Biomedical subjects

Charles E McCulloch

Publications and source records attributed to Charles E McCulloch.

At least 19 recordsLinked to original sources

PubMed2006

Body mass index and risk for end-stage renal disease.

BACKGROUND: Although interest in the relationship between obesity and kidney disease is increasing, few epidemiologic studies have examined whether excess weight is an independent risk factor for end-stage renal disease (ESRD). OBJECTIVE: To determine the association between increased body mass index (BMI) and risk for ESRD. DESIGN: Historical (nonconcurrent) cohort study. SETTING: A large integrated health care delivery system in northern California. PARTICIPANTS: 320,252 adult members of Kaiser Permanente who volunteered for screening health checkups between 1964 and 1985 and who had height and weight measured. MEASUREMENTS: The authors ascertained ESRD cases by matching data with the U.S. Renal Data System registry through 2000. RESULTS: A total of 1471 cases of ESRD occurred during 8,347,955 person-years of follow-up. Higher BMI was a risk factor for ESRD in multivariable models that adjusted for age, sex, race, education level, smoking status, history of myocardial infarction, serum cholesterol level, urinalysis proteinuria, urinalysis hematuria, and serum creatinine level. Compared with persons who had normal weight (BMI, 18.5 to 24.9 kg/m2), the adjusted relative risk for ESRD was 1.87 (95% CI, 1.64 to 2.14) for those who were overweight (BMI, 25.0 to 29.9 kg/m2), 3.57 (CI, 3.05 to 4.18) for those with class I obesity (BMI, 30.0 to 34.9 kg/m2), 6.12 (CI, 4.97 to 7.54) for those with class II obesity (BMI, 35.0 to 39.9 kg/m2), and 7.07 (CI, 5.37 to 9.31) for those with extreme obesity (BMI > or = 40 kg/m2). Higher baseline BMI remained an independent predictor for ESRD after additional adjustments for baseline blood pressure level and presence or absence of diabetes mellitus. LIMITATIONS: Primary analyses were based on single measurements of exposures. CONCLUSIONS: High BMI is a common, strong, and potentially modifiable risk factor for ESRD.

Adult↗

PubMed2005

Tumor necrosis factor-alpha-238G>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Identification of single-nucleotide polymorphisms (SNPs) associated with increased risk of new intracranial hemorrhage (ICH) after brain arteriovenous malformation (BAVM) diagnosis would facilitate risk stratification and identify potential targets for therapeutic intervention. METHODS: Patients with BAVM were longitudinally followed. Primary outcome was new ICH after diagnosis; censoring events were last follow-up or any BAVM treatment. We genotyped 4 promoter SNPs in 2 inflammatory cytokine genes: interleukin-6 (IL-6-174G>C; IL-6-572G>C) and tumor necrosis factor-alpha (TNF-alpha-238G>A; TNF-alpha-308G>A). Association of genotype with risk of new ICH was screened using chi2; SNPs associated with new ICH were further characterized using Cox proportional hazards. RESULTS: We genotyped 280 patients (50% female; 59% white, mean+/-SD age at diagnosis 37+/-17 years; 40% presenting with ICH). TNF-alpha-238G>A was associated with increased risk of new ICH after diagnosis (chi2; P=0.003). After adjusting for age, race/ethnicity, and clinical presentation, the risk of new ICH was increased for patients with TNF-alpha-238 AG genotype (hazard ratio, 4.01; P=0.015). No other SNP was found to be associated with new ICH. CONCLUSIONS: A TNF-alpha SNP was associated with increased risk of new ICH in the natural course of BAVMs. The role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage merits further study.

Adult↗

PubMed2005

Polymorphisms in transforming growth factor-beta-related genes ALK1 and ENG are associated with sporadic brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Mutations in endoglin (ENG) and activin-like kinase (ALK1) cause hereditary hemorrhagic telangiectasias, disorders characterized by pulmonary and brain arteriovenous malformations (BAVMs). We investigated whether polymorphisms in these genes are also associated with sporadic BAVM. METHODS: A total of 177 sporadic BAVM patients and 129 controls (all subjects white) were genotyped for 2 variants in ALK1 and 7 variants in ENG. RESULTS: The ALK1 IVS3-35A>G polymorphism was associated with BAVM: (AnyA [AA+AG] genotype: odds ratio, 2.47; 95% CI, 1.38 to 4.44; P=0.002). Two ENG polymorphisms, ENG -1742A>G and ENG 207G>A, showed a trend toward association with BAVM that did not reach statistical significance. CONCLUSIONS: A common polymorphism in ALK1 is associated with sporadic BAVM, suggesting that genetic variation in genes mutated in familial BAVM syndromes may play a role in sporadic BAVMs.

