Water deprivation decreases strength in fast twitch muscle in contrast to slow twitch muscle in rat.

AIM: The effects of dehydration on muscle performance in human are still contradictory, notably regarding muscle force. The effect of water deprivation (WD) on mechanical properties of skeletal muscle, and more precisely its impact on slow and fast muscles, remains largely unknown. The aim of this study was to determine for the first time whether WD leads to changes in contractile properties of skeletal muscle and whether these changes were muscle-type-specific. METHODS: Sixteen-week-old male rats were assigned to either a control group (C) with water or a 96-hour WD group. At the end of the period, twitch and tetanus properties, as well as biochemical and structural analysis, were performed on soleus (SOL) and extensor digitorum longus (EDL) muscles. RESULTS: Absolute twitch (Pt) and tetanic (P0 ) tension were, respectively, 17% and 14% lower in EDL of WD rats as compared with C rats, whereas unexpected increases of 43% and 25% were observed in SOL. Tensions normalized with respect to muscle mass were not affected by WD in EDL, whereas they were increased by more than 40% in SOL. A 96-hour WD period leads to a decrease in fibre cross-sectional area and absolute myofibrillar content only in EDL. CONCLUSION: It is hypothesized that differences in the results between slow and fast muscles may come from (i) a muscle-type-specific effect of WD on protein balance, EDL showing a greater myofibrillar protein breakdown and (ii) a greater sensitivity to osmolality changes induced by WD in EDL than in SOL.

Skeletal muscle morphology and regulatory signalling in endurance-trained and sedentary individuals: The influence of ageing.

Muscle mass in humans is inversely associated with circulating levels of inflammatory cytokines, but the interaction between ageing and training on muscle composition and the intra-muscular signalling behind inflammation and contractile protein synthesis and degradation is unknown. We studied 15 healthy life-long endurance runners, 12 age-matched untrained controls, 10 young trained and 12 young untrained individuals. Thigh muscle composition was investigated by magnetic resonance imaging (MRI), where non-contractile intramuscular tissue (NCIT) area (fat and connective tissue) was found to be greater in older but lower in trained individuals. Subcutaneous adipose tissue was also lower in trained individuals but was not affected by age. In vastus lateralis biopsies, no influence of age or training was found on levels of endomysial collagen, determined by Sirius Red and Collagen III staining, whereas perimysial organisation tended to be more complex in older individuals. No clear difference with training was seen on intramuscular inflammatory signalling, whereas lower protein levels of NFkB subunits p105, p50 and p65 were observed with ageing. Gene expression of IL6 and TNFα was not different between groups, while IL1-receptor and TNFα-receptor1 levels were lower with age. Myostatin mRNA was lower in older and trained groups, while expression of MuRF1 was lower in trained individuals and FoxO3 expression was greater in aged groups. The association of increased muscle NCIT with age-associated muscle loss in humans is not accompanied by any major alterations in intramuscular signalling for inflammation, but rather by direct regulatory factors for protein synthesis and proteolysis in skeletal muscle.

Denoising of HD-sEMG signals using canonical correlation analysis.

High-density surface electromyography (HD-sEMG) is a recent technique that overcomes the limitations of monopolar and bipolar sEMG recordings and enables the collection of physiological and topographical informations concerning muscle activation. However, HD-sEMG channels are usually contaminated by noise in an heterogeneous manner. The sources of noise are mainly power line interference (PLI), white Gaussian noise (WGN) and motion artifacts (MA). The spectral components of these disruptive signals overlap with the sEMG spectrum which makes classical filtering techniques non effective, especially during low contraction level recordings. In this study, we propose to denoise HD-sEMG recordings at 20 % of the maximum voluntary contraction by using a second-order blind source separation technique, named canonical component analysis (CCA). For this purpose, a specific and automatic canonical component selection, using noise ratio thresholding, and a channel selection procedure for the selective version (sCCA) are proposed. Results obtained from the application of the proposed methods (CCA and sCCA) on realistic simulated data demonstrated the ability of the proposed approach to retrieve the original HD-sEMG signals, by suppressing the PLI and WGN components, with high accuracy (for five different simulated noise dispersions using the same anatomy). Afterward, the proposed algorithms are employed to denoise experimental HD-sEMG signals from five healthy subjects during biceps brachii contractions following an isometric protocol. Obtained results showed that PLI and WGN components could be successfully removed, which enhances considerably the SNR of the channels with low SNR and thereby increases the mean SNR value among the grid. Moreover, the MA component is often isolated on specific estimated sources but requires additional signal processing for a total removal. In addition, comparative study with independent component analysis, CCA-wavelet and CCA-empirical mode decomposition (EMD) proved a higher efficiency of the presented method over existing denoising techniques and demonstrated pointless a second filtering stage for denoising HD-sEMG recordings at this contraction level.

