Biomedical subjects

V Chandrasekaran

Publications and source records attributed to V Chandrasekaran.

At least 19 recordsLinked to original sources

PubMed2006

Initial drug susceptibility profile of M. tuberculosis among patients under TB programme in South India.

SETTING: Pulmonary tuberculosis (PTB) patients enrolled for treatment at government health facilities in a sub-district of Thiruvallur district, Tamil Nadu, India. OBJECTIVES: To determine the drug susceptibility profile among PTB patients admitted to treatment according to the Revised National Tuberculosis Control Programme (RNTCP). METHODOLOGY: From May 1999 to December 2003, two additional sputum samples were collected from all patients at the start of anti-tuberculosis treatment under DOTS and were transported to a central laboratory for Mycobacterium tuberculosis culture and drug susceptibility testing (DST). RESULTS: DST results were available for 1603 new sputum smear-positive patients; 85% of patients had organisms fully susceptible to streptomycin (S), isoniazid (H) and rifampicin (R), 10.4% any resistance to H and 1.7% to HR. Of 443 patients with history of previous anti-tuberculosis treatment, 59% had organisms susceptible to S, H and R, 37% had any resistance to H and 11.7% to HR. CONCLUSION: The DST profile showed that the vast majority of patients have drug-susceptible organisms, and that currently recommended regimens under the RNTCP would be effective in the treatment of TB.

Antitubercular Agents↗

PubMed2006

Status of bacillary tuberculosis cases identified in a community survey under different control programmes.

We report the status of bacillary tuberculosis (TB) cases identified in community surveys undertaken at 2.5-year intervals. We observed three cohort periods to represent the different TB control programmes, namely 12-18 months of treatment (pre-short-course chemotherapy [pre-SCC]), 6-8 months SCC and DOTS in the area. There was a significant reduction in deaths from 23% to 17%, and an increase in the proportion of cases negative by smear and/or culture for Mycobacterium tuberculosis, from 54% to 58% in the pre-SCC and SCC cohorts to 80% in the DOTS cohort. These findings suggest that the DOTS strategy could have a significant influence on TB epidemiology.

Adult↗

PubMed2006

Association of conversion & cure with initial smear grading among new smear positive pulmonary tuberculosis patients treated with Category I regimen.

BACKGROUND & OBJECTIVES: Early diagnosis of tuberculosis (TB) is important for initiating treatment to gain cure. The present investigation was undertaken to study the association of conversion and cure with initial smear grading among pulmonary tuberculosis (TB) patients registered in a directly observed treatment - short course (DOTS) programme in Tiruvallur district, south India. METHODS: All new smear positive cases registered from May, 1999 to December, 2002 were analysed for conversion and cure related to initial smear grading. RESULTS: Of the 1463 patients, 1206(82.4%) were converted at the end of the intensive phase and 1109 (75.8%) were declared 'cured' after the completion of treatment. The cure rate decreased as the initial smear grading increased and the decrease in trend was statistically significant (P=0.01). Similarly, a significant decrease in conversion rate was also observed with increase in initial smear grading (P<0.001). In multivariate analysis, lower cure rate was significantly associated with patient's age (AOR=1.5, 95% CI=1.1-2.1), alcoholism (AOR=1.7, 95% CI 1.2- 2.4) and conversion at the end of intensive phase (AOR=3.5, 95% CI= 2.6-4.8). INTERPRETATION & CONCLUSION: Cure and conversion rates were linearly associated with initial smear grading. High default and death rates were responsible for low cure and conversion. The proportion of patients who required extension of treatment and those who had an unfavourable treatment outcome were significantly higher among patients with a 3+ initial smear grading. This reiterates the need to pay more attention in motivating these patients to return to regular treatment and sustained commitment in the control of tuberculosis. There is a need to extend the treatment for one more month in the intensive phase of treatment.

Adult↗

PubMed2006

A rural public-private partnership model in tuberculosis control in south India.

