James Mirocha

The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial.

Context Few trials have evaluated the effects of antibiotics on symptoms of the irritable bowel syndrome (IBS). Contribution In this double-blind trial, 87 patients with IBS were randomly assigned to either rifaximin (400 mg 3 times daily) or placebo for 10 days. Over a 10-week follow-up period, the rifaximin recipients reported global improvements in overall symptoms and less bloating more frequently than the placebo recipients. No major differences in abdominal pain, diarrhea, or constipation were observed between the groups. Cautions The duration of therapy and follow-up was short. Implications Rifaximin may improve some symptoms in some patients with IBS. The Editors The irritable bowel syndrome (IBS) is one of the most common chronic medical conditions (16), yet its cause is unknown. Among other contributors, alterations in gut flora have been identified as potentially important. Results of recent studies indicate that up to 84% of patients with IBS have an abnormal lactulose breath test result, suggesting small-intestinal bacterial overgrowth (7, 8). On the basis of this concept, the antibiotic neomycin can statistically significantly improve the symptoms of IBS (7, 8). In addition, the effect of neomycin correlates with the elimination of bacterial overgrowth, as indicated by the normalization of the lactulose breath test result (7, 8). Although neomycin seems to improve symptoms, it effectively eliminates bacterial overgrowth in only about 25% of patients with IBS (8). Furthermore, side effects limit the use of neomycin. Low efficacy also applies to other antibiotics (for example, doxycycline and amoxicillinclavulanate) that have been previously investigated for treating bacterial overgrowth (9). An ideal antibiotic for IBS is, arguably, one with negligible systemic absorption, minimal side effects, and high efficacy for bacterial overgrowth. Rifaximin is a gut-selective antibiotic with negligible systemic absorption (0.4%) and broad-spectrum activity in vitro against gram-positive and gram-negative aerobes and anaerobes (10). On the basis of this broad spectrum, eradication rates with rifaximin in bacterial overgrowth are as high as 70% (11). Furthermore, rifaximin has a similar tolerability profile to that of placebo and has known activity against Clostridium difficile (12). These properties make it a good candidate for treating a condition that is as common as IBS. Our study aimed to determine whether the nonabsorbed antibiotic rifaximin is more effective than placebo in reducing symptoms in adults with IBS. Methods Setting and Participants Our study was conducted at the Cedars-Sinai Medical Center, Los Angeles, California, and the University of Chicago, Chicago, Illinois. We recruited patients with IBS through advertising in local media (radio and news publications). We did not recruit patients from the IBS clinics of the Cedars-Sinai Gastrointestinal Motility Program to avoid enrollment of tertiary care patients. The institutional review board of both centers approved the study, and all patients provided written informed consent. Patients between 18 and 65 years of age who met Rome I criteria (13) were eligible. Exclusion criteria were the presence of underlying conditions that are known to predispose to bacterial overgrowth, including diabetes; narcotic use; previous bowel resection; inflammatory bowel disease; cirrhosis; known bowel adhesions; or any known chronic gastroenterological disease, such as celiac disease. We excluded patients who were taking tegaserod and antidepressants unless these treatments were discontinued before study entry. We also excluded participants who reported taking an oral antibiotic within the previous 3 months. After participant inclusion and exclusion, we recruited 84 participants from the Cedars-Sinai Medical Center and 3 participants from the University of Chicago. We followed participants in special research clinics at both centers. Randomization and Interventions Eligible patients completed a 7-day stool diary that was based on the Bristol stool form scale (14). Patients returned to the clinic after a 12-hour fast and completed a symptom questionnaire about the preceding 7 days of symptoms. We then randomly assigned patients to double-blind treatment with 400 mg of rifaximin 3 times daily for 10 days or a matching placebo. We chose this dosage on the basis of a previous study that demonstrated the efficacy of rifaximin in bacterial overgrowth (11). The randomization of rifaximin versus placebo was conducted outside of Cedars-Sinai Medical Center in a 1:1 ratio into blocks of 4 patients. The allocation sequence was determined and coded at Salix Pharmaceuticals, Morrisville, North Carolina. Since this was an investigator-initiated study, the rifaximin and placebo were distributed to the Cedars-Sinai Medical Center, and nonstratified medicine and placebo were sent to the University of Chicago in groups of 4 as enrollment