Activin Receptors, Type I↗

PubMed2005

Long-term hemorrhage risk in children versus adults with brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Children with brain arteriovenous malformations (BAVMs) are said to be at higher risk for intracranial hemorrhage (ICH) than adults. Although this notion affects treatment decisions, the evidence to support this claim is limited. METHODS: To compare the risk of ICH in children versus adults with BAVM, we studied all cases of BAVM evaluated at the University of California, San Francisco (January 2000 to December 2004; n=400) and Kaiser Permanente Northern California (January 1993 to December 2004; n=819). In Kaplan-Meier survival analyses, the index date was the date of initial BAVM detection; cases were censored at time of subsequent ICH (the primary outcome, defined as ICH after initial presentation), first BAVM treatment, or loss to follow-up. Cox proportional hazards models included childhood presentation (<20 years old), hemorrhagic presentation, and other potential confounders. RESULTS: Our study included 996 person-years of follow-up in the childhood presentation group and 3260 in the adult presentation group. In the unadjusted survival analysis, the subsequent ICH rates were similar for the 2 age groups (average annual rate 2.0% for children; 2.2% for adults; P=0.82 by log-rank test). BAVMs in childhood were more likely to present initially with ICH (P<0.001). After adjustment for presentation in the multivariate model, subsequent ICH rates were lower in children (hazard ratio, 0.10; 95% CI, 0.01 to 0.86; P=0.036). CONCLUSIONS: Children with BAVMs do not appear to be at increased risk for a subsequent ICH compared with adults, and may even be relatively protected. Confounding by hemorrhagic presentation should be considered in any study comparing BAVM hemorrhage rates in children versus adults.

Adolescent↗

PubMed2005

Association between phonocardiographic third and fourth heart sounds and objective measures of left ventricular function.

CONTEXT: The third (S3) and fourth (S4) heart sounds detected by phonocardiography are considered to represent the criterion standards of the gallop sounds, but their test characteristics have not been explored. OBJECTIVE: To determine the diagnostic test characteristics of the S3 and S4 for prediction of left ventricular dysfunction using a computerized heart sound detection algorithm. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 90 adult patients undergoing elective left-sided heart catheterization at a single US teaching hospital between August 2003 and June 2004. The mean age was 62 (SD, 13) years (range, 24-90 years) and 61 (68%) were male. Within a 4-hour period, participants underwent computerized heart sound phonocardiographic analysis, cardiac catheterization, transthoracic echocardiography, and blood sampling for assessment of an S3/S4, left ventricular end-diastolic pressure (LVEDP), left ventricular ejection fraction (LVEF), and B-type natriuretic peptide (BNP), respectively. MAIN OUTCOME MEASURES: Diagnostic test characteristics of the computerized phonocardiographic S3 and S4 using markers of left ventricular function as criterion standards. RESULTS: Mean (SD) LVEDP was significantly elevated (18.4 [6.9] mm Hg vs 12.1 [7.3] mm Hg; P<.001), mean (SD) LVEF was reduced (49.4% [20.2%] vs 63.6% [14.8%]; P<.001), and median (interquartile range) BNP was elevated (330 [98-1155] pg/mL vs 86 [41-192] pg/mL; P<.001) in those with an S3, S4, or both compared with patients without a diastolic heart sound. The sensitivities of these heart sounds to detect an elevated LVEDP, reduced LVEF, or elevated BNP were 41%, 52%, and 32% for an S3, and 46%, 43%, and 40% for an S4, respectively. For abnormal levels of the same markers of ventricular function, the specificities of the S3 were 92%, 87%, and 92%, while the specificities of the S4 were 80%, 72%, and 78%, respectively. CONCLUSIONS: Neither the phonocardiographic S3 nor the S4 is a sensitive marker of left ventricular dysfunction. The phonocardiographic S3 is specific for left ventricular dysfunction and appears to be superior to the moderate specificity of the phonocardiographic S4.

