A novel mutation in BAP/SIL1 gene causes Marinesco-Sjögren syndrome in an extended pedigree.
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Adult↗
Biomedical subjects
M A Cleves
Publications and source records attributed to M A Cleves.
Congenital heart defects and genetic variants in the methylenetetrahydroflate reductase gene.
BACKGROUND: Most non-syndromic congenital heart defects (CHD) are caused by a complex interaction between maternal lifestyle factors, environmental exposures, and maternal and fetal genetic variants. Maternal periconceptional intake of folic acid containing vitamin supplements is reported to decrease the risk of CHD. The 677C-->T and 1298A-->C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene decrease enzyme activity. OBJECTIVE: To examine the relation between CHD and maternal and fetal MTHFR polymorphisms. METHODS: 375 nuclear families were studied. The transmission/disequilibrium test was used to test for transmission distortion in complete triads. A log-linear approach was used to test for associations between CHD and maternal and offspring polymorphisms, and to estimate independently the contributions of maternal and fetal variants to relative risks. Haplotype frequencies were estimated and a haplotype transmission disequilibrium test carried out. RESULTS: The 1298C allele was transmitted less often than expected (p = 0.0013). There was no distortion in the transmission of the 677T allele, neither was there evidence of a parent of origin effect in the transmission of either of the single nucleotide polymorphisms. The 677C-1298C haplotype was also transmitted less often than expected (p = 0.0020). The relative risk associated with inheriting one copy of the 1298C allele was 0.64 (95% confidence interval, 0.48 to 0.87) and the that associated with inheriting two copies of the 1298C allele, 0.38 (0.21 to 0.70). CONCLUSIONS: The apparent protective effect of the MTHFR 1298C allele against CHD could have several explanations and further study is needed.
Alleles↗
Collaborative strategies for unraveling the complexity of birth defects.
This article summarizes a presentation by one of the authors (CAH) to the Fifth Annual Meeting of the Diabetes in Pregnancy Study Group of North America. Dr Hobbs, MD, PhD, the Director of the Arkansas Center for Birth Defects Research and Prevention, presented an overview of the collaborative strategies developed for investigating the etiology of birth defects. A multidisciplinary group of scientists and clinicians explores current hypotheses in diabetic embryopathy, drawing upon expertise in experimental biology, genetic epidemiology, genomics, metabolomics and translational research. The prevalence rate of birth defects among infants of diabetic mothers is as high as 11%, despite the knowledge that maternal metabolic control is strongly correlated with the risk of malformations. Specifically, caudal dysgenesis, renal anomalies, heart and neural tube defects and situs abnormalities occur more often among infants of diabetic women than non-diabetic women. Researchers are also working to discover the underlying mechanisms that make some women with diabetes more susceptible than others to having infants with birth defects.
Animals↗
Polymorphisms near a chromosome 6q QTL area are associated with modulation of fetal hemoglobin levels in sickle cell anemia.
In patients with sickle cell anemia, fetal hemoglobin (HbF) concentrations vary by 2 orders of magnitude. This variance may be a result of heterogeneity in gene regulatory elements; accordingly, we searched for single nucleotide polymorphisms (SNPs) that might identify this variation. More than 180 SNPs were studied in 38 genes in 280 sickle cell anemia patients. The strongest association with HbF was found with SNPs near a QTL previously localized on chromosome 6q22.3-q23.2. Initially, two SNPs were identified in intergenic portions of this QTL and were associated with about a 20% difference in percent HbF. Subsequently, we genotyped 44 additional SNPs in the genomic region between 136.1 Mb and 137.5 Mb on chromosome 6q. Twelve SNPs, associated with a 20%-30% difference in HbF concentrations, were located in the introns of four genes, PDE7B, MAP7, MAP3K5 and PEX7. In K562 cells, the p38-MAPK pathway has been associated with the activation of gamma-globin gene expression by histone deacetylase inhibitors. Haplotypes C-T-T-T in MAP7 and T-C-C in PEX7 were significantly associated with increases in concentration of HbF, both showing strong dominance. Genetic elements abutting the 6q22.3-q23.2 QTL, may harbor trans-acting elements that help modulate baseline HbF level in sickle cell anemia.
Black or African American↗
Long-term followup of treatment for Peyronie's disease: modeling the penis over an inflatable penile prosthesis.
