BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities.

The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels. The sustained administration of SSRIs increases the serotonergic neurotransmission in response to a functional desensitization of the inhibitory 5-HT1A autoreceptor in the dorsal raphe. At nerve terminal such as the hippocampus, the enhancement of 5-HT availability increases brain-derived neurotrophic factor (BDNF) synthesis and signaling, a major event in the stimulation of adult neurogenesis. In physiological conditions, BDNF would be expressed at functionally relevant levels in neurons. However, the recent observation that SSRIs upregulate BDNF mRNA in primary cultures of astrocytes strongly suggest that the therapeutic activity of antidepressant drugs might result from an increase in BDNF synthesis in this cell type. In this study, by overexpressing BDNF in astrocytes, we balanced the ratio between astrocytic and neuronal BDNF raising the possibility that such manipulation could positively reverberate on anxiolytic-/antidepressant-like activities in transfected mice. Our results indicate that BDNF overexpression in hippocampal astrocytes produced anxiolytic-/antidepressant-like activity in the novelty suppressed feeding in relation with the stimulation of hippocampal neurogenesis whereas it did not potentiate the effects of the SSRI fluoxetine on these parameters. Moreover, overexpressing BDNF revealed the anxiolytic-like activity of fluoxetine in the elevated plus maze while attenuating 5-HT neurotransmission in response to a blunted downregulation of the 5-HT1A autoreceptor. These results emphasize an original role of hippocampal astrocytes in the synthesis of BDNF, which can act through neurogenesis-dependent and -independent mechanisms to regulate different facets of anxiolytic-like responses.

[Primary pulmonary myxoid liposarcoma discovered fortuitously]. / Liposarcome myxoïde pulmonaire primitif de découverte fortuite.

We report a fortuitous discovery of primary pulmonary myxoid liposarcoma in an HIV-positive patient. Primary pulmonary localizations are uncommon. Generally, pulmonary localizations are metastatic. There is a male predominance and diagnosis is generally made around 40 years of age. The two main features of liposarcoma are the large tumor size and the complex histology that evolves over time. Pathology findings are rarely reproducible and vary from one pathologist to another. Macroscopically, liposarcomas can mimic benign tumors. The risk of recurrence is high after simple enucleation due to microscopic extracapsular extensions. Surgery remains the predominant treatment. Wide complete excision, if possible, provides long-term survival.

[Clinical, radiographic and ultrasonographic aspects of mediastinal nodular tuberculosis in the era of HIV infection]. / Aspects cliniques, radiologiques et endoscopiques de la tuberculose ganglionnaire médiastinale.

OBJECTIVE: The purpose of this study was to determine the clinical, radiographic, and ultrasonographic aspects of mediastinal nodal tuberculosis and ascertain its clinical course in the era of HIV infection. PATIENTS AND METHODS: We reviewed retrospectively 39 patients referred to the Ouédraogo Yalgado National Hospital Center and the National Anticancer Institute between February 1996 and December 1999 for mediastinal nodal tuberculosis. Endoscopic proof of tuberculosis was obtained in 30 cases (81.8%). HIV serology was positive in 26 of the 30 patients tested (86.6%). RESULTS: Nodal mediastinal tuberculosis accounted for 1.7% of the cases of tuberculosis recorded over the same period at the Anticancer Institute. Mean age of the patients was 32.8 years and the sex ratio was 1.05 in favor of men. Clinically, a past medical history was found in 18 cases (46%) including a herpes zoster in 6 (15.4%), cough in 38 (97.5%). Weight loss (95%), fever (100%) and peripheral node enlargement (20%) were found frequently, probably related to HIV infection more than tuberculosis. Radiographically, standard x-rays evidenced associated lesions in 22 cases, with 59% having predominant parenchymatous lesions. Other localizations of tuberculosis were very frequent (42.5%). DISCUSSION: Bronchial fibroscopy is most contributive to diagnosis of mediastinal nodal tuberculosis with an 81.8% yield in our series. HIV infection had a determining effect on the disease course since among the 16 patients who died, 14 were HIV-positive (52%).

A combination of two genetic markers is sufficient for restriction fragment length polymorphism typing of Mycobacterium tuberculosis complex in areas with a high incidence of tuberculosis.

