(Re)moving the needle: prospects for all-oral treatment for multidrug-resistant tuberculosis.

BACKGROUND: Currently recommended regimens for multidrug-resistant tuberculosis (MDR-TB) contain painful daily injections and are unsuccessful in approximately half of patients. Removal of the injectable agent to fashion all-oral regimens could transform MDR-TB treatment and access to care. OBJECTIVE: To explore evidence for all-oral treatment regimens. DESIGN: We review evidence on drugs that could be included in injection-free MDR-TB regimens. The oral drugs considered have an indication for or are recommended for off-label use for TB or MDR-TB, and have demonstrated bactericidal activity. Drugs with weak bactericidal activity should have limited prior population exposure and evidence of effectiveness in MDR-TB regimens. RESULTS: Bedaquiline, delamanid, and linezolid all display strong bactericidal activity, while clofazimine has weak bactericidal activity. They all have limited prior population exposure and demonstrated effectiveness in MDR-TB regimens. Despite widespread exposure to pyrazinamide and late-generation fluoroquinolones in the population, all are bactericidal and have shown great value when included in treatment regimens for MDR-TB. CONCLUSION: The evidence supports the use of all-oral regimens comprising new and existing drugs for MDR-TB treatment. Existing evidence of bactericidal activity and efficacy for these drugs provides a convincing argument for transitioning MDR-TB treatment towards all-oral regimens. These new regimens could mitigate the delivery, cost, and adherence challenges inherent to the current standard.

Amino acid position 11 of HLA-DRß1 is a major determinant of chromosome 6p association with ulcerative colitis.

The major histocompatibility complex (MHC) on chromosome 6p is an established risk locus for ulcerative colitis (UC) and Crohn's disease (CD). We aimed to better define MHC association signals in UC and CD by combining data from dense single-nucleotide polymorphism (SNP) genotyping and from imputation of classical human leukocyte antigen (HLA) types, their constituent SNPs and corresponding amino acids in 562 UC, 611 CD and 1428 control subjects. Univariate and multivariate association analyses were performed, controlling for ancestry. In univariate analyses, absence of the rs9269955 C allele was strongly associated with risk for UC (P = 2.67 × 10(-13)). rs9269955 is a SNP in the codon for amino acid position 11 of HLA-DRß1, located in the P6 pocket of the HLA-DR antigen binding cleft. This amino acid position was also the most significantly UC-associated amino acid in omnibus tests (P = 2.68 × 10(-13)). Multivariate modeling identified rs9269955-C and 13 other variants in best predicting UC vs control status. In contrast, there was only suggestive association evidence between the MHC and CD. Taken together, these data demonstrate that variation at HLA-DRß1, amino acid 11 in the P6 pocket of the HLA-DR complex antigen binding cleft is a major determinant of chromosome 6p association with UC.

Climacteric symptoms in women undergoing risk-reducing bilateral salpingo-oophorectomy.

BACKGROUND: The most effective strategy for prevention of ovarian and breast cancer in high-risk women is bilateral salpingo-oophorectomy. The inevitable consequence of the procedure is early menopause with the associated climacteric symptoms. Little is known about the nature of the symptoms in women who undergo risk-reducing bilateral salpingo-oophorectomy. OBJECTIVES: To compare the nature, frequency, severity, duration, and overall effects of climacteric symptoms in a group of women who underwent preventive bilateral salpingo-oophorectomy as compared to women who experienced natural menopause. METHODS: Forty-eight women at high risk for ovarian cancer who had risk-reducing bilateral salpingo-oophorectomy were compared to 60 postmenopausal women who had natural menopause. The participants were interviewed about their climacteric complaints, thoughts and feelings regarding the surgical procedure and their general well-being. The climacteric symptoms were evaluated by a modified Greene Climacteric Scale. RESULTS: Surgical menopause, as compared to natural menopause, was associated with more severe psychological, vasomotor and somatic climacteric symptoms (total score 17.36 vs. 8.65, respectively, p < 0.001) and more significant sexual dysfunction (1.848 vs. 0.900, respectively, p < 0.01). On a 0-10 scale, the satisfaction rate from the surgical procedure was 8.23 +/- 2.21. The surgery did not affect the perceived quality of life (p = 0.347) and decreased the score of anxiety and cancer fear (from 7.75 +/- 3.31 preoperatively to 2.94 +/- 3.08 postoperatively, p < 0.001). CONCLUSIONS: Risk-reducing bilateral salpingo-oophorectomy as compared to natural menopause is associated with more severe climacteric symptoms. However, the procedure does not interfere with the overall perceived quality of life and improves the perception of cancer risk.

