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Biomedical subjects

J A Simon

Publications and source records attributed to J A Simon.

At least 37 records · Page 2Linked to original sources
PubMed2000

Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause.

CONTEXT: Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for coronary heart disease (CHD) events. However, few data exist on the clinical importance of Lp(a) lowering for CHD prevention. Hormone therapy with estrogen has been found to lower Lp(a) levels in women. OBJECTIVE: To determine the relationships among treatment with estrogen and progestin, serum Lp(a) levels, and subsequent CHD events in postmenopausal women. DESIGN AND SETTING: The Heart and Estrogen/progestin Replacement Study (HERS), a randomized, blinded, placebo-controlled secondary prevention trial conducted from January 1993 through July 1998 with a mean follow-up of 4.1 years at 20 centers. PARTICIPANTS: A total of 2763 postmenopausal women younger than 80 years with coronary artery disease and an intact uterus. Mean age was 66.7 years. INTERVENTION: Participants were randomly assigned to receive either conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, in 1 tablet daily (n = 1380), or identical placebo (n = 1383). MAIN OUTCOME MEASURES: Lipoprotein(a) levels and CHD events (nonfatal myocardial infarction and CHD death). RESULTS: Increased baseline Lp(a) levels were associated with subsequent CHD events among women in the placebo arm. After multivariate adjustment, women in the second, third, and fourth quartiles of baseline Lp(a) level had relative hazards (RHs) (compared with the first quartile) of 1.01 (95% confidence interval [CI], 0.64-1.59), 1.31 (95% CI, 0.85-2.04), and 1.54 (95% CI, 0.99-2.39), respectively, compared with women in the lowest quartile (P for trend = .03). Treatment with estrogen and progestin reduced mean (SD) Lp(a) levels significantly (-5.8 [15] mg/dL) (-0.20 [0.53] micromol/L) compared with placebo (0.3 [17] mg/dL) (0.01 [0.60] micromol/L) (P<.001). In a randomized subgroup comparison, women with low baseline Lp(a) levels had less benefit from estrogen and progestin than women with high Lp(a) levels; the RH for women assigned to estrogen and progestin compared with placebo were 1.49 (95% CI, 0.97-2.26) in the lowest quartile and 1.05 (95% CI, 0.67-1.65), 0.78 (0.52-1.18), and 0.85 (0.58-1.25) in the second, third, and fourth quartiles, respectively (P for interaction trend = .03). CONCLUSIONS: Our data suggest that Lp(a) is an independent risk factor for recurrent CHD in postmenopausal women and that treatment with estrogen and progestin lowers Lp(a) levels. Estrogen and progestin therapy appears to have a more favorable effect (relative to placebo) in women with high initial Lp(a) levels than in women with low levels. This apparent interaction needs confirmation in other trials.

Aged↗
PubMed2000

Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third National Health and Nutrition Examination Survey (NHANES III).

BACKGROUND: Ascorbic acid-deficient guinea pigs frequently develop gallstones, and ascorbic acid status may also affect the risk of gallbladder disease in humans. To examine the relationship of ascorbic acid, an antioxidant nutrient involved in cholesterol catabolism, to gallbladder disease, we analyzed data collected from a probability sample of US adults. METHODS: Analyses of data from 7042 women and 6088 men enrolled in the Third National Health and Nutrition Examination Survey, 1988-1994, were performed. Multiple logistic regression models stratified by sex were examined, controlling for the effects of age, race, diet, body mass index, and other potential confounders. RESULTS: A total of 761 women (11%) and 235 men (4%) reported a history of clinical gallbladder disease (symptomatic gallstones or cholecystectomy). Of the 9650 participants without a history of clinical gallbladder disease or abdominal pain consistent with gallbladder disease, and with valid abdominal ultrasonography, 408 (8%) of 4863 women and 274 (6%) of 4787 men had asymptomatic gallstones. Serum ascorbic acid level was inversely related to prevalence of clinical and asymptomatic gallbladder disease among women, but not among men. Among women, each SD (27 micromol/L) increase in serum ascorbic acid level was independently associated with a 13% lower prevalence of clinical gallbladder disease (P = .006) and asymptomatic gallstones (P = .048). CONCLUSION: Ascorbic acid, which affects the catabolism of cholesterol to bile acids and, in turn, the development of gallbladder disease in experimental animals, may affect the risk of gallbladder disease among women.

