Alan Bostrom

Design, power, and interpretation of studies in the standard murine model of ALS

Identification of SOD1 as the mutated protein in a significant subset of familial amyotrophic lateral sclerosis (FALS) cases has led to the generation of transgenic rodent models of autosomal dominant SOD1 FALS. Mice carrying 23 copies of the human SOD1G93A transgene are considered the standard model for FALS and ALS therapeutic studies. To date, there have been at least 50 publications describing therapeutic agents that extend the lifespan of this mouse. However, no therapeutic agent besides riluzole has shown corresponding clinical efficacy. We used computer modeling and statistical analysis of 5429 SOD1G93A mice from our efficacy studies to quantify the impact of several critical confounding biological variables that must be appreciated and should be controlled for when designing and interpreting efficacy studies. Having identified the most critical of these biological variables, we subsequently instituted parameters for optimal study design in the SOD1G93A mouse model. We retested several compounds reported in major animal studies (minocycline, creatine, celecoxib, sodium phenylbutyrate, ceftriaxone, WHI‐P131, thalidomide, and riluzole) using this optimal study design and found no survival benefit in the SOD1G93A mouse for any compounds (including riluzole) administered by their previously reported routes and doses. The presence of these uncontrolled confounding variables in the screening system, and the failure of these several drugs to demonstrate efficacy in adequately designed and powered repeat studies, leads us to conclude that the majority of published effects are most likely measurements of noise in the distribution of survival means as opposed to actual drug effect. We recommend a minimum study design for this mouse model to best address and manage this inherent noise and to facilitate more significant and reproducible results among all laboratories employing the SOD1G93A mouse.

Comparative outcomes for individual cognitive-behavior therapy, supportive-expressive group psychotherapy, and sertraline for the treatment of Depression in multiple sclerosis

This study compared the efficacy of 3 16-week treatments for depression in 63 patients with multiple sclerosis (MS) and major depressive disorder (MDD): individual cognitive-behavioral therapy (CBT), supportive-expressive group therapy (SEG). and the antidepressant sertraline. Significant reductions were seen from pre- to posttreatment in all measures of depression. Intent-to-treat and completers analyses using the Beck Depression Inventory (BDI; A. T. Beck, C. H. Ward. M. Medelson. J. Mock, & J. Erbaugh, 1961) and MDD diagnosis found that CBT and sertraline were more effective than SEG at reducing depression. These results were largely supported by the BDI-18, which eliminates BDI items confounded with MS. However, the Hamilton Rating Scale for Depression (M. Hamilton, 1960) did not show consistent differences between treatments. Reasons for this inconsistency are discussed. These findings suggest that CBT or sertraline is more likely to be effective in treating MDD in MS compared with supportive group treatments.

Fresh Blood and Aged Stored Blood Are Equally Efficacious in Immediately Reversing Anemia-induced Brain Oxygenation Deficits in Humans

Background:Erythrocytes are transfused to treat or prevent imminent inadequate tissue oxygenation. 2,3-diphosphoglycerate concentration decreases and oxygen affinity of hemoglobin increases (P50 decreases) with blood storage, leading some to propose that erythrocytes stored for 14 or more days do not release sufficient oxygen to make their transfusion efficacious. The authors tested the hypothesis that erythrocytes stored for 3 weeks are as effective in supplying oxygen to human tissues as are erythrocytes stored for less than 5 h. Methods:Nine healthy volunteers donated 2 units of blood more than 3 weeks before they were tested with a standard, computerized neuropsychological test (digit–symbol substitution test [DSST]) on 2 days, 1 week apart, before and after acute isovolemic reduction of their hemoglobin concentration to 7.4 and 5.5 g/dl. Volunteers randomly received autologous erythrocytes stored for either less than 5 h (“fresh”) or 3 weeks (“stored”) to return their hemoglobin concentration to 7.5 g/dl (double blinded). Erythrocytes of the alternate storage duration were transfused on the second experimental day. The DSST was repeated after transfusion. Results:Acute anemia slowed DSST performance equivalently in both groups. Transfusion of stored erythrocytes with decreased P50 reversed the altered DSST (P < 0.001) to a time that did not differ from that at 7.4 g/dl hemoglobin during production of acute anemia (P = 0.88). The erythrocyte transfusion–induced DSST improvement did not differ between groups (P = 0.96). Conclusion:Erythrocytes stored for 3 weeks are as efficacious as are erythrocytes stored for 3.5 h in reversing the neurocognitive deficit of acute anemia. Requiring fresh rather than stored erythrocytes for augmentation of oxygen delivery does not seem warranted.