SETTING: A rural tuberculosis (TB) unit in South India, 2001-2003. OBJECTIVE: To evaluate a rural public-private partnership model (PPPM) within the TB control programme (RNTCP). DESIGN: All of the private practitioners trained in modern medicine (PPs, n = 52) and the private laboratories (PLs, n = 13) in the area were listed. The PPs underwent training about the RNTCP, and PL staff were trained in sputum microscopy. PPPM included referral of TB suspects to the smear microscopy centres (government or PLs) for diagnosis and treatment of patients as per RNTCP guidelines. Patients were back-referred to the PPs. The directly observed treatment providers and centres were chosen by the PPs in consultation with their patients. The case detection rate, cure rate and profile of patients referred by the PPs were compared with those of self-reported patients. RESULTS: Of 489 TB suspects referred by the PPs, 24% were smear-positive compared to 10% of 15 278 self-reported patients (P < 0.001). Of 319 referred to PLs, 7% were smear-positive. The annual average case detection rate increased from 66 to 75 per 100 000 population. The cure rates of patients referred by the PPs were comparable to those of self-reported patients. CONCLUSIONS: This rural PPPM is effective and does not require additional staff or any direct financial incentives.

Adult↗

PubMed2005

Summarizing data through a piecewise linear growth curve model.

Most of the research in clinical trials is based on longitudinal designs, which involve repeated measurements of a variable of interest. Such designs are very powerful, both statistically and scientifically. Recent advances in statistical theory and software development incorporate the covariance structures such as unstructured, compound symmetry, auto-regressive and random effects, etc., for analysing longitudinal data. Hathaway et al. propose a technique for summarizing longitudinal data using linear growth curve model and establish that the number of summary statistics is fixed as four irrespective of the length of study. In this paper, we develop a procedure for analysing the longitudinal data through a piecewise linear growth curve model on the lines of Hathaway et al. Under different covariance structures, the linear model is fitted for Leprosy data and the residual sum of squares computed. Goodness of fit has also been considered for various models. In order to prove that the proposed method is robust and better than the others in terms of goodness of fit, simulation studies are carried out and the results presented.

Biometry↗

PubMed2005

Parathyroid hormone and biochemical profile in chronic kidney disease patients in South India.

Renal osteodystrophy is an important complication of chronic kidney disease characterized by abnormal bone turnover with varied bone histologic changes. Etiology is multifactorial including abnormalities of serum calcium, phosphorus, and 1,25(OH)(2)-vitamin D deficiency; secondary hyperparathyroidism; age; cause of kidney disease; diet; renal replacement therapy; and drug therapy. In addition, there is evidence that there may be ethnic differences. Our study is a description of a case series of hormonal and biochemical abnormalities of bone disease in end-stage renal disease patients in South India. A total of 115 patients were studied; 86% were on hemodialysis and 14% were on peritoneal dialysis (age, 47.31 +/- 14.66 years). Sixty-eight percent were men. Diabetes was the cause of end-stage renal disease in 29.5%. Intact parathyroid hormone (PTH) level was 124.6 +/- 174.9 pg/mL and less than twice normal in 69.5% of patients. Hypocalcemia was present in 16.5% and hyperphosphatemia in 35.7% of patients. Empirical vitamin D was prescribed in 40% of patients. Age, sex, diabetic status, and vitamin D use were similar in patients with high PTH (130 pg/mL) and low PTH levels (< 130 pg/mL). Bone histologic studies were not performed owing to economic limitation. But the biochemical and hormonal results are suggestive of a mild form of osteodystrophy in Indian patients. Etiology remains uncertain but differences in dietary intake, tropical climate, vitamin D activation, vitamin D receptor polymorphism, parathyroid gland sensitivity, and PTH target organ sensitivity may account for the difference in pattern in bone disease.

Adult↗

PubMed2005

Comparison of cough of 2 and 3 weeks to improve detection of smear-positive tuberculosis cases among out-patients in India.

SETTING: Governmental health facilities in six districts of India. OBJECTIVE: To estimate the prevalence of cough and to compare the detection of smear-positive tuberculosis (TB) among out-patients with cough of > or =2 or > or =3 weeks. DESIGN: Trained health workers questioned each out-patient for presence of cough. Those with cough > or =2 weeks underwent sputum microscopy. RESULTS: Of 55561 out-patients interviewed, 2210 (4%) had cough > or =2 weeks, of whom 267 had sputum-positive TB, compared to 182/1370 with cough > or =3 weeks. The 31% who did not spontaneously complain of cough were less likely to be sputum-positive than those who did (45/680 [7%] vs. 222/1530 [15%], P < 0.001), but they accounted for 45/267 smear-positive cases. Using cough > or =2 weeks as the screening criterion, the estimated number of smears performed per day at each primary and secondary health care facility was respectively 8 and 19, compared to 5 and 12 using cough > or =3 weeks. CONCLUSION: The detection of smear-positive TB cases can be substantially improved by actively eliciting history of cough from all out-patients, and by changing the screening criterion for performing sputum microscopy among out-patients from cough > or =3 weeks to > or =2 weeks. Before implementing this change nationally, its programmatic feasibility should be assessed.