Evaluation of HD-sEMG Probability Density Function deformations in ramp exercise.

The aim of the present study is to propose a subject-specific screening approach of High Density surface EMG (HD-sEMG) Probability Density Function (PDF) shape evolution in experimental conditions following a ramp exercise from 0% to 50% of the Maximum Voluntary Contraction (MVC) during 25 seconds of isometric contractions of the Biceps Brachii from six healthy subjects. This method uses High Order Statistics (HOS), namely the kurtosis and the skewness for PDF shape screening examined on selectively positioned Laplacian sEMG channels obtained on an 8×8 HD-sEMG grid. For each subject, the position of the Laplacian channels was chosen based on the level of muscle activation obtained from the Signal to Noise Ratio (SNR) matrix computed for the 64 sEMG signals of the grid in order to obtain independent Laplacian configurations localized in areas with high SNRs indicating high muscle activation. Afterwards, we used the Principal Component Analysis (PCA) to obtain the principal trend of the kurtosis and the skewness computed from the selected Laplacian signals according to force level variation. The obtained results show a globally common increasing HOS trend according to force increase from 0% to 50% MVC for all the subjects regardless of the anatomical, instrumental and physiological variability that usually strongly influences these trends.

Life-long endurance exercise in humans: circulating levels of inflammatory markers and leg muscle size.

Human aging is associated with a loss of skeletal muscle and an increase in circulating inflammatory markers. It is unknown whether endurance training (Tr) can prevent these changes. Therefore we studied 15 old trained (O-Tr) healthy males and, for comparison, 12 old untrained (O-Un), 10 Young-Tr (Y-Tr) and 12 Young-Un (Y-Un). Quadriceps size, VO2 peak, CRP, IL-6, TNF-α and its receptors, suPAR, lipid profile, leucocytes and glucose homeostasis were measured. Tr was associated with an improved insulin profile (p<0.05), and lower leucocyte (p<0.05) and triglyceride levels (p<0.05), independent of age. Aging was associated with poorer glucose control (p<0.05), independent of training. The age-related changes in waist circumference, VO2 peak, cholesterol, LDL, leg muscle size, CRP and IL-6 were counteracted by physical activity (p<0.05). A significant increase in suPAR with age was observed (p<0.05). Most importantly, life-long endurance exercise was associated with a lower level of the inflammatory markers CRP and IL-6 (p<0.05), and with a greater thigh muscle area (p<0.05), compared to age-matched untrained counterparts. These findings in a limited group of individuals suggest that regular physical endurance activity may play a role in reducing some markers of systemic inflammation, even within the normal range, and in maintaining muscle mass with aging.

New drugs for the treatment of tuberculosis: hope and reality.

The objective of this review is to report evidence about the efficacy and potential of currently licensed drugs and new molecules beyond pre-clinical development for improving the chemotherapy of tuberculosis (TB). Rifapentine, a rifamycin with low minimum inhibitory concentration, long half-life and potent sterilizing activity in mice did not confirm its potential in a recent short-term clinical trial and is being extensively re-evaluated. Moxifloxacin, a fluoroquinolone, improved the activity of the standard drug regimen when substituted for ethambutol (EMB). It is being studied to shorten the duration of treatment for fully drug-susceptible TB (Remox study). Clofazimine, a fat-soluble dye with experimental activity against TB, but used only for leprosy in the last 50 years, requires further study because it has been included in a successful short 9-month combined drug regimen for the treatment of multidrug-resistant TB. The diarylquinoline TMC207 is the most promising among the new TB drugs because of its experimental and clinical rate of culture conversion. Also exciting, 200 mg daily doses in humans of the nitroimidazo-oxazine PA-824 and the nitro-dihydro-imidazooxazole OPC-67683 were safe and induced a bactericidal effect of respectively 0.098 ± 0.072 log(10) and 0.040 ± 0.056 log(10) per day. The new oxazolidinones PNU-100480 and AZD-5847 might be at least as active as linezolid and much less toxic. SQ109 is an EMB analogue that does not have cross-resistance with EMB and might have synergistic activity in combined regimens. Benzothiazinones and dinitrobenzamides show exciting in vitro anti-microbial activity and deserve careful attention.