Adult↗

PubMed2005

Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease.

BACKGROUND: Many cases of end-stage renal disease (ESRD) are ascribed to hypertension. However, because renal disease itself can raise blood pressure, some investigators argue that ESRD seen in patients with hypertension is due to underlying primary renal disease. Previous cohort studies of the relationship between blood pressure and ESRD did not uniformly screen out baseline kidney disease. METHODS: We conducted a historical cohort study among members of Kaiser Permanente of Northern California, a large integrated health care delivery system. The ESRD cases were ascertained by matching with the US Renal Data System registry. RESULTS: A total of 316 675 adult Kaiser members participated in the Multiphasic Health Checkups from 1964 to 1985. All subjects had estimated glomerular filtration rates of 60 mL /min per 1.73 m(2) or higher and negative dipstick urinalysis results for proteinuria or hematuria. During 8 210 431 person-years of follow-up, 1149 cases of ESRD occurred. Compared with subjects with a blood pressure less than 120/80 mm Hg, the adjusted relative risks for developing ESRD were 1.62 (95% confidence interval [CI], 1.27-2.07) for blood pressures of 120 to 129/80 to 84 mm Hg, 1.98 (95% CI, 1.55-2.52) for blood pressures of 130 to 139/85 to 89 mm Hg, 2.59 (95% CI, 2.07-3.25) for blood pressures of 140 to 159/90 to 99 mm Hg, 3.86 (95% CI, 3.00-4.96) for blood pressures of 160 to 179/100 to 109 mm Hg, 3.88 (95% CI, 2.82-5.34) for blood pressures of 180 to 209/110 to 119 mm Hg, and 4.25 (95% CI, 2.63-6.86) for blood pressures of 210/120 mm Hg or higher. Similar associations between blood pressure level and ESRD risk were seen in all subgroup analyses. CONCLUSIONS: Even relatively modest elevation in blood pressure is an independent risk factor for ESRD. The observed relationship does not appear to be due to confounding by clinically evident baseline kidney disease.

Adult↗

PubMed2005

Human T lymphotropic virus type II infection and humoral responses to pneumococcal polysaccharide and tetanus toxoid vaccines.

Infection with human T lymphotropic virus type II (HTLV-II) has been linked to an increased incidence of bacterial pneumonia. To determine whether HTLV-II infection is associated with impaired humoral immune responses, we immunized a cohort of HTLV-II-infected subjects and matched uninfected control subjects with 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines. The pneumococcal polysaccharide vaccine elicited comparable and significant increases in concentrations of IgG against all 5 serotypes tested at 1 and 6 months after immunization in both groups. The avidity and opsonophagocytic functions of the anticapsular IgG were similar. The concentrations of tetanus toxoid-specific IgG also increased comparably and significantly over time in both groups. Thus, HTLV-II-infected persons develop robust humoral responses to potentially protective polysaccharide and protein vaccines.

Adult↗

PubMed2005

Ethics and sample size.

The belief is widespread that studies are unethical if their sample size is not large enough to ensure adequate power. The authors examine how sample size influences the balance that determines the ethical acceptability of a study: the balance between the burdens that participants accept and the clinical or scientific value that a study can be expected to produce. The average projected burden per participant remains constant as the sample size increases, but the projected study value does not increase as rapidly as the sample size if it is assumed to be proportional to power or inversely proportional to confidence interval width. This implies that the value per participant declines as the sample size increases and that smaller studies therefore have more favorable ratios of projected value to participant burden. The ethical treatment of study participants therefore does not require consideration of whether study power is less than the conventional goal of 80% or 90%. Lower power does not make a study unethical. The analysis addresses only ethical acceptability, not optimality; large studies may be desirable for other than ethical reasons.

Bias↗

PubMed2005

Treatment of depression in low-income older adults.

The purpose of this study was to compare cognitive-behavioral group therapy (CBGT), clinical case management (CCM), and their combination (CBGT + CCM) to treat depression in low-income older adults (60+). Sixty-seven participants with major depressive disorder or dysthymia were randomly assigned and entered into 1 of the 3 treatment conditions for 6 months. They were followed for 18 months after treatment initiation on depression and functional outcomes. CCM and CBGT + CCM led to greater improvements in depressive symptoms than CBGT, but CBGT led to greater improvements in physical functioning. All 3 conditions resulted in similar reduction of needs. Findings suggest that disadvantaged older adults with depression benefit from increased access to social services either alone or combined with psychotherapy.