Raloxifene: cardiovascular considerations.

Ovarian hormone deficiency status is associated with increased cardiovascular morbidity and mortality, suggesting that estrogen might exhibit a favorable cardiovascular effect. Estrogen has a multitude of beneficial biological effects on surrogate markers of cardiovascular disease that may account for this hypothesis. However, none of the randomized trials already conducted with hormone replacement therapy showed overall benefit by means of reducing clinical ischemic cardiovascular events and/or suppressing atherogenesis. Moreover, the Women's Health Initiative study (WHI) has suggested a possible detrimental effect for hormone replacement therapy including increased cardiovascular morbidity, ovarian and breast cancer. Hence, any beneficial effect of estrogen must be carefully weighed against its carcinogenic properties together with its side effects. The need for a more efficient and specific molecule led to the development of the selective estrogen receptor modulators (SERMs). This new generation of drugs mimic the effect of estrogen in some tissues while antagonize several estrogen effects in other tissues. These unique properties offer the possibility to attain the beneficial effects of estrogen while avoiding its carcinogenic effect and the accompanying adverse reactions. Here we review the different effects of raloxifene- a protype second generation SERM on the cardiovascular system. We discuss raloxifene's role at different levels of the atherothrombotic cascade addressing each level separately; trying to clarify the net effect of raloxifene in modulating thrombosis in the arterial tree.

Maintenance therapy with a probiotic in antibiotic-dependent pouchitis: experience in clinical practice.

BACKGROUND: Management of antibiotic-dependent pouchitis is often challenging. Oral bacteriotherapy with probiotics (such as VSL #3) as maintenance treatment has been shown to be effective in relapsing pouchitis in European trials. However, this agent has not been studied in the US, and its applicability in routine clinical practice has not been evaluated. AIM: To determine compliance and efficacy of probiotic treatment in patients with antibiotic-dependent pouchitis. METHODS: Thirty-one patients with antibiotic-dependent pouchitis were studied. VSL #3 is a patented probiotic preparation of live freeze-dried bacteria. All patients received 2 weeks of ciprofloxacin 500 mg b.d. followed by VSL #3 6 g/day for 8 months. Baseline Pouchitis Disease Activity Index scores were calculated. Patients' symptoms were reassessed at week 3 when VSL #3 therapy was initiated and at the end of the 8-month trial. Some patients underwent repeat pouch endoscopy at the end of the trial. RESULTS: All 31 patients responded to the 2-week ciprofloxacin trial with resolution of symptoms and they were subsequently treated with VSL #3. The mean duration of follow-up was 14.5+/-5.3 months (range: 8-26 months). At the 8-month follow-up, six patients were still on VSL #3 therapy, and the remaining 25 patients had discontinued the therapy due to either recurrence of symptoms while on treatment or development of adverse effects. All six patients who completed the 8-month course with a mean treatment period of 14.3+/-7.2 months (range: 8-26 months) had repeat clinical and endoscopic evaluation as out-patients. At the end of 8 months, these six patients had a mean Pouchitis Disease Activity Index symptom score of 0.33+/-0.52 and a mean Pouchitis Disease Activity Index endoscopy score of 1.83+/-1.72, which was not statistically different from the baseline Pouchitis Disease Activity Index endoscopy score of 2.83+/-1.17 (P=0.27). CONCLUSION: This study was conducted to evaluate bacteriotherapy in routine care. The use of probiotics has been adopted as part of our routine clinical practice with only anecdotal evidence of efficacy. Our review of patient outcome from the treatment placebo showed that only a minority of patients with antibiotic-dependent pouchitis remained on the probiotic therapy and in symptomatic remission after 8 months.