Risks of a range of alcohol intake on hepatitis C-related fibrosis.

Heavy alcohol use contributes to liver disease in the setting of chronic hepatitis C virus (HCV) infection. Whether this is true for light or moderate alcohol use has not been demonstrated. Light alcohol use has survival benefits at a population level and is practiced by most patients with chronic HCV infection. In this study, 800 patients with HCV undergoing liver biopsy at three sites had detailed alcohol histories recorded and the relationship between alcohol and hepatic fibrosis was assessed. On univariate analysis, heavy alcohol use (>50 g/day) was associated with an increase in mean fibrosis (P = .01). Such an association could not be demonstrated for light and moderate alcohol use. For each category of alcohol intake (none, light, moderate, and heavy), a spectrum of fibrosis was observed. On multivariate analysis, age, serum alanine aminotransferase (ALT), and histological inflammation were the independent predictors of fibrosis (P = <.0001, .0003, <.0001, respectively). In conclusion, heavy alcohol use exerts a greater effect on fibrosis than light or moderate use. There is a range of fibrosis at each level of alcohol use. Age, serum ALT, and inflammation are independently associated with fibrosis in multivariate analysis, highlighting the fact that variables other than alcohol intake predominate in the production of hepatic fibrosis. (HEPATOLOGY 2004;39:826–834.)

Smoking Prevalence in Addiction Treatment: A Review

INTRODUCTION This review explores whether smoking prevalence in addiction treatment samples exceeds that shown in epidemiological data for persons with alcohol or other drug use disorders and whether smoking may have decreased over time in the addiction treatment population as it has done in the general population. METHODS English language papers published between 1987 and 2009 were searched electronically. Forty papers reporting smoking prevalence for addiction treatment samples in the United States were identified, and key predictor variables were abstracted. Random logistic models were used to assess relationships between each individual predictor (year, treatment modality, primary drug treated, government status, and public/private funding status) and smoking prevalence. RESULTS The lowest smoking prevalence aggregated for studies reported in any single year was 65%, well above epidemiological estimates reported among those with alcohol use and drug use disorders. The odds of smoking were higher in methadone maintenance programs (odds ratio [OR] = 2.25, CI = 1.08, 4.68) as compared with outpatient programs. No other variables in the model were significant. Reanalysis omitting recent studies that may represent outliers or confounding with type of treatment showed a small but significant decrease in smoking over time (OR = 0.9891, CI = 0.9888, 0.9893). CONCLUSIONS The very high smoking rates reported in addiction treatment samples warrant significant, organized, and systemic response from addiction treatment systems, from agencies that fund and regulate those systems, and from agencies concerned with tobacco control.