PURPOSE: We originally reported inflatable penile implants used to treat impotence in patients with Peyronie's disease in 1993. We now present a historical prospective study of 104 patients in whom the modeling procedure was used to correct Peyronie's curvature after implantation with the Mentor Alpha 1dagger and AMS 700CXdouble dagger penile prostheses. We compared revision-free survival experience of these implants with 905 similar implants in men with nonPeyronie's disease. MATERIALS AND METHODS: The reasons for revision were classified as mechanical failure, patient dissatisfaction, infection and medical causes, including reoperation for straightening. Overall and cause specific revision-free survival in the 2 study cohorts was compared. Maximum followup was more than 12 years and average followup was more than 5. RESULTS: No significant difference in device survival was observed in the 2 study cohorts in 5 years. Similarly each prosthesis provided the same permanent straightening without the need for revision. In Peyronie's disease cases mechanical survival of the Mentor Alpha 1 was superior to that of the AMS 700CX (p = 0.0270). There was no significant difference in mechanical reliability of the devices in nonPeyronie's disease cases. CONCLUSIONS: Implantation and modeling appear to provide permanent straightening without an increase in revisions. In the nonmodeled group there was no significant difference in mechanical reliability of the AMS 700CX or Mentor Alpha 1. In modeled cases the Mentor Alpha 1 appeared less likely to fail mechanically than the AMS 700CX when followed more than 5 years. Based on this single series modeling may predispose the AMS 700CX to earlier mechanical failure.
Adult↗
Measles vaccine immunogenicity and antibody persistence in 12 vs 15-month old infants.
HYPOTHESIS: Maternal measles immunity in the United States today is primarily vaccine induced, with corresponding lower antibody titers in infants, as compared to infants born in an earlier era to mothers with naturally acquired measles immunity. We hypothesized that, due to lower titer of passively transferred maternal measles antibody, administration of measles vaccine at 12 months of age would result in seroconversion and antibody persistence comparable to vaccination at 15 months of age. POPULATION: Children at both an urban hospital and a suburban clinic. METHODS: Informed consent was obtained from mothers for the infants to receive M-M-R(R)II vaccine at either 12 or 15 months and to have serum samples obtained before vaccination and 4 weeks post-vaccination (PV). Between 9 and 39 months PV, a third serum sample was obtained from 28% of seroconverters. A diary of adverse experiences was kept for 3 weeks PV. Sera were assayed by a microneutralization assay (NT) and an enzyme immunoassay (EIA) for measles antibody. RESULTS: Both age groups tolerated vaccination well with minor and transient side effects. Forty-four of 47 (94%) 12-month-old infants seroconverted by NT, compared to 45 of 46 (98%) 15-month-olds (p=NS). There was no statistically significant decline in median NT titers or EIA titers in nineteen 12-month-olds and thirteen 15-month olds followed for 9-39 months PV. CONCLUSION: This study showed comparable serologic responses in 12- vs 15-month-old infants born to measles vaccine-immune mothers; however, the sample size was too small to have adequate power and further study is indicated. Titers of antibody were constant in both the 12-month-old and the 15-month-old infants, over a 9-39 month period, suggesting that waning immunity over this period of time is not a problem in either age group.
Age Factors↗
Association of Alzheimer's disease and smoking: the case for sibling controls.
OBJECTIVES: To study the association between cigarette smoking and Alzheimer's Disease (AD). DESIGN: Intrafamily case-control, with sibling controls and a variable number of controls per case. SETTING: AD cases were identified through the Research Registry of the University Hospitals of the Cleveland/Case Western Reserve University Alzheimer Center. PARTICIPANTS: Study subjects were 86 probable AD cases (index cases) and all of their full siblings, alive or dead, aged > or = 50 years, a total of 238 subjects. MEASUREMENTS: Exposure for each individual was ascertained with a questionnaire answered by several informants. Cognitive status of siblings of the AD cases (impaired or intact) was ascertained by telephone using validated instruments. Diagnosis of dementia in cognitively impaired siblings of index cases was not attempted. RESULTS: Chi-square analysis tested for departure from a random distribution of disease across smokers and nonsmokers within families. No significant departure was found utilizing all families (P > .40) nor utilizing those families where only the index case was affected (P > .90). Conditional logistic regression evaluated the association within families, controlling for age, sex, and education. Analyses both included and excluded secondary cases of cognitive impairment. No association was found between smoking and disease (OR = 1.26; 95% confidence interval, 0.66-2.42, and OR = 1.42; 95% confidence interval, 0.69-2.89, respectively). CONCLUSIONS: No significant association was found between smoking and cognitive status. Further, analyses based on the comparison of persons with AD with their unaffected siblings also suggest that smoking does not decrease the risk of AD.
