Richard E. Thompson

Underlying Causes and Long-Term Survival in Patients with Initially Unexplained Cardiomyopathy

BACKGROUND Previous studies of the prognosis of patients with heart failure due to cardiomyopathy categorized patients according to whether they had ischemic or nonischemic disease. The prognostic value of identifying more specific underlying causes of cardiomyopathy is unknown. METHODS We evaluated the outcomes of 1230 patients with cardiomyopathy. The patients were grouped into the following categories according to underlying cause: idiopathic cardiomyopathy (616 patients), peripartum cardiomyopathy (51); and cardiomyopathy due to myocarditis (111), ischemic heart disease (91), infiltrative myocardial disease (59), hypertension (49), human immunodeficiency virus (HIV) infection (45), connective-tissue disease (39), substance abuse (37), therapy with doxorubicin (15), and other causes (117). Cox proportional-hazards analysis was used to assess the association between the underlying cause of cardiomyopathy and survival. RESULTS During a mean follow-up of 4.4 years, 417 patients died and 57 underwent cardiac transplantation. As compared with the patients with idiopathic cardiomyopathy, the patients with peripartum cardiomyopathy had better survival (adjusted hazard ratio for death, 0.31; 95 percent confidence interval, 0.09 to 0.98), and survival was significantly worse among the patients with cardiomyopathy due to infiltrative myocardial disease (adjusted hazard ratio, 4.40; 95 percent confidence interval, 3.04 to 6.39), HIV infection (adjusted hazard ratio, 5.86; 95 percent confidence interval, 3.92 to 8.77), therapy with doxorubicin (adjusted hazard ratio, 3.46; 95 percent confidence interval, 1.67 to 7.18), and ischemic heart disease (adjusted hazard ratio, 1.52; 95 percent confidence interval, 1.07 to 2.17). CONCLUSIONS The underlying cause of heart failure has prognostic value in patients with unexplained cardiomyopathy. Patients with peripartum cardiomyopathy appear to have a better prognosis than those with other forms of cardiomyopathy. Patients with cardiomyopathy due to infiltrative myocardial diseases, HIV infection, or doxorubicin therapy have an especially poor prognosis.

The use of alternative therapies by patients with Parkinson’s disease

Objective: To determine the prevalence and spectrum of use of alternative therapy (AT) by patients with PD and to determine whether use of AT correlates with demographic, social, or disease-specific characteristics. Methods: The authors administered a structured questionnaire, by interview, regarding the use of AT to 201 patients with PD. Demographic, social, and disease-specific characteristics were recorded for all patients. Results: Eighty-one patients (40%) used at least one AT. Vitamins and herbs, massage, and acupuncture were most common. Users of AT were younger (p = 0.0021) and had a younger age at onset of PD (p = 0.0011) than nonusers of AT. There was no correlation with sex or race. Patients who used AT had a higher income (p = 0.038) and education level (p = 0.006) than did nonusers of AT. There was no association between the use of AT and the Hoehn and Yahr score, duration of PD, duration of treatment with levodopa, surgery for PD, and presence of fluctuations. Conclusions: The use of AT is common in patients with PD. The age at onset of PD is the most potent predictor of AT use. There is no association between the use of AT and the severity of PD. The widespread and largely unexamined use of AT for PD requires more attention. This should be directed at testing their safety and efficacy and improving physician and patient knowledge about the potential benefits, costs, limitations, and risks of AT.

Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease.

BACKGROUND & AIMS Genetic polymorphism in thiopurine methyltransferase (TPMT) activity may influence clinical responsiveness to azathioprine (AZA) therapy. Our aim was to determine if the measurement of erythrocyte TPMT enzyme activity could be used to optimize clinical responsiveness to AZA therapy in patients with inflammatory bowel disease (IBD). METHODS A total of 142 consecutive patients were studied. Forty-one patients (32 with Crohns disease [CD] and 9 with ulcerative colitis [UC]) were enrolled in a 4-month prospective nonrandomized study with AZA, and 101 (65 with CD and 36 with UC) were on either maintenance AZA or 6-mercaptopurine (6-MP). Erythrocyte TPMT activity and AZA metabolite levels were measured blinded to the clinical response. RESULTS The response rate after 4 months of continuous AZA therapy was 69% (9/13) in those patients with below-average (</=12 U/mL blood) TPMT activity, and 29% (8/27) in patients with enzyme activity levels >12 U/mL blood (P < 0.001). Patients with TPMT activity </=12 achieved a mean (SEM) erythrocyte 6-thioguanine ribonucleotide (6-TGn) level of 394 +/- 29 pmol/8 x 10(8) red blood cells (RBCs); higher than in patients with TPMT activity >12 (218 +/- 28), despite similar mean (1.6 mg/kg/day) dosages of AZA (P < 0.001). By multivariate logistic regression analysis, patients with a TPMT level <15.3 U/mL blood were 6.2 times more likely to respond to AZA therapy. A 6-TGn level of >292 pmol/8 x 10(8) RBCs was associated with a positive predictive value of clinical response of 85.7%. CONCLUSIONS Patients with higher than average TPMT activity (>12) may remain refractory to conventional dosages of AZA, and may require high (>292) 6-TGn levels. Prospective, randomized, controlled trials are needed to determine whether prior TPMT phenotype testing can be used to adjust the dose of AZA effectively to improve clinical response time and rate.