Pharmacokinetics of rifampin and clarithromycin in patients treated for Mycobacterium ulcerans infection.

In a randomized controlled trial in Ghana, treatment of Mycobacterium ulcerans infection with streptomycin (SM)-rifampin (RIF) for 8 weeks was compared with treatment with SM-RIF for 4 weeks followed by treatment with RIF-clarithromycin (CLA) for 4 weeks. The extent of the interaction of RIF and CLA combined on the pharmacokinetics of the two compounds is unknown in this population and was therefore studied in a subset of patients. Patients received CLA at a dose of 7.5 mg/kg of body weight once daily, rounded to the nearest 125 mg. RIF was administered at a dose of 10 mg/kg, rounded to the nearest 150 mg. SM was given at a dose of 15 mg/kg once daily as an intramuscular injection. Plasma samples were drawn at steady state and analyzed by liquid chromatography-tandem mass spectroscopy. Pharmacokinetic parameters were calculated with the MW/Pharm (version 3.60) program. Comedication with CLA resulted in a 60% statistically nonsignificant increase in the area under the plasma concentration-time curve (AUC) for RIF of 25.8 mg x h/liter (interquartile ratio [IQR], 21.7 to 31.5 mg x h/liter), whereas the AUC of RIF was 15.2 mg x h/liter (IQR, 15.0 to 17.5 mg x h/liter) in patients comedicated with SM (P = 0.09). The median AUCs of CLA and 14-hydroxyclarithromycin (14OH-CLA) were 2.9 mg x h/liter (IQR, 1.5 to 3.8 mg x h/liter) and 8.0 mg x h/liter (IQR, 6.7 to 8.6 mg x h/liter), respectively. The median concentration of CLA was above the MIC of M. ulcerans, but that of 14OH-CLA was not. In further clinical studies, a dose of CLA of 7.5 mg/kg twice daily should be used (or with an extended-release formulation, 15 mg/kg should be used) to ensure higher levels of exposure to CLA and an increase in the time above the MIC compared to those achieved with the currently used dose of 7.5 mg/kg once daily.

Training-induced changes in structural and mechanical properties of the patellar tendon are related to muscle hypertrophy but not to strength gains.

To obtain a better understanding of the adaptations of human tendon to chronic overloading, we examined the relationships between these adaptations and the changes in muscle structure and function. Fifteen healthy male subjects (20+/-2 yr) underwent 9 wk of knee extension resistance training. Patellar tendon stiffness and modulus were assessed with ultrasonography, and cross-sectional area (CSA) was determined along the entire length of the tendon by using magnetic resonance imaging. In the quadriceps muscles, architecture and volume measurements were combined to obtain physiological CSA (PCSA), and maximal isometric force was recorded. Following training, muscle force and PCSA increased by 31% (P<0.0001) and 7% (P<0.01), respectively. Tendon CSA increased regionally at 20-30%, 60%, and 90-100% of tendon length (5-6%; P<0.05), and tendon stiffness and modulus increased by 24% (P<0.001) and 20% (P<0.01), respectively. Although none of the tendon adaptations were related to strength gains, we observed a positive correlation between the increase in quadriceps PCSA and the increases in tendon stiffness (r=0.68; P<0.01) and modulus (r=0.75; P<0.01). Unexpectedly, the increase in muscle PCSA was inversely related to the distal and the mean increases in tendon CSA (in both cases, r=-0.64; P<0.05). These data suggest that, following short-term resistance training, changes in tendon mechanical and material properties are more closely related to the overall loading history and that tendon hypertrophy is driven by other mechanisms than those eliciting tendon stiffening.

Promising antituberculosis activity of the oxazolidinone PNU-100480 relative to that of linezolid in a murine model.