Adult↗
PubMed2000

Functional analysis of repressor binding sites in the iab-2 regulatory region of the abdominal-A homeotic gene.

Spatial boundaries of homeotic gene expression are initiated and maintained by two sets of transcriptional repressors: the gap gene products and the Polycomb group proteins. Previously, the Hunchback (HB) protein has been implicated in setting the anterior expression limit of the UBX homeotic protein in parasegment 6. Here we investigate DNA elements and trans-acting repressors that control spatial expression of the Abdominal-A (ABD-A) homeotic protein. Analysis of a 1.7-kb enhancer element [iab-2(1.7)] from the iab-2 regulatory region shows that in contrast to Ubx enhancer elements, both HB and Krüppel (KR) are required to set the ABD-A anterior boundary in parasegment 7. DNase I footprinting and site-directed mutagenesis show that HB and KR are direct regulators of this iab-2 enhancer. The single KR site can be moved to a new location 100 bp away and still maintain repressive activity, whereas relocation by 300 bp abolishes activity. These results suggest that KR repression occurs through a local quenching mechanism. We also show that the gap repressor Giant (GT) initially establishes a posterior expression limit at PS9, which shifts posteriorly after the blastoderm stage. Finally, we show that this iab-2 enhancer contains multiple binding sites for the Polycomb group protein Pleiohomeotic (PHO). These iab-2 PHO sites are required in vivo for chromosome pairing-dependent repression of a mini-white reporter. However, the PHO sites are not sufficient to maintain repression of a homeotic reporter gene anterior to PS7. Full maintenance at late embryonic stages requires additional sequences adjacent to the iab-2(1.7) enhancer.

Animals↗
PubMed2000

Differential toxicities of anticancer agents among DNA repair and checkpoint mutants of Saccharomyces cerevisiae.

Most cytotoxic anticancer agents damage DNA directly, interfere with DNA metabolism or chromosome segregation, and are particularly toxic in dividing cells. Although a considerable amount of information on the mechanisms of action of these agents is available, the molecular bases for selective tumor cell killing by chemotherapy are largely unknown. Many genetic alterations found in sporadic and hereditary cancers affect functions in DNA repair and cell cycle control and result in sensitivity to DNA damaging agents. We have therefore set out to determine the effects of these cancer mutations on sensitivity or resistance to various chemotherapeutic agents. Because most of the affected genes are well conserved among eukaryotes, we have carried out a comprehensive analysis of a panel of isogenic yeast strains, each defective in a particular DNA repair or cell cycle checkpoint function, for sensitivity to the Food and Drug Administration-approved cytotoxic anticancer agents. Widely different toxicity profiles were observed for 23 agents and X-rays, indicating that the type of DNA repair and cell cycle checkpoint mutations in individual tumors could strongly influence the outcome of a particular chemotherapeutic regimen.

Antimetabolites, Antineoplastic↗
PubMed2000

Fixation of periprosthetic femoral shaft fractures occurring at the tip of the stem: a biomechanical study of 5 techniques.

This study evaluated 5 currently used periprosthetic femoral shaft fracture fixation techniques to determine which technique provided the greatest fixation stability. Periprosthetic fractures in 30 synthetic femurs were fixed with a plate with cables, plate with proximal cables and distal bicortical screws (Ogden concept), plate with proximal unicortical screws and distal bicortical screws, plate with proximal unicortical screws and cables and distal bicortical screws, or 2 allograft cortical strut grafts with cables. These specimens were then tested in 3 physiologic loading modes. The plate constructs with proximal unicortical screws and distal bicortical screws or with proximal unicortical screws, proximal cables, and distal bicortical screws were significantly more stable in axial compression, lateral bending, and torsional loading than the other fixation constructs studied.

