Thomas Cook

Probiotic helminth administration in relapsing–remitting multiple sclerosis: a phase 1 study

Background: Probiotic treatment strategy based on the hygiene hypothesis, such as administration of ova from the non-pathogenic helminth, Trichuris suis, (TSO) has proven safe and effective in autoimmune inflammatory bowel disease. Objective: To study the safety and effects of TSO in a second autoimmune disease, multiple sclerosis (MS), we conducted the phase 1 Helminth-induced Immunomodulatory Therapy (HINT 1) study. Methods: Five subjects with newly diagnosed, treatment-naive relapsing–remitting multiple sclerosis (RRMS) were given 2500 TSO orally every 2 weeks for 3 months in a baseline versus treatment control exploratory trial. Results: The mean number of new gadolinium-enhancing magnetic resonance imaging (MRI) lesions (n-Gd+) fell from 6.6 at baseline to 2.0 at the end of TSO administration, and 2 months after TSO was discontinued, the mean number of n-Gd+ rose to 5.8. No significant adverse effects were observed. In preliminary immunological investigations, increases in the serum level of the cytokines IL-4 and IL-10 were noted in four of the five subjects. Conclusion: TSO was well tolerated in the first human study of this novel probiotic in RRMS, and favorable trends were observed in exploratory MRI and immunological assessments. Further investigations will be required to fully explore the safety, effects, and mechanism of action of this immunomodulatory treatment.

Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure results from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program.

OBJECTIVES Our aim was to examine continental and regional differences in baseline characteristics and post-discharge clinical outcomes in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial. BACKGROUND Continental and regional differences in clinical trials of acute heart failure syndromes (AHFS) have not been well studied. METHODS We analyzed data from the EVEREST trial, which randomized 4,133 patients hospitalized for worsening (HF) and left ventricular ejection fraction < or =40% to oral tolvaptan, a vasopressin antagonist, or placebo and followed for a median of 9.9 months. Baseline characteristics, mortality, and outcomes were analyzed across North America (n = 1,251), South America (n = 688), Western Europe (564 patients), and Eastern Europe (n = 1,619). RESULTS There were major differences between the 4 groups in the severity, etiology, and management of HF. Unadjusted 1-year mortality and cardiovascular mortality/HF hospitalization were 30.4% and 52.5% in North America, 27.2% and 41.6% in South America, 27.1% and 47.3% in Western Europe, and 20.5% and 35.3% in Eastern Europe. After adjustment, South American patients had the highest overall mortality (hazard ratio: 1.42, 95% confidence interval: 1.15 to 1.76), while Eastern European patients had the lowest cardiovascular death and HF hospitalization rate (hazard ratio: 0.84, 95% confidence interval: 0.73 to 0.97), compared with patients in North America. CONCLUSIONS Major continental and regional differences in HF severity, etiology, and management exist among AHFS patients, resulting in varied post-discharge outcomes, despite pre-defined selection criteria. These differences should be taken into account when planning global trials in AHFS. (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan [EVEREST]; NCT00071331).

Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: Findings from the EVEREST trial

AIMS Signs and symptoms of congestion are the most common cause for hospitalization for heart failure (HHF). The clinical course and prognostic value of congestion during HHF has not been systemically characterized. METHODS AND RESULTS A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 h of admission (median ~24 h) for worsening HF with an EF ≤ 40% and two or more signs or symptoms of fluid overload [dyspnoea, oedema, or jugular venous distension (JVD)] for a median follow-up of 9.9 months. Clinician-investigators assessed patients daily for dyspnoea, orthopnoea, fatigue, rales, pedal oedema, and JVD and rated signs and symptoms on a standardized 4-point scale ranging from 0 to 3. A modified composite congestion score (CCS) was calculated by summing the individual scores for orthopnoea, JVD, and pedal oedema. Endpoints were HHF, all-cause mortality (ACM), and ACM + HHF. Multivariable Cox regression models were used to evaluate the risk of CCS at discharge on outcomes at 30 days and for the entire follow-up period. The mean CCS obtained after initial therapy decreased from the mean ± SD of 4.07 ± 1.84 and the median (25th, 75th) of 4 (3, 5) at baseline to 1.11 ± 1.42 and 1 (0, 2) at discharge. At discharge, nearly three-quarters of study participants had a CCS of 0 or 1 and fewer than 10% of patients had a CCS >3. B-type natriuretic peptide (BNP) and amino terminal-proBNP, respectively, decreased from 734 (313, 1523) pg/mL and 4857 (2251, 9642) pg/mL at baseline to 477 (199, 1079) pg/mL, and 2834 (1218, 6075) pg/mL at discharge/Day 7. A CCS at discharge was associated with increased risk (HR/point CCS, 95% CI) for a subset of endpoints at 30 days (HHF: 1.06, 0.95-1.19; ACM: 1.34, 1.14-1.58; and ACM + HHF: 1.13, 1.03-1.25) and all outcomes for the overall study period (HHF: 1.07, 1.01-1.14; ACM: 1.16, 1.09-1.24; and ACM + HHF 1.11, 1.06-1.17). Patients with a CCS of 0 at discharge experienced HHF of 26.2% and ACM of 19.1% during the follow-up. CONCLUSION Among patients admitted for worsening signs and symptoms of HF and reduced EF, congestion improves substantially during hospitalization in response to standard therapy alone. However, patients with absent or minimal resting signs and symptoms at discharge still experienced a high mortality and readmission rate.