Case Management↗

PubMed2005

The conundrum of increased burden of end-stage renal disease in Asians.

BACKGROUND: Few cohort studies have examined the risk of end-stage renal disease (ESRD) among Asians compared with whites and blacks. METHODS: To compare the incidence of ESRD in Asians, whites, and blacks in Northern California, we examined sociodemographic and clinical data on 299,168 adults who underwent a screening health checkup at Kaiser Permanente between 1964 and 1985. Incident cases of ESRD were ascertained by matching patient identifiers with the nationally comprehensive United States Renal Data System ESRD registry. RESULTS: Overall, 1346 cases of ESRD occurred during 7,837,310 person-years of follow-up. The age-adjusted rate of ESRD (per 100,000 person-years) was 14.0 [95% confidence interval (CI) 10.5-18.5] among Asians, 7.9 (95% CI 6.5-9.5) among whites, and 43.4 (95% CI 36.6-51.4)] among blacks. Controlling for age, gender, educational attainment, diabetes, prior myocardial infarction, serum creatinine, systolic and diastolic blood pressure, proteinuria, hematuria, cigarette smoking, serum total cholesterol, and body mass index increased the risk of ESRD in Asians relative to whites from 1.69 to 2.08 (95% CI 1.61-2.67). By contrast, adjustment for the same covariates decreased the risk of ESRD in blacks relative to whites from 5.30 to 3.28 (95% CI 2.91-3.69). CONCLUSION: Factors contributing to the excess ESRD risk in Asians relative to whites extend beyond usually considered sociodemographic and comorbidity disparities. Strategies aimed at examining novel risk factors for kidney disease and efforts to increase awareness of kidney disease among Asians may reduce ESRD incidence in this high-risk group.

Adolescent↗

PubMed2005

Health-related quality of life and estimates of utility in chronic kidney disease.

BACKGROUND: Health-related quality of life and estimates of utility have been carefully evaluated in persons with end-stage renal disease. Fewer studies have examined these parameters in persons with chronic kidney disease (CKD). METHODS: To determine the relations among kidney function, health-related quality of life, and estimates of utility, we administered the Kidney Disease Quality of Life Short Form 36 (KDQOL-36), Health Utilities Index (HUI)-3, and Time Trade-off (TTO) questionnaires to 205 persons with CKD. Persons with CKD stages 4 and 5 (estimated GFR <30 mL/min/1.73 m2, N= 115) were tested two to eight times over the subsequent two years. The relations among estimated glomerular filtration rate (eGFR), and changes in health-related quality of life and utility over time were estimated using mixed effect regression models. Models were adjusted for age, sex, race, and diabetes. RESULTS: Mean scores on the KDQOL-36 generic components, HUI-3, and TTO suggested considerable loss of function and well-being in CKD relative to population norms. On cross-sectional analysis, lower levels of kidney function were associated with significantly lower scores on the SF-12 Physical Health Composite (P= 0.002), the Burden of Kidney Disease subscale (P < 0.0001), and the Effects of Kidney Disease subscale (P < 0.0001) of the KDQOL-36trade mark. Kidney function was significantly associated with the TTO (P= 0.008) and global HUI-3 utility (P= 0.016) although these associations were attenuated after adjustment for diabetes. A decline in eGFR was associated with a significant increase in the reported Burden of Kidney Disease (5.0 point change per year per mL/min/1.73 m2 decline in eGFR) and with marginally significant changes in the Dexterity and Pain attributes of the HUI-3. Mean HUI-3 scores for persons with CKD stages 4 and 5, absent dialysis, were in the range previously reported for persons with stroke and severe peripheral vascular disease. CONCLUSION: Health-related quality of life and estimates of utility are distressingly low in persons with CKD. Self-reported outcomes should be considered when evaluating health policy decisions that affect this population.

Adult↗

PubMed2005

Does experience matter? A comparison of the practice of attendings and residents.