progressed. The medicine and placebo were prepackaged to conceal content at all times. Research personnel who were involved in product distribution were also blinded to package content. Assessments and Follow-up After completing the 10-day course of study medication, patients immediately began another stool diary for 7 days then returned to complete a follow-up questionnaire and to return their pill container for a pill count to determine adherence. Patients then entered the follow-up phase, during which they completed a weekly self-administered symptom questionnaire at home that documented their symptoms for an additional 9 weeks (for a total of 10 weeks of post-treatment follow-up). During this time, we asked participants to fax their responses to the research office. When a fax was not received on the appropriate day, research assistants called patients to ensure adherence. During this phase of study, no physician interaction occurred. During the last week of follow-up, patients completed a daily stool diary. At the end of the follow-up period, patients returned to the clinic for a final visit, which included another symptom questionnaire. For the initial symptom questionnaire, patients were asked to indicate the severity of each of 9 symptoms (abdominal pain, diarrhea, constipation, bloating, urgency, incomplete evacuation, mucus, sense of incomplete evacuation, and gas) on a visual analogue scale (VAS) ranging from 0 mm to 100 mm, with 100 mm being extreme. We used all 9 symptoms to verify IBS criteria in patients, but we assigned only diarrhea, constipation, abdominal pain, and bloating a priori as treatment end points. We asked patients to rate the severity of their symptoms on the VAS again 7 days after the completion of rifaximin treatment or placebo. Furthermore, we asked patients to provide a percentage of global improvement in their overall IBS symptoms from 0% to 100%. We chose global improvement since the Rome Consensus Group considers it to be the preferred end point measure in IBS treatment studies (15). Patients then rated the severity of their symptoms on the VAS and rated global improvement again each week for 8 weeks of follow-up and at the final visit to provide a total of 10 weeks of follow-up data. Table 1 depicts the number of patients with outcomes at various time points during the study. Table 1. Study Recruitment and Enrollment Summary At the first follow-up visit, physicians evaluated adverse events by asking patients, in an open-ended manner, whether they had experienced adverse events while receiving therapy and to elaborate on any that occurred. Although breath testing and breath methane level determinations were performed, we do not report them in our paper. Statistical Analysis We determined the number of patients for the study on the basis of the neomycin effect in a recent double-blind study for IBS on global improvement (8). To detect a difference of 35% (SD, 50%) with a power of 90%, we needed to assign 44 participants per group. Assuming a dropout rate of 10%, we calculated that approximately 96 patients would need to be recruited. The primary end point was global improvement in IBS symptoms during follow-up. As seen in Figure 1 , data were not available for all 10 weeks of follow-up. Figure 1. Study flow chart. We assessed the primary end point (percentage of global improvement) across the 10 weeks of follow-up by using an approach analogous to a repeated measures analysis of variance. Specifically, we used a mixed model with visit week (at 10 levels), treatment group (rifaximin or placebo), and group-by-week interaction as the fixed factors and patient as the random factor. The interaction and group factors were the main factors of interest in the analyses. We estimated mixed models by using the restricted maximum likelihood method. Because the global improvement percentage varied widely across week for most individuals, we considered week to be a categorical variable in the mixed model. Within-patient correlation across time was addressed by an autoregressive (first-order) model for the covariance structure. Missing data were mostly intermittent, and we assumed them to be missing at random. The normality assumption was rarely satisfied in either group at any week. However, at least 34 observations were recorded per group per week and the sample sizes were well-balanced, so we used the mixed-model analysis. We analyzed models with a single covariate (baseline diarrhea, constipation, abdominal pain, or bloating severity score). The covariate models did not improve the fit nor did they change the substantive results. Hence, we presented the simpler (no covariate) model results. We used a similar mixed-model approach to assess the secondary end points of abdominal pain, bloating, diarrhea, and constipation. Within-patient correlation was modeled by an autoregressive covariance structure. The normality assumption was rarely satisfied for the diarrhea outcome, with a similar floor effect for the primary outcome.

Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life

Purpose: To determine if there is significant symptomatology in women with heterozygous α-galactosidase mutations.Methods: Data from medical records of the 44 heterozygous females followed at Cedars-Sinai Medical Center were compiled and analyzed for symptoms of Fabry disease. Quality of life data were also analyzed.Results: Seventy-six percent were referred due to an affected male relative; 76% reported acroparesthesias as their first symptom. A mean of 15.7 years elapsed from onset of first symptoms to the diagnosis. Quality of life, measured by the SF-36 survey, was globally reduced. Pain affected mood and enjoyment of life. Central/peripheral nervous, cardiopulmonary, and renal system manifestations of Fabry disease were present far above that predicted for random X-inactivation of the normal allele. Fatigue, present in 59%, was associated with reduced maximum oxygen consumption (P = 0.049); exercise intolerance, present in 83%, was associated with reduced maximal heart rate during exercise testing (P = 0.0089). Women diagnosed via family history experienced more angina (P = 0.035), decreased vibration sense (P = 0.026), and had a worse percentage predicted FEF25–75 (P = 0.037) compared to women diagnosed because of symptoms.Conclusions: This study indicates that the asymptomatic female carrier of Fabry disease is the exception, not the rule: heterozygotes suffer from significant multisystemic disease and reduced quality of life and must be monitored and treated accordingly.

The Akt pathway in human breast cancer: a tissue-array-based analysis.

The Akt pathway, an important regulator of cell proliferation and survival, is deregulated in many cancers. The pathway has achieved considerable importance due to the development of kinase inhibitors that are able to successfully reduce tumor growth. This study was conducted to determine the status of the Akt pathway in human breast cancers and to study the relationship between the different component proteins. Expression levels of PTEN, phosphorylated forms of the constituent proteins (Akt, FKHR, mTOR, and S6) and cyclin D1 were evaluated by immunohistochemistry, on consecutive sections from a tissue microarray containing 145 invasive breast cancers and 140 pure ductal carcinomas in-situ. Aberrant expression was correlated statistically with tumor characteristics and disease outcome. The Akt pathway was found to be activated early in breast cancer, in the in-situ stage. In all, 33, 15, 32, and 60% of ductal carcinoma in-situ showed overexpression of Akt, FKHR, mTOR, and cyclin D1. PTEN loss did not correlate statistically with expression of AKT or any of the other proteins with the exception of S6, indicating that Akt activation was not a result of PTEN loss. Expression levels of PTEN and S6 were significantly different in in-situ and invasive cancers, indicating association with disease progression. Loss of PTEN was noted in 11% of in-situ as compared to 26% of invasive cancers, while S6 overexpression was seen in 47% in-situ and in 72% invasive cancers. High-grade carcinomas were associated with PTEN loss, while low-grade carcinomas with good prognostic features showed cyclin D1 overexpression and were associated with longer disease free survival. Additionally, cancers with mTOR overexpression showed a three times greater risk for disease recurrence. Overall, a large proportion of in-situ and invasive breast cancers overexpressed cyclinD1 and S6. Our results may have significant implications in the development and application of targeted therapy.

Clinical Profile and Predictors of Complications in Peripartum Cardiomyopathy

BACKGROUND Clinical profile and predictors of major adverse events (MAE) associated with peripartum cardiomyopathy (PPCM) have not been characterized. METHODS AND RESULTS A retrospective review and analysis of clinical data of 182 patients with PPCM. Forty-six patients had >or=1 MAE, including death (13), heart transplantation (11), temporary circulatory support (4), cardiopulmonary arrest (6), fulminant pulmonary edema (17), thromboembolic complications (4), and defibrillator or pacemaker implantation (10). Diagnosis of PPCM was delayed >or=1 week in 48% of patients with MAE that preceded the diagnosis in 50% of these patients. Seven (32%) of the surviving patients who had MAE and did not undergo heart transplantation had residual brain damage. Significant predictors of MAE were: left ventricular ejection fraction <or=25% (HR 4.20, CI 2.04-8.64) and non-Caucasian background(HR 2.16, CI 1.17- 3.97). These predictors in addition to diagnosis delay (HR 5.51, CI 1.21-25.04) were also associated with death or heart transplantation. CONCLUSIONS 1. PPCM may be associated with mortality or severe and lasting morbidity. 2. Incidence of MAE is higher in non-Caucasians and in women with left ventricular ejection fraction <or=25%. 3. Diagnosis of PPCM is often delayed and preceded by MAE. 4. Increased awareness of PPCM is required for early diagnosis and aggressive therapy in an attempt to prevent complications.

