Biomedical subjects

J Fang

Publications and source records attributed to J Fang.

At least 109 records · Page 6Linked to original sources

PubMed2000

Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey.

CONTEXT: Although many epidemiological studies have suggested that increased serum uric acid levels are a risk factor for cardiovascular mortality, this relationship remains uncertain. OBJECTIVE: To determine the association of serum uric acid levels with cardiovascular mortality. DESIGN AND SETTING: Cross-sectional population-based study of epidemiological follow-up data from the First National Health and Nutrition Examination Survey (NHANES I) from 1971-1975 (baseline) and data from NHANES I Epidemiologic Follow-up Study (NHEFS). PARTICIPANTS: A total of 5926 subjects who were aged 25 to 74 years and had serum uric acid level measurements at baseline. MAIN OUTCOME MEASURES: Ischemic heart disease mortality, total cardiovascular mortality, and all-cause mortality, compared by quartiles of serum uric acid level. RESULTS: In an average of 16.4 years of follow-up, 1593 deaths occurred, of which 731 (45.9%) were ascribed to cardiovascular disease. Increased serum uric acid levels had a positive relationship to cardiovascular mortality in men and women and in black and white persons. Deaths due to ischemic heart disease in both men and women increased when serum uric acid levels were in the highest quartile compared with the lowest quartile (men, >416 vs <321 micromol/L; risk ratio, 1.77 [95% confidence interval [CI], 1.08-3.98]; women, >333 vs <238 micromol/l; risk ratio, 3.00 [95% CI, 1.45-6.28]). Cox regression analysis showed that for each 59.48-micromol/L increase in uric acid level, cardiovascular mortality and ischemic heart disease mortality increased. Hazard ratios for men were 1.09 (95% CI, 1.02-1.18) and 1.17 (95% CI, 1.06-1.28), and for women were 1.26 (95% CI, 1.16-1.36) and 1.30 (95% CI, 1.17-1.45), respectively, after adjustment for age, race, body mass index, smoking status, alcohol consumption, cholesterol level, history of hypertension and diabetes, and diuretic use. Further analysis, stratifying by cardiovascular risk status, diuretic use, and menopausal status, confirmed a significant association of uric acid and cardiovascular mortality in all subgroups except among men using diuretics (n=79) and men with 1 or more cardiovascular risk factors (n=1140). CONCLUSION: Our data suggest that increased serum uric acid levels are independently and significantly associated with risk of cardiovascular mortality.

Adult↗

PubMed2000

p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells.

Induction of a cyclin-dependent kinase inhibitor p21Waf1/ Cip1/Sdi1 is an integral part of cell growth arrest associated with senescence and damage response. p21 overexpression from an inducible promoter resulted in senescence-like growth arrest in a human fibrosarcoma cell line. After release from p21-induced growth arrest, cells re-entered the cell cycle but displayed growth retardation, cell death and decreased clonogenicity. The failure to form colonies was associated with abnormal mitosis and endoreduplication in the recovering cells and was correlated with the induced level of p21 and the duration of p21 induction. p21 induction was found to inhibit the expression of multiple proteins involved in the execution and control of mitosis. p21-induced depletion of the cellular pools of mitosis-control proteins was followed by asynchronous resynthesis of such proteins after release from p21, which explains the observed mitotic abnormalities. Genetic destabilization in cells recovering from p21-induced growth arrest may conceivably play a role in carcinogenesis and tumor progression.

Autoantigens↗

PubMed2000

Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model.