Adolescent↗

PubMed2005

Predictors of relapse among pulmonary tuberculosis patients treated in a DOTS programme in South India.

OBJECTIVE: To identify risk factors associated with relapse among cured tuberculosis (TB) patients in a DOTS programme in South India. DESIGN: Sputum samples collected from a cohort of TB patients registered between April 2000 and December 2001 were examined by fluorescence microscopy for acid-fast bacilli and by culture for Mycobacterium tuberculosis at 6, 12 and 18 months after treatment completion. RESULTS: Of the 534 cured patients, 503 (94%) were followed up for 18 months after treatment completion. Of these, 62 (12%) relapsed during the 18-month period; 48 (77%) of the 62 relapses occurred during the first 6 months of follow-up. Patients who took treatment irregularly were twice more likely to have a relapse than adherent patients (20% vs. 9%; adjusted odds ratio [aOR] 2.5; 95% CI 1.4-4.6). Other independent predictors of relapse were initial drug resistance to isoniazid and/or rifampicin (aOR 4.8; 95% CI 2.0-11.6) and smoking (aOR 3.1; 95% CI 1.6-6.0). The relapse rate among non-smoking, treatment adherent patients with drug-sensitive organisms was 4.8%. CONCLUSIONS: The relapse rate under the DOTS programme may be reduced by ensuring that patients take their treatment regularly and are counselled effectively about quitting smoking.

Adult↗

PubMed2005

Estimation of burden of tuberculosis in India for the year 2000.

BACKGROUND AND OBJECTIVE: Data on the burden of tuberculosis (TB) in India are vital for programme planners to plan the resource requirements and for monitoring the nation-wide TB control programme. There was a need to revise the earlier estimate on the burden of TB in India based on the increase in population and current epidemiological data. This study estimates the burden of disease for the year 2000 based on recent prevalence of TB and annual risk of tuberculosis infection (ARTI) estimates. METHODS: Data on prevalence generated among adults by the Tuberculosis Research Centre (TRC), Chennai, among children by National Tuberculosis Institute (NTI), Bangalore, and the ARTI estimates from the nation-wide sample survey by NTI and TRC were used for the estimation. The prevalence of disease corresponding to 1 per cent ARTI was extrapolated to different parts of the country using the estimates of ARTI and the population in those areas and added together to get the total cases. Abacillary cases that required treatment were estimated from X-ray abnormals. The estimates of bacillary, abacillary and extrapulmonary cases were then combined to get the national burden. RESULTS: The estimated number of bacillary cases was 3.8 million (95% CI: 2.8-4.7). The number of abacillary cases was estimated to be 3.9 million and that for extrapulmonary cases was 0.8 million giving a total burden of 8.5 million (95% CI: 6.3-10.4) for 2000. INTERPRETATION AND CONCLUSION: The present estimate differs from the earlier estimates because we have included the disease burden of X-ray cases that are likely to breakdown to bacillary cases in a one year period, and extrapulmonary TB cases. The current estimates provided baseline information for advocacy and planning resource allocation for TB control activities. Also, these estimates can be compared with that in future years to measure the long term impact of TB control activities in India.

Adult↗

PubMed2004

Gender disparities in tuberculosis: report from a rural DOTS programme in south India.

