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Titrating Theileria parva: single stocks against combination of stocks
No full textTheileria parva is the causative agent of East Coast fever (ECF), an important cattle disease in East and Central Africa. One of the methods for control of ECF is 'infection and treatment', a procedure in which an animal is infected with the live parasite and at the same time treated with a long-acting oxytetracycline formulation, restraining the infection and allowing a protective cellular immune response to develop. Optimal immunizing doses were estimated using models of trichotomous response: dysimmunization (death or severe reaction during immunization), immunization failure (death or severe reaction during lethal challenge) and successful immunization (neither dysimmunization nor immunization failure). In this paper we present methods of interpreting immunization trials and apply these methods to previously unpublished data from two such trials: one with a mixture of three T. parva stocks and one with a single T. parva stock. We explain why titration trials conducted with a cocktail of antigens could predict a suboptimal immunization dose. Indeed it is possible for a combination of three individually efficient stocks to result in a mixture with which optimal immunization response might be difficult to achieve, because of averaging effects. The corresponding interpretation provides insights into why standard immunization trials for T. parva have not yielded the results that might be expected of them. The results of this work may also have implications for the use of antigen cocktails in cancer, HIV and malaria vaccine trials
Correct use of a metered dose inhaler: a prospective interventional study among healthcare professionals in a Nepalese teaching hospital
No full textCADA, potential anti-HIV microbicide that specifically targets the cellular CD4 receptor
No full textThe cyclotriazadisulfonamide (CADA) compounds are a new class of specific CD4-targeted HIV entry inhibitors. The in vitro anti-HIV activity of CADA was shown to correlate with its ability to specifically downmodulate cell surface expression of the CD4 receptor in human cells. Here, we evaluated its potential as an anti-HIV microbicide. CADA exerted a clear CD4 receptor downregulating effect in dendritic cells (DC) and subsequently inhibited HIV-1(BaL) replication in DC/T cell co-cultures. The compound proved to be active against a variety of clinical isolates belonging to the HIV-1 subtypes A, B, C, D, F, G, H, AE and O. Furthermore, it prevented human T cells from being infected with the laboratory-adapted strains X4 HIV-1(NL4.3) and R5 SIV(mac251). Flow cytometric analysis demonstrated a significant and dose-dependent downregulation of CD4 on macaque PBMCs. In addition, the compound exerted a marked anti-SIV(mac251) activity in these cells from simian origin. The combination of CADA with cellulose acetate phthalate (CAP) resulted in a synergistic inhibition of HIV-1 and SIV infection. Finally, gel formulated CADA proved to preserve the CD4 downmodulating and antiviral activity of this compound when formulated as a microbicide gel. Thus, our data suggest that CADA may have potential as a broad-spectrum anti-HIV microbicide drug candidate. The preservation of the activity of gel formulated CADA will make it now feasible for testing this unique entry inhibitor in non-human primates, not only as a single drug but also in a synergistic conjunction with other anti-HIV compounds
Accessibility and utilisation of delivery care within skilled care initiative in rural Burkina Faso
No full textThe definitive version is available at www3.interscience.wiley.comObjectives The Skilled Care Initiative (SCI) was a comprehensive skilled attendance at delivery strategy implemented by the Ministry of Health and Family Care International in Ouargaye district (Burkina Faso) from 2002 to 2005. We aimed to evaluate the relationships between accessibility, functioning of health centres and utilisation of delivery care in the SCI intervention district (Ouargaye) and compare this with another district (Diapaga).
Methods Data were collected on staffing, equipment, water and energy supply for all health centres and a functionality index for health centres were constructed. A household census was carried out in 2006 to assess assets of all household members, and document pregnancies lasting more than 6 months between 2001 and 2005, with place of delivery and delivery attendant. Utilisation of delivery care was defined as birth in a health institution or birth by Caesarean section. Analyses included univariate and multivariate logistic regression.
Results Distance to health facility, education and asset ownership were major determinants of delivery care utilisation, but no association was found between the functioning of health centres (as measured by infrastructure, energy supply and equipment) and institutional birth rates or births by Caesarean section. The proportion of births in an institution increased more substantially in the SCI district over time but no changes were seen in Caesarean section rates.
Conclusion The SCI has increased uptake of institutional deliveries but there is little evidence that it has increased access to emergency obstetric care, at least in terms of uptake of Caesarean sections. Its success is contingent on large-scale coverage and 24-h availability of referral for life saving drugs, skilled personnel and surgery for pregnant women
The spectrum of liver diseases in HIV infected individuals at an HIV treatment clinic in Kampala, Uganda
No full textBackground: Liver diseases are common in patients with HIV due to viral hepatitis B and C co-infections, opportunistic infections or malignancies, antiretroviral drugs and drugs for opportunistic infections.
Objective: To describe the spectrum of liver diseases in HIV-infected patients attending an HIV clinic in Kampala, Uganda.
Method: Consecutive patients presenting with jaundice, right upper quadrant pain with fever or malaise, ascites and/or tender hepatomegaly were recruited and underwent investigations to evaluate the cause of their liver disease.
Results: Seventy-seven consecutive patients were recruited over an eleven month period. Of these, 23 (30%) had increased transaminases because of nevirapine (NVP) and/or isoniazid (INH) hepatotoxicity. Although 14 (61%) patients with drug-induced liver disease presented with jaundice, all recovered with drug discontinuation. Hepatitis B surface antigen was positive in 11 (15%) patients while anti-hepatitis C antibody was reactive in only 2 (3%). Probable granulomatous hepatitis due to tuberculosis was diagnosed in 7 (9%) patients and all responded to anti-TB therapy. Other diagnoses included alcoholic liver disease, AIDS cholangiopathy, hepatocellular carcinoma, schistosomiasis, haemangioma and hepatic adenoma. Twelve (16%) patients died during follow-up of which 7 (9%) died because of liver disease.