Among the earliest and most important stages during tumorigenesis is the activation of the angiogenic process, an event that is termed the "switch to the angiogenic phenotype." We have developed an in vivo system that can reliably recapitulate the stages in tumor development that represent this transition. Using this model, we have harvested and studied tumor nodules that can be distinguished from each other on the basis of their degree of vascularization. Angiogenic tumor nodules were characterized by the presence of capillary vessels as determined by factor VIII immunohistochemistry, and both angiogenic and proteolytic activities in vitro. In contrast, preangiogenic nodules were devoid of microvessels and showed little angiogenic or proteolytic activity in vitro. Addition of a specific metalloproteinase inhibitor resulted in the abrogation of both angiogenic and proteolytic activities of the angiogenic nodules in vitro. Comparative substrate gel electrophoresis detected the presence of a prominent matrix metalloproteinase (MMP-2) in the angiogenic nodules when compared with the preangiogenic ones. Suppression of MMP-2 activity by antisense oligonucleotides in the vascular nodules resulted in the loss of angiogenic potential both in vitro and in vivo in the chick chorioallantoic membrane assay. Moreover, this suppression of MMP-2 activity in angiogenic nodules inhibited tumor growth in vivo by approximately 70%. These results strongly implicate the activity of MMP-2 as a requirement for the switch to the angiogenic phenotype and validate this model as a reliable and reproducible tool by which to study other cellular and biochemical factors involved in the acquisition of the angiogenic phenotype.

Animals↗

PubMed2000

Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases.

Induction of cyclin-dependent kinase inhibitor p21(Waf1/Cip1/Sdi1) triggers cell growth arrest associated with senescence and damage response. Overexpression of p21 from an inducible promoter in a human cell line induces growth arrest and phenotypic features of senescence. cDNA array hybridization showed that p21 expression selectively inhibits a set of genes involved in mitosis, DNA replication, segregation, and repair. The kinetics of inhibition of these genes on p21 induction parallels the onset of growth arrest, and their reexpression on release from p21 precedes the reentry of cells into cell cycle, indicating that inhibition of cell-cycle progression genes is a mechanism of p21-induced growth arrest. p21 also up-regulates multiple genes that have been associated with senescence or implicated in age-related diseases, including atherosclerosis, Alzheimer's disease, amyloidosis, and arthritis. Most of the tested p21-induced genes were not activated in cells that had been growth arrested by serum starvation, but some genes were induced in both forms of growth arrest. Several p21-induced genes encode secreted proteins with paracrine effects on cell growth and apoptosis. In agreement with the overexpression of such proteins, conditioned media from p21-induced cells were found to have antiapoptotic and mitogenic activity. These results suggest that the effects of p21 induction on gene expression in senescent cells may contribute to the pathogenesis of cancer and age-related diseases.

Aging↗

PubMed2000

Synthesis and evaluation of furo[3,4-d]pyrimidinones as selective alpha1a-adrenergic receptor antagonists.

Furo[3,4-d]pyrimidinones were found to be metabolites of dihydropyrimidinones such as 1a-b that are subtype-selective antagonists of the alpha1a-adrenergic receptor. A versatile synthesis that provides access to furo[3,4-d]pyrimidinones in high yield and in enantiomerically pure forms is described along with structure-activity relationships in the series.

Adrenergic alpha-Antagonists↗

PubMed2000

Diagnosis and classification of lymphoma based on cytospin preparations: a comparison of hematopathologists and cytopathologists.

The diagnosis of malignant lymphoma based on cytologic preparations is a source of much debate. The purpose of this study was to assess the ability of a number of pathologists to diagnose and classify lymphoma using cytospin preparations, and to compare the rate of agreement between cytopathologists and hematopathologists. One hundred twenty-five cytospins prepared from histologically confirmed hematologic lesions were examined retrospectively and independently by four hematopathologists/fellows and two cytopathologists without knowledge of the final diagnosis; the results were compared with the final diagnoses derived from histology and immunophenotyping. Eighty-one cases were histologically diagnosed as lymphoma (including 67 cases of B-cell non-Hodgkin's lymphoma), and 44 cases represented a reactive process histologically. The distinction of a malignant from a benign process was made in 75% of the cases by cytospin examination, with cytopathologists correctly diagnosing 75% and hematopathologists 76% of the cases. The accuracy rate for subclassification of the lymphoma cases was 49% (46% for cytopathologists, 52% for hematopathologists). The cytopathologists correctly recognized large-cell lymphoma at an increased frequency compared with the hematopathologists (70% vs. 56%, P = 0.11), while the hematopathologists showed a greater ability to recognize and classify nonfollicle center low-grade B-cell lymphomas (57% vs. 28%, P = 0.01). We conclude that cytopathologists and hematopathologists generally achieve similar accuracy rates in the morphologic evaluation of cytologic preparations of lymphoid lesions, though some differences in their performance do exist.