Biomechanical Phenomena↗
PubMed2000

Correlates of high HDL cholesterol among women with coronary heart disease.

BACKGROUND: The National Cholesterol Education Program (NCEP) has designated high-density lipoprotein cholesterol (HDL-C) > or =60 mg/dL a "negative" coronary heart disease (CHD) risk factor, but a substantial proportion of coronary events occur among women despite high HDL-C levels. METHODS AND RESULTS: The objective of this study was to characterize postmenopausal women with prevalent CHD despite HDL-C > or =60 mg/dL and to identify factors that may attenuate the protective effect of high HDL-C. We analyzed baseline data from a randomized, double-blind study of estrogen/progestin replacement therapy in 2763 postmenopausal women <80 years old with CHD. Demographics, CHD risk factors, medications, anthropometrics, and lipid levels were compared among women with low, normal, and high HDL-C by NCEP criteria with and without stratification by use of lipid-lowering medications. Independent correlates of high HDL-C were determined by logistic regression analysis. HDL-C > or =60 mg/dL was present in 20% of participants. Women with high HDL-C were older, better educated, had fewer CHD risk factors, lower triglyceride levels and total cholesterol/HDL-C ratio, and were more likely to report past estrogen and current calcium antagonist, niacin, and statin use. beta-Blocker, diuretic, and fibrate use was less common. Older age, alcohol consumption, niacin, and calcium antagonist use and prior estrogen use were independently associated with high HDL-C, whereas waist-to-hip ratio, smoking, triglyceride level, and beta-blocker and fibrate use were inversely associated (all P <.05). CONCLUSIONS: High HDL-C, as defined by the NCEP, occurred in 20% of women with CHD in this cohort without a concomitantly higher prevalence of other CHD risk factors. Redefinition of "high" HDL-C levels for women may be warranted.

Adult↗
PubMed2000

A biomechanical comparison of Schuhli nuts or cement augmented screws for plating of humeral fractures.

Schuhli locking nuts can be used in poor quality cortical bone to enhance fixation stability as an alternative to cement augmented screws. This study compared the fixation strength and stability of plate constructs using Schuhli locking nuts with standard screws and cement augmented screws for fixation of simulated humeral shaft fractures in a test model with osteoporosis. The constructs were tested in axial compression, 4-point bending, and torsion to determine fixation stability. The humeri were cycled in torsion (4.5 Nm) for 1000 cycles to simulate upper extremity use during the early postoperative period and retested for stability. The Schuhli locking nuts and cement augmented screws had significantly greater fixation stability than the standard screws before (range, 6-14 times greater) and after cycling in torsional loading (range, 3-3.6 times greater). Although cement augmented screws and Schuhli augmentation showed increased fixation stability compared with the standard screws in axial and 4-point bending before cycling (range, 1.3-1.4 times greater), this was not significant. Compared with Schuhli fixation, cement augmented screws showed no significant difference in fixation stability in all loading modes before and after cycling. Schuhli locking nuts offer the stability of cement augmentation while avoiding its potential adverse effects on fracture healing with extravasation and thermal necrosis.

Biomechanical Phenomena↗
PubMed2000

New technique for treatment of unstable distal femur fractures by locked double-plating: case report and biomechanical evaluation.