Azathioprine formulation optimizes metabolite profile in inflammatory bowel disease.

BACKGROUND: Recent studies have suggested that mercaptopurine metabolism is influenced by drug formulation (mercaptopurine vs. azathioprine) and concomitant use of 5-aminosalicylic acid medications. AIM: To determine the influence of dose, formulation and 5-aminosalicylic acid use on mercaptopurine metabolism. METHODS: Metabolites from 131 inflammatory bowel disease patients were analysed. Logistic regression was used to analyse correlations between dose and metabolite levels. Multivariate analysis was used to determine the effects of drug formulation and 5-aminosalicylic acid use. RESULTS: A positive correlation was detected between dose and 6-tioguanine nucleotides levels for azathioprine/Imuran formulation (P = 0.005) but not for mercaptopurine formulation. Adjusted mean 6-tioguanine nucleotides levels were similar for both formulations. Adjusted mean 6-methylmercaptopurine levels were higher for mercaptopurine formulation than for azathioprine formulation (1950 vs. 1056, P = 0.04). 5-Aminosalicylic acid use: 6-tioguanine nucleotides levels did not differ based on concomitant 5-aminosalicylic acid use. However, 5-aminosalicylic acid use did result in higher adjusted mean 6-methylmercaptopurine levels: 2078 on 5-aminosalicylic acid vs. 991 off 5-aminosalicylic acid (P = 0.004). CONCLUSIONS: (i) Azathioprine may have metabolic benefits by achieving a correlation of dose with 6-tioguanine nucleotides levels and by leading to lower mean 6-methylmercaptopurine levels. (ii) 5-aminosalicylic acid use does not significantly impact 6-tioguanine levels and may lead to higher 6-methylmercaptopurine levels.

Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open-label pilot study.

BACKGROUND: Mast cells isolated from the colonic mucosa in active ulcerative colitis appear to be partially degranulated, suggesting the release of tryptase. AIM: To investigate the safety and activity of APC 2059, a highly specific tryptase inhibitor, in the treatment of ulcerative colitis. METHODS: This was an open-label, Phase 2, multicentre pilot study in patients with mildly to moderately active ulcerative colitis, with a disease activity index of 6-9 on a 12-point scale. Fifty-six adults received 20 mg APC 2059 subcutaneously twice daily and 53 completed 28 days of treatment. The primary end-point was response, defined as a final disease activity index of < or = 3. Supplementary analyses were also performed. RESULTS: Sixteen (29%) of 56 patients responded. Five (9%) showed complete remission (disease activity index=0). Twenty-seven (49%) improved, with a final disease activity index of < or = 3 or a four-point reduction. Improvement or normalization in each category of the disease activity index was as follows: stool frequency, 64%; bleeding, 64%; endoscopy, 50%; physicians' rating, 63%. There were no significant relationships between outcome and pharmacokinetics. The most common adverse events were related to the injection site (32.1%). CONCLUSIONS: In this pilot study, the tryptase inhibitor APC 2059 was safe and there was evidence of activity in the treatment of ulcerative colitis.

A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis.