Biopsy, Needle↗

PubMed2000

CD34 selection as a stem cell purging strategy for neuroblastoma: preclinical and clinical studies.

BACKGROUND: The suitability of CD34 selection for purging peripheral blood progenitor cells (PBPC) collected from patients with neuroblastoma (NB) has been called into question, largely because of reports of detection of low levels of CD34 on the surface of some NB cell lines and tumors. PROCEDURE: We used three approaches to address the issue of purging of NB from stem cell specimens and possible labeling of NB: 1) Flow cytometric detection of CD34 on NB cell lines. We assessed CD34 expression using a panel of anti-CD34 monoclonal antibodies (MoAbs) including 9C5, 12.8, and QBend10 and showed no increase in labeling over secondary-only control. 2) Spiking experiments with the Isolex 50 system. NB cell lines were used to contaminate aliquots of PBPC collections, after which the products were purified using the Isolex 50. Purging of NB was assessed by quantitative multiplex RT-PCR (TaqMan system) using a tumor-specific transcript, GAGE. We demonstrated >2 logs of tumor cell depletion from these specimens. 3) Analysis of clinical specimens. PBPC pre- and post-CD34 selection were analyzed from patients treated on the CHP-594 transplant trial. RESULTS: In nine specimens selected using the Ceprate LC CD34 selection system where tumor was detectable by immunocytochemistry preselection, we observed >2.4 to >4.6 logs of NB purging after selection. We then analyzed 23 aliquots of PBPC infused into patients post-CD34 selection and compared them to the product preselection; 20/23 specimens showed depletion of NB, although some level of GAGE message was observed in most post-CD34 selection specimens. CONCLUSION: These data show that purging of NB from PBPC specimens using CD34 selection is feasible, yielding infused products that are negative at the level of ICC but often positive at the level of RT-PCR.

Antigens, CD34↗

PubMed2000

Dose staggering as a strategy to reduce drug--drug interactions due to reversible enzyme inhibition between orally administered drugs with high first pass effect: a computer simulation study.

A physiological computer model was designed to simulate the metabolic drug-drug interactions between two orally co-administered drugs due to reversible enzyme inhibition using drug concentrations in the portal vein. The extent of interactions was compared at steady-state for the effects of a delay in time between the administration of the substrate and the inhibitor. It was demonstrated that the extent of the interactions can be strongly affected by a time interval between the two drug administrations. By delaying the administration of the inhibitor until after the absorption phase of the substrate, one can significantly reduce the extent of the drug--drug interactions. This is because drug concentrations in the portal vein and the liver are much higher than that in the systemic circulation during the absorption phase. The model also showed that interactions involving substrates with a high extraction ratio (E(H)), i.e., drugs with higher first-pass effect, can be more strongly affected by dose staggering. Substrates with a low absorption rate constant (k(a)) require a longer interval with the inhibitor in order to reduce the extent of the interactions. This observation suggests dose staggering as a simple and cost-effective way to reduce the extent of unwanted drug--drug interactions in clinical practice.

Administration, Oral↗

PubMed2000

Maternal mortality in New York City: excess mortality of black women.

To assess maternal mortality in New York City, birth certificates and mortality records for New York City from 1988 through 1994 were linked and examined. During these 7 years, maternal mortality in New York City (defined by the International Classification of Diseases, 9th edition [ICD-9], as 630-676) per 100,000 live births significantly exceeded that of the country as a whole (20.2 vs. 8.2, respectively). Within New York City, an even greater variation of maternal mortality by race/ethnicity was noted, with the mortality ratio of whites, blacks, and Hispanics being 7.1, 39.5, and 14.4 per 100,000 live births, respectively. Socioeconomic characteristics such as educational attainment, marital status, and income influenced maternal mortality more in non-blacks than blacks. Analyses of cause-specific mortality revealed that, overall, ectopic pregnancy, embolism, and hypertension were the leading causes of death. However, the major factors explaining the excess maternal mortality among blacks were hypertension (mortality ratio of blacks to whites 5.57, 95% confidence interval 2.30-13.39), ectopic pregnancy (4.78, 95% confidence interval 2.40-9.51), and abortion (4.58, 95% confidence interval 1.72-12.22). These findings confirm a persisting gap in maternal death between black and white women. Indeed, if all New Yorkers who became pregnant enjoyed the survival of the city's non-Hispanic white residents, the difference in maternal mortality between the city and the nation would be eliminated.