Presentation and Disease Course in Early- Compared to Later-Onset Pediatric Crohn’s Disease

BACKGROUND:The relationship between the age at diagnosis and disease course is poorly defined in children with Crohns disease (CD). We examined the presentation and course of disease in patients 0–5 compared to 6–17 yr of age at diagnosis.METHODS:We analyzed uniform data from 989 consecutive CD patients collected between January 2000 and November 2003, and stored in the Pediatric IBD Consortium Registry. The statistical tests account for the length of follow-up of each patient.RESULTS:In total, 98 patients (9.9%) were of 0–5 yr of age at diagnosis. The mean follow-up time was 5.6 ± 5.0 yr in the younger group and 3.3 ± 2.8 yr in the older group (P < 0.001). Race/ethnicity differed by the age group (P= 0.015); a larger proportion of the younger group was Asian/Pacific Islander or Hispanic, and a larger proportion of the older group was African American. The initial classification as ulcerative colitis or indeterminate colitis was more common among the 0–5 yr of age group (P < 0.001). The 6–17 yr of age patients presented with more abdominal pain (P < 0.001), weight loss (P= 0.001), or fever (P= 0.07), while the 0–5 yr of age patients presented with more rectal bleeding (P= 0.008). The 6–17 yr of age patients were more likely to be treated with antibiotics (P < 0.001), 6-mercaptopurine/azathioprine (P < 0.001), infliximab (P= 0.001), or corticosteroids (P= 0.0006). The 6–17 yr of age patients had a higher cumulative incidence of treatment with 5-aminosalicylates (P= 0.009) or methotrexate (P= 0.04). The risk for developing an abscess (P= 0.001), a fistula (P= 0.02), a stricture (P= 0.05), or a perianal fissure (P= 0.06) was greater in the 6–17 yr of age patients.CONCLUSIONS:The 6–17 yr of age patients with CD appear to have a more complicated disease course compared to 0–5 yr of age children. The 0–5 yr of age group may represent a unique disease phenotype and benefit from different approaches to management. Long-term prospective studies are required to validate these findings.

Correlation between intraocular pressure, central corneal thickness, stage of glaucoma, and demographic patient data: prospective analysis of biophysical parameters in tertiary glaucoma practice populations.

PurposeTo determine the correlation of central corneal thickness (CCT) to Goldmann applanation tonometry (GAT) and dynamic contour tonometry (DCT, PASCAL®), and to glaucoma stage as assessed by cup-to-disc ratio (CDR). DesignProspective, cross-sectional tricenter observation study. Patients and MethodsFrom three glaucoma specialty practices a sample of 406 independent eyes was included. After ultrasound pachymetry, intraocular pressure was measured using PASCAL® and Goldmann applanation tonometry and cup-to-disc ration was reassessed. Demographic data were included in the multivariate analysis. ResultsMean corneal thickness was 540 μm. African Americans and normal-tension glaucoma patients showed the lowest values (518 μm and 522 μm, respectively). These values were significantly thinner than the central corneal thickness of Caucasians (549 μm) and ocular hypertensives (564 μm). Intraocular pressure assessed by Goldmann applanation tonometry shows a significant correlation with central corneal thickness (r2=0.068, P<0.001), whereas PASCAL® is not significantly associated with central corneal thickness (r2<0.001, P=0.997). Increased IOP is significantly correlated with large ocular pulse amplitudes (r2=0.13, P<0.001), which is predominantly seen in ocular hypertensives. A significant negative correlation was detected between cup-to-disc ratio and central corneal thickness (r2=0.102, P<0.001). ConclusionGlaucoma patients with thin central corneal thickness are more likely to be found at an advanced stage of the disease and among those with normal-tension glaucoma and black African ancestry. Underestimation of intraocular pressure by Goldmann applanation tonometry could be one causative factor.

Early predictors of severe lower gastrointestinal bleeding and adverse outcomes: a prospective study.