Conclusion: Drug history, liver enzyme studies, ultrasound, and hepatitis B and C investigations identified the probable etiology in 60 (78%) of 77 patients with HIV infection presenting with symptoms and/or signs of liver disease
Exploring acyclic nucleoside analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase
No full textIn the search for novel inhibitors of the enzyme thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt), an attractive target for novel antituberculosis agents, we report herein the discovery of the first acyclic nucleoside analogues that potently and selectively inhibit TMPKmt. The most potent compounds in this series are (Z)-butenylthymines carrying a naphtholactam or naphthosultam moiety at position 4, which display Ki values of 0.42 and 0.27 M, respectively. Docking studies followed by molecular dynamics simulations performed to rationalize the interaction of this new family of inhibitors with the target enzyme revealed a key interaction between the distal substituent and Arg 95 in the target enzyme. The fact that these inhibitors are more easily synthesizable than previously identified TMPKmt inhibitors, together with their potency against the target enzyme, makes them attractive lead compounds for further optimization
The relationship between the haemoglobin concentration and the haematocrit in Plasmodium falciparum malaria
No full textBackground: Malaria is a very important cause of anaemia in tropical countries. Anaemia is
assessed either by measurement of the haematocrit or the haemoglobin concentration. For
comparisons across studies, it is often necessary to derive one measure from the other.
Methods: Data on patients with slide-confirmed uncomplicated falciparum malaria were pooled
from 85 antimalarial drug trials conducted in 25 different countries, to assess the haemoglobin/
haematocrit relationship at different time points in malaria. Using a linear random effects model, a
conversion equation for haematocrit was derived based on 3,254 measurements from various time
points (ranging from day 0 to day 63) from 1,810 patients with simultaneous measurements of both
parameters. Haemoglobin was also estimated from haematocrit with the commonly used threefold
conversion.
Results: A good fit was obtained using Haematocrit = 5.62 + 2.60 * Haemoglobin. On average,
haematocrit/3 levels were slightly higher than haemoglobin measurements with a mean difference
(± SD) of -0.69 (± 1.3) for children under the age of 5 (n = 1,440 measurements from 449 patients).
Conclusion: Based on this large data set, an accurate and robust conversion factor both in acute
malaria and in convalescence was obtained. The commonly used threefold conversion is also valid
Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission
No full textBackground Women make up more than 50% of adults living with human immunodeficiency virus (HIV) infection or the acquired immunodeficiency syndrome (AIDS) in sub-Saharan Africa. Thus, female-initiated HIV prevention methods are urgently needed.
Methods We performed a randomized, double-blind, placebo-controlled trial of cellulose sulfate, an HIV-entry inhibitor formulated as a vaginal gel, involving women at high risk for HIV infection at three African and two Indian sites. The primary end point was newly acquired infection with HIV type 1 or 2. The secondary end point was newly acquired gonococcal or chlamydial infection. The primary analysis was based on a log-rank test of no difference in the distribution of time to HIV infection, stratified according to site.
Results A total of 1398 women were enrolled and randomly assigned to receive cellulose sulfate gel (706 participants) or placebo (692 participants) and had follow-up HIV test data. There were 41 newly acquired HIV infections, 25 in the cellulose sulfate group and 16 in the placebo group, with an estimated hazard ratio of infection for the cellulose sulfate group of 1.61 (P=0.13). This result, which is not significant, is in contrast to the interim finding that led to the trial being stopped prematurely (hazard ratio, 2.23; P=0.02) and the suggestive result of a preplanned secondary (adherence-based) analysis (hazard ratio, 2.02; P=0.05). No significant effect of cellulose sulfate as compared with placebo was found on the risk of gonorrheal infection (hazard ratio, 1.10; 95% confidence interval [CI], 0.74 to 1.62) or chlamydial infection (hazard ratio, 0.71; 95% CI, 0.47 to 1.08).
Conclusions Cellulose sulfate did not prevent HIV infection and may have increased the risk of HIV acquisition. (ClinicalTrials.gov number, NCT00153777 ; and Current Controlled Trials number, ISRCTN95638385.
Exploring HIV risk perception and behaviour in the context of antiretroviral treatment: results from a township household survey
No full textThis is an electronic version of an article published in AIDS Care. 2008 Aug;20(7):771-81. AIDS Care is available online at informaworldTMThe objective of this cross-sectional household survey was to assess factors influencing HIV risk perception, behaviour and intervention uptake in a community characterised by high HIV prevalence and availability of antiretroviral therapy (ART). The survey was conducted in Khayelitsha, South Africa and involved two-stage sampling with self-weighting clusters and random selection of households within clusters. One man and woman between 14 and 49 years old was interviewed in each household; 696 men and 879 women were interviewed for a response rate of 84% and 92% respectively. Ninety-three percent and 94% were sexually active with median age of sexual debut 15.3 and 16.5 years. Eighty-three percent and 82% reported a partner at the time of interview and 29% and 8% had additional partner(s). Forty-one percent and 33% reported condom use during the last sexual encounter. Thirty-seven percent of men not using condoms did not as they believed their partner to be faithful, whilst 27% of women did not as their partner refused. Twenty-eight percent and 53% had been tested for HIV. Having undergone HIV testing was not associated with condom usage, whilst current relationship status was the strongest association with condom usage for both men and women. In spite of a relatively high uptake of condoms and testing as well as ART availability, the HIV epidemic has continued unabated in Khayelitsha. Even greater coverage of preventive interventions is required, together with a national social and political environment that builds on the availability of both preventive and treatment services