The incidence of tuberculosis (TB) in Madagascar is 150 cases per 100,000 people. Because of this endemicity, we studied the genetic diversity of Mycobacterium tuberculosis strains isolated in four big cities in 1994 to 1995 with the aim of monitoring TB transmission. Isolates from 316 cases of pulmonary TB (PTM(+)) were typed by Southern hybridization with genetic markers IS6110 and DR. Of the 316 PTM(+) strains, 66 (20.8%) had a single IS6110 band and were differentiated by the DR marker into 33 profiles. Using both markers, 37.7% (119) of the patients were clustered, a proportion similar to that in countries with a high prevalence of TB. There was no significant difference between clustered and nonclustered patients in age, sex, Mycobacterium bovis BCG status, and drug susceptibility of strains. Clustering was significantly greater in the capital, Antananarivo, than in the other cities, suggesting a higher rate of transmission. However, most of the patients in clusters were living in different areas, and, within a distance of 0.7 km, we did not find epidemiologically unrelated strains with the same restriction fragment length polymorphism profile. Despite an apparently low polymorphism, genetic markers such as IS6110 are potentially valuable for monitoring TB transmission. However, the high proportion of Malagasy isolates with a single IS6110 copy makes this marker alone unsuitable for typing. Additional markers such as DR are necessary for the differentiation of the isolates and for epidemiological surveys.

45/47 kilodalton (APA) antigen capture and antibody detection assays for the diagnosis of tuberculosis.

SETTING: APA complex (45/47 kDa) is an antigen specifically excreted by Mycobacterium tuberculosis and could therefore be a good candidate for diagnosis. OBJECTIVES: To develop three APA immunocapture ELISA assays using monoclonal antibodies (Mabs) and one IgG anti-APA ELISA test, and to determine their usefulness for the diagnosis of tuberculosis in Madagascar. DESIGN: For the Ag assays, 23 negative sputum and serum samples and 64 pairs of sputum and serum from active smear-positive patients (PTM+) were tested. For antibody assay, 116 negative controls, 143 PTM+ and 54 extra-pulmonary tuberculosis patients were tested. RESULTS: The sensitivities of the APA antigen detection assays were low (less than 40%) for a specificity of 95.6%, using either monoclonal antibodies or clinical specimens. The anti-APA serology was more sensitive (76.9% for PTM+ patients) but less specific (73.2%). Due to their poor predictive values, these tests cannot be recommended for the routine diagnosis of tuberculosis in Madagascar.

Affordability of inhaled corticosteroids as a potential barrier to treatment of asthma in some developing countries.

SETTING: The cost and availability of the medications required for the treatment of asthma may represent potential barriers to effective management. METHOD: A survey of prices and policies for components of asthma treatment in 1998, in Algeria, Burkina Faso, Ivory Coast, Guinea, Mali, Syria, Turkey and Vietnam. RESULTS: Medications were consistently available in only four of the eight countries studied. The cost of essential medications for standard case management varied by over five times for beclomethasone and by over three times for inhaled salbutamol. In all but two countries, the cost of one year of drugs for treatment of a moderate, persistent case exceeded the monthly salary of a nurse in that country. The essential drugs list included inhaled salbutamol in five of eight countries and beclomethasone in three of eight. The costs of medications were lower where generic preparations were available and, to a lesser extent, where the medications are on the essential drugs list. CONCLUSIONS: The cost and availability of medications vary widely, and may represent an important barrier to effective management in some low and middle income countries.

Transmission of tuberculosis in the prison of Antananarivo (Madagascar).

The prevalence of tuberculosis in the Antananarivo prison is 16 times higher than that in the general population of Madagascar. We compared the clustering of Mycobacterium tuberculosis strains within and outside the prison and studied the transmission of strains in the prison. M. tuberculosis strains isolated in 1994 to 1995 from 146 prisoners and from 260 nonprisoner patients from Antananarivo were typed using the genetic markers IS6110 and direct repeat. We compared the strains isolated from prisoners and nonprisoners and found that the clustering rate was higher within (58.9%) than outside the prison (40%) suggesting that the transmission rate was higher in prison. Of the 146 incarcerated patients, 82 were grouped into 22 clusters. We checked for possible tuberculosis transmission between prisoners with identical strains by epidemiological investigation of the various prison clusters. We found that 9.5% of the incarcerated patients could have been sources of infection and that only 15.1% could have been infected in the prison. One hundred and twenty-seven prison patients were new cases. Epidemiological data suggested that 37% of them resulted from a reactivation of an old infection, due to poor living conditions or recent transmission from an index case outside the prison.

Prevalence of Mycobacterium bovis in human pulmonary and extra-pulmonary tuberculosis in Madagascar.

The prevalence of human tuberculosis (TB) due to Mycobacterium bovis was determined in Madagascar in 1994-1995. A prevalence of M. bovis of 1.25% was observed among sputum smear-positive patients and 1.3% among extra-pulmonary TB patients. This study was conducted in urban areas and will be extended to rural zones, where the majority of the population lives.

