients were counselled pre-test, 964 (91%) underwent HIV testing and 938 (88%) were counselled post-test. The overall HIV-seroprevalence rate was 77%. A total of 693 patients were given cotrimoxazole of whom 14 (2%) manifested minor dermatological reactions. The adjusted relative risk of death in the intervention group compared with the control group was 0.81 (P < 0.001). The number needed to treat with VCT and adjunctive cotrimoxazole to prevent one death during anti-TB treatment was 12.5. INTERPRETATION: This study shows that VCT and adjunctive cotrimoxazole is feasible, safe and reduces mortality rates in TB patients under routine programme conditions

Electrocardiographic changes during continuous intravenous application of bupivacaine in neonatal pigs

Background It is controversial as to whether T-wave elevation is caused by local anaesthetics, epinephrine, or their combination. It has been shown that T-elevation after intravascular injection of a small bupivacaine test dose is caused by epinephrine and not by bupivacaine. The aim of this study was to investigate ECG changes with higher doses of i.v. bupivacaine. Methods Thirty neonatal pigs were anaesthetized with sevoflurane and their tracheas intubated and artificially ventilated. Under steady-state conditions, bupivacaine was continuously infused (flow rate 3.2 ml kg−1 min−1) by a syringe infusion pump through a central venous catheter. Group 1 received bupivacaine 0.125%, Group 2 bupivacaine 0.5%. The ECG was continuously printed and subsequently analysed for alterations in heart rate, ventricular de- and repolarization, and arrhythmias at 1.25, 2.5, and 5 mg kg−1 bupivacaine infused. Results Sinus rhythm persisted in all pigs. Heart rate decreased progressively in both groups, but this was significantly more pronounced in Group 1. T-wave elevation occurred in 40% and 0% (Groups 1 and 2) at 1.25 mg kg−1, in 80% and 0% at 2.5 mg kg−1, and in 93% and 80% at 5 mg kg−1 bupivacaine infused. There were significant differences between the two groups at 1.25 and 2.5 mg kg−1 infused. Conclusions Higher doses of i.v. infused bupivacaine can cause T-elevation. With slower injection technique, T-elevation can already be detected at lower bupivacaine doses administere

The plasmodium lactate/H+ transporter PfFNT is essential and druggable in vivo

Malaria parasites in the blood stage express a single transmembrane transport protein for the release of the glycolytic end product l-lactate/H(+) from the cell. This transporter is a member of the strictly microbial formate-nitrite transporter (FNT) family and a novel putative drug target. Small, drug-like FNT inhibitors potently block lactate transport and kill Plasmodium falciparum parasites in culture. The protein structure of Plasmodium falciparum FNT (PfFNT) in complex with the inhibitor has been resolved and confirms its previously predicted binding site and its mode of action as a substrate analog. Here, we investigated the mutational plasticity and essentiality of the PfFNT target on a genetic level, and established its in vivo druggability using mouse malaria models. We found that, besides a previously identified PfFNT G107S resistance mutation, selection of parasites at 3 x IC(50) (50% inhibitory concentration) gave rise to two new point mutations affecting inhibitor binding: G21E and V196L. Conditional knockout and mutation of the PfFNT gene showed essentiality in the blood stage, whereas no phenotypic defects in sexual development were observed. PfFNT inhibitors mainly targeted the trophozoite stage and exhibited high potency in P. berghei- and P. falciparum-infected mice. Their in vivo activity profiles were comparable to that of artesunate, demonstrating strong potential for the further development of PfFNT inhibitors as novel antimalarials

13th Meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC): alternative testing methodologies for organ toxicity.