Obesity Impacts Access to Kidney Transplantation

Current billing practices and mandates to report surgical outcomes are disincentives to surgical treatment of obese patients, who are at increased risk for longer hospital stays and higher complication rates. The objective of this study was to quantify the independent association between body mass index (BMI) and waiting time for kidney transplantation to identify potential provider bias against surgical treatment of the obese. A secondary data analysis was performed of a prospective cohort of 132,353 patients who were registered for kidney transplantation in the United States between 1995 and 2006. Among all patients awaiting kidney transplantation, the likelihood of receiving a transplant decreased with increasing degree of obesity, categorized by ranges of BMI (adjusted hazard ratios 0.96 for overweight, 0.93 for obese, 0.72 for severely obese, and 0.56 for morbidly obese, compared with a reference group of patients with normal BMI). Similarly, the likelihood of being bypassed when an organ became available increased in a graded manner with category of obesity (adjusted incidence rate ratio 1.02 for overweight, 1.05 for obese, 1.11 for severely obese, and 1.22 for morbidly obese). Although matching an available organ with an appropriate recipient requires clinical judgment, which could not be fully captured in this study, the observed differences are dramatic and warrant further studies to understand this effect better and to design a system that is less susceptible to unintended bias.

Spontaneous bacterial peritonitis - In-hospital mortality, predictors of survival, and health care costs from 1988 to 1998

Spontaneous bacterial peritonitis—in-hospital mortality, predictors of survival, and health care costs from 1988 to 1998

Improving the management of family psychosocial problems at low-income children's well-child care visits: the WE CARE Project.

OBJECTIVE. Our goal was to evaluate the feasibility and impact of an intervention on the management of family psychosocial topics at well-child care visits at a medical home for low-income children. PATIENTS AND METHODS. A randomized, controlled trial of a 10-item self-report psychosocial screening instrument was conducted at an urban hospital-based pediatric clinic. Pediatric residents and parents were randomly assigned to either the intervention or control group. During a 12-week period, parents of children aged 2 months to 10 years presenting for a well-child care visit were enrolled. The intervention components included provider training, administration of the family psychosocial screening tool to parents before the visit, and provider access to a resource book that contained community resources. Parent outcomes were obtained from postvisit and 1-month interviews, and from medical chart review. Provider outcomes were obtained from a self-administered questionnaire collected after the study. RESULTS. Two hundred parents and 45 residents were enrolled. Compared with the control group, parents in the intervention group discussed a significantly greater number of family psychosocial topics (2.9 vs 1.8) with their resident provider and had fewer unmet desires for discussion (0.46 vs 1.41). More parents in the intervention group received at least 1 referral (51.0% vs 11.6%), most often for employment (21.9%), graduate equivalent degree programs (15.3%), and smoking-cessation classes (14.6%). After controlling for child age, Medicaid status, race, educational status, and food stamps, intervention parents at 1 month had greater odds of having contacted a community resource. The majority of residents in the intervention group reported that the survey instrument did not slow the visit; 54% reported that it added <2 minutes to the visit. CONCLUSIONS. Brief family psychosocial screening is feasible in pediatric practice. Screening and provider training may lead to greater discussion of topics and contact of community family support resources by parents.

Abnormalities of cholesterol metabolism in autism spectrum disorders

Although Smith‐Lemli‐Opitz Syndrome (SLOS), a genetic condition of impaired cholesterol biosynthesis, is associated with autism [Tierney et al., 2001 ; Am J Med Genet 98:191‐200.], the incidence of SLOS and other sterol disorders among individuals with autism spectrum disorders (ASD) is unknown. This study investigated (1) the incidence of biochemically diagnosed SLOS in blood samples from a cohort of subjects with ASD from families in which more than one individual had ASD and (2) the type and incidence of other sterol disorders in the same group. Using gas chromatography/mass spectrometry, cholesterol, and its precursor sterols were quantified in 100 samples from subjects with ASD obtained from the Autism Genetic Resource Exchange (AGRE) specimen repository. Although no sample had sterol levels consistent with SLOS, 19 samples had total cholesterol levels lower than 100 mg/dl, which is below the 5th centile for children over age 2 years. These findings suggest that, in addition to SLOS, there may be other disorders of sterol metabolism or homeostasis associated with ASD.