Metronidazole is effective for the treatment of acute pouchitis after ileal pouch-anal anastomosis, but it has not been directly compared with other antibiotics. This randomized clinical trial was designed to compare the effectiveness and side effects of ciprofloxacin and metronidazole for treating acute pouchitis. Acute pouchitis was defined as a score of 7 or higher on the 18-point Pouchitis Disease Activity Index (PDAI) and symptom duration of 4 weeks or less. Sixteen patients were randomized to a 2-week course of ciprofloxacin 1,000 mg/d (n = 7) or metronidazole 20 mg/kg/d (n = 9). Clinical symptoms, endoscopic findings, and histologic features were assessed before and after therapy. Both ciprofloxacin and metronidazole produced a significant reduction in the total PDAI score as well as in the symptom, endoscopy, and histology subscores. Ciprofloxacin lowered the PDAI score from 10.1+/-2.3 to 3.3+/-1.7 (p = 0.0001), whereas metronidazole reduced the PDAI score from 9.7+/-2.3 to 5.8+/-1.7 (p = 0.0002). There was a significantly greater reduction in the ciprofloxacin group than in the metronidazole group in terms of the total PDAI (6.9+/-1.2 versus 3.8+/-1.7; p = 0.002), symptom score (2.4+/-0.9 versus 1.3+/-0.9; p = 0.03), and endoscopic score (3.6+/-1.3 versus 1.9+/-1.5; p = 0.03). None of patients in the ciprofloxacin group experienced adverse effects, whereas three patients in the metronidazole group (33%) developed vomiting, dysgeusia, or transient peripheral neuropathy. Both ciprofloxacin and metronidazole are effective in treating acute pouchitis with significant reduction of the PDAI scores. Ciprofloxacin produces a greater reduction in the PDAI and a greater improvement in symptom and endoscopy scores, and is better tolerated than metronidazole. Ciprofloxacin should be considered as one of the first-line therapies for acute pouchitis.

Ovulation induction and risk of endometrial cancer: a pilot study.

OBJECTIVE: To determine whether women with endometrial carcinoma are more likely to have been exposed to fertility drugs, in particular clomiphene, than healthy population controls. STUDY DESIGN: A nationwide case-control, pilot study. About 128 living women 35-64 years old, with a histologically confirmed diagnosis of endometrial carcinoma that was first diagnosed and reported to The Israel Cancer Registry between 1 January 1989 and 31 December 1992 were enrolled. The controls were 255 women from the same dialing areas selected by random digit dialing. A variety of demographic and clinical parameters were compared between cases and controls. A multivariate logistic model, controlling for age, was used to assess the independent effects of factors found to be significantly associated with endometrial cancer on univariate analysis. RESULTS: About 7 women with endometrial carcinoma (5.5%) and 10 healthy controls (3.9%) reported that they had used any fertility drug (crude odds ratio (OR) 1.4; 95% confidence interval (CI) 0.47-4.2). Use of fertility drugs did not meet the criteria for entry into the logistic model. The following parameters were found to be independently associated with endometrial cancer controlling for age, European-American background OR=2.2, (95% CI 1.3-3.7, P=0.004); nulliparity OR=2.7 (95% CI 1.1-6.5, P=0.03); history of infertility OR=1.8 (95% CI 1.0-3.3, P=0.05); BMI> or =27 OR=2.3 (95% CI 1.4-3.9, P=0.001). The use of oral contraceptives and IUD were found to be protective, OR=0.29 and 0.37, respectively, (95% CI 0.14-0.61, P=0.001 and 0.19-0.70, P=0.003, respectively). CONCLUSIONS: We found no evidence that the use of ovulation induction agents, including clomiphene citrate, are associated with a higher risk of endometrial carcinoma. The association between infertility drugs and endometrial carcinoma should be examined in other, larger studies.

Endoscopic and histologic evaluation together with symptom assessment are required to diagnose pouchitis.

BACKGROUND & AIMS: Pouchitis often is diagnosed based on symptoms alone. In this study, we evaluate whether symptoms correlate with endoscopic and histologic findings in patients with ulcerative colitis and an ileal pouch-anal anastomosis. METHODS: Symptoms, endoscopy, and histology were assessed in 46 patients using Pouchitis Disease Activity Index (PDAI). Patients were classified as either having pouchitis (PDAI score > or =7; N = 22) or as not having pouchitis (PDAI score <7; N = 24). RESULTS: Patients with pouchitis had significantly higher mean total PDAI scores, symptom scores, endoscopy scores, and histology scores. There was a similar magnitude of contribution of each component score to the total PDAI for the pouchitis group. Of note, 25% of patients with symptoms suggestive of pouchitis did not meet the PDAI diagnostic criteria for pouchitis. In both groups, the correlation coefficients between symptom, endoscopy, and histology scores were near zero (range, -0.26 to 0.20; P > 0.05). CONCLUSIONS: The symptom, endoscopy, and histology scores each contribute to the PDAI and appear to be independent of each other. Symptoms alone do not reliably diagnose pouchitis.