[Congenital tuberculosis: difficulties in early diagnosis]. / Tuberculose néonatale: difficulté du diagnostic précoce.

BACKGROUND: Neonatal and/or congenital tuberculosis is insufficiently understood. CASE REPORTS: Case 1. A premature hypotrophic neonate presented at the age of 45 days, without any maternal contact, a bilateral bronchopneumopathy. Whilst the pregnancy and birth had not been affected by any noteworthy problem, the mother died from miliary tuberculosis despite rifampin, isoniazid and pyrazinamide treatment. Her baby also died on day 52 from multivisceral failure. Culture of tracheal secretions confirmed a few weeks later the diagnosis of tuberculosis. Case 2. A premature, hypotrophic neonate presented on day 22 signs of respiratory distress (miliary), icterus and hepatosplenomegaly. Whilst the pregnancy and birth had not been affected by any particular problem, the mother, 18 days after giving birth, presented miliary and pleural tuberculosis. Despite treatment with rifampin, isoniazid and pyrazinamid started on day 22, the baby died on day 27 from multivisceral failure. The post-mortem liver biopsy confirmed the diagnosis of tuberculosis. Case 3. A baby born at term was hospitalized on day 4 for jaundice. Whilst the pregnancy and birth had not presented any problem, the mother developed a pleural tuberculosis on day 10. Breast-feeding was stopped. Due to the presence of opacities at the top of the right lung, the child was given rifampin, isioniazid, and pyrazinamide. The course was marked by the appearance of hepatomegaly and poor weight gain up to day 25, followed by an improvement. CONCLUSION: The frequency of congenital tuberculosis is probably under-estimated. Its early diagnosis is essential but often difficult as the initial manifestations are delayed. Improved screening of women at risk and sensitization of the medical community are necessary.

Replacement of streptomycin by ethambutol in the intensive phase of tuberculosis treatment: no effect on compliance.

SETTING: Seven tuberculosis clinics in the National Tuberculosis Programme of Madagascar. OBJECTIVE: To compare the treatment efficacy and tolerance of regimens including either streptomycin or ethambutol for patient compliance during initial treatment of smear-positive tuberculosis. DESIGN: The 1023 patients included in the study were randomly divided into two treatment groups-one to receive streptomycin (S), isoniazid (H), rifampicin (R) and pyrazinamide (Z) (SHRZ), and the other to receive EHRZ, where streptomycin was replaced by ethambutol (E). During the 2-month intensive phase, drug delivery was completely supervised. The same 6-month continuation regimen was then given in both groups. Follow-up consisted of a clinical and bacteriological examination at the end of the second, fifth and eighth months. RESULTS: There was no significant difference between the two regimens as regards compliance with treatment, the number of patients lost or who died, or for bacteriological response during the intensive phase. EHRZ was better tolerated. During the continuation phase, the results of the two groups remained comparable, but treatment failures occurred earlier in the patients who had received streptomycin. CONCLUSION: Patient compliance was not better with streptomycin. The ethambutol-containing regimen was as efficient as the other, and better tolerated. There is no argument for preferring streptomycin in the intensive phase of treatment of smear-positive tuberculosis.

[Profile of the patients lost to treatment in the National Anti-Tuberculosis Program in Madagascar]. / Profil des malades perdus de vue en cours de traitment dans le Programme national de lutte contre la tuberculose à Madagascar.

A national anti-tuberculosis program has been in operation in Madagascar since 1991. Despite the significant efforts made in the management, education and surveillance of patients, the number of patients lost to treatment remains high (18.8%). Noncompliance with treatment is the principal cause of treatment failure and of the development of resistance to tuberculosis drugs. This study investigated the profile of the patients who discontinue treatment. The study population consisted of the patients withdrawing from a clinical trial carried out between August 1994 and September 1996. The aim of the trial was to compare several treatments in routine practice conditions in Madagascar. The treatments tested were streptomycin (S) or ethambutol (E) associated with isoniazid (H), rifampicin (R) or pyrazinamide (Z) for the first two months, followed by 6 months of treatment H and thiacetazone (T). The trial involved four public and three private diagnosis and treatment centers in Antananarivo, Fianarantsoa and Mahajanga. A total of 1, 023 patients were included in the trial and 192 (18.8%) withdrew during the eight-month treatment period. We tracked down 109 of these patients (56.8%) and 19 patients came back to the treatment center on their own initiative for a checkup. The rate of response to a recall letter sent by mail was low. The 106 patients interviewed mostly gave professional, financial or family reasons for discontinuing treatment. Many patients stopped the treatment as soon as they began to feel better. To reduce the number of patients discontinuing treatment, the National Anti-Tuberculosis Program should improve the education of patients and their families.