Anti-angiotensin type 1 receptor antibodies associated with antibody mediated rejection in donor HLA antibody negative patients.

Background. Angiotensin type 1 receptor (AT1R) mediates most physiologic and pathophysiologic actions of its endogenous ligand, angiotensin II, with overactivity leading to vascular remodeling and hypertension. Antibodies to AT1R are implicated in several vascular pathologies. The aim of our study was to determine the impact of antibody to AT1R on clinical outcomes including antibody mediated rejection (AMR), with or without C4d deposition, in patients whose sera contained no donor human leukocyte antigen (HLA)-specific antibody (HLA-DSA). Methods. Pretransplant sera from 97 recipients and sera obtained at the time of acute rejection (AR) were tested by Luminex-based single-antigen bead assays to determine HLA-DSA and antibodies to major histocompatibility class I chain-related gene A (MICA). The presence of antibody to AT1R was determined by a cell-based ELISA method using a cutoff of 17 units to distinguish high from low binding. Results. Sera from 63 recipients were determined to have no HLA-DSA and no donor-specific MICA antibodies pretransplant and at the time of AR, and 16 of these recipients were diagnosed with AR including 7 with AMR and 9 with cellular AR (cell-mediated rejection). High-binding AT1R antibodies were identified for six of seven in the AMR+ group and zero of nine in the cell-mediated rejection+ group (P=0.0009). Conclusions. A strong association was observed between the presence of high binding to AT1R and AMR in recipients whose sera contained no antibody to donor HLA or MICA. Assessing the AT1R antibody status along with the HLA-DSA provides additional information to determine the immunologic risk for recipients.

Aortic annular sizing for transcatheter aortic valve replacement using cross-sectional 3-dimensional transesophageal echocardiography.

OBJECTIVES This study compared cross-sectional three-dimensional (3D) transesophageal echocardiography (TEE) to two-dimensional (2D) TEE as methods for predicting aortic regurgitation after transcatheter aortic valve replacement (TAVR). BACKGROUND Data have shown that TAVR sizing using cross-sectional contrast computed tomography (CT) parameters is superior to 2D-TEE for the prediction of paravalvular aortic regurgitation (AR). Three-dimensional TEE can offer cross-sectional assessment of the aortic annulus but its role for TAVR sizing has been poorly elucidated. METHODS All patients had severe symptomatic aortic stenosis and were treated with balloon-expandable TAVR in a single center. Patients studied had both 2D-TEE and 3D imaging (contrast CT and/or 3D-TEE) of the aortic annulus at baseline. Receiver-operating characteristic curves were generated for each measurement parameter using post-TAVR paravalvular AR moderate or greater as the state variable. RESULTS For the 256 patients studied, paravalvular AR moderate or greater occurred in 26 of 256 (10.2%) of patients. Prospectively recorded 2D-TEE measurements had a low discriminatory value (area under the curve = 0.52, 95% confidence interval: 0.40 to 0.63, p = 0.75). Average cross-sectional diameter by CT offered a high degree of discrimination (area under the curve = 0.82, 95% confidence interval: 0.73 to 0.90, p < 0.0001) and mean cross-sectional diameter by 3D-TEE was of intermediate value (area under the curve = 0.68, 95% confidence interval: 0.54 to 0.81, p = 0.036). CONCLUSIONS Cross-sectional 3D echocardiographic sizing of the aortic annulus dimension offers discrimination of post-TAVR paravalvular AR that is significantly superior to that of 2D-TEE. Cross-sectional data should be sought from 3D-TEE if good CT data are unavailable for TAVR sizing.

