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Corticosteroids in the treatment of tuberculous pleurisy. A double-blind, placebo-controlled, randomized study.

Although several studies on tuberculous (TB) pleurisy suggest that the addition of corticosteroids to anti-TB therapy may have beneficial effects, these agents are not used routinely. To assess the effects of short-term oral prednisone therapy in TB pleurisy, 74 patients were randomly assigned in a double-blind fashion to treatment with either placebo or prednisone at a dose of 0.75 mg/kg/d for up to 4 weeks with gradual reduction over an additional 2 weeks. All subjects received a standard 3-drug anti-TB chemotherapy regimen for 6 months. TB pleurisy was diagnosed by histologic study and/or culture of pleural biopsy specimens obtained at thoracoscopy. Complete drainage of the effusion was performed simultaneously. Outcome measures were assessed periodically for 24 weeks, including indexes of morbidity and pleural thickening. After randomization, four patients were excluded from the final analysis. Of the 70 patients analyzed, 34 received prednisone and 36 received placebo. Demographic and clinical characteristics of the treatment groups were comparable at the time of hospital admission. Although a statistically significant improvement in symptoms occurred earlier in the prednisone group (8 weeks) than in the placebo group (12 weeks), between-group comparison showed no significant differences at any of the follow-up evaluations. The proportion of subjects in the prednisone group (53.1%) with residual pleural thickening at 6 months did not differ significantly from that of the placebo group (60%). Pleural effusions did not recur in any of the patients. Initial complete drainage of the effusion was associated with greater symptomatic improvement than any subsequent therapy. We conclude that standard anti-TB therapy and early complete drainage is adequate for the treatment of TB pleurisy. The addition of short-term oral prednisone therapy neither results in clinically relevant earlier symptom relief nor confers a beneficial effect on residual pleural thickening.

Adult↗

Pigtail drainage in the treatment of tuberculous pleural effusions: a randomised study.

BACKGROUND: Tuberculous pleurisy can result in obvious clinical symptoms, pleural fibrosis, and pleural thickening. Some studies of tuberculous pleurisy have suggested that symptomatic improvement and minimisation of sequelae can be achieved by completely draining the effusion during treatment, although the results have not been conclusive. METHODS: Sixty one patients with tuberculous pleurisy were divided into two groups; 30 patients received pigtail drainage combined with antituberculosis (TB) drug treatment and 31 received only anti-TB drugs. Outcome measurements were assessed for a period of 24 weeks after treatment and included symptom scores and the incidence of residual pleural thickening (RPT). RESULTS: Although the duration of dyspnoea was significantly shortened by the use of pigtail drainage (median 4 days (IQR 4-5) v 8 days (IQR 7-16), p<0.001), a comparison of combined mean (SD) visual analogue scale (VAS) scores showed no significant difference between the groups after one week of treatment (57.1 (33.2) v 68.5 (44.7) or at any time during the follow up period. The incidence of RPT of more than 10 mm in the group treated with pigtail drainage and anti-TB drugs was 26% compared with 28% in the group receiving drug treatment only. The incidence of RPT levels of more than 2 mm in the two groups was 50% and 51%, respectively. No statistical difference between the two groups in terms of forced vital capacity was found at the end of treatment (median (IQR) 85.5% (69-94) of predicted v 88% (78-96) of predicted). CONCLUSION: The addition of pigtail drainage to an effective anti-TB regimen is not clinically relevant and does not reduce the level of RPT.

Adolescent↗

Diagnostic significance of gamma-interferon in tuberculous pleurisy.

We studied ADA and gamma interferon (gamma-IFN) levels in pleural fluid of 45 cases presenting with pleural effusion to the Ankara University School of Medicine Chest Diseases Hospital between September 2001 and September 2002. Fifteen patients had TB pleurisy, 20 patients had malignant pleurisy and 10 patients had transudative pleural effusion. The cut-off value for pleural fluid gamma-IFN levels were 12 pg/mL. According to this, all patients with transudative effusions, 19 of 10 patients with malignant effusions and 2 of 15 patients with tuberculous (TB) effusions had pleural fluid gamma-IFN levels under the cut-off value. In exudative effusions, sensitivity and specificity of gamma-IFN were 87% and 95% respectively. The sensitivity of pleural fluid ADA levels was 86% and specificity of pleural fluid ADA levels was 100%. Pleural fluid ADA levels in TB effusions were significantly higher than the non-TB effusions. Also there were no statistically significant differences between pleural fluid ADA and g-IFN levels according to sensitivity and specificity. As a result, we have shown that gamma-IFN is a valuable test in diagnosis of TB pleurisy. We think that when it is used routinely, it will be a good alternative to the conventional invasive diagnostic tests.