SETTING: Tiruvallur District, south India. OBJECTIVES: To examine gender differences in tuberculosis among adults aged >14 years with respect to infection and disease prevalence, health care service access, care seeking behaviour, diagnostic delay, convenience of directly observed treatment (DOT), stigma and treatment adherence. METHODS: Data were collected from 1) community survey, 2) self-referred out-patients seeking care at governmental primary health institutions (PHIs), 3) tuberculosis suspects referred for sputum microscopy at PHIs, and 4) tuberculosis patients notified under DOTS. Community survey results were compared with those for patients notified at PHIs. RESULTS: In the community, 66% of males and 57% of females had tuberculosis infection. The prevalence of smear-positive tuberculosis was 568 and 87/100,000, respectively, among males and females. Fewer males than females attended PHIs (68 men for every 100 women). Females constituted 13% of all smear-positive patients detected in the community survey, and 20% of those detected at PHIs (P < 0.05). The probability of notification decreased significantly with age among both males and females. Significantly more females than males felt inhibited discussing their illness with family (21% vs. 14%) and needed to be accompanied for DOT (11% vs. 6%). Males had twice the risk of treatment default than females (19% vs. 8%; P < 0.01). CONCLUSIONS: Despite facing greater stigma and inconvenience, women were more likely than men to access health services, be notified under DOTS and adhere to treatment. Men and elderly patients need additional support to access diagnostic and DOT services.

Adolescent↗

PubMed2003

Are community surveys to detect tuberculosis in high prevalence areas useful? Results of a comparative study from Tiruvallur District, South India.

BACKGROUND: In Tiruvallur District, South India, tuberculosis cases are detected at health facilities (HF) as part of a DOTS programme, and by screening adults through community survey (CS) as part of ongoing epidemiological research. OBJECTIVE: To compare socio-demographic, clinical and bacteriological characteristics and treatment outcomes of all patients detected at HF with those of all patients detected by CS during a 12-month period. RESULTS: Of 32,663 adults surveyed, 100 had smear-positive and 116 had smear-negative tuberculosis; of 65 smear-positive patients who began treatment, 44 were cured. Compared to HF patients, CS patients were significantly more likely to be older (AOR = 1.9), male (AOR = 2.7), non-literate (AOR = 1.7), and living in poor quality housing (AOR = 2.0), and were less likely to have cough >3 weeks (AOR = 3.4) or smear-positive tuberculosis (AOR = 4.2). Of 61 new smear-positive CS patients, 40 reported chest symptoms; of these, 32 (80%) had already consulted a health-care provider, but remained undiagnosed. CONCLUSIONS: The community survey was of little value in tuberculosis case detection even in this high-prevalence setting. Patients identified by the survey were less symptomatic and less infectious, and less than half were cured. Diagnostic services should be made more accessible to the elderly, the non-literate and men.

Adult↗

PubMed2003

Bioavailability of rifampicin following concomitant administration of ethambutol or isoniazid or pyrazinamide or a combination of the three drugs.

BACKGROUND & OBJECTIVES: Poor bioavailability of rifampicin (R) in combination with other anti-tuberculosis drugs such as isoniazid (H), pyrazinamide (Z), and ethambutol (E) is a subject of much concern for the last few decades. This could be due to an interaction between R and other drugs. An investigation was therefore undertaken to examine the bioavailability of R in the presence of H, Z and E or a combination of the three drugs. METHODS: The study included eight healthy volunteers, each being investigated on four occasions at weekly intervals once with R alone and with three of the four combinations on the three remaining occasions. A partially balanced incomplete block design was employed and the allocation of R or the drug combinations was random. Plasma concentrations of R at intervals up to 12 h were determined by microbiological assay using Staphylococcus aureus as the test organism. The proportion (%) dose of R as R plus desacetyl R (DR) in urine excreted over the periods 0-8 and 8-12 h was also determined. Bioavailability was expressed as an index (BI) of area under time concentration curve (AUC) calculated from the plasma concentrations or proportion of dose of R excreted as R plus DR in urine with the combinations to that with R alone. RESULTS: The bioavailability indices based on AUC were 0.96 with RE, 0.76 with RH, 1.08 with RZ and 0.65 with REHZ. The indices based on urine estimations (0-8 h) were similar, the values being 0.94, 0.84, 0.94 and 0.75, respectively. A second investigation revealed that the decrease of bioavailability of R with H was not due to the excipients present in H tablets. INTERPRETATION & CONCLUSION: Isoniazid alone or in combination with E and Z reduces the bioavailability of R. Urinary excretion data offer a simple and non invasive method for the assessment of bioavailability of R.

Adolescent↗

PubMed2002

Bone morphogenetic protein-7 stimulates initial dendritic growth in sympathetic neurons through an intracellular fibroblast growth factor signaling pathway.