Aged↗
Comparison of mechanical reliability of original and enhanced Mentor Alpha I penile prosthesis.
PURPOSE: We report the results of a prospective study of 1,381 Mentor Alpha I penile prostheses implanted to treat impotence, and compare original and enhanced penile prosthesis mechanical reliability. MATERIALS AND METHODS: The study consisted of 410 original models manufactured before November 1992 and 971 enhanced models manufactured since December 1992. Implants were further stratified as first time (virgin) or replacements of a previous implant. Mechanical failure-free survival rates for the original prosthetic and enhanced models were compared. RESULTS: The 5-year survival rate increased from 75.3% for the original to 92.6% for the enhanced model overall (log rank p<0.0001), and from 75.3 to 93.6%, respectively, for the virgin implants only (log rank p<0.0001). The estimated failure rate of approximately 5.6% for the original model was fairly consistent during followup, while the significantly lower failure rate of 1.3% for the enhanced model was not. The failure rate of the enhanced model implants was about 0.8% per year during the first 3.5 years and increased to approximately 3.1% per year thereafter. CONCLUSIONS: Our results strongly support the premise that mechanical reliability is superior with the enhanced compared to the original model.
Adult↗
Quantifying risk of penile prosthesis infection with elevated glycosylated hemoglobin.
PURPOSE: Elevation of glycosylated hemoglobin above levels of 11.5 mg.% has been considered a contraindication to penile prosthesis implantation in diabetic patients. We determine the predictive value of glycosylated hemoglobin A1C in penile prosthesis infections in diabetic and nondiabetic patients to confirm or deny this prevalent opinion. MATERIALS AND METHODS: We conducted a 2-year prospective study of 389 patients, including 114 diabetics, who underwent 3-piece penile prosthesis implantation. All patients had similar preoperative preparation without regard to diabetic status, control or glycosylated hemoglobin A1C level. Risk of infection was statistically analyzed for diabetics versus nondiabetics, glycosylated hemoglobin A1C values above and below 11.5 mg.%, insulin dependent versus oral medication diabetics, and fasting blood sugars above and below 180 mg.%. RESULTS: Prosthesis infections developed in 10 diabetics (8.7%) and 11 nondiabetics (4.0%). No increased infection rate was observed in diabetics with high fasting sugars or diabetics on insulin. There was no statistically significant increased infection risk with increased levels of glycosylated hemoglobin A1C among all patients or among only the diabetics. In fact, there was no meaningful difference in the median or mean level of glycosylated hemoglobin A1C in the infected and noninfected patients regardless of diabetes. CONCLUSIONS: Use of glycosylated hemoglobin A1C values to identify and exclude surgical candidates with increased risk of infections is not proved by this study. Elevation of fasting sugar or insulin dependence also does not increase risk of infection in diabetics undergoing prosthesis implantation.
Diabetes Complications↗
Alternative test for linkage between two loci.
When using the maximum likelihood method to test for linkage it is traditionally assumed that the female (theta f) and male (theta m) recombination fractions are equal. However, this assumption is not always realistic. In this paper we present a testing for linkage that does not require this assumption. Specifically, we propose testing for linkage by testing the null hypothesis H0: theta f + theta m = 1 vs. the alternative HA: theta f + theta m < 1, treating theta f - theta m as a nuisance parameter. This leads to a likelihood ratio test statistic that is asymptotically distributed as a chi-square with one degree of freedom. By examining the expected values of the maximum lod scores, we show that for data from phase-known meioses this test can provide a more powerful test for linkage-especially so when theta f not equal to theta m-unless the recombination fraction is zero. For data from phase-unknown meioses, the proposed test is a more powerful test for linkage only for large values of theta f - theta m; otherwise, the traditional test has higher power. Thus, the proposed test can lead to gain in power for detecting linkage when either phase is known for most meioses or when there is a large absolute difference between the male and female recombination fractions.
Chromosome Mapping↗
Exact transmission-disequilibrium tests with multiallelic markers.
The transmission-disequilibrium (TD) test is a powerful method for detecting linkage between marker and disease loci in the presence of linkage disequilibrium. For multiallelic markers, we propose the use of exact tests, which are implemented using both an exact algorithm and Markov chain Monte Carlo simulation. Simulation studies show that exact tests improve both the small sample validity and the power of the TD method. We also compared the usual single-affected-offspring sampling scheme to one in which pairs of affected siblings are sampled. Affected-sib-pair sampling greatly increases the power of the TD method and will be most useful when a sample of affected sib pairs is available from prior linkage studies.