Adenosine Deaminase↗

Hypnosis for asthma--a controlled trial. A report to the Research Committee of the British Tuberculosis Association.

An investigation of hypnosis in asthma was made among patients aged 10 to 60 years with paroxysmal attacks of wheezing or tight chest capable of relief by bronchodilators. One group of patients was given hypnosis monthly and used autohypnosis daily for one year. Comparisons were made with a control group prescribed a specially devised set of breathing exercises aimed at progressive relaxation. Treatment was randomly allocated and patients were treated by physicians in nine centres. Results were assessed by daily diary recordings of wheezing and the use of bronchodilators, and by monthly recordings of F.E.V.(1) and vital capacity. At the end of the year independent clinical assessments were made by physicians unaware of the patients' treatment.There were 252 patients (127 hypnosis and 125 controls) accepted for analysis, but a number of them did not continue the prescribed treatment for the whole year: 28 hypnosis and 22 control patients failed to co-operate, left the district, or had family problems; one hypnosis and one control patient died. Seven hypnosis and 17 control patients were withdrawn as treatment failures, the difference between the two groups being statistically significant.As judged by analyses based on the daily "score" of wheezing recorded in patients' diaries, by the number of times bronchodilators were used, and by independent clinical assessors, both treatment groups showed some improvement Among men the assessments of wheezing score and use of bronchodilators showed similar improvement in the two treatment groups; among women, however, those treated by hypnosis showed improvement similar to that observed in the men, but those given breathing exercises made much less progress, the difference between the two treatment groups reaching statistical significance. Changes in F.E.V.(1) and V.C. between the control and hypnosis groups were closely similar.Independent clinical assessors considered the asthma to be "much better" in 59% of the hypnosis group and in 43% of the control group, the difference being significant There was little difference between the sexes. Physicians with previous experience of hypnosis obtained significantly better results than did those without such experience.

Adolescent↗

Total lymphocyte counts in adult HIV/AIDS patients in Port Moresby General Hospital.

We carried out a prospective study of total lymphocyte counts in 124 adult patients who were diagnosed with HIV (human immunodeficiency virus) infection and/or AIDS (acquired immune deficiency syndrome) and were admitted to Port Moresby General Hospital (PMGH) from January to June 2003. The median and mean values of lymphocyte counts in these patients were found to be 0.7 x 10(9)/l and 0.9 x 10(9)/l, respectively, with a standard deviation of 0.7, both of which counts are significantly lower (p < 0.0001) than those found in members of a control population who were well and HIV-antibody-negative. We found that the lower the total lymphocyte count, the more clinically advanced was the HIV disease state. Haemoglobin values were also significantly lower in these patients. For 35% of these patients, tuberculosis was the principal diagnosis made upon being admitted. An apparent 11% of the patients who had a clinical suspicion of AIDS were HIV-antibody-negative. Total lymphocyte count methods could be used in developing countries that do not have appropriate facilities for CD4 count and viral load assays in order to monitor the patient's disease state and progression towards AIDS.

Adolescent↗

Isoniazid chemoprophylaxis. Association with detection and incidence of liver toxicity.

The hepatotoxicity of isoniazid was studied in a double blind fashion in 120 adult patients receiving the drug for chemoprophylaxis. The incidence of abnormal SGOT values was significantly higher in those on the drug, 18.3% having elevated values as compared to 6.7% of those on placebo during the three-month study period. There was no statistical difference in the frequency of symptoms suggestive of liver diseases between the isoniazid and placebo groups. Furthermore, there was no significant relationship between symptoms and elevated SGOTs. Therefore, symptomatology would not appear to be a sensitive method for detecting early isoniazid liver toxicity. From available evidence, biochemical monitoring would appear to detect liver toxicity at an earlier and more reversible stage.

