SummaryThe development of a statistical model based on simple immunological markers which could predict the response to tuberculosis treatment would facilitate clinical trials of new anti-tuberculosis drugs. We have examined the ability of immunological biomarkers, measured at diagnosis and after 4 weeks of treatment, to predict sputum smear status at week 8. Eighteen tuberculosis patients with positive Ziehl-Nielsen (ZN)-stained sputum smears 8 weeks after initiation of treatment (slow response) were matched for age, gender, sputum smear grade and extent of disease on chest radiograph to 18 patients with negative sputum smears at week 8 (fast response). In addition to total white blood cell (WBC) counts and absolute lymphocyte, monocyte and neutrophil numbers, concentrations of six serum markers were measured by enzyme-linked immunosorbent assay (ELISA) in all patients (soluble interleukin-2 receptor alpha (sIL-2Ra), granzyme B, soluble tumour necrosis factor alpha receptors 1 and 2 (sTNF-R1 and -2), nitrotyrosine and interferongamma (IFN-g). At diagnosis, 4 biomarkers (sTNF-R1, total WBC, absolute monocyte and absolute neutrophil numbers) were significantly higher in slow response patients. At week 4, total WBC count and absolute monocyte and neutrophil numbers remained significantly higher in slow responders. Discriminant analysis of the diagnosis and week 4 data provided models for classification of slow response patients with 67% and 83% predictive accuracy. We suggest that treatment response phenotypes can be determined before the start of treatment. Reliable predictive models would allow targeted interventions for patients at risk for slow treatment response to standard tuberculosis therapy.

To identify Mycobacterium leprae-specific human T-cell epitopes, which could be used to distinguish exposure to M. leprae from exposure to Mycobacterium tuberculosis or to environmental mycobacteria or from immune responses following Mycobacterium bovis BCG vaccination, 15-mer synthetic peptides were synthesized based on data from the M. leprae genome, each peptide containing three or more predicted HLA-DR binding motifs. Eighty-one peptides from 33 genes were tested for their ability to induce T-cell responses, using peripheral blood mononuclear cells (PBMC) from tuberculoid leprosy patients (n ‫؍‬ 59) and healthy leprosy contacts (n ‫؍‬ 53) from Brazil, Ethiopia, Nepal, and Pakistan and 20 United Kingdom blood bank donors. Gamma interferon (IFN-␥) secretion proved more sensitive for detection of PBMC responses to peptides than did lymphocyte proliferation. Many of the peptides giving the strongest responses in leprosy donors compared to subjects from the United Kingdom, where leprosy is not endemic, have identical, or almost identical, sequences in M. leprae and M. tuberculosis and would not be suitable as diagnostic tools. Most of the peptides recognized by United Kingdom donors showed promiscuous recognition by subjects expressing differing HLA-DR types. The majority of the novel T-cell epitopes identified came from proteins not previously recognized as immune targets, many of which are cytosolic enzymes. Fifteen of the tested peptides had >5 of 15 amino acid mismatches between the equivalent M. leprae and M. tuberculosis sequences; of these, eight gave specificities of >90% (percentage of United Kingdom donors who were nonresponders for IFN-␥ secretion), with sensitivities (percentage of responders) ranging from 19 to 47% for tuberculoid leprosy patients and 21 to 64% for healthy leprosy contacts. A pool of such peptides, formulated as a skin test reagent, could be used to monitor exposure to leprosy or as an aid to early diagnosis.The completion of the sequencing of the genome of Mycobacterium tuberculosis (7) and the availability of almost 98% of the genome sequence of Mycobacterium leprae (http://www .sanger.ac.uk) provide a unique opportunity to identify specific antigens within these pathogens, which could be used as diagnostic tools. One approach, which has been used previously to develop M. tuberculosis-specific diagnostic antigens, is to identify genes present in M. tuberculosis which have been deleted from Mycobacterium bovis BCG (20) Previous studies of the human T-cell response in leprosy patients have identified a number of antigens that induce T-cell responses, measured by lymphocyte proliferation or gamma interferon (IFN-␥) secretion, in patients with tuberculoid leprosy. Such antigens include the M. leprae 70-kDa, 65-kDa, 45-kDa, 35-kDa, 18-kDa, and 10-kDa antigens (1,2,6,12,16,29,31). The members of the heat shock family of proteins are highly conserved, and homologues of the M. leprae 70-kDa, 65-kDa, and 10-kDa antigens show over 90% homology between M. leprae and M. tuberculosis. It is the...

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To evaluate the feasibility of transjugular intrahepatic portosystemic shunt (TIPS) in children with portal hypertensive complications, PubMed and Cochrane Library were queried to identify clinical studies evaluating TIPS in patients <18 years old. Baseline clinical characteristics, laboratory values, and clinical outcomes were extracted. Eleven observational studies totaling 198 subjects were included in the study. The pooled technical success rate and hemodynamic success rate were 94% (95% confidence interval [CI]: 86–99%) and 91% (95% CI: 82–97%), respectively; ongoing variceal bleeding resolved in 99.5% (95% CI: 97–100%); refractory ascites was improved in 96% (95% CI: 69–100%); post-TIPS bleeding rate was 14% (95% CI: 1–33%); 88% of patients were alive or successfully received liver transplant (95% CI: 79–96%); and shunt dysfunction rate was 27% (95% CI: 17–38%). Hepatic encephalopathy occurred in 10.6% (21/198), though 85.7% (18/21) resolved with medical management only. In conclusion, based on moderate levels of evidence, TIPS is a safe and effective intervention that should be considered in pediatric patients with portal hypertensive complications. Future comparative studies are warranted.