Oxazolidinone antibiotics have activity against Mycobacterium tuberculosis. Linezolid, the only marketed oxazolidinone, has been used off-label in combination regimens to treat multidrug-resistant tuberculosis, but its precise contribution to the efficacy of such combinations is unclear. Another oxazolidinone, PNU-100480, has been demonstrated to have more potent activity in vitro and in a murine model of tuberculosis. In this study, we compared the pharmacokinetics and the antituberculosis activities of these two oxazolidinones over a range of doses and found that linezolid has limited activity at clinically relevant doses in the murine model compared to that of PNU-100480, which has potent bactericidal activity, even at lower drug exposures. These findings were unexpected, given the similar in vitro activities of PNU-100480, its major metabolites, and linezolid. Moreover, the incorporation of PNU-100480 dramatically improved the bactericidal activities of regimens containing current first-line antituberculosis drugs and moxifloxacin. For example, the addition of PNU-100480 (100 mg/kg of body weight/day) to the standard daily regimen of rifampin (rifampicin), isoniazid, and pyrazinamide resulted in an additional 2.0-log(10)-unit reduction in lung CFU counts during the first 2 months of treatment. The combination of PNU-100480, moxifloxacin, and pyrazinamide, which does not contain either rifampin or isoniazid, was also more active than rifampin, isoniazid, and pyrazinamide. These results suggest that PNU-100480 may have the potential to significantly shorten the duration of therapy for drug-susceptible as well as multidrug-resistant tuberculosis.

Patients suffering from acute graft-versus-host disease after bone-marrow transplantation have functional CD4+CD25hiFoxp3+ regulatory T cells.

Acute Graft-Versus-Host Disease (aGVHD), mediated by CD4(+) and CD8(+) effector T cells, is a life-threatening complication in hematopoietic stem cell (HSC) transplantation. Naturally-occurring CD4(+)CD25(hi)(Foxp3(+)) regulatory T cells (T(reg)) have been shown to modulate tolerance to aGVHD in murine graft models. In this report, we investigated their role in the prevention of aGVHD in patients transplanted with bone-marrow-derived HSC. When CD4(+)CD25(hi)Foxp3(+) T cells were isolated from bone-marrow grafts, they showed no suppressive activity. The analysis of their function in patients suffering from aGVHD after transplantation revealed a gain of suppressive activity indicating their inability to control the aGVHD induction. Thus, our findings clearly demonstrate that CD4(+)CD25(+) and CD4(+)CD25(hi)Foxp3(+) T cells, when administered in steady-state physiological conditions, do not influence the outcome of aGVHD after bone-marrow transplantation.

Soluble human leucocyte antigen-G molecules in peripheral blood haematopoietic stem cell transplantation: a specific role to prevent acute graft-versus-host disease and a link with regulatory T cells.

Haematopoietic stem cell transplantation is often complicated by the life-threatening graft-versus-host disease (GVHD) which consists of an allogeneic reaction of the graft cells against the host organs. The aim of this study was to investigate the putative involvement of soluble human leucocyte antigen (sHLA) class I molecules, and particularly sHLA-G molecules, in the occurrence and/or prevention of acute GVHD (aGVHD) in allogeneic peripheral blood stem cell (PSC) transplantation. Whole sHLA class I molecules seem to be involved in aGVHD pathogenesis because detection of a high concentration of these molecules in the first month post allograft is correlated with aGVHD occurrence. Conversely, a high level of sHLA-G molecules before and after allograft could indicate good prognosis in PSC allograft transplantation. sHLA-G molecules seem to be involved in aGVHD prevention, not only because they are enriched in plasma of patients without aGVHD, but also because: (i) a positive correlation has been found between sHLA-G level and CD4+ CD25+ CD152+ natural regulatory T cell (T(reg)) frequency in the blood of transplanted patients; and (ii) the presence of CD4+ CD25+ CD152+ natural T(reg) is correlated with increased sHLA-G expression in in vitro mixed leucocyte reaction cultures. Altogether, these results support the immunomodulatory function of sHLA-G molecules that might create a regulatory network together with the natural T(reg) to foster the induction of a tolerogenic environment and improve PSC transplantation favourable outcome.

Sentinel-site surveillance of Mycobacterium avium complex pulmonary disease.

The incidence of Mycobacterium avium complex (MAC) pulmonary disease in HIV-negative patients was studied prospectively from January 1, 2000 to December 31, 2002 through 32 sentinel sites distributed all over France. Among the 275 patients who yielded MAC isolates from respiratory clinical specimens, 101 (36.7%) met the bacteriological, radiographical and clinical criteria established by the American Thoracic Society for nontuberculous mycobacterial respiratory disease. Of these 101 patients, 81 had underlying lung disease, mainly previous tuberculosis, bronchectasis or chronic obstructive pulmonary disease. Among the 20 patients with no underlying lung disease, 12 had a predisposing factor such as leukaemia or immunosuppressive treatment and eight had no predisposing factor. All patients with MAC respiratory disease had clinical symptoms, commonly cough and fatigue, and 52 (51.5%) were sputum smear positive for acid-fast bacillus. The ratio of patients with Mycobacterium avium complex pulmonary disease to patients with pulmonary tuberculosis in France was estimated to be 3% and the incidence of Mycobacterium avium complex pulmonary disease in France was 0.2 per 100,000 inhabitants.

Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans.

Mycobacterium ulcerans disease is common in some humid tropical areas, particularly in parts of West Africa, and current management is by surgical excision of skin lesions ranging from early nodules to extensive ulcers (Buruli ulcer). Antibiotic therapy would be more accessible to patients in areas of Buruli ulcer endemicity. We report a study of the efficacy of antibiotics in converting early lesions (nodules and plaques) from culture positive to culture negative. Lesions were excised either immediately or after treatment with rifampin orally at 10 mg/kg of body weight and streptomycin intramuscularly at 15 mg/kg of body weight daily for 2, 4, 8, or 12 weeks and examined by quantitative bacterial culture, PCR, and histopathology for M. ulcerans. Lesions were measured during treatment. Five lesions excised without antibiotic treatment and five lesions treated with antibiotics for 2 weeks were culture positive, whereas three lesions treated for 4 weeks, five treated for 8 weeks, and three treated for 12 weeks were culture negative. No lesions became enlarged during antibiotic treatment, and most became smaller. Treatment with rifampin and streptomycin for 4 weeks or more inhibited growth of M. ulcerans in human tissue, and it provides a basis for proceeding to a trial of antibiotic therapy as an alternative to surgery for early M. ulcerans disease.

Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis.

The nitroimidazopyran PA-824 has potent in vitro activity against Mycobacterium tuberculosis, a narrow spectrum of activity limited primarily to the M. tuberculosis complex, and no demonstrable cross-resistance to a variety of antituberculosis drugs. In a series of experiments, we sequentially characterized the activity of PA-824 in an experimental murine model of tuberculosis. The minimal effective dose was 12.5 mg/kg of body weight/day. The minimal bactericidal dose (MBD) was 100 mg/kg/day. When PA-824 was used as monotherapy at the MBD, it exhibited promising bactericidal activity during the initial intensive phase of therapy that was similar to that of the equipotent dose of isoniazid in humans. In combination with isoniazid, PA-824 prevented the selection of isoniazid-resistant mutants. Perhaps more importantly, PA-824 also demonstrated potent activity during the continuation phase of therapy, during which it targeted bacilli that had persisted through an initial 2-month intensive phase of treatment with rifampin, isoniazid, and pyrazinamide. Together, these data strongly support further evaluation of PA-824 in combination with first- or second-line antituberculosis drugs to determine its potential contribution to the treatment of drug-susceptible or multidrug-resistant tuberculosis, respectively.

A case-control study for multidrug-resistant tuberculosis: risk factors in four European countries.

The aim of this study was to detect risk factors for multidrug resistance in patients with pulmonary tuberculosis in four European Union countries: France, Germany, Italy, and Spain. A prospective epidemiological case control study was conducted, made up of patients with clinically diagnosed and microbiologically confirmed pulmonary tuberculosis in the four countries between 1997 and 2000. A total of 138 cases and 276 controls were studied. Considering the four countries as a whole, the most statistically significant risk factors were as follows: intravenous drug use (OR 4.68); asylum-seeker support (OR 2.55) as income factor; living in a nursing home (OR 2.05); previous tuberculosis (OR 2.03) with pulmonary location; prison (OR 2.02); known tuberculosis contacts (OR 2.01); immunosuppression other than human immunodeficiency virus (HIV) (OR 1.96); acquired immunodeficiency syndrome (AIDS) (OR 1.96); current tuberculosis with pulmonary location (OR 1.77); and health-care worker (OR 1.69). These risk factors will have to be taken into account in the European Union as a whole, as well as in each individual country, to establish a health policy of monitoring and control for these cases of multidrug resistance. Although rare, their seriousness makes them particularly important.

Pharmacokinetic and pharmacodynamic issues in the treatment of mycobacterial infections.