Adult↗

Serum angiotensin converting enzyme in sarcoidosis: sensitivity and specificity in diagnosis: correlations with disease activity, duration, extra-thoracic involvement, radiographic type and therapy.

Serum angiotensin converting enzyme (SACE), despite certain limitations, has been found to be a useful adjunct to the diagnosis, assessment of disease activity, and management of sarcoidosis. The spectrofluorimetric assay was used to measure SACE in 50 normal controls, 76 patients with tuberculosis (42 pulmonary, 16 lymphatic and 18 military cases), 20 patients with cryptogenic fibrosing alveolitis, 50 patients with silicosis, three patients with extrinsic allergic alveolitis, 10 patients with Crohn's disease, two patients with Gaucher's disease, and 128 patients with sarcoidosis on 303 occasions (144 during periods judged as clinically active and 189 inactive). Our results show a normal range (mean +/- 2SD) of 19-54 nmol/ml/min. The false positive rate is 2 per cent in normal controls, 9.2 per cent in tuberculosis (38.9 per cent in military but 0 per cent in the other forms), 48 per cent in silicosis, 100 per cent in Gaucher's disease, and 0 per cent in the other diseases. The sensitivity, specificity, positive and negative predictive values were 58.1, 83.8, 83.8 and 58.1 per cent respectively. The sensitivity rose to 85.9 per cent if only those samples taken from patients in whom sarcoidosis was suspected on initial presentation were included, and 92.1 per cent if only those with clinically active sarcoidosis were included. The sensitivity of SACE as a diagnostic test in sarcoidosis is thus influenced by the relative frequency of active and inactive sarcoidosis. The specificity is influenced by the prevalence of military tuberculosis and silicosis, but is uninfluenced by other common varieties of interstitial lung disease such as cryptogenic fibrosing alveolitis and extrinsic allergic alveolitis, or by other non-pulmonary granulomatous disease. There was no correlation of the SACE level with age, sex, population group, associated other illness or duration of sarcoidosis. Statistically, SACE levels were significantly higher in patients with Types II and III chest radiographs as compared to Type I and 0, and also in those with additional clinically evident extra-thoracic disease e.g. in lymph node, eye and especially multiple systems. SACE also reflected clinical activity with levels being statistically significantly greater in those patients assessed as having active disease, although 7.9 per cent of these had normal levels. Our observations indicate that SACE levels correlate well with disease activity longitudinally, both in relation to spontaneous remission and steroid therapy, and are thus helpful in patient management.

Adrenal Cortex Hormones↗

Increased risk of Pneumocystis carinii and community-acquired pneumonia with tobacco use in HIV disease.

OBJECTIVES: Tobacco smoking-related diseases continue to be of great health concern for the public, in general, and may be particularly deleterious for immunosuppressed HIV-positive individuals, who exhibit widespread tobacco use. METHODS: A total of 521 HIV-infected subjects consecutively admitted to Jackson Memorial Hospital between 2001-2002 were enrolled in the study. Research data included a medical history, details of tobacco and illicit drug use and complete computerized hospital information. Blood was drawn to obtain T lymphocyte profiles and viral load levels. Statistical analysis methods included Pearson, Student's t- and Chi-square tests and SAS Proc CATMOD. RESULTS: Tobacco use was prevalent, with 65% of the 521 HIV-positive hospitalized patients being current smokers. Overall, current tobacco users reported smoking an average of 15+/-13 cigarettes per day for an average of 15+/-14 years, with 40% smoking more than one pack per day. Pulmonary infections accounted for 49% of the total hospital admissions: 52% bacterial pneumonias, 24% Pneumocystis carinii pneumonia (PCP), 12% non-tuberculous mycobacterial diseases (NTM), 11% tuberculosis and 1% bronchitis. Many of the respiratory patients (46%) had been on highly active antiretroviral therapy (HAART) for over six months and 42% had received PCP and/or NTM prophylaxis. After matching the cases by HAART and CDC stage, the hazardous risk of being hospitalized with a respiratory infection was significantly higher for smokers than non-smokers (95% CI 1.33-2.83; p=0.003). Respiratory infections were noted in (37%) of the HAART-treated patients, and most (67%) occurred in smokers. CATMOD analyses controlling for HAART, viral load and CD4, indicated that HIV-infected smokers were three times more likely to be hospitalized with PCP and twice as likely to be hospitalized with community-acquired pneumonia than non-smokers, with increased risk related to the number of cigarettes/day in a dose-dependent manner. CONCLUSIONS: Tobacco use, which is widespread among HIV-infected subjects, increases the risk of pulmonary diseases, particularly PCP and CAP, two respiratory infections with high prevalence and morbidity risks even in the era of HAART.