Procedures for developing a simple scoring method based on unsophisticated criteria for screening children for tuberculosis.

OBJECTIVE: To develop a scoring system for screening children for tuberculosis (TB) and for selecting suspects for further investigation in tuberculosis control programmes. Application of the score model, which would not require sophisticated or expensive technology, would be directed towards resource-poor countries with high prevalences of tuberculosis, where health care workers have to deal with diagnostic problems away from district hospitals or diagnostic facilities. DESIGN: Based on contributions from members of an IUATLD task group from 10 countries on the use of diagnostic criteria in childhood tuberculosis, criteria were selected to be used as elements in a score model. Data were collected by standardised questionnaire on 879 subjects aged under 15 years. Of these, 794 were considered probable or confirmed cases of tuberculosis by the diagnosing doctors. From each record, the criteria/procedures used in the diagnosis of probable/confirmed TB and regarded by the doctors as relevant criteria were selected. Bacteriology, histology and chest radiography were used either singly or collectively as the definitive reference (gold standard) against which the more subjective criteria (symptoms, clinical signs, skin test) would be evaluated. The latter criteria cited as relevant were then ranked and further explored for inclusion in the score model. The relative importance of each criterion to every other criterion on the list was expressed as weights, determined by employing a logarithmic least squares method to solve the ratio scale estimation problem which underlies decision-making involving more than one criterion. The resultant values were then assigned to each criterion in the final score model. RESULTS: The five clinical criteria thought to be most relevant as predictors of disease in children were history of contact with a case of tuberculosis, positive skin test, persistent cough, low weight for age, and unexplained/prolonged fever. In selecting the optimal cut-off points for the model at which tuberculosis would be suspected, low sensitivity and specificity (below 70%) but reasonably good positive predictive values (60%-77%) were obtained, depending on age group and epidemiological setting. In low tuberculosis prevalence settings, heavy reliance is placed by the model on a history of contact with a household case of tuberculosis and on a positive skin test, both of which have to be true. For high prevalence settings, more or less equal weighting is assigned to all five elements. Case contact and skin tests are less important, with low body weight, prolonged fever and cough being more indicative of tuberculosis. CONCLUSION: The model provides for epidemiological differences between target populations and should prove successful as a screening tool to select children for further investigation by radiography and bacteriology.

[Pulmonic plague]. / La peste pulmonaire.

One hundred years after Yersin discovered Yersinia pestis during the plague epidemic in Hong Kong in 1894, human plague still has not been eliminated. The epidemic in 1994 in India, a country where no cases had been observed since 1996, raised great concern. Plague is an epizootic bacterial infection caused by a Gram negative coccobacillus, Y. pestis, transmitted by the bite of infected fleas. Bubonic plague is the most common form. Other clinical presentations include asymptomatic plague, abortive plague, pharyngeal plague, septicemic plague, meningeal plague, and primary or secondary pneumonic plague which is observed in 5 to 20% of cases. Plague is a highly communicable disease between humans despite antibiotic therapy which has reduced mortality by 80%. The prognosis depends on early diagnosis. Streptomycin and cyclines are the gold standard treatment.

[Epidemiologic indicators of tuberculosis]. / Les indicateurs épidémiologiques de la tuberculose.

The indicators used in the struggle against tuberculosis, particularly in developing countries, can be separated into two groups. First, the variables, are indicators of the overall damage caused by the disease in the community. Secondly, the parameters, are the calculated indicators of the risk for tuberculosis faced by the individual. Their presentation here follows the pragmatic concerns of the coordinators of the programs: evaluating the scale of the tuberculosis problem; ensuring its surveillance and the supervision of a prevention program; and diffusing the information required to stir the program workers and the population into action to fight tuberculosis. Among the variables, the incidence of mortality lost significance. The emphasis is now on the incidence of the new cases of contagious pulmonary tuberculosis as well as the calculation of the Annual Risk of Infection (ARI). The ARI, despite serious criticisms, remains one of the best indicators for the study of tuberculosis. The data obtained from an active program must be standardized to allow comparisons of the declared cases as well as their follow-up after the initiation of the treatment. The parameters enable a mathematical representation of the different stages in the natural development of the disease: the risk to be infected; the risk of becoming ill; and the development of the illness. These parameters can be advantageously used to mobilize the people into action. The pandemic of HIV drastically changed the natural history of tuberculosis. HIV infection is the most important factor of the transition from tuberculosis infection to active tuberculosis. The HIV pandemic also modified the epidemiological estimations of tuberculosis. In particular, it reinforced the criticisms made against the ARI. The surveillance of the prevalence of HIV among tuberculosis patients is thus important data.