BACKGROUND: A comminuted, intra-articular distal femur fracture was surgically treated by the authors with a locked, double-plating technique because fixation stability could not be initially achieved by using a standard double-plating technique. The purpose of this study was to determine biomechanically whether a locked double-plate construct would enhance fixation stability compared with a nonlocked double-plate construct. METHODS: Six matched pairs of mildly osteopenic femurs were selected and all had a reproducible intra-articular fracture pattern created. Each pair underwent fixation with either a double-plating construct or a locked, double-plating construct that was randomly assigned. The instrumented femurs were then mechanically tested in several loading modes to determine fixation stability. After initial testing, specimens were cyclically loaded and retested for stability. RESULTS: The locked, double-plating construct provided significantly greater fixation stability than the standard double-plating construct in precycling and postcycling biomechanical testing. CONCLUSION: The technique described is particularly applicable for severely comminuted fractures of the distal femur and fractures in osteopenic bone with poor screw purchase. It offers a simple alternative for enhancing fixation stability, which avoids the potential complications of methylmethacrylate-enhanced screw fixation.

Biomechanical Phenomena↗
PubMed2000

A Drosophila ESC-E(Z) protein complex is distinct from other polycomb group complexes and contains covalently modified ESC.

The extra sex combs (ESC) and Enhancer of zeste [E(Z)] proteins, members of the Polycomb group (PcG) of transcriptional repressors, interact directly and are coassociated in fly embryos. We report that these two proteins are components of a 600-kDa complex in embryos. Using gel filtration and affinity chromatography, we show that this complex is biochemically distinct from previously described complexes containing the PcG proteins Polyhomeotic, Polycomb, and Sex comb on midleg. In addition, we present evidence that ESC is phosphorylated in vivo and that this modified ESC is preferentially associated in the complex with E(Z). Modified ESC accumulates between 2 and 6 h of embryogenesis, which is the developmental time when esc function is first required. We find that mutations in E(z) reduce the ratio of modified to unmodified ESC in vivo. We have also generated germ line transformants that express ESC proteins bearing site-directed mutations that disrupt ESC-E(Z) binding in vitro. These mutant ESC proteins fail to provide esc function, show reduced levels of modification in vivo, and are still assembled into complexes. Taken together, these results suggest that ESC phosphorylation normally occurs after assembly into ESC-E(Z) complexes and that it contributes to the function or regulation of these complexes. We discuss how biochemically separable ESC-E(Z) and PC-PH complexes might work together to provide PcG repression.

Animals↗
PubMed1999

Relation of serum ascorbic acid to serum vitamin B12, serum ferritin, and kidney stones in US adults.

BACKGROUND: Concern has been raised that high levels of ascorbic acid consumption may lead to potential adverse effects, such as vitamin B12 deficiency, iron overload, and kidney stones. OBJECTIVE: To examine the relation of serum ascorbic acid level, which reflects intake, to serum vitamin B12 level, serum ferritin level, and kidney stones. METHODS: We analyzed data collected on a random sample of the US population enrolled in the Second National Health and Nutrition Examination Survey, 1976-1980. We analyzed data using linear and logistic regression models. Serum ascorbic acid, serum vitamin B12, hemoglobin, red blood cell mean corpuscular volume (MCV), and serum ferritin levels were measured using standardized protocols. History of kidney stones was determined by self-report. RESULTS: After multivariate adjustment, serum ascorbic acid level was associated with higher serum vitamin B12 levels among women in regression models that assumed a linear relationship; each 57-pmol/L (1.0-mg/dL) increase in serum ascorbic acid level (range, 6-153 micromol/L [0.1 to 2.7 mg/dL]) was independently associated with a serum vitamin B12 level increase of 60 pmol/L (81 pg/ mL) (P<.001). Among men, serum ascorbic acid level was marginally associated with higher serum vitamin B12 levels: each 57-micromol/L (1.0-mg/dL) increase in serum ascorbic acid level was associated with a serum vitamin B12 level increase of 27 pmol/L (36 pg/mL) (P = .10). In addition, serum ascorbic acid level was not associated with correlates of vitamin B12 deficiency, such as higher MCV levels, macrocytosis (MCV >100), or lower hemoglobin concentrations. Serum ascorbic acid level was not independently associated with serum ferritin levels. However, among women only, serum ascorbic acid levels were associated in a nonlinear fashion with prevalence of elevated serum ferritin levels (P = .02). We found no association between serum ascorbic acid level and prevalence of kidney stones in women or men (both P>.05). CONCLUSIONS: Serum ascorbic acid levels were not associated with decreased serum vitamin B12 levels (or indicators of vitamin B12 deficiency), prevalence of kidney stones, serum ferritin levels, or-among men-prevalence of elevated serum ferritin levels. Serum ascorbic acid levels were associated with prevalence of elevated serum ferritin levels among women. Although the clinical relevance of these findings is uncertain, it seems prudent to suggest that women with a genetic susceptibility to iron overload should consider moderating their intake of ascorbic acid.