Multiple sclerosis and the hygiene hypothesis.

In 1966 Leibowitz et al.1 first suggested that the prevalence of MS was correlated with a childhood environment characterized by a high level of sanitation. Similar observations have led to the formulation of the hygiene hypothesis, which holds that a relative lack of “evolutionarily normal” childhood infectious exposures may predispose susceptible individuals to allergic and autoimmune diseases later in life. Recent findings that are consistent with the hygiene hypothesis have come from studies in epidemiology, immunology, and animal models, as well as successful clinical trials of probiotic treatment for allergic and autoimmune diseases.2-4 In this regard, many observers have noted that the prevalence of MS in the developed world far exceeds that of regions characterized by widespread childhood infection or poor sanitation. Nevertheless, to the best of our knowledge, to date the global relationship between MS incidence and parasitic exposure has only been addressed in qualitative terms. To address this issue quantitatively, we first noted the global prevalence of Trichuris trichiura , a common human helminth with world-wide distribution and a surrogate marker for 1) infection with other macroparasites as well a marker for 2) low levels of community sanitation. Initial …

Clinical Implications of QRS Duration in Patients Hospitalized With Worsening Heart Failure and Reduced Left Ventricular Ejection Fraction

CONTEXT Hospitalization for heart failure is associated with high postdischarge mortality and morbidity. The predictive value of the QRS duration during admission for heart failure has not been well studied. OBJECTIVE To investigate the predictive value of the QRS duration in patients hospitalized for heart failure with reduced left ventricular ejection fraction (LVEF). DESIGN, SETTING, AND PARTICIPANTS Retrospective, post hoc analysis from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven, randomized, double-blind, placebo-controlled study in patients hospitalized for heart failure and having an LVEF of 40% or less. A total of 4133 patients were enrolled at 359 North American, South American, and European sites between October 7, 2003, and February 3, 2006. After excluding 1029 patients with a pacemaker, implantable cardioverter-defibrillator, or both at enrollment and 142 patients without a reported baseline QRS duration, 2962 patients were included in the analysis: 1641 had a normal QRS duration (< 120 ms) and 1321 had a prolonged QRS duration (> or = 120 ms). MAIN OUTCOME MEASURES Dual primary end points were all-cause mortality and the composite of cardiovascular death or hospitalization for heart failure. RESULTS During a median follow-up of 9.9 months, all-cause mortality was 18.7% for patients with a normal baseline QRS duration and 28.1% for patients with a prolonged baseline QRS duration (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.38-1.87). The composite of cardiovascular death or hospitalization for heart failure was 32.4% for patients with a baseline QRS duration less than 120 ms and 41.6% for patients with a baseline QRS duration of 120 ms or greater (HR, 1.40; 95% CI, 1.24-1.58). The increased risk associated with prolonged QRS duration was confirmed after adjusting for multiple variables for all-cause mortality (HR, 1.24; 95% CI, 1.02-1.50) and the composite of cardiovascular death or hospitalization for heart failure (HR, 1.28; 95% CI, 1.10-1.49). Only 105 patients (3.6%) who presented with a prolonged baseline QRS duration had a normal QRS duration on their last inpatient electrocardiogram. CONCLUSION A prolonged QRS duration appears common in patients with reduced LVEF who are hospitalized for heart failure and is an independent predictor of high postdischarge morbidity and mortality.

Changes in renal function during hospitalization and soon after discharge in patients admitted for worsening heart failure in the placebo group of the EVEREST trial