Algorithms↗
A new test statistic for linkage applied to bipolar disorder and marker D18S41.
We applied a new test statistic for linkage that removes the traditional assumption of equal female (theta f) and male (theta m) recombination fractions by testing Ho: theta f + theta m = 1 vs. HA: theta f + theta m < 1 to GAW10 Problem 1. Specifically we reanalyzed the reported possible linkage between a suggested susceptibility locus for bipolar affective disorder and marker D18S41 on chromosome 18 [Stine et al., 1995]. We used penetrance functions fitting the description of those used by Stine et al. [1995] assuming a continuous age-dependent logistic distribution. Maximum likelihood marker allele frequencies were estimated assuming Hardy-Weinberg equilibrium. Results from the traditional lod-score analyses do not strongly support the existence of linkage between the disease locus and marker D18S41. Similarly, the new test statistic for linkage failed to provide evidence in support of linkage. This was true whether dominant or recessive models of inheritance were assumed, and whether the analyses included all available pedigrees or were confined to paternally transmitted pedigrees. The appreciable difference found between our lod scores and those obtained by Stine et al. [1995] can be attributed to differences in the assumptions made regarding the age-dependent penetrance function, the marker allele frequencies, or both.
Alleles↗
Evaluation of two competing methods for calculating Charlson's comorbidity index when analyzing short-term mortality using administrative data.
The performance and predictive power of the Deyo-Charlson and the Romano-Charlson comorbidity indices were compared when short-term mortality after hospitalization was the outcome of interest. These indices are commonly used to adjust for the effect of comorbidities when using administrative data in comparative studies. In hospital Medicare clam data for patients admitted to one of six medical categories (back pain, stroke, pneumonia, hip replacement, transurethral radical prostatectomy, or lysis of peritoneal adhesion), were selected for analyses. Logistic regression models were employed to evaluate the relative importance and the explanatory power of these indices for predicting mortality 30, 90, and 180 days after admission. The contribution of each index to mortality was assessed via the likelihood ratio chi-square statistic (G2), and the area under the receiver operator characteristic (ROC) curve was used to assess predictive power. Indices were evaluated using weights suggested by Charlson et al. and using empirically derived weights. Both indices improved the base model equally, although the predictive power of both indices was poor with values of the C statistic ranging from 0.60 to 0.78. Our results suggest limited applicability of these approaches when examining short-term mortality. A slight increase in predictive power was observed when indices were calculated using empirical weights derived from our data.
Chi-Square Distribution↗
Assessing HCFA's Health Care Quality Improvement Program.
BACKGROUND: In 1992 the Health Care Financing Administration introduced the Health Care Quality Improvement Program (HCQIP), through which quality improvement projects are conducted in partnership with quality improvement organizations (QIOs), hospitals, health plans, or physicians. An evaluation of HCQIP began in May 1996 in response to the QIOs' request for an independent assessment of their activities. METHODOLOGY: The methodology and objectives of the evaluation were determined by an independent panel. The QIOs' full cohort of 970 HQIP projects could not be reviewed in the 10-month time frame available, but two topics were chosen: the management of warfarin or aspirin in patients with atrial fibrillation and the management of community-acquired pneumonia. FINDINGS: Analyses were limited to the 49 of the 68 projects that had progressed to the "improvement plan implemented" stage. However, only 39 of these 49 projects had information on outcomes, organization changes, and/or changes in process of care--and only 20 of the 49 had moved beyond the "improvement plan implemented" phase. Feedback of data led hospitals collaborating on improvement projects to revise or create processes of care. DISCUSSION: Although the assessment is the most comprehensive of its type to date, it should be viewed as a pilot study of some of the methods that could be incorporated in a more extensive and rigorous future evaluation of the impact of the HCQIP projects. Specific recommendations include random sampling of HCQIP projects across all clinical areas, conducting both prospective and retrospective assessments, developing uniform process and outcome program impact measures, and developing sustainable, ongoing automated data abstraction and analysis systems.
Atrial Fibrillation↗
Ultrex cylinders: problems with uncontrolled lengthening (the S-shaped deformity).
PURPOSE: We investigated whether the AMS Ultrex cylinder, developed to provide cylinder lengthening while controlling girth expansion, acted as a tissue expander and, thus, promoted penile lengthening. MATERIALS AND METHODS: Between December 1990 and January 1992, 59 AMS Ultrex prostheses were implanted. Cylinder length corresponded to intracorporeal measurements. The results of lengthening and occurrence of an S-shaped deformity were statistically analyzed. RESULTS: No penile lengthening occurred. In 19 patients (32%) cylinder replacement was required for the S-shaped deformity. CONCLUSIONS: Ultrex cylinders should be downsized and prolonged inflation should be avoided. They should not be implanted in cases of Peyronie's disease, or to replace malleable or self-contained inflatable implants.