In the past decade in vitro tests have been developed that represent a range of anatomic structure from perfused whole organs to subcellular fractions. To assess the use of in vitro tests for toxicity testing, we describe and evaluate the current status of organotypic cultures for the major target organs of toxic agents. This includes liver, kidney, neural tissue, the hematopoietic system, the immune system, reproductive organs, and the endocrine system. The second part of this report reviews the application of in vitro culture systems to organ specific toxicity and evaluates the application of these systems both in industry for safety assessment and in government for regulatory purposes. Members of the working group (WG) felt that access to high-quality human material is essential for better use of in vitro organ and tissue cultures in the risk assessment process. Therefore, research should focus on improving culture techniques that will allow better preservation of human material. The WG felt that it is also important to develop and make available relevant reference compounds for toxicity assessment in each organ system, to organize and make available via the Internet complete in vivo toxicity data, including human data, containing dose, end points, and toxicokinetics. The WG also recommended that research should be supported to identify and to validate biological end points for target organ toxicity to be used in alternative toxicity testing strategies

Quantum Noise and Superluminal Propagation

Causal "superluminal" effects have recently been observed and discussed in various contexts. The question arises whether such effects could be observed with extremely weak pulses, and what would prevent the observation of an "optical tachyon." Aharonov, Reznik, and Stern (ARS) [Phys. Rev. Lett., vol. 81, 2190 (1998)] have argued that quantum noise will preclude the observation of a superluminal group velocity when the pulse consists of one or a few photons. In this paper we reconsider this question both in a general framework and in the specific example, suggested by Chiao, Kozhekin, and Kurizki [Phys. Rev. Lett., vol. 77, 1254 (1996)], of off-resonant, short-pulse propagation in an optical amplifier. We derive in the case of the amplifier a signal-to-noise ratio that is consistent with the general ARS conclusions when we impose their criteria for distinguishing between superluminal propagation and propagation at the speed c. However, results consistent with the semiclassical arguments of CKK are obtained if weaker criteria are imposed, in which case the signal can exceed the noise without being "exponentially large." We show that the quantum fluctuations of the field considered by ARS are closely related to superfluorescence noise. More generally we consider the implications of unitarity for superluminal propagation and quantum noise and study, in addition to the complete and truncated wavepackets considered by ARS, the residual wavepacket formed by their difference. This leads to the conclusion that the noise is mostly luminal and delayed with respect to the superluminal signal. In the limit of a very weak incident signal pulse, the superluminal signal will be dominated by the noise part, and the signal-to-noise ratio will therefore be very small.Comment: 30 pages, 1 figure, eps

Somatic neurofibromatosis type 1 (NF1) inactivation events in cutaneous neurofibromas of a single NF1 patient

Neurofibromatosis type 1 (NF1) (MIM#162200) is a relatively frequent genetic condition that predisposes to tumor formation. The main types of tumors occurring in NF1 patients are cutaneous and subcutaneous neurofibromas, plexiform neurofibromas, optic pathway gliomas, and malignant peripheral nerve sheath tumors. To search for somatic mutations in cutaneous (dermal) neurofibromas, whole-exome sequencing (WES) was performed on seven spatially separated tumors and two reference tissues (blood and unaffected skin) from a single NF1 patient. Validation of WES findings was done using routine Sanger sequencing or Sequenom IPlex SNP genotyping. Exome sequencing confirmed the existence of a known familial splice-site mutation NM_000267.3:c.3113+1G>A in exon 23 of NF1 gene (HGMD ID CS951480) in blood, unaffected skin, and all tumor samples. In five out of seven analyzed tumors, we additionally detected second-hit mutations in the NF1 gene. Four of them were novel and one was previously observed. Each mutation was distinct, demonstrating the independent origin of each tumor. Only in two of seven tumors we detected an additional somatic mutation that was not associated with NF1. Our study demonstrated that somatic mutations of NF1 are likely the main drivers of cutaneous tumor formation. The study provides evidence for the rareness of single base pair level alterations in the exomes of benign NF1 cutaneous tumors.European Journal of Human Genetics advance online publication, 8 October 2014; doi:10.1038/ejhg.2014.210