Bone morphogenetic protein-7 (BMP-7), a member of the transforming growth factor (TGF)-beta superfamily of signaling cytokines, induces dendritic growth in rat sympathetic neurons. In this study, we present evidence that the recently discovered integrative nuclear FGFR1 signaling (INFS) pathway is involved in dendrite outgrowth mediated by BMP-7. Immunocytochemical analysis of expressed fibroblast growth factors (FGFs) showed that little FGF-2 was detected in control neurons, but the expression of this molecule in the cytoplasm and nucleus increased within 6 h after BMP-7 treatment. In contrast, FGF-1 was constitutively present in the peripheral cytoplasm and in neurites under control conditions, and its distribution did not change with BMP-7 exposure. The high-affinity receptor FGFR1 was present in low amounts in control neurons and was associated with the cytoplasm, the plasma membrane, and the nucleus. Twenty-four hours of BMP-7 treatment elicited an increase in FGFR1 nuclear localization. Overexpressed constructs of FGFR1 that lack the tyrosine kinase domain, and have been shown to act in a dominant-negative manner on FGFR1 signaling, inhibited BMP-7 mediated initial dendrite outgrowth in transfected neurons by approximately 50%. However, targeted inhibition of extracellular FGF-2 by overexpression of a secreted receptor mutant FGFR1(TM-) lacking the transmembrane domain failed to affect BMP-7 induced dendritic growth, as did treatment with the extracellular FGFR antagonist inositol hexakisphosphate. These results suggest that the INFS, which has already been implicated in a broad range of activities in other cell types, may also be required for BMP-7 to stimulate dendritic development.

Animals↗

PubMed2002

Two cases of immune haemolytic anaemia, associated with anti-piperacillin, detected by the 'immune complex' method.

BACKGROUND AND OBJECTIVES: Sera containing antibodies to penicillin and penicillin-related drugs are typically thought to react with drug-coated red blood cells (RBCs) (drug adsorption method), but not when the sera are added to drug and RBCs in the same tube ('immune complex' method). Two cases of immune haemolytic anaemia caused by anti-piperacillin have been previously described. Serological details were given in only one patient. In that subject, the antibody was immunoglobulin (Ig)M + IgG and reacted by both the drug adsorption and 'immune complex' methods. MATERIALS AND METHODS: Two patients with cystic fibrosis developed positive direct antiglobulin tests (DATs) and haemolytic anaemia after 11-12 days of piperacillin therapy. Serological studies were performed with piperacillin, Zosyn (piperacillin + tazobactam) and penicillin by using the drug adsorption and 'immune complex' methods. RESULTS: The first patient's serum contained an IgG, complement-activating anti-piperacillin that reacted by the 'immune complex' method only. The second patient's IgM + IgG, complement-activating anti-piperacillin reacted by the 'immune complex' method and agglutinated piperacillin-treated RBCs. An eluate from the patient's RBCs reacted weakly with all RBCs tested without the presence of drug. This patient had evidence of intravascular haemolysis and died. CONCLUSIONS: We describe the third and fourth examples of immune haemolytic anaemia caused by anti-piperacillin; one was associated with fatal haemolytic anaemia. As piperacillin is commonly used in the treatment of cystic fibrosis, anti-piperacillin should be considered whenever patients with cystic fibrosis develop haemolytic anaemia and/or positive DATs.

Adult↗

PubMed2002

Surveillance of drug resistance in tuberculosis in two districts of South India.

SETTING: Tuberculosis Research Centre, Chennai, India. OBJECTIVES: To determine the levels of drug resistance in new and previously treated cases of pulmonary tuberculosis in the composite districts of North Arcot (Tamil Nadu State) and Raichur (Karnataka State) in South India. DESIGN: Two specimens of sputum from 320 patients attending 23 participating centres in North Arcot district and 314 patients from 20 participating centres in Raichur district were tested for drug susceptibility to isoniazid (H), rifampicin (R), ethambutol (E), streptomycin (S) and ofloxacin (O). The studies were undertaken using the guidelines prescribed by the WHO/IUATLD Working Group on Anti-tuberculosis Drug Resistance Surveillance. RESULTS: In North Arcot district, resistance to any drug tested was found in 27.7% of new cases; any H resistance in 23.4%, any R resistance in 2.8% and multidrug resistance (resistance to at least H and R: MDR) in 2.8%. In previously treated cases, resistance to any drug was observed in 81.2%, and any resistance to H, R and HR in 81%, 69% and 69%, respectively. In Raichur district, resistance to any drug was observed in 21.9% of new cases; any resistance to H, R and HR (MDR) was found in 18.7%, 2.5% and 2.5%, respectively. All previously treated patients were resistant to H and R (100%). CONCLUSION: In North Arcot district, the proportion of MDR-TB in newly diagnosed patients has marginally increased over the last 10-15 years, whereas it has remained fairly constant in Raichur district. An increase in resistance was noted in previously treated cases in both districts, although the numbers of patients are small.