Adolescent↗

PubMed2000

Phospholipid compositional changes of five pseudomonad archetypes grown with and without toluene.

Bacterial physiological responses to toluene exposure were investigated in five reference pseudomonad strains that express different toluene degradation pathways: Pseudomonas putida mt-2, Pseudomonas putida F1, Burkholderia cepacia G4, Burkholderia pickettii PKO1, and Pseudomonas mendocina KR1. The intact phospholipids of these archetypes, grown with and without toluene, were characterized using liquid chromatography/electrospray ionization/mass spectrometry. All strains showed significant changes in phospholipid content and composition as an adaptive response to toluene exposure, as well as considerable diversity in response mechanisms. For example, the phospholipid content of toluene-grown PKO1, F1, and KR1 were 10.9-34.7% of that found in succinate-grown strains, while the phospholipid content of mt-2 and G4 increased by 56% and 94%, respectively, when grown on toluene. In addition, PKO1, F1, and mt-2 responded to the presence of toluene by synthesizing more phosphatidylglycerol, whereas G4 and KR1 synthesized phospholipids with polyunsaturated fatty acids (C18:2) on one or both of the sn-2 positions. These changes in phospholipid composition and concentration probably reflect the sensitivity and degree of tolerance of these strains to toluene, and suggest that different mechanisms are utilized by dissimilar bacteria to maintain optimal lipid ordering in the presence of such environmental pollutants.

Burkholderia↗

PubMed2000

Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs.

Cystinuria is an inherited renal and intestinal disease characterized by defective amino acid reabsorption and cystine urolithiasis. Different forms of the disease, designated type I and non-type I in cystinuric humans, can be distinguished clinically and biochemically, and have been associated with mutations in the SLC3A1 (rBAT) and SLC7A9 genes, respectively. Type I cystinuria is the most common form and is inherited as an autosomal recessive trait in humans. Cystinuria has been recognized in more than 60 breeds of dogs and a severe form, resembling type I cystinuria, has been characterized in the Newfoundland breed. Here we report the cloning and sequencing of the canine SLC3A1 cDNA and gene, and the identification of a nonsense mutation in exon 2 of the gene in cystinuric Newfoundland dogs. A mutation-specific test was developed for the diagnosis and control of cystinuria in Newfoundland dogs. In cystinuric dogs of six other breeds, either heterozygosity at the SLC3A1 locus or lack of mutations in the coding region of the SLC3A1 gene were observed, indicating that cystinuria is genetically heterogeneous in dogs, as it is in humans. The canine homologue of human type I cystinuria provides the opportunity to use a large animal model to investigate molecular approaches for the treatment of cystinuria and other renal tubular diseases.

Amino Acid Sequence↗

PubMed2000

The role of the graft endothelium in transplant rejection: evidence that endothelial activation may serve as a clinical marker for the development of chronic rejection.

In this review, we discuss the role of the allograft endothelium in the recruitment and activation of leukocytes during acute and chronic rejection. We discuss associations among endothelial activation responses, the expression of adhesion molecules, chemokines and chemokine receptors, and rejection; and we propose that endothelial vascular cellular adhesion molecule-1 (VCAM-1) may be used as a surrogate marker of acute rejection and allograft vasculopathy. In addition, we describe potential mechanistic interpretations of persistent endothelial cell (EC) expression of major histocompatibility complex (MHC) class II molecules in allorecognition. The graft endothelium may provide an antigen-specific signal to transmigrating, previously activated, T cells and may induce B7 expression on locally transmigrating leukocytes to promote costimulation. Taken together, these functions of the EC provide it with a potent regulatory role in rejection and in the maintenance of T-cell activation via the direct and/or the indirect pathways of allorecognition.

Biomarkers↗

PubMed2000

Relation of Fos-IR expression in the pelvic ganglion to sexual behavior in laboratory rats.