Effects of homeopathic treatment in women with premenstrual syndrome: a pilot study.

Alternative therapies in general, and homeopathy in particular, lack clear scientific evaluation of efficacy. Controlled clinical trials are urgently needed, especially for conditions that are not helped by conventional methods. The objective of this work was to assess the efficacy of homeopathic treatment in relieving symptoms associated with premenstrual syndrome (PMS). It was a randomised controlled double-blind clinical trial. Two months baseline assessment with post-intervention follow-up for 3 months was conducted at Hadassah Hospital outpatient gynaecology clinic in Jerusalem in Israel 1992-1994. The subjects were 20 women, aged 20-48, suffering from PMS. Homeopathic intervention was chosen individually for each patient, according to a model of symptom clusters. Recruited volunteers with PMS were treated randomly with one oral dose of a homeopathic medication or placebo. The main outcome measure was scores of a daily menstrual distress questionnaire (MDQ) before and after treatment. Psychological tests for suggestibility were used to examine the possible effects of suggestion. Mean MDQ scores fell from 0.44 to 0.13 (P<0.05) with active treatment, and from 0.38 to 0.34 with placebo (NS). (Between group P=0.057). Improvement >30% was observed in 90% of patients receiving active treatment and 37.5% receiving placebo (P=0.048). Homeopathic treatment was found to be effective in alleviating the symptoms of PMS in comparison to placebo. The use of symptom clusters in this trial may offer a novel approach that will facilitate clinical trials in homeopathy. Further research is in progress.

Influence of hormone replacement therapy on postmenopausal pelvic organs.

OBJECTIVE: To assess the influence of hormone replacement therapy (HRT) on the pelvic organs of postmenopausal women by vaginal ultrasonography. DESIGN: The study (case-control) included 753 consecutive, postmenopausal women who were referred for routine transvaginal ultrasound examination. A total of 290 women who were using HRT at the time of examination (study group) were compared with 463 who were not treated (control group). RESULTS: The women using HRT were younger and had been menopausal for a shorter period, compared with those who had not been treated. Mean uterine volume, endometrial thickness and ovarian area were all increased in the HRT group, compared to the control group. A negative correlation was found between menopausal age and uterine volume, and ovarian area in both treated and untreated groups. However, endometrial thickness was negatively correlated with menopausal age in the untreated group only. After controlling for various parameters, a multivariate logistic analysis demonstrated that endometrial thickness was treatment status-dependent only. Uterine volume was also treatment status-dependent, but was also negatively correlated with menopausal age. As expected, the endometrium was thicker and the uterine volume was larger in the treated group. Ovarian area was not found to be treatment-dependent for all menopausal ages. CONCLUSIONS: Postmenopausal women treated with HRT have a larger uterus and thicker endometrium than those of non-treated matched controls. There is a negative correlation between menopausal age and uterine and ovarian size. Endometrial thickness was found to be negatively correlated with menopausal age in only the untreated group, and is almost entirely HRT-dependent. In contrast to the uterus and the endometrium, the ovaries are not influenced by HRT.

Effects of homeopathic treatment in women with prementrual syndrome: a pilot study

Alternative therapies in general, and homeopathy in particular, lack clear scientific evaluation of efficacy. Controlled clinical trials are urgently needed, especially for conditions that are not helped by... (AU)

Bladder exstrophy associated with complete urethral duplication: a rare malformation with excellent prognosis.