[A case of Mycobacterium shimoïdei lung infection in Madagascar]. / Un cas d'infection pulmonaire à Mycobacterium shimoïdei à Madagascar.

In 1980, a 32 years-old Madagascan female developed a pulmonary tuberculosis, bacteriologically confirmed. She cured with right apical cavitary sequellae. In 1989, she presented haemoptysis again. Antituberculous treatment was adopted without bacteriological confirmation and did not improve clinical symptoms. In 1991 and 1992 cultures from sputa and bronchi aspiration yielded acid-fast bacilli identified as Mycobacterium shimoïdei. M. tuberculosis could not be detected. The patient died during treatment. This case is the fourth one in the literature. Whereas previous cases have been reported in Europe, Australia, Asia, this new case shows M. shimoïdei is also present in Africa.

Anti-tuberculosis drug resistance in Madagascar in 1994-1995.

SETTING: A new tuberculosis control programme has been implemented in Madagascar since 1991. A survey on Mycobacterium tuberculosis resistance to the major drugs was conducted between August 1994 and December 1995. OBJECTIVE: To determine primary and acquired resistance in pulmonary tuberculosis patients in four main cities. DESIGN: Were included 401 randomly sampled new smear positive patients (36.2% of declared new patients) and 137 recurrent cases (72.9% of declared cases) from 8 centres. Drug susceptibility testing was performed on Löwenstein Jensen medium according to the proportion method. RESULTS: The male to female ratio was 1.35:1 in new patients (age range 11-74 years) and 1.98:1 in recurrent patients (age range 16-76 years). The primary resistance rate to any drug was 20% (95% Confidence Interval [CI] 16-23) and the acquired resistance rate 40% (95% CI 32-48, P < 2.10(-7). Primary resistance to one drug was 18% (95% CI 15-22), mainly attributable to streptomycin resistance (14.5%). Multidrug resistance (MDR) to isoniazid and rifampicin was 0.25% (95% CI 0-0.7) for primary resistance and 5% (95% CI 2.6-10.6) for secondary resistance. No difference was observed between sexes or ages. CONCLUSION: This survey conducted in big cities gives a very negative picture of resistance in Madagascar.

[Tuberculosis in the prison milieu at Antananarivo from 1990 to 1993]. / La tuberculose en milieu carcéral à Antananarivo de 1990 a 1993.

Within 42 months, from June 1990 to December 1993, 454 cases of tuberculosis have been recorded in the central remand home of Antananarivo. The tubercular prevalence observed was there eight times superior to that of the global population of Madagascar. Among the 360 pulmonary tuberculosis, only one did not have any bacteriological proof; among the 94 extrapulmonary tuberculosis, 37 have been proved by histology or bacteriology. Among the extrapulmonary tuberculosis, pleurisies were obviously preeminent (79/94). Association of tubercular localizations could be observed with 21% of the patients. New cases of smear-positive pulmonary tuberculosis (PMT+) represented 81% of all the PMT+, recurrences were 9% and revivals 10%. Since February 1991, the 8 months short course regimen was the standard applied; before, the lack of stock did not allowed any standardization. The PMT+ new cases recovery rate increased from 42.5% in 1990 to 74% in 1993, whereas lethality decreased from 23% in 1990 to 8% in 1993. Patient dropouts were noted only with released or escaped individuals. Treatment failure rate was 4%. The diminution of cases despite the constancy of prisoners number and the carrying out of activities by the same health team make questionable the explanatory factors of the burst of tuberculosis-diseases in a prison milieu. Because of the importance of prison tubercular foci in terms of public health and the satisfactory results obtained, the Programme proposes to apply the model of partnership developed between the Tonga soa NGO and the prison administration to other prisons in Madagascar.

[AIDS and tuberculosis: the situation in Madagascar]. / SIDA et tuberculose: la situation à Madagascar.

Because of the known epidemiological links between tuberculosis and HIV infection in developing countries, a systematic study of HIV infection prevalence among tuberculous patients has been conducted since 1989 in some centres of the capital and extended to other towns in 1992. HIV infection prevalence is still low (<200/100,000) with tuberculous patients. This result must incite to continue the surveillance of the ineluctable growth of HIV prevalence and to strengthen the tuberculosis Program in anticipation of subsequent problems.