The pelvic ganglion (PG) provides both sympathetic and parasympathetic innervation to the genitalia and other pelvic structures. To determine whether neuronal activity; of the PG, as detected by Fos-like immunoreactivity (Fos-IR), is related to sexual stimulation, male and female rats were tested under a variety of conditions. In males, Fos-IR expression in the PG was positively correlated with the amount of both genital and noncontact stimulation. In females, only ejaculation preceded by multiple intromissions induced a significant increase in Fos-IR; multiple intromissions or ejaculation preceded by only 0-1 intromission did not affect Fos-IR. Additional experiments comparing Fos-IR expression, in which some females were allowed to pace their sexual contact and others were not, revealed that ejaculation duration was the key factor in the induction of Fos-IR in female rats. Because the conditions under which Fos-IR expression occurred in females are identical to those required for sperm transport, we suggest that, in the female, sperm transport is regulated in part by autonomic outflow from the PG after copulation. These relations between sexual behavior and measures of PG activity are consistent with the idea that the sexually dimorphic organization of the peripheral nervous system plays a major role in mediating the gender-specific outcome of copulation: ejaculation in the male and sperm transport in the female.

Animals↗

PubMed2000

Serum potassium and cardiovascular mortality.

BACKGROUND: The impact of serum potassium on mortality is inadequately defined. OBJECTIVE: To determine the association of serum potassium with mortality. METHODS: We analyzed NHANES I Epidemiological Follow-up Study data from 1974-1992. Of 2,992 subjects with baseline serum potassium, 156 were excluded because their vital status was not known. A total of 2,836 subjects with serum potassium within 2.7-5.4 mmol/L were studied. All-cause and cardiovascular mortality were assessed controlling for sociodemographic status, smoking, medical history, and clinical characteristics. RESULTS: At baseline, mean age was 46.6 years, and mean serum potassium was 4.07 mmol/L. Subjects were stratified into three groups by mean +/-1 standard deviation of serum potassium: low, 2.7-3.7 mmol/L (N = 477); middle, 3.8-4.4 mmol/L (N = 1,982); and high, 4.5-5.4 mmol/L (N = 377). The cardiovascular mortality rate per 1,000 person-years adjusted for age, gender, and race for the high serum potassium group (8.1) was significantly higher than the middle (5.3) and low (6.5) serum potassium groups. Further analysis, controlling for age, gender, race, smoking status, cholesterol, and history of diabetes, renal disease, and cardiovascular disease, revealed that the increased cardiovascular mortality among subjects with moderately increased serum potassium was most prominent in those reporting use of diuretics (hazard ratio, 2.65; 95% confidence interval [95% CI], 1.20 to 5.85) and those with abnormal renal function (hazard ratio, 1.89; 95% CI, 1.05 to 3.41). CONCLUSION: In this general population sample with mostly normal serum potassium, higher serum potassium was independently associated with increased cardiovascular mortality.

Cardiovascular Diseases↗

PubMed2000

Pulse pressure: a predictor of cardiovascular mortality among young normotensive subjects.

Wide pulse pressure has been associated with increased cardiovascular disease events among hypertensive subjects. To test the hypothesis that this association also exists among normotensive subjects, data from the first National Health and Nutritional Examination Survey and the 1992 Epidemiological Follow-up Study were analyzed. The study group included 7346 participants, aged 25-74 years, with baseline blood pressure levels <140/90 mmHg and without a history of hypertension. Deaths from cardiovascular disease and all other causes were determined. At entry, mean age and blood pressure level were 43.4 years and 118/76 mmHg. During an average follow-up period of 17.4 years, there were 1443 (19.6%) deaths, 557 of them ascribed to cardiovascular disease. Age-race-adjusted cardiovascular mortality was significantly higher for those in the highest quartile of pulse pressure (> or = 50 mmHg). However, after stratification into age <55 years and > or = 55 years, and controlling for other cardiovascular risk factors, increased pulse pressure was associated with cardiovascular mortality only in younger men and women. In these subjects, men and women with pulse pressures > or = 48, and > or = 46 mmHg, respectively, had a relative risk (95% confidence in terval) of 2.35 (1.21-4.38) and 2.90 (1.34-4.98) for cardiovascular mortality with those with pulse pressures of less than 36 and 34 mmHg, respectively (p < 0.05) as reference. While systolic blood pressure by itself was a weaker predictor of cardiovascular mortality than pulse pressure, diastolic and mean arterial pressure were not predictive at all. No measure of blood pressure was related to mortality in those aged > or = 55 years. In conclusion, among young subjects, but not older normotensive persons, at very low risk of cardiovascular disease, a wide pulse pressure is associated with increased cardiovascular mortality.