Adult↗
PubMed1999

White matter dementia in CADASIL.

Cerebral white matter disorders may be associated with profound neurobehavioral dysfunction. We report a 62-year-old man who had a slowly progressive 25-year history of personality change, psychosis, mood disorder, and dementia. Neurologic examination disclosed abulia, impaired memory retrieval, and preserved language, with only minimal motor impairment. Neuropsychological testing found a sustained attention deficit, cognitive slowing, impaired learning with intact recognition, and perseveration. Magnetic resonance imaging of the brain revealed extensive leukoencephalopathy. Right frontal brain biopsy showed ill-defined white matter pallor with hyaline narrowing of white matter arterioles. Granular osmiophilic material adjacent to vascular smooth muscle cells on electron microscopy of a skin biopsy, and an arginine for cysteine replacement at position 169 in the 4 EGF motif of the notch 3 region on chromosome 19q12 established the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This case illustrates that CADASIL can manifest as an isolated neurobehavioral disorder over an extended time period. The dementia associated with CADASIL closely resembles that which may occur with other white matter disorders, and represents an example of white matter dementia.

Brain↗
PubMed1999

Serum ascorbic acid and other correlates of self-reported cataract among older Americans.

The purpose of this study was to examine the correlates of self-reported cataract among older Americans, and specifically, to determine whether serum ascorbic acid levels are associated with a decreased prevalence of cataract. A national probability survey of Americans, the Second National Health and Nutrition Examination Survey (NHANES II), was conducted between 1976 and 1980. A total of 4001 participants were included between the ages of 60 and 74 years with data on serum ascorbic acid level and other variables of interest. A total of 252 women (12%) and 164 men (9%) reported a history of cataract. Serum ascorbic acid level was inversely associated with prevalence of cataract in multiple logistic regression analyses; each 1 mg/dl increase was independently associated with a 26% decrease in cataract (P = 0.03). Other independent correlates of cataract included increasing age, female sex, smoking, and diabetes mellitus (all P<0.01). We identified four correlates of cataract among older Americans: serum ascorbic acid level, increasing age, smoking, and diabetes mellitus. Ascorbic acid, a water-soluble antioxidant found in high concentrations in the lens, may be of importance for the prevention of cataract among older Americans.

Aged↗
PubMed1999

Serum ascorbic acid and cardiovascular disease prevalence in U.S. adults: the Third National Health and Nutrition Examination Survey (NHANES III).

PURPOSE: To examine the relation between serum ascorbic acid concentration, which reflects dietary and supplement intake, and the prevalence of cardiovascular disease. METHODS: We analyzed data from 7658 men and women enrolled in the Third National Health and Nutrition Examination Survey (NHANES III). We calculated odds ratios and 95% confidence intervals (CI) to estimate the relative prevalence of cardiovascular disease, defined as self-reported angina, myocardial infarction, or stroke. Because we detected an interaction between serum ascorbic acid concentration and alcohol intake, we performed analyses stratified by drinking status. RESULTS: Among participants who reported no alcohol consumption, serum ascorbic acid concentrations were not independently associated with cardiovascular disease prevalence. Among participants who consumed alcohol, serum ascorbic acid concentrations consistent with tissue saturation (1.0-3.0 mg/dl) were associated with a decreased prevalence of angina (multivariate odds ratio (OR): 0.48; 95% CI: 0.23% to 1.03; p for trend = 0.06), but were not significantly associated with myocardial infarction or stroke prevalence. CONCLUSIONS: These results suggest the possibility of a biologic interaction between ascorbic acid and alcohol and that higher intakes of ascorbic acid may be associated with a decreased risk of angina among drinkers.