OBJECTIVE: To compare the utilization of health care resources and patterns of chronic disease care by patients of medical residents and patients of their attending physicians. MATERIALS AND METHODS: This study involved a longitudinal cohort of 14,554 patients seen over a 1-year period by 149 residents and 36 attendings located in an urban academic medical center. Data were acquired prospectively through a practice management system used to order tests, write prescriptions, and code ambulatory visits. We assessed resource utilization by measuring the total direct costs of care over a 1-year period, including ambulatory and inpatient costs, and the numbers and types of resources used. RESULTS: Residents' patients were similar to attendings' patients in age and gender, but residents' patients were more likely to have Medicaid or Medicare and to have a higher burden of comorbidity. Total annual ambulatory care costs were almost 60% higher for residents' patients than for attendings' patients in unadjusted analyses, and 30% higher in analyses adjusted for differences in case mix (adjusted mean 888 dollars vs 750 dollars; P=.0001). The primary cost drivers on the outpatient side were consultations and radiological procedures. Total inpatient costs were almost twice as high for residents' patients compared to attendings' patients in unadjusted analyses, but virtually identical in analyses adjusted for case mix differences (adjusted mean of 849 dollars vs 860 dollars). Admission rates were almost double for residents' patients. Total adjusted costs for residents' patients were slightly, but not significantly, higher than for attendings' patients (adjusted mean 1,651 dollars vs 1,540 dollars; P>.05). Residents' and attendings' patients generally did not differ in the patterns of care for diabetes, asthma/chronic obstructive pulmonary disease (COPD), congestive heart failure, ischemic heart disease, and depression, except that residents' patients with asthma/COPD, ischemic heart disease, and diabetes were admitted more frequently than attendings' patients. CONCLUSIONS: Our results indicate that residents' patients had higher costs than attendings' patients, but the differences would have been seriously overestimated without adjustment. We conclude that it costs about 7% more for residents to manage patients than for attendings. On the ambulatory side, the larger number of procedures and consults ordered for residents' patients appears to drive the higher costs.

Academic Medical Centers↗

PubMed2005

Effect of presenting hemorrhage on outcome after microsurgical resection of brain arteriovenous malformations.

OBJECTIVE: We hypothesized that patients with unruptured arteriovenous malformations (AVMs) at presentation have an increased risk of deterioration compared with patients with ruptured AVMs. METHODS: A consecutive series of 224 patients treated microsurgically by a single neurosurgeon during a period of 6.4 years was analyzed. Initial hemorrhagic presentation was the primary predictor variable. Neurological outcomes were assessed by use of the Modified Rankin Scale (MRS) and Glasgow Outcome Scale (GOS), and logistic regression identified predictors of deterioration at follow-up (mean duration, 1.3 yr) relative to baseline before any intervention. RESULTS: Overall, 120 patients (54%) presented with hemorrhage, and all 224 patients underwent microsurgical resection. Complete resection was achieved in 220 patients (98%). According to GOS score, 13 patients (5.8%) deteriorated; according to MRS score, 45 patients (20.1%) deteriorated. Fifteen patients (6.7%) died. Hemorrhagic presentation was associated with improved outcomes, with a mean change in MRS score of +0.89 in patients with ruptured AVMs and -0.38 in patients with unruptured AVMs (P < 0.001). The final mean MRS scores in patients with unruptured AVMs were better than those in patients with ruptured AVMs (1.44 versus 1.90; P = 0.048). Presentation with an unruptured AVM was a predictor of worsening MRS score (odds ratio, 2.33; 95% confidence interval, 1.3-4.3; P = 0.006) but not of worsening GOS score. CONCLUSION: Presentation with AVM hemorrhage is an underappreciated predictor of outcome after therapy that includes microsurgical resection. Patients with ruptured AVMs tended to have deficits at presentation and generally improved after surgery, whereas patients with unruptured AVMs tended to have normal or nearly normal neurological function at presentation and were susceptible to worsening, albeit slight, as measured by MRS scores. Sensitive outcome measures such as MRS detect subtle symptoms and impairments missed by coarser measures such as GOS. Patients should be counseled that the risks associated with elective resection of unruptured AVMs may be higher than recognized previously. Hemorrhagic brain injury and its secondary effects may mask this surgical morbidity.

Adolescent↗

PubMed2004

Effects of hospitalist attending physicians on trainee satisfaction with teaching and with internal medicine rotations.