Anti-HIV Agents↗

[Evaluation of the streptomycin twice weekly with INH and RFP for initial therapy of pulmonary tuberculosis].

For the purpose to compare the effectiveness of SM and EB as a third drug in the standard regimens and to know whether the addition of SM twice weekly to INH and RFP could be acceptable for the treatment of pulmonary tuberculosis, the efficacy, adverse effects and results of long-term follow-up of the groups consisting of 105 patients treated with SM twice weekly for 6 months in addition to INH and RFP for 9 months (S2 group) and 107 patients treated with EB for 6 months in addition to INH and RFP for 9 months (E group) were observed. The speed of negative conversion of sputum and that of X-ray findings improvement were slightly faster in S2 group than E group but the difference was statistically not significant. The incidence of adverse effects such as elevation of serum transaminase values, gastrointestinal troubles, drug allergy and others was not similar in two groups. The relapse was observed in 2 cases of S2 group and 5 cases of E group. We concluded that SM twice weekly to INH and RFP is similarly effective as EB in combination with INH and RFP, and the this regimen could be used as standard regimen for pulmonary tuberculosis.

Adult↗

Evaluation of the drug interaction between rifabutin and efavirenz in patients with HIV infection and tuberculosis.

BACKGROUND: Because of drug-drug interactions mediated by hepatic cytochrome P450, tuberculosis treatment guidelines recommend an increase in rifabutin from 300 mg to 450 or 600 mg when combined with efavirenz-based antiretroviral therapy. To assess this recommendation, rifabutin and efavirenz pharmacokinetic parameters were investigated. METHODS: Plasma concentrations of rifabutin were determined as a baseline control in 15 patients with tuberculosis and human immunodeficiency virus (HIV) infection who were treated with rifabutin 300 mg and isoniazid 15 mg/kg (up to 900 mg) twice weekly. Rifabutin, isoniazid, and efavirenz concentrations were determined after a median of 21 days (interquartile range, 20-34 days) of daily efavirenz-based antiretroviral therapy with twice-weekly rifabutin 600 mg and isoniazid 15 mg/kg. RESULTS: The mean rifabutin area under the concentration-time curve (AUC(0-24)) increased 20% from the baseline value (geometric mean, 5.0 vs. 4.2 microg.h/mL; ratio of geometric means, 1.2 [90% confidence interval, 1.0-1.4]). Also, the mean efavirenz AUC(0-24) in the 15 patients taking concomitant rifabutin 600 mg twice-weekly was 10% higher than that in 35 historical subjects with HIV infection who were not taking rifabutin. Efavirenz-based antiretroviral therapy was effective; HIV load decreased 2.6 log copies/mL, and the median CD4+ T cell count increased from 141 to 240 cells/mm3 after a median of 21 days of efavirenz-based antiretroviral therapy. No statistically significant differences in isoniazid pharmacokinetic parameters were found. CONCLUSIONS: The rifabutin dose increase from 300 mg to 600 mg was adequate to compensate for the efavirenz drug interaction in most patients, and no drug interaction with isoniazid was detected. Efavirenz therapy administered at a standard 600-mg dose achieved adequate plasma concentrations in patients receiving intermittent rifabutin and isoniazid therapy, was generally well tolerated, and demonstrated potent antiretroviral activity.

Adult↗

Hyponatremic natriuretic syndrome in tuberculous meningitis: the probable role of atrial natriuretic peptide.