Adult↗

PubMed2000

Nuclear factor-kappaB inhibitor peptide inhibits spontaneous and interleukin-1beta-induced sleep.

Nuclear factor-kappaB (NF-kappaB) is a transcription factor that when activated promotes production of several sleep-promoting substances such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, and nerve growth factor. Therefore, we hypothesized that inhibition of NF-kappaB activation would attenuate sleep. A NF-kappaB cell-permeable inhibitor peptide (IP) was injected intracerebroventricularly (5 and 50 microg for rats, 100 microg for rabbits). On a separate day, time-matched control injections of a cell-permeable inactive control peptide were done in the same animals. The 50-microg dose of IP in rats and the 100-microg dose in rabbits significantly inhibited non-rapid eye movement sleep and rapid eye movement sleep if administered during the light period. Moreover, pretreatment of rabbits with 100 microg of the IP 12 h before intracerebroventricular injection of IL-1beta (10 ng) significantly attenuated IL-1beta-induced sleep and febrile responses. The current data support the hypothesis that a brain cytokine network is involved in sleep regulation and that NF-kappaB is a crucial factor in physiological sleep regulation.

Animals↗

PubMed2000

Interleukin-13 and transforming growth factor-beta1 inhibit spontaneous sleep in rabbits.

Proinflammatory cytokines, including interleukin-1beta and tumor necrosis factor-alpha are involved in physiological sleep regulation. Interleukin (IL)-13 and transforming growth factor (TGF)-beta1 are anti-inflammatory cytokines that inhibit proinflammatory cytokines by several mechanisms. Therefore, we hypothesized that IL-13 and TGF-beta1 could attenuate sleep in rabbits. Three doses of IL-13 (8, 40, and 200 ng) and TGF-beta1 (40, 100, and 200 ng) were injected intracerebroventricularly 3 h after the beginning of the light period. In addition, one dose of IL-13 (200 ng) and one dose of TGF-beta1 (200 ng) were injected at dark onset. The two higher doses of IL-13 and the highest dose of TGF-beta1 significantly inhibited spontanenous non-rapid eye movement sleep (NREMS) when they were given in the light period. IL-13 also inhibited NREMS after dark onset administration; however, the inhibitory effect was less potent than that observed after light period administration. The 40-ng dose of IL-13 inhibited REMS duration during the dark period. TGF-beta1 administered at dark onset had no effect on sleep. These data provide additional evidence for the hypothesis that a brain cytokine network is involved in regulation of physiological sleep.

Animals↗

PubMed2000

An ether stressor increases REM sleep in rats: possible role of prolactin.

Sleep alterations after a 1-min exposure to ether vapor were studied in rats to determine if this stressor increases rapid eye-movement (REM) sleep as does an immobilization stressor. Ether exposure before light onset or dark onset was followed by significant increases in REM sleep starting approximately 3-4 h later and lasting for several hours. Non-REM (NREM) sleep and electroencephalographic slow-wave activity during NREM sleep were not altered. Exposure to ether vapor elicited prolactin (Prl) secretion. REM sleep was not promoted after ether exposure in hypophysectomized rats. If the hypophysectomy was partial and the rats secreted Prl after ether exposure, then increases in REM sleep were observed. Intracerebroventricular administration of an antiserum to Prl decreased spontaneous REM sleep and inhibited ether exposure-induced REM sleep. The results indicate that a brief exposure to ether vapor is followed by increases in REM sleep if the Prl response associated with stress is unimpaired. This suggests that Prl, which is a previously documented REM sleep-promoting hormone, may contribute to the stimulation of REM sleep after ether exposure.

Administration, Inhalation↗