BACKGROUND & AIMS Unlike in upper tract bleeding, prognostic factors for ongoing or recurrent bleeding from the lower gastrointestinal tract have not been well-defined. The aim of this study was to identify risk factors for severe lower gastrointestinal bleeding and for significant adverse outcomes. METHODS All patients seeking attention at a university emergency department for gastrointestinal bleeding were prospectively identified during a 3-year period. Ninety-four of 448 (21%) admitted patients had lower gastrointestinal bleeding. Clinical predictors available in the first hour of evaluation were recorded. The primary outcome, severe lower gastrointestinal bleeding, was defined as gross blood per rectum after leaving the emergency department associated with either abnormal vital signs (systolic blood pressure < 100 mm Hg or heart rate > 100/min) or more than a 2-unit blood transfusion during the hospitalization. Significant adverse outcomes, including death, were tabulated. RESULTS Thirty-seven patients (39%) had severe lower gastrointestinal bleeding. Independent risk factors for severe lower gastrointestinal bleeding were initial hematocrit </=35% (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.2-16.7); presence of abnormal vital signs (systolic blood pressure < 100 mm Hg or heart rate > 100/min) 1 hour after initial medical evaluation (OR, 4.3; 95% CI, 1.4-12.5); and gross blood on initial rectal examination (OR, 3.9; 95% CI, 1.2-13.2). Nineteen patients (20%) experienced a significant adverse outcome, including 3 deaths. The main independent predictor of adverse outcomes was severe lower gastrointestinal bleeding (OR, 5.3; 95% CI, 1.7-16.5). CONCLUSIONS Risk factors are available in the first hour of evaluation in the emergency department to identify patients at risk for severe lower gastrointestinal bleeding. Severe lower gastrointestinal bleeding is a significant risk factor for global adverse outcomes.

Gender Differences in Presentation and Course of Disease in Pediatric Patients With Crohn Disease

OBJECTIVE. The objective of this study was to determine gender differences in pediatric patients with Crohn disease. METHODS. We conducted a retrospective cohort study of 989 consecutive pediatric patients (566 boys, 423 girls) who had Crohn disease (aged 0 to 17 years at diagnosis) by using the Pediatric IBD Consortium Registry. Uniform data were analyzed to compare the presentation and course of disease according to gender. RESULTS. Median follow-up time was 2.8 years. Mean ± SD age at diagnosis of inflammatory bowel disease (11.5 ± 3.8 years) did not differ by gender. Compared with boys, girls had a higher prevalence of mouth sores at symptom onset and a higher prevalence of hypoalbuminemia at the time of diagnosis. Location of disease did not differ by gender. A higher proportion of girls had abnormal anti–outer membrane porin of Escherichia coli levels compared with boys. Girls were at increased risk for erythema nodosum/pyoderma gangrenosum and decreased risk for growth failure compared with boys. CONCLUSIONS. Girls appear to have an overall more severe course of disease; however, boys are at increased risk for developing growth failure. Disease course and the impact of disease severity on growth according to gender in pediatric Crohn disease require prospective study.

Acute isovolemic anemia impairs central processing as determined by P300 latency

OBJECTIVE Acute anemia slows the responses to clinical tests of cognitive function. We tested the hypothesis that these slowed responses during acute severe isovolemic anemia in healthy unmedicated humans result from impaired central processing. METHODS A blinded operator measured the latency of the P300 peak in nine healthy volunteers at each volunteers baseline hemoglobin concentration (Hb), and again after isovolemic hemodilution to Hb 5 g/dL. At both Hb concentrations, the P300 latency was measured twice: with the blinded subject breathing air or 100% oxygen, administered in random order. RESULTS Anemia increased P300 latency significantly from baseline values (P < 0.05). Breathing oxygen during induced anemia resulted in a P300 latency not different from that at baseline when breathing air (P = 0.5) or oxygen (P = 0.8). CONCLUSIONS Impaired central processing is, at least in part, responsible for the slowed responses and deficits of cognitive function that occur during acute isovolemic anemia at Hb 5-6 g/dL. SIGNIFICANCE The P300 latency appears to be a potential measure of inadequate central oxygenation. In healthy young adults with acute anemia, erythrocytes should be transfused to produce Hb>5-6 g/dL. As a temporizing measure, administration of oxygen can reverse the cognitive deficits and impaired central processing associated with acute anemia.