Hyponatremia has been reported in up to one third of patients with intracranial disease and has frequently been associated with tuberculous meningitis, often complicated by hydrocephalus. The lowered plasma sodium levels were previously attributed to the syndrome of inappropriate secretion of antidiuretic hormone. A controlled prospective study of 24 patients with tuberculous meningitis and hydrocephalus was carried out. Analyses of serum electrolytes and cerebrospinal fluid were performed. Plasma and cerebrospinal fluid levels of atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH) were measured by radioimmunoassay. Fifteen patients were found to be hyponatremic (plasma sodium < 130 mmol/L) and ANP levels of 12 to 1,488 pg/ml were present (median, 26 pg/ml). The remaining 9 patients had normal plasma sodium values between 130 and 145 mmol/L, and in these, plasma ANP values varied between 12 and 21.7 pg/ml (median, 12 pg/ml). The difference between these two groups was not statistically significant. (Control values from patients undergoing myelography were established to range between 12 and 40 pg/ml; median, 14.4 pg/ml.) ANP levels were undetectable in the cerebrospinal fluid in all. Plasma ADH levels in the hyponatremic group were between 7 and 159 pg/ml (median, 40 pg/ml). In the normonatremic group, plasma ADH levels of 25 to 250 pg/ml (median, 29 pg/ml) were obtained. (The controls ranged between 3.6 and 35 pg/ml; median, 10.4 pg/ml). In the hyponatremic group, there was a moderate negative correlation (r = -0.683) between plasma ANP and plasma sodium (P = 0.02). No correlation between plasma ADH and plasma sodium was found (r = -0.168; P = 0.62).(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Factor↗

Spinal deformity after childhood surgery for tuberculosis of the spine. A comparison of radical surgery and debridement.

We have reviewed 80 children who were involved in the Medical Research Council (UK) trial of surgical treatment for tuberculosis of the spine in Hong Kong. Radical surgery or debridement had been performed at mean ages of 7.6 years (n = 47) and 5.1 years (n = 33) respectively. The patients were followed up to skeletal maturity (mean 17 years). Spinal deformity was measured on lateral radiographs taken preoperatively, at six months, one year, five years and at final follow-up. Radical surgery and grafting produced a reduction in kyphos and deformity angles at six months; this correction was maintained during the growth period. By contrast, after debridement surgery there was an increase in deformity at six months, with a tendency to some spontaneous correction during the growth period. There were statistically significant differences between angles for the radical and debridement groups only at six months postoperatively, but the changes during later follow-up were similar in the radical and debridement groups. Our findings highlight the importance of the surgical correction of deformity, and provide no evidence to suggest that disproportionate posterior spinal growth contributes to progression of deformity after anterior spinal fusion in children.

Adult↗

Lpr and MRL background gene involvement in the control of adjuvant enhanced arthritis in MRL-lpr mice.

The MRL-lpr mouse strain develops a mild spontaneous arthritis which can be enhanced by the intradermal injection of complete Freund's adjuvant (CFA). In this study we examined the requirement of the lpr gene and background MRL genes on CFA-enhanced murine arthritis. MRL+, MRL-lpr, AKR/J, and B6-lpr mice (experimental) and B6 mice (control) were injected intradermally with CFA containing M. tuberculosis H37 RA. The development of swelling and erythema was monitored for 1 month after the injection, when the histopathology of the joints was investigated. It was found that while 74% of both 7-month-old MRL + and 3-month-old MRL-lpr mice and 11% of AKR/J mice displayed clinically visible arthritis, B6, B6-lpr, and 3-month-old MRL+ did not develop the condition after CFA treatment. In accordance with the clinical observations, the histopathological changes were manifested only in older MRL+, AKR/J and 3-month-old MRL-lpr mice. One month after the CFA injection, milder changes were observed in the MRL+ than in the MRL-lpr mice, with the MRL+ mice developing a disease of similar severity to uninjected MRL-lpr mice. The AKR/J mice demonstrated the least severe histopathological changes. In the long term (150 days) more severe destructive changes could be demonstrated in the cartilage and bone of the MRL+ mice although the average histological scores did not show statistically significant differences from those found in the MRL+ 30 days after injection. The serological evaluation of the adjuvant-injected mice demonstrated significantly enhanced antibody production to type II collagen and M. tuberculosis, but did not correlate with the disease activity. These observations suggest that while the lpr gene causes a more severe early effect, background genes other than the lpr are more involved in the adjuvant-enhanced arthritis-afflicted mice.