BACKGROUND: Hospitalists are increasingly serving as inpatient attendings at teaching hospitals. The educational impact of this new model is unclear. We evaluated the relationship between type of attending (hospitalist vs traditional) and trainees' ratings of attending teaching and the overall ward rotation. METHODS: We analyzed data from a Web-based evaluation system containing all house staff and student evaluations of their attendings and internal medicine ward rotations at 2 university-affiliated teaching hospitals over a 2-year period (1999-2001). RESULTS: The overall evaluation completion rate was 91% (1587 of 1742 evaluations) by trainees working with 17 hospitalists and 52 traditional attendings. Trainees reported significantly more overall satisfaction with hospitalists than traditional attendings (8.3 vs 8.0 on a 9-point scale; P<.001) and rated hospitalists' overall teaching effectiveness as superior (4.8 vs 4.5 on a 5-point scale; P<.001). Perceived overall educational value of rotations was higher with hospitalist attendings (3.9 vs 3.7 on a 5-point scale; P =.04). Trainees evaluated hospitalists' knowledge, teaching, and feedback as superior to that of traditional attendings. There were no significant differences in reports of attendings' interest in teaching or patients, availability, or emphasis on cost-effectiveness. CONCLUSIONS: Trainees reported more effective teaching and more satisfying inpatient rotations when supervised by hospitalists. This analysis suggests that hospitalists may possess or accrue a specific inpatient knowledge base and teaching skill that distinguishes them from nonhospitalists.

Attitude of Health Personnel↗

PubMed2004

Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.

BACKGROUND: End-stage renal disease substantially increases the risks of death, cardiovascular disease, and use of specialized health care, but the effects of less severe kidney dysfunction on these outcomes are less well defined. METHODS: We estimated the longitudinal glomerular filtration rate (GFR) among 1,120,295 adults within a large, integrated system of health care delivery in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation. We examined the multivariable association between the estimated GFR and the risks of death, cardiovascular events, and hospitalization. RESULTS: The median follow-up was 2.84 years, the mean age was 52 years, and 55 percent of the group were women. After adjustment, the risk of death increased as the GFR decreased below 60 ml per minute per 1.73 m2 of body-surface area: the adjusted hazard ratio for death was 1.2 with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 (95 percent confidence interval, 1.1 to 1.2), 1.8 with an estimated GFR of 30 to 44 ml per minute per 1.73 m2 (95 percent confidence interval, 1.7 to 1.9), 3.2 with an estimated GFR of 15 to 29 ml per minute per 1.73 m2 (95 percent confidence interval, 3.1 to 3.4), and 5.9 with an estimated GFR of less than 15 ml per minute per 1.73 m2 (95 percent confidence interval, 5.4 to 6.5). The adjusted hazard ratio for cardiovascular events also increased inversely with the estimated GFR: 1.4 (95 percent confidence interval, 1.4 to 1.5), 2.0 (95 percent confidence interval, 1.9 to 2.1), 2.8 (95 percent confidence interval, 2.6 to 2.9), and 3.4 (95 percent confidence interval, 3.1 to 3.8), respectively. The adjusted risk of hospitalization with a reduced estimated GFR followed a similar pattern. CONCLUSIONS: An independent, graded association was observed between a reduced estimated GFR and the risk of death, cardiovascular events, and hospitalization in a large, community-based population. These findings highlight the clinical and public health importance of chronic renal insufficiency.