The therapy of mycobacterial infections is challenging for a number of reasons. Because mycobacteria are not susceptible to many classes of antibacterial agents, treatment typically requires the use of antimicrobial drugs that are not commonly used and may have small therapeutic windows. For many species, procedures for drug susceptibility testing and optimal treatment regimens have yet to be defined. Finally, because mycobacteria are generally slow to succumb to antimicrobial agents, therapy must be given with multiple drugs for prolonged periods of time, making it necessary to monitor for drug toxicity, drug interactions, and patient nonadherence. Better understanding of the pharmacokinetics and pharmacodynamics of antimycobacterial agents should improve the therapy of mycobacterial infections. Using current treatment strategies for tuberculosis and Mycobacterium avium complex infections as examples, this review highlights basic pharmacokinetic and pharmacodynamic principles and the rationale for combination chemotherapy that should also be applicable to other mycobacterial infections.

Paucibacillary tuberculosis in mice after prior aerosol immunization with Mycobacterium bovis BCG.

To develop a murine model of paucibacillary tuberculosis for experimental chemotherapy of latent tuberculosis infection, mice were immunized with viable Mycobacterium bovis BCG by the aerosol or intravenous route and then challenged six weeks later with virulent Mycobacterium tuberculosis. The day after immunization, the counts were 3.71 +/- 0.10 log(10) CFU in the lungs of aerosol-immunized mice and 3.65 +/- 0.11 and 4.93 +/- 0.07 log(10) CFU in the lungs and spleens of intravenously immunized mice, respectively. Six weeks later, the lungs of all BCG-immunized mice had many gross lung lesions and splenomegaly; the counts were 5.97 +/- 0.14 and 3.54 +/- 0.07 log(10) CFU in the lungs and spleens of aerosol-immunized mice, respectively, and 4.36 +/- 0.28 and 5.12 +/- 0.23 log(10) CFU in the lungs and spleens of intravenously immunized mice, respectively. Mice were then aerosol challenged with M. tuberculosis by implanting 2.37 +/- 0.13 log(10) CFU in the lungs. Six weeks after challenge, M. tuberculosis had multiplied so that the counts were 6.41 +/- 0.27 and 4.44 +/- 0.14 log(10) CFU in the lungs and spleens of control mice, respectively. Multiplication of M. tuberculosis was greatly limited in BCG-immunized mice. Six weeks after challenge, the counts were 4.76 +/- 0.24 and 3.73 +/- 0.34 log(10) CFU in the lungs of intravenously immunized and aerosol-immunized mice, respectively. In contrast to intravenously immunized mice, there was no detectable dissemination to the spleen in aerosol-immunized mice. Therefore, immunization of mice with BCG by the aerosol route prior to challenge with a low dose of M. tuberculosis resulted in improved containment of infection and a stable paucibacillary infection. This model may prove to be useful for evaluation of new treatments for latent tuberculosis infection in humans.

Drug resistance among failure and relapse cases of tuberculosis: is the standard re-treatment regimen adequate?

OBJECTIVE: To determine acquired drug resistance among failure and relapse cases after treatment of new smear-positive tuberculosis. METHODS: A cohort of 2901 patients with new smear-positive tuberculosis was enrolled in Vietnam. Sputum samples were stored at enrolment. Upon failure or relapse, another sputum sample was collected. Both were cultured and underwent drug susceptibility testing and restriction fragment length polymorphism (RFLP) typing. RESULTS: Of 40 failure cases, 17 had multidrug resistance (MDR) at enrolment. At failure, 15 of the 23 (65%) patients without primary MDR had acquired MDR. Of 39 relapse cases and 143 controls, none had primary MDR. CONCLUSION: Primary drug resistance was a strong risk factor for failure and relapse and for acquiring further resistance. As 80% of failure cases had MDR, the standard re-treatment regimen appears inadequate for failure cases in this control programme with a very high cure rate among new cases.

Impact of iron loading on the activity of isoniazid or ethambutol in the treatment of murine tuberculosis.

OBJECTIVE: To assess the impact of iron loading on the activity of isoniazid and ethambutol in the treatment of murine tuberculosis. DESIGN: Iron-loaded and iron-normal female Balb/C mice infected with 1.5 x 10(7) colony forming units of Mycobacterium tuberculosis were treated with either isoniazid or ethambutol for 28 days. RESULTS: For both treatments, the outcome was impaired by the iron loading: bactericidal activity of isoniazid was partially but significantly reduced and ethambutol bactericidal activity was totally inhibited. CONCLUSION: The treatment of tuberculosis in patients with iron loading should be longer than for normal patients or should contain an additional drug.