Age Factors↗

Comparing like with like: some historical milestones in the evolution of methods to create unbiased comparison groups in therapeutic experiments.

Histories of clinical trials have recorded and analysed the development of quantification in therapeutic evaluation, the emergence of probabilistic thinking, the application of statistical methods and theory, and the sociology, ethics and politics of clinical trials; but it is surprising that they only rarely identify as a distinct theme the development of efforts to control biases. An exception is Kaptchuk's recent account of the history of blinding and placebos for reducing observer biases. In this complementary paper I introduce and discuss some milestones between 1662 and 1948 in the development of methods to control selection biases when assembling therapeutic comparison groups, to ensure, as far as possible, that 'like is compared with like'. In the paper I note (i) that treatment allocation based on strict alternation abolishes selection bias as effectively as treatment allocation based on strict random allocation; (ii) that use of schedules based on random numbers is more likely to prevent foreknowledge of allocation schedules, and thus the risk of introducing selection bias at the point of recruitment to trials; (iii) that a concern to conceal allocation schedules was the rationale for using schedules based on random numbers in the Medical Research Council trials of vaccination for whooping cough and streptomycin for pulmonary tuberculosis; and (iv) that the introduction of allocation concealment more than half a century ago remains the most recent substantive milestone in the history of efforts to control selection biases in therapeutic experiments.

Epidemiologic Methods↗

[Evaluation of 2 tuberculosis chemoprophylaxis regimens in patients infected with human immunodeficiency virus. The GECMEI Group].

OBJECTIVE: To assess the compliance, tolerance and efficacy of a short chemoprophylaxis regimen (IR) for tuberculosis using isoniazid (INH) plus rifampin (RIF) during 3 months versus a standard regimen (I) of isoniazid during 12 months in HIV positive patients. MATERIAL AND METHODS: Prospective, comparative, randomized and open clinical trial in four general hospitals and one prison hospital of Castilla-La Mancha. Prophylaxis was administered to PPD-positive patients and to anergic patients according to the CDC recommendations (1991). Patients were randomized in two treatment groups: regimen IR, isoniazid 300 mg daily and rifampin 600 mg daily; regimen I, isoniazid 300 mg during 12 months. RESULTS: 133 patients were included, 64 to regimen I and 69 to regimen IR. Regimen IR had a better tolerance with a 28% of adverse effects versus 55% in regimen I. Hepatotoxicity was more frequent in regimen I with a RR = 2.2 (CI 95% 1.23-4.01). Severe hepatotoxicity leading to treatment withdrawal was related to drug administration time and was more frequent in the 12 months regimen group. Short regimen showed a better compliance, without significant differences. Tuberculosis incidence rate was a 4.23 cases/100 persons--year for regimen I and 2.08 in regimen IR, with a relative risk for developing tuberculosis with regimen IR group of 0.51 (CI 95% 0.09-2.8) versus regimen I group, without statistical significance. Prison stay was associated to a significant risk for tuberculosis, regardless of both regimens (RR = 9.2 CI 95%, 1.06-80.2). CONCLUSIONS: In HIV-infected patients with PPD(+) or anergic, regimen with IR is at least as effective as regimen I for preventing the development of tuberculous disease, and has less adverse effects.

AIDS-Related Opportunistic Infections↗

The serodiagnosis of tuberculosis in children: an evaluation of an ELISA test using IgG antibodies to M. tuberculosis, strain H37 RV.