Aged↗

PubMed2004

Polymorphisms in genes involved in inflammatory and angiogenic pathways and the risk of hemorrhagic presentation of brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Accurate estimates of intracranial hemorrhage (ICH) risk in patients harboring brain arteriovenous malformation (BAVM) are needed to evaluate interventional strategies and to help guide clinical management. Identification of genetic polymorphisms associated with ICH would facilitate risk stratification in BAVM patients. METHODS: We identified patients with BAVM and documented clinical presentation, demographic data, venous drainage pattern, and BAVM size. Patients were genotyped for 5 polymorphisms in 3 inflammatory cytokine genes, and 9 polymorphisms in 5 angiogenesis-related genes. Association of genotype with risk of hemorrhagic BAVM presentation was evaluated using logistic regression analysis. RESULTS: We genotyped 180 patients with BAVM (53% female, 57% white, mean age at diagnosis 35+/-17 years, 41% presenting with ICH). BAVM patients homozygous for the interleukin 6 (IL6)-174G allele had a greater risk of ICH presentation (OR, 2.62, P=0.003) than IL6-174C carriers. In a multivariate logistic regression model, IL6-174G>C genotype, small BAVM size, and exclusively deep venous drainage were independent predictors of ICH presentation. A similar univariate trend was noted for the TNFalpha-308 GG genotype (P=0.055). The other polymorphisms genotyped were not associated with ICH. CONCLUSIONS: A polymorphism in the inflammatory cytokine IL6, but not polymorphisms in angiogenesis-related genes, was associated with ICH presentation of BAVM. Further studies are needed to define the role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage.

Adult↗

PubMed2004

Theophylline for the prevention of radiocontrast nephropathy: a meta-analysis.

BACKGROUND: Radiocontrast nephropathy is a common cause of acute renal failure in hospitalized patients. Several studies have examined the capacity of theophylline or aminophylline to prevent radiocontrast nephropathy, with conflicting results. We conducted a meta-analysis of published randomized controlled trials to determine if the pre-procedural administration of theophylline or aminophylline prevents radiocontrast-induced declines in kidney function. METHODS: We searched MEDLINE, EMBASE, the Cochrane Collaboration Database, bibliographies of retrieved articles, and consulted with experts to identify relevant studies. Randomized controlled trials of theophylline or aminophylline in hospitalized patients receiving radiocontrast were included. Studies were excluded if they did not report changes in serum creatinine or creatinine clearance within 48 h after radiocontrast exposure. RESULTS: Seven randomized controlled trials satisfied all inclusion criteria and were included in the analysis (pooled sample size n = 480). The difference in mean change in serum creatinine was 11.5 micromol/l (95% confidence intervals 5.3-19.4 micromol/l, P = 0.004) lower in the theophylline- or aminophylline-treated groups than controls. One participant (0.6%) required dialysis. CONCLUSIONS: Prophylactic administration of theophylline or aminophylline appears to protect against radiocontrast-induced declines in kidney function. Whether these agents reduce the proportion of patients who experience large decrements in serum creatinine concentration, or require dialysis, is unknown.

Aminophylline↗

PubMed2004

Doxycycline suppresses cerebral matrix metalloproteinase-9 and angiogenesis induced by focal hyperstimulation of vascular endothelial growth factor in a mouse model.

BACKGROUND AND PURPOSE: A number of central nervous system (CNS) disorders are associated with abnormalities in or activation of angiogenesis, including vascular malformations. To test the hypothesis that the nonspecific matrix metalloproteinase (MMP) inhibitor, doxycycline, suppresses vascular endothelial growth factor (VEGF)-induced cerebral angiogenesis through inhibition of MMPs, we used a mouse model with enhanced cerebral angiogenesis induced by focal hyperstimulation of VEGF from adenovirus DNA (AdVEGF) transduction. METHODS: The time course study of MMP activity was performed at 7 and 14 days after AdVEGF transduction. MMP activity and expression were examined by zymography and immunohistochemistry, respectively. As an index of cerebral angiogenesis, microvessel counting was performed in the brains of 3 groups of mice (n=6): (1) control; (2) AdVEGF only; and (3) AdVEGF plus doxycycline (30 mg/kg per day). RESULTS: Brain MMP-9 activities increased 4-fold (883+/-137 versus 179+/-179; 1-sided P<0.001) at 7 days after AdVEGF transduction. VEGF transduction increased vessel counts by 19% (255+/-27 versus 215+/-15, 1-sided P<0.01). Doxycycline treatment decreased MMP-9 activity (89+/-72 versus 883+/-137; 1-sided P<0.001) and cerebral microvessel number (231+/-17 versus 255+/-27; 1-sided P<0.05). CONCLUSIONS: Doxycycline is effective in decreasing stimulated cerebral MMP-9 activity and parenchymal angiogenesis. The decrease in MMP-9 activity is associated with decreased microvessel counts. Brain pathophysiological processes that involve abnormally enhanced angiogenesis may be amenable to manipulation by MMP inhibitors, including tetracycline derivatives.

Adenoviridae↗