PURPOSE: We report the association of complete urethral duplication and bladder exstrophy in 5 males, and describe the main characteristics to achieve diagnosis. MATERIALS AND METHODS: From 1983 to 2000, 5 males with single bladder exstrophy and complete urethral duplication were seen at 3 institutions. Although bladder exstrophy was obvious at birth, only 1 patient had the preoperative diagnosis of associated urethral duplication. All patients were evaluated with abdominal ultrasound, voiding cystourethrogram after bladder closure and cystoscopy. RESULTS: All patients were totally incontinent, including 4 after primary bladder exstrophy closure. Although it was initially unnoticed by the urologist, most patients had leakage from the tip of the penis during the Valsalva maneuver. In all cases bladder exstrophy was single and deeply situated in the pelvis with excellent elasticity. All patients had a normal sized penis with less severe dorsal chordee and conical shaped glans. The duplicate epispadiac urethra did not have a verumontanum. Only 1 of the 5 patients had the correct diagnosis made before primary closure of bladder exstrophy, while in the other 4 diagnosis of a duplicate ventral urethra was made at the time of epispadias or fistula repair. There were no other associated malformations. In all cases the dorsal epispadiac urethral plate was excised and bladder emptying occurred through the ventral urethra, which at cystoscopy had a normal verumontanum. Postoperatively, all patients became continent and voided with good flow through the ventral urethra and, as opposed to many cases of exstrophy and epispadias, had normal size and excellent cosmesis of the penis. CONCLUSIONS: Complete urethral duplication is a rare variant of the exstrophy-epispadias complex. Patients with this anomaly present with a larger and more deeply situated bladder plate than classical exstrophy and a larger penis. A high index of suspicion is necessary to make a preoperative diagnosis. Excision of the dorsal urethral plate and maintenance of the ventral urethra are the treatment of choice, resulting in a continence and normal voiding.

Celiac disease is highly prevalent in lymphocytic colitis.

A high frequency of celiac disease is reported in patients with collagenous colitis. Limited information is available on the frequency of celiac disease in lymphocytic colitis. The aim of our study was to determine the prevalence of celiac disease in microscopic colitis (collagenous and lymphocytic colitis). Patients were identified from a pathology registry of microscopic colitis from 1987 to 1999. Pathology reports and medical records were reviewed for previous small bowel biopsies and/or celiac serology. We identified 113 patients with microscopic colitis, and 46 patients underwent a small bowel biopsy and/or celiac serology. Of these, 27 patients had lymphocytic colitis (63% female; age, 58.6 +/- 16.2 years) and 19 patients had collagenous colitis (79% female; age, 61.8 +/- 13.6 years). Small bowel biopsy alone was performed in 28 of 46 patients, celiac serology alone was performed in 10, and both small bowel biopsy and celiac serology were performed in 8. Celiac disease was identified in 4 patients by small bowel histology; all had lymphocytic colitis (4 of 27 patients, 15%). This frequency of celiac disease is significantly higher than the highest reported U.S. prevalence of celiac disease (4/1,000 individuals; p < 0.01). There is a high frequency of celiac disease in patients with lymphocytic colitis. Given the importance of the early detection of celiac disease, it should be excluded in all patients with lymphocytic colitis, particularly if diarrhea does not respond to conventional treatment.

Urethral duplication in the male: review of 16 cases.

PURPOSE: Urethral duplication is a rare congenital anomaly. The clinical presentation varies because of the different anatomical patterns of this abnormality. We describe our experience with 16 male patients with this anomaly. MATERIALS AND METHODS: We retrospectively reviewed the records of 16 male patients treated for urethral duplication in the last 10 years. Age at presentation ranged from newborn to 8 years. Evaluation included ultrasound, voiding cystourethrography, retrograde urethrography and endoscopy. RESULTS: A blind ending duplicated urethra (type I) was present in 4 patients, 2 independent urethras with distinct bladder necks (type IIA1) in 6, 2 urethras originating from a common bladder neck (type IIA2) in 4, and complete urethral and bladder duplication (type III) in 2. Six patients had associated vesicoureteral reflux. Duplication was an incidental finding at epispadias repair in 3 patients with bladder exstrophy, at hypospadias repair in 1 and at hydrocele repair in 1. One patient with bilateral dysplastic kidneys died in the newborn period. Surgical management included excision of the duplicated urethra in 8 cases and urethroplasty using a pedicle flap in 2, while surgical management was not required in 3. CONCLUSIONS: Urethral duplication is a rare congenital anomaly with a variable clinical presentation. This pathological condition may easily be under diagnosed, especially in patients with other associated anomalies, such as hypospadias or bladder exstrophy. Surgical management should be planned individually according to the anatomical findings of the abnormality.