Autism Spectrum Disorder in Fragile X Syndrome: A Longitudinal Evaluation

The present study extends our previous work on characterizing the autistic behavior profile of boys with fragile X syndrome (FXS) who meet Diagnostic and Statistical Manual for Mental Disorders, 4th Edition criteria for autism spectrum disorder (ASD) into a longitudinal evaluation of ASD in FXS (FXS + ASD). Specifically, we aimed to determine the stability of the diagnosis and profile of ASD in FXS over time. Through regression models, we also evaluated which autistic and social behaviors and skills were correlates of diagnosis and autistic behavior severity (i.e., Autism Diagnostic Interview‐Revised total scores). Finally, we assessed the evolution of cognitive parameters in FXS + ASD. A population of 56 boys (30–88 months at baseline) with FXS was evaluated using measures of autistic, social, and cognitive behaviors and skills at three yearly evaluations. We found that the diagnosis of ASD in FXS was relatively stable over time. Further emphasizing this stability, we found a set of behaviors and skills, particularly those related to peer relationships and adaptive socialization, that differentiated FXS + ASD from the rest of the FXS cohort (FXS + None) and contributed to autistic severity at all time points. Nevertheless, the general improvement in autistic behavior observed in FXS + ASD coupled with the concurrent worsening in FXS + None resulted in less differentiation between the groups over time. Surprisingly, FXS + ASD IQ scores were stable while FXS + None non‐verbal IQ scores declined. Our findings indicate that ASD is a distinctive subphenotype in FXS characterized by deficits in complex social interaction, with similarities to ASD in the general population.

Distinct subtypes of myelitis in systemic lupus erythematosus

OBJECTIVE Myelitis causes pain, weakness, and sphincteric deficits, and is 1,000-fold more prevalent in patients with systemic lupus erythematosus (SLE) than in the general population. For the last century, descriptions of SLE myelitis have been primarily limited to case reports. In contrast, larger-scale cohort studies have revealed that myelitis occurring in the idiopathic demyelinating diseases (i.e., multiple sclerosis versus neuromyelitis optica) represents distinct syndromes. This study was undertaken to determine whether SLE myelitis similarly encapsulates distinct syndromes. METHODS We analyzed a cohort of 22 patients with SLE and myelitis. Patients were assessed for neurologic variables related to myelitis and for clinical and serologic features of SLE. Magnetic resonance images of the spine, cerebrospinal fluid profiles, and autoantibody profiles were obtained. RESULTS Eleven patients presented with signs of gray matter dysfunction (i.e., flaccidity and hyporeflexia), whereas 11 patients presented with signs of white matter dysfunction (i.e., spasticity and hyperreflexia). Patients with gray matter dysfunction were more likely to have irreversible paraplegia (P < 0.01), despite presenting with a monophasic versus polyphasic course (P = 0.01), higher levels of SLE activity (mean SLE Disease Activity Index 9.8 versus 2.0; P = 0.01), and a cerebrospinal fluid profile indistinguishable from bacterial meningitis. Prior to irreversible paraplegia, these patients presented with prodromes of fever and urinary retention, but were misdiagnosed by physicians of different specialties as having urinary tract infections. Patients with white matter dysfunction were more likely to meet criteria for neuromyelitis optica (P = 0.04) and were also more likely to have antiphospholipid antibodies (lupus anticoagulant) (P = 0.01). CONCLUSION Our findings indicate that SLE myelitis encapsulates 2 distinct and previously unrecognized syndromes that can be distinguished clinically by gray matter versus white matter findings. Recognition of fever and urinary retention as prodromes of irreversible paraplegia may allow earlier diagnosis and treatment in SLE patients presenting with gray matter findings.

Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction

We have created a clinical molecular diagnostic assay to test for microsatellite instability (MSI) at multiple loci simultaneously in paraffin-embedded surgical pathology colon resection specimens. This fluorescent multiplex polymerase chain reaction (PCR) assay analyzes the five primary microsatellite loci recommended at the 1997 National Cancer Institute-sponsored conference on MSI for the identification of MSI or replication errors in colorectal cancer: Bat-25, Bat-26, D2S123, D5S346, and D17S250. Amplicon detection is accomplished by capillary electrophoresis using the ABI 310 Genetic Analyzer. Assay validation compared 18 specimens previously assessed by radioactive PCR and polyacrylamide gel electrophoresis detection to results generated by the reported assay. Germline and tumor DNA samples were amplified in separate multiplex PCR reactions, sized in separate capillary electrophoresis runs, and compared directly to identify novel length alleles in tumor tissue. A concordance of 100% between the two modalities was achieved. The multiplex assay routinely detected a subpopulation of 10% tumor alleles in the presence of 90% normal alleles. A novel statistical model was generated that corroborates the validity of using results generated by analysis of five independent microsatellites to achieve a single overall MSI diagnosis. The assay presented is superior to standard radioactive monoplex PCR, polyacrylamide gel electrophoretic analysis, primarily due to the multiplex PCR format.