AIM To provide an in-depth clinical characterization and analysis of outcomes of the patients hospitalized for heart failure (HF) who subsequently develop worsening renal function (WRF) during hospitalization or soon after discharge. METHODS AND RESULTS Of the 4133 patients hospitalized with worsening HF and reduced left ventricular ejection fraction (LVEF) (≤40%) in the EVEREST trial, 2072 were randomized to tolvaptan, a selective vasopressin-2 receptor antagonist, and 2061 were randomized to placebo, both in addition to standard therapy. This analysis included the 2021 (98%) patients in the placebo group with a complete set of renal function parameters. Renal function parameters and clinical variables were measured prospectively during hospitalization and after discharge. Worsening renal function was defined as an increase in sCr ≥0.3 mg/dL during the in-hospital (randomization to discharge or Day 7) and post-discharge (discharge or Day 7 to 4 weeks post-discharge) periods. Blood pressure (BP), body weight (BW), natriuretic peptides (NPs), and congestion score were correlated with WRF. The prognostic value of baseline renal function at admission and WRF during hospitalization and post-discharge on long-term outcomes were assessed using a Cox proportional hazards model adjusted for other baseline covariates. At randomization, 53.2% of patients had moderately or severely reduced estimated glomerular filtration rate (eGFR) (<60.0 mL/min/1.73 m2). Worsening renal function was observed in 13.8% in-hospital and 11.9% post-discharge. Worsening renal function during hospitalization and post-discharge was associated with greater reductions in BP, BW, and NPs. Baseline renal dysfunction as well as in-hospital and post-discharge WRF were predictive of a composite endpoint of cardiovascular (CV) mortality/HF rehospitalization. CONCLUSION The prevalence of renal dysfunction is high in patients hospitalized for HF with reduced LVEF. Worsening renal function may occur not only during hospitalization, but also in the early post-discharge period. Since worsening renal function during hospitalization is associated with a significant decrease in signs and symptoms of congestion, body weight and natriuretic peptides, which are good prognostic indicators, worsening renal function during hospitalization as an endpoint in clinical trials should be re-evaluated.

Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.

ANALYSIS OF VARIATION IN PROSTATE-SPECIFIC ANTIGEN VALUES

This retrospective study analyzes variation in prostate-specific antigen (PSA) levels in 129 males who were not diagnosed with prostate cancer or other known malignancies. The extent to which the assay and the biologic variation contributed to the variation in PSA concentration was evaluated from analysis of slopes characterizing PSA concentration as a function of time. The mean coefficient of variation on observations was 58.0 percent. The estimated mean biologic coefficient of variation was 55.3 percent versus a mean assay coefficient of variation of 13.2 percent, indicating that the assay variation contributed negligibly to variation compared with the biologic variation. The concept that a PSA level which rises more than that attributable to assay variation indicates the need for invasive testing for prostate cancer is questionable. A decreasing PSA level was seen as often and of the same magnitude as an increasing level within a relatively narrow window of approximately one year. We are aware of no reason why this variability in PSA values would not be observed in patients with occult prostate cancer.

Safety, Tolerance, and Efficacy of Adenosine as an Additive to Blood Cardioplegia in Humans During Coronary Artery Bypass Surgery

Myocardial stunning after heart surgery is associated with increased morbidity and mortality in patients with severe multivessel disease and reduced myocardial function. The purpose of this study was to evaluate the safety, tolerance, and efficacy of adenosine as a cardioprotective agent when added to blood cardioplegia in patients undergoing coronary artery bypass surgery. Sixty-one patients were randomized to standard cold-blood cardioplegia, or cold-blood cardioplegia containing 1 of 5 adenosine doses (100 microM, 500 microM, 1 mM, 2 mM, and 2 mM with a preischemic infusion of 140 microg/kg/min of adenosine). Invasive and noninvasive measurements of ventricular performance and rhythm were obtained preoperatively, prebypass, and then at 1, 2, 4, 8, 16, and 24 hours postbypass. Use of inotropic agents and vasoactive drugs pastoperatively was recorded; blood samples were collected for measurement of nucleoside levels. High-dose adenosine treatment was associated with a 249-fold increase in the plasma adenosine concentration and a 69-fold increase in the combined levels of adenosine, inosine, and hypoxanthine (p <0.05). Increasing doses of the adenosine additive were also associated with lower requirements of dopamine (p = 0.003) and nitroglycerine (p = 0.001). The 24-hour average doses for dopamine and nitroglycerine in the placebo group were 28-fold and 2.6-fold greater than their respective high-dose adenosine treatment cohorts. Finally, the placebo- and 100 microM-adenosine group was associated with a lower ejection fraction when compared to patients receiving the intermediate dose or high-dose treatment. These findings are consistent with the hypothesis that adenosine is effective in attenuating myocardial stunning in humans.

Folic acid supplementation enhances repair of the adult central nervous system.

Folic acid supplementation has proved to be extremely effective in reducing the occurrence of neural tube defects (NTDs) and other congenital abnormalities in humans, suggesting that folic acid can modulate key mechanisms for growth and differentiation in the central nervous system (CNS). To prevent NTDs, however, supplemental folate must be provided early in gestation. This suggests that the ability of folic acid to activate growth and differentiation mechanisms may be confined to the early embryonic period. Here, we show that folic acid can enhance growth and repair mechanisms even in the adult CNS. Using lesion models of CNS injury, we found that intraperitoneal treatment of adult rats with folic acid significantly improves the regrowth of sensory spinal axons into a grafted segment of peripheral nerve in vivo. Regrowth of retinal ganglion cell (RGC) axons into a similar graft also was enhanced, although to a smaller extent than spinal axons. Furthermore, folic acid supplementation enhances neurological recovery from a spinal cord contusion injury, showing its potential clinical impact. The results show that the effects of folic acid supplementation on CNS growth processes are not restricted to the embryonic period, but can also be effective for enhancing growth, repair, and recovery in the injured adult CNS. Ann Neurol 2004;56:221–227