Antitubercular Agents↗

PubMed2002

Risk factors associated with default, failure and death among tuberculosis patients treated in a DOTS programme in Tiruvallur District, South India, 2000.

OBJECTIVE: To identify risk factors associated with default, failure and death among tuberculosis patients treated in a newly implemented DOTS programme in South India. DESIGN: Analysis of all patients registered from May 1999 through April 2000. A community survey for active tuberculosis was underway in the area; patients identified in the community survey were also treated in this programme. RESULTS: In all, 676 patients were registered during the period of the study. Among new smear-positive patients (n = 295), 74% were cured, 17% defaulted, 5% died and 4% failed treatment. In multivariate analysis (n = 676), higher default rates were associated with irregular treatment (adjusted odds ratio [AOR] 4.3; 95%CI 2.5-7.4), being male (AOR 3.4; 95%CI 1.5-8.2), history of previous treatment (AOR 2.8; 95%CI 1.6-4.9), alcoholism (AOR 2.2; 95%CI 1.3-3.6), and diagnosis by community survey (AOR 2.1; 95%CI 1.2-3.6). Patients with multidrug-resistant tuberculosis (MDR-TB) were more likely to fail treatment (33% vs. 3%; P < 0.001). More than half of the patients receiving Category II treatment who remained sputum-positive after 3 or 4 months of treatment had MDR-TB, and a large proportion of these patients failed treatment. Higher death rates were independently associated with weight <35 kg (AOR 3.8; 95%CI 1.9-7.8) and history of previous treatment (AOR 3.3; 95%CI 1.5-7.0). CONCLUSIONS: During this first year of DOTS implementation with sub-optimal performance, high rates of default and death were responsible for low cure rates. Male patients and those with alcoholism were at increased risk of default, as were patients identified by community survey. To prevent default, directly observed treatment should be made more convenient for patients. To reduce mortality, the possible role of nutritional interventions should be explored among underweight patients.

Adult↗

PubMed2002

Factors associated with patient and health system delays in the diagnosis of tuberculosis in South India.

OBJECTIVES: To investigate the factors associated with delay in 1) care-seeking (patient delay), and 2) diagnosis by health providers (health system delay), among smear-positive tuberculosis patients, before large-scale DOTS implementation in South India. METHODS: New smear-positive patients were interviewed using a structured questionnaire. RESULTS: Among 531 participants, the median patient, health system and total delays were 20, 23 and 60 days, respectively. Twenty-nine per cent of patients delayed seeking care for > 1 month, of whom 40% attributed the delay to their lack of awareness about TB. Men postponed seeking care for longer periods than women (P = 0.07). In multivariate analysis, the patient delay was greater if the patient had initially consulted a government provider (adjusted odds ratio [AOR] 2.2, P < or = 0.001), resided at a distance >2 km from a health facility (AOR 1.6, P = 0.04), and was an alcoholic (AOR 1.6, P = 0.04). Health system delay was >7 days among 69% of patients. Factors associated with health system delay were: first consultation with a private provider (AOR 4.0, P < 0.001), a shorter duration of cough (AOR 2.6, P = 0.001), alcoholism (P = 0.04) and patient's residence >2 km from a health facility (AOR 1.8, P = 0.02). The total delay resulted largely from a long patient delay when government providers were consulted first, and a long health system delay when private providers were consulted first. CONCLUSION: Public awareness about chest symptoms and the availability of free diagnostic services should be increased. Government and private physicians should be educated to be aware about the possibility of tuberculosis when examining out-patients. Effective referrals for smear microscopy should be developed between private and public providers.

Adult↗

PubMed2001

Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13). Analysis of patients' genomic DNA identified 12 mutations in the ADAMTS13 gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.

Chromosome Mapping↗