An enzyme-linked immunosorbent assay (ELISA) for detecting serum IgG antibodies to an autoclaved suspension of Mycobacterium tuberculosis H37 RV was evaluated as a diagnostic tool in 132 clinical cases of childhood tuberculosis. The mean (SD) optical density value in these patients was 0.115 (0.122) compared with 0.022 (0.017) in the control group of patients who had non-tuberculous acute respiratory tract infections. Using as a cut-off level the mean of the control plus 2 standard deviations, the test sensitivity was 62% and the specificity was 98% in all the patients with a clinical diagnosis of tuberculosis. In the culture-positive group (n = 35), the sensitivity was 69%. A positive correlation was shown between the optical density levels and increasing age and chronicity of infection but not with respect to tuberculin skin reactivity, nutritional status and the duration of prior therapy. In addition, BCG vaccination (presence of a scar) did not affect the ELISA result. We conclude that this ELISA test is a useful diagnostic test in children.

Adolescent↗

CYP1B1 expression in human lung.

Cytochrome P450 1B1 is a recently recognized phase I bioactivating enzyme with high affinity for both inhaled tobacco carcinogens and 17beta-estradiol. We evaluated the human lung expression of this multifunctional member of the P450 superfamily across 16 individuals. Expression of CYP1B1 was evaluated by qualitative reverse transcription-polymerase chain reaction and Western immunoblots performed on human tumor and nontumor lung tissue. Expression at both mRNA and protein levels was then correlated with smoking history, plasma biomarkers of tobacco exposure (nicotine and cotinine), gender, and tumor histology. CYP1B1 mRNA and protein were detected in 94 and 100% of individuals, respectively. Multivariate analysis confirmed that there were more subjects displaying CYP1B1 mRNA expression in tumor than nontumor tissue (p = 0.0003). Correlation of CYP1B1 protein with plasma cotinine levels was statistically marginal (p = 0.027). Self-reported smoking history, gender, and tumor histology did not correlate with gene expression in the multivariate model. After multivariate modeling for confounding factors, the expression patterns of 5 of 16 individuals appeared to differ from the group as a whole for mRNA and/or protein. We conclude that CYP1B1 is commonly expressed in human lung and hypothesize that it may be an important phase I enzyme with respect to human lung carcinogen metabolism, warranting an understanding of regulatory control and coding region polymorphisms.

Aryl Hydrocarbon Hydroxylases↗

Infliximab for severe, treatment-resistant psoriasis: a prospective, open-label study.

BACKGROUND: Infliximab, a mouse-human chimeric monoclonal antibody directed against tumour necrosis factor-alpha, has been shown to be effective for moderate to severe psoriasis, but there are few data published on its use in recalcitrant, treatment-resistant disease or in combination with other antipsoriatic therapies. OBJECTIVES: To report our experience with infliximab in the treatment of patients attending a tertiary referral service with severe recalcitrant disease. METHODS: All patients attending a tertiary referral service for severe psoriasis who were treated with infliximab between 2002 and July 2005 were entered into a prospective, open-label study. Details on disease phenotype, clinical course and adverse events were recorded together with measures of disease severity [Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index, clinical photography] at baseline, weeks 2 and 6, and then at 2-monthly intervals throughout the treatment period. RESULTS: Twenty-three patients were treated with infliximab during the study; one patient had pustular psoriasis and was therefore excluded from statistical analysis. All had severe disease (baseline PASI 26.5+/-6.7, mean+/-SD, n=22) and had received at least two systemic therapies for psoriasis in the past; 16 were taking one or more concomitant therapies at the time of treatment initiation. At week 10, 95% had achieved a 50% or greater improvement in baseline PASI (PASI 50), and 77% had achieved a 75% or greater improvement (PASI 75). Efficacy was sustained in the longer term, with eight of 10 patients on treatment for more than 11 months maintaining at least a PASI 50. Only one patient had treatment withdrawn due to lack of efficacy, two suffered severe systemic infections including extrapulmonary tuberculosis (splenic abscess) and cellulitis, and six have discontinued due to adverse effects including infusion reactions (two), severe thrombocytopenia (one), hepatitis (one) and malignancy (two). CONCLUSIONS: Data from this open-label study suggest that infliximab is a rapidly effective treatment for patients with severe, treatment-resistant disease, although approximately 25% of patients had to discontinue therapy due to the development of serious adverse effects. Long-term follow-up, continued pharmacovigilance, and further controlled comparative studies will be required to evaluate fully the risks associated with infliximab in the context of this already difficult to treat population.

Abscess↗