Adult↗
PubMed1999

Pregnancy-specific glycoprotein gene expression in recurrent aborters: a potential correlation to interleukin-10 expression.

PROBLEM: The expression of the pregnancy-specific glycoprotein (PSG) genes in the uterine endometrium of women experiencing recurrent first-trimester abortions, and potential correlations to cytokine expression were examined. METHOD OF STUDY: Endometrial RNA, isolated from women with a history of either repetitive first-trimester pregnancy losses or uncomplicated pregnancies, was isolated and analyzed for PSG transcripts by the reverse transcriptase-polymerase chain reaction method. PSG genes showing different patterns of expression were expressed in baculovirus, and the purified proteins examined for their effects on cytokine expression. RESULTS: The expression of PSG11 in the endometria of recurrent aborters was significantly lower than in that of controls (P < 0.01). When tested on monocytes, PSG11 stimulated secretion of interleukin (IL)-10. CONCLUSIONS: The level of expression of the PSG11 gene in the uterine endometrium, during the peri-implantation period, correlates with the risk of pregnancy loss in some women experiencing recurrent spontaneous abortions. The ability of PSG11 to influence the secretion of IL-10 suggests that PSG11 may contribute to the local modulation of the inflammatory T helper-1 response seen in the endometrium of these women.

Abortion, Habitual↗
PubMed1999

Progestogens in the treatment of secondary amenorrhea.

Secondary amenorrhea is usually the primary purpose for which manufacturers of new progestogens seek FDA approval. Standards for safe and efficacious treatment of this condition have evolved throughout the past two decades. Studies have evaluated a variety of patient populations, corresponding with the several definitions of secondary amenorrhea that may be found in the literature. Ongoing research seeks to expand the indications for progestogen therapy to include hormone replacement in perimenopausal and postmenopausal women.

Administration, Oral↗
PubMed1998

Serum fatty acids and the risk of fatal cancer. MRFIT Research Group. Multiple Risk Factor Intervention Trial.

To examine the relation between serum fatty acids and cancer, the authors conducted a nested case-control study of 108 middle-aged men who died of cancer and 215 men without cancer, who were enrolled in the Multiple Risk Factor Intervention Trial (MRFIT) between 1973 and 1976. Control subjects were matched to case subjects on age, smoking status, treatment assignment, date of randomization, and clinical center. After confirming the stability of the stored serum samples, the authors measured serum fatty acid levels by gas-liquid chromatography and analyzed their association with cancer. In stepwise logistic regression analyses that controlled for the MRFIT selection criteria variables and for alcohol consumption, no fatty acid was significantly associated with overall risk of cancer death (all p > 0.05). Serum levels of phospholipid dihomogammalinolenic acid (20:3), an essential fatty acid, were inversely associated with the risk of dying from lung cancer; a standard deviation increase was associated with a 32% decrease in risk (p = 0.05). Dietary cholesterol intake was associated with the risk of nonlung, non-digestive tract cancers; a standard deviation increase (331 mg/day) was associated with a 75% increase in risk (p = 0.02). The authors found no evidence to suggest that increased dietary intake or serum levels of polyunsaturated fatty acids were associated with an increased risk of fatal cancer among middle-aged men at high risk for coronary heart disease. The clinical significance of the inverse association between dihomogammalinolenic acid and lung cancer death is uncertain and requires confirmation.

Biomarkers, Tumor↗