The utility of oral glucose tolerance testing for diagnosis and assessment of treatment outcomes in 166 patients with acromegaly.

CONTEXT GH suppression after oral glucose load [oral glucose tolerance test (OGTT)] and normal age- and gender-matched IGF-I levels reflect biochemical control of acromegaly. The OGTT is the gold standard for determining control of GH secretion at diagnosis and after surgical treatment, but the usefulness of performing an OGTT in patients treated with medical therapy has not been determined. OBJECTIVE Our objective was to assess relationships between basal GH levels (basal GH), GH responses to OGTT [GH nadir (GHn)], and IGF-I levels. DESIGN This was a retrospective electronic database review. SETTING This study was performed at a tertiary outpatient pituitary center. PATIENTS A total of 166 patients with acromegaly (79 females, 87 males) were included in the study. Four categories of testing were performed: diagnosis, postoperative assessment without medication, testing during somatostatin analog (SA) therapy, and testing during dopamine agonist (DA) therapy. MAIN OUTCOME MEASURES Basal serum GH and IGF-I levels and GH levels 2 h after 75 g OGTT were measured. RESULTS A total of 482 simultaneous OGTT and IGF-I measurements were observed from 1985--2008. Discordant results of oral glucose tolerance testing (GHn and IGF-I) were observed 33, 48, and 18% in postoperative assessment without medication, SA, and DA categories, respectively. In the SA category, 42% of tests were discordant with normal IGF-I and nonsuppressed GHn. In contrast, 4% of tests were discordant with normal IGF-I and nonsuppressed GH in those treated with DA. No significant differences in discordance were observed when basal GH was used. CONCLUSIONS Both basal and GHn levels are highly discordant with IGF-I levels during medical therapy with SAs. The OGTT is not useful in assessing biochemical control in these subjects.

Comparison of Coronary Artery Bypass Surgery and Percutaneous Drug-Eluting Stent Implantation for Treatment of Left Main Coronary Artery Stenosis

OBJECTIVES The purpose of this study was to compare outcomes for drug-eluting stents (DES) and coronary artery bypass graft (CABG) surgery in patients with unprotected left main coronary artery (ULMCA) stenosis. BACKGROUND Expert guidelines recommend coronary artery bypass graft (CABG) surgery for the treatment of significant stenosis of the unprotected left main coronary artery (ULMCA) if the patient is eligible for CABG; however, treatment by percutaneous coronary intervention (PCI) is common. METHODS Details of patients (n = 343, ages 69.9 +/- 11.9 years) undergoing coronary revascularization for ULMCA stenosis (April 2003 to January 2007) were recorded. A total of 223 patients were treated with CABG (mean [interquartile range]: follow-up 600 [226 to 977) days) and 120 by PCI (follow-up 362 [192 to 586) days). The hazard ratios (HRs) for death and major adverse cardiovascular and cerebrovascular events (MACCE) were calculated incorporating propensity score adjustment. Survival comparisons were conducted in propensity-matched subjects (n = 134), and in low- and high-risk subjects for CABG. RESULTS Patients treated by PCI were more likely to be >or=75 years of age (49% vs. 33%; p = 0.005), and of greater surgical risk (Parsonnet score 17.2 +/- 11.2 vs. 13.0 +/- 9.3; p < 0.001) than patients treated by CABG. Overall, the propensity-adjusted HR for death was not statistically different (HR 1.93, 95% confidence interval [CI] 0.89 to 4.19, p = 0.10), but MACCE was greater in the PCI group (HR 1.83, 95% CI 1.01 to 3.32, p = 0.05). In propensity-matched individuals, neither survival nor MACCE-free survival were different. Survival was equivalent among low-risk candidates, but PCI had a tendency to inferior survival in high-risk candidates (Ellis category IV, log-rank p = 0.05). Interaction testing, however, failed to demonstrate a difference in outcomes of the 2 revascularization techniques as a function of baseline risk assessment. CONCLUSIONS Overall, the propensity-adjusted risk of mortality for treatment of ULMCA disease does not differ between PCI- and CABG-treated groups. There appears to be sufficient equipoise that a randomized clinical trial to compare the techniques would not be ethically contraindicated.