Erectile Dysfunction↗
Laparoscopic cholecystectomy in the geriatric population.
OBJECTIVE: To assess effectiveness and conversion rates of inpatient laparoscopic cholecystectomy in older people living in the community. SETTING AND SUBJECTS: All acute care hospitals providing cholecystectomy in a single state. Medicare patients who underwent inpatient cholecystectomy in fiscal year 1994 in Arkansas. METHODS: A random sample comprising 449 of 2182 geriatric patients who underwent inpatient cholecystectomy in fiscal year 1994, stratified by hospital bed size, had charts reviewed for type of cholecystectomy performed, occurrence of conversion from a laparoscopic to an open cholecystectomy, surgical complications, and need for transfusion. RESULTS: Eighty-two percent of nonincidental cholecystectomies were initially laparoscopic. Total conversion rate for all inpatient laparoscopic cases was 20%. Forty-two percent of this group suffered acute cholecystitis with male patients exhibiting a higher rate of acute cholecystitis than female patients. Conversion rates for elective cholecystectomy for both sexes was between 13 and 14%. Conversion rate to an open procedures was 28% for patients with acute disease, with male patients again having a higher rate than female patients (40% vs 19%, P < .001). Surgical complications and intraoperative transfusions were rare. Conversion rates did not vary between large and small hospitals or among different age groups within the older population. CONCLUSIONS: Inpatient laparoscopic cholecystectomy is common in older people both for acute and chronic gallbladder conditions. Conversion rates ranged from 13% for elective cholecystectomy to 28% for acute disease. These rates are higher than published literature, which focuses on younger populations undergoing elective procedures. Audit committees need to be aware of this higher conversion rate in older people when assessing surgical proficiency.
Acute Disease↗
Assessment of HCFA's 1992 Medicare hospital information report of mortality following admission for hip arthroplasty.
OBJECTIVE: The Health Care Financing Administration (HCFA) produced annually from 1987 through 1994 mortality data information as part of the Medicare Hospital Information Project (MHIP) report. We assessed the validity of these data for hip arthroplasty for one state Medicare population and we analyzed the accuracy of the predictions derived from the Bailey-Makeham mortality model for this procedure. DATA SOURCES AND STUDY SETTING: The study sample consisted of claims and model data from 1,421 Medicare patients who underwent hip arthroplasty at acute care Arkansas hospitals from October 1990 through September 1991. STUDY DESIGN: Patients were stratified into two groups based on reason for surgery (fracture status): reconstruction or fracture management. Patient survival experience was compared between the two groups. The effect of fracture status on the HCFA model's predictive ability was examined empirically and via a simulation study. RESULTS: Our results indicate that hip arthroplasty patients are not uniform with regard to outcome, depending on the reason for the surgery. Patients with fracture had a much higher 30-day mortality rate than those who underwent reconstruction (p < .001). The empirical data and the simulation study suggest that the Bailey-Makeham model underestimates mortality for reconstructive surgery in fracture patients, providing a false benchmark for those institutions that perform hip arthroplasty on predominantly one category of patients. CONCLUSION: Published HCFA data concerning mortality for hip arthroplasty combines two different patient populations into one statistic. Casual examination of these data could result in a false benchmark for analysis of institutional performance. An important implication from this study for policymakers who base decisions on "report cards" or performance measurement reports is that, although they are necessary,generic case-mix, comorbidity, and severity of illness adjustments may not be sufficient to achieve accurate representations of outcomes, and that more disease/procedure--specific adjustments may be needed to avoid inappropriate conclusions.
Arkansas↗
Health care report cards. Validity of case definitions.
Administrative databases are increasingly being used to construct health care report cards. We analyzed information from one of the original report cards, the Medicare Hospital Information Project. Assessment of mortality statistics for three clinical entities--coronary artery bypass surgery, hip reconstruction, and treatment of sepsis--demonstrated widespread outcome variances that reflected imperfect definitions rather than performance issues in clinical care. The use of administrative data sets to design report cards requires clinical expertise to ensure validity of the data. Designers of report card measures should share preliminary data with providers to enable feedback in methods and uncover definitional and validity concerns before widespread dissemination.
Bias↗