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Biomedical subjects

B Kennedy

Publications and source records attributed to B Kennedy.

At least 37 records · Page 2Linked to original sources
PubMed1999

Income inequality, primary care, and health indicators.

BACKGROUND: The significant association of income inequality with a variety of health indicators is receiving increasing attention. There has also been increasing evidence of a link between primary care and improved health status. We examined the joint relationship between income inequality, availability of primary care, and various health indicators to determine whether primary care has an impact on health indicators by modifying the adverse effect of income inequality. METHODS: Our ecologic study used the US states as the units of analysis. In analyzing the data, we looked at the associations among income inequality, primary care, specialty care, smoking, and health indicators, using Pearson's correlation coefficients for intercorrelations and the adjusted multiple regression procedure. To examine the effect of inequality and primary care on health outcome indicators, we conducted path analyses according to a causal model in which inequality affects health both directly and indirectly through its impact on primary care. RESULTS: Our study indicates that both primary care and income inequality exerted a strong and significant direct influence on life expectancy and total mortality (P <.01). Primary care also exerted a significant direct influence on stroke and postneonatal mortality (P <.01). Although levels of smoking are also influential, the effect of income inequality and primary care persists after controlling for smoking. Primary care serves as one pathway through which income inequality influences population-level mortality and at least some other health outcome indicators. CONCLUSIONS: It appears possible that a primary care orientation may, in part, overcome the severe adverse effects on health of income inequalities.

Cerebrovascular Disorders↗
PubMed1999

Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles.

The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins (PGs) in the gastrointestinal tract have provided a rationale for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. In the present study, the preclinical pharmacological and biochemical profiles of rofecoxib [Vioxx, also known as MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent inhibitor of the COX-2-dependent production of PGE(2) in human osteosarcoma cells (IC(50) = 26 +/- 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC(50) = 18 +/- 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC(50) > 50 microM in U937 cells and IC(50) > 15 microM in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC(50) = 0.34 microM) but caused inhibition of purified human COX-1 in a non-time-dependent manner that could only be observed at a very low substrate concentration (IC(50) = 26 microM at 0.1 microM arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE(2) synthesis with an IC(50) value of 0.53 +/- 0.02 microM compared with an IC(50) value of 18.8 +/- 0.9 microM for the inhibition of COX-1-derived thromboxane B(2) synthesis after blood coagulation. Using the ratio of the COX-1 IC(50) values over the COX-2 IC(50) values in the human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent models, rofecoxib is a potent inhibitor of carrageenan-induced paw edema (ID(50) = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID(50) = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID(50) = 0.24 mg/kg), and adjuvant-induced arthritis (ID(50) = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a (51)Cr excretion assay for detection of gastrointestinal integrity in either rats or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis with improved gastrointestinal tolerability.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1998

Mycoplasma hyorhinis infection of pigs selectively bred for high and low immune response.

Pigs have been selected for high (H) or low (L) combined antibody and cell-mediated immune response to test the high immune response phenotype as a candidate for an indirect approach to improving health and productivity in livestock. Mycoplasma hyorhinis infection was induced in H and L pigs of the 4th generation of selection to test the hypothesis that immune response lines differ in response to infection. The major disease sign, arthritis, was more severe in the H pigs both clinically and at necropsy. M. hyorhinis was isolated at higher colony counts from synovial fluids of the H pigs. In contrast, pleuritis and peritonitis were less severe in pigs of the H than those of the L line. Pericarditis, although less in H than L pigs, did not differ significantly by line. Synovial fluid antibody to M. hyorhinis did not differ by line but H pigs produced serum antibody earlier and to a higher titre than did L pigs. Selection for H or L immune response therefore alters response to M. hyorhinis, however there is no indication of a consistent line-related health advantage.

Animals↗
PubMed1998

Induction of secretory phospholipase A2 confirms the systemic inflammatory nature of adjuvant arthritis.

Adjuvant arthritis (AA) is an accepted model of inflammatory arthritis. Until now, however, there is little information about inflammatory mediators, specifically in relation to the arachidonic acid cascade in AA. Our objective was to study the expression of secretory (sPLA2) and cytosolic (cPLA2) phospholipases A2 in various organs during the course of AA. AA was induced in Lewis rats which were sacrificed at days 0, 7, 14, 21, 28 and 42. Expression of sPLA2 mRNA and protein and mRNA of cPLA2 in paws, regional lymph nodes, spleen, liver, lungs and aorta was investigated. Serum sPLA2 activity increased from 15213 +/- 1131 to a maximum of 32,455 +/- 4109 nmol/30' on day 21. Maximal increase in sPLA2 mRNA in paws, lung and aorta was observed on day 14, and in the lymph nodes and spleen on day 28. In the liver, trace levels were found with no corresponding protein expression. In paws, lung, aorta and lymph nodes maximum increase in sPLA2 protein was noted on day 14 whereas the spleen showed constant sPLA2 protein level during AA. cPLA2 mRNA detected in all organs, did not significantly change during the course of AA, with the exception of regional lymph nodes where the message increased between 14 and 28 day. Induction of mRNA and protein of sPLA2 in several organs is an evidence that AA is a systemic inflammatory process. The parallelity of the sPLA2 expression to the severity of inflammatory process, implies that sPLA2 may play pathogenic role in AA. Lack of enhancement of cPLA2 mRNA may mean that this enzyme is either not induced in AA, or it increases earlier in the course of the inflammatory process.

Animals↗
PubMed1998

Recruitment and retention of minority participants in the DASH controlled feeding trial. DASH Collaborative Research Group. Dietary Approaches to Stop Hypertension.

The Dietary Approaches to Stop Hypertension (DASH) study was a National Heart, Lung, and Blood Institute multicenter trial that compared the impact of three dietary patterns on blood pressure (BP) among adults with high normal blood pressure or mild (Stage I) hypertension. DASH's high minority representation (two-thirds of the 459 randomized participants came from minority populations, and 60% of the cohort were African American) offered a valuable opportunity to assess factors affecting minority enrollment and retention in clinical trials of lifestyle modification. Recruitment strategies included targeted mailings to specific groups, mass mailings, community and worksite screenings, and mass media advertising; the four DASH clinical centers also reimbursed participants from $150 