Predictive accuracy of SYNTAX score for predicting long-term outcomes of unprotected left main coronary artery revascularization.

The American College of Cardiology/American Heart Association recently updated recommendations for percutaneous coronary intervention (PCI) of unprotected left main coronary artery (ULMCA) disease from class III to II(b) according to the results of the SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) trial. The SYNTAX score is an angiographic tool using solely the coronary anatomy. We studied the effect of co-morbidities (Parsonnets score) on the ability of the SYNTAX score to predict long-term outcomes in patients with ULMCA disease treated by revascularization. A total of 328 patients underwent revascularization of ULMCA from April 2003 to February 2007. Of the 328 patients, 120 underwent PCI (median follow-up 973 days) and 208 underwent coronary artery bypass grafting (CABG) (median follow-up 1,298 days). The ability of the SYNTAX score to predict outcomes was assessed using the Cox proportional hazards model. The outcomes between the PCI and CABG groups were compared by propensity analysis. The median SYNTAX score was 26 in the PCI and 28 in the CABG group (p = 0.5). In the PCI group, greater quartiles were associated with worse survival (62.1% at SYNTAX score of ≥36 vs 82.4% at SYNTAX score of <36, p = 0.03) and all-cause mortality, myocardial infarction, cerebrovascular events, and target vessel revascularization-free (MACCE) survival (47.7%, SYNTAX score ≥20 vs 76.6%, SYNTAX score <20, p = 0.02). Using the Parsonnet score as a covariate, the SYNTAX score continued to be an independent predictor of MACCE and demonstrated a trend toward predicting mortality in the PCI group. In contrast, the SYNTAX score did not predict the outcomes for the CABG group. No difference was found in mortality between the PCI and CABG groups for ULMCA disease, regardless of coronary complexity; although greater SYNTAX scores were associated with increased MACCE rates with PCI compared to CABG. Both the coronary anatomy (SYNTAX score) and co-morbidities (Parsonnets score) predicted long-term outcomes for PCI of ULMCA disease. In contrast, the SYNTAX score did not predict the outcomes after CABG. In conclusion, the ideal scoring system to guide an appropriate revascularization decision for ULMCA disease should take into account both the coronary anatomy and the co-morbidities.

Emergency department crystalloid resuscitation of 1.5 L or more is associated with increased mortality in elderly and nonelderly trauma patients.

BACKGROUND Recent evidence suggests a survival advantage in trauma patients who receive controlled or hypotensive resuscitation volumes. This study examines the threshold crystalloid volume that is an independent risk factor for mortality after trauma. METHODS This study analyzed prospectively collected data from a Level I Trauma Center between January 2000 and December 2008. Demographics and outcomes were compared in elderly (≥70 years) and nonelderly (<70 years) trauma patients who received crystalloid fluid in the emergency department (ED) to determine a threshold volume that was an independent predictor for mortality. RESULTS A total of 3,137 patients who received crystalloid resuscitation in the ED were compared. Overall mortality was 5.2%. Mortality among the elderly population was 17.3% (41 deaths), whereas mortality in the nonelderly population was 4% (116 deaths). After multivariate logistic regression analysis, fluid volumes of 1.5 L or more were significantly associated with mortality in both elderly (odds ratio [OR]: 2.89, confidence interval [CI] [1.13-7.41], p=0.027) and nonelderly patients (OR: 2.09, CI [1.31-3.33], p=0.002). Fluid volumes up to 1 L were not associated with significantly increased mortality. At 3 L, mortality was especially pronounced in the elderly (OR: 8.61, CI [1.55-47.75] p=0.014), when compared with the nonelderly (OR=2.69, CI [1.53-4.73], p=0.0006). CONCLUSION ED volume replacement of 1.5 L or more was an independent risk factor for mortality. High-volume resuscitations were associated with high-mortality particularly in the elderly trauma patient. Our finding supports the notion that excessive fluid resuscitation should be avoided in the ED and when required, operative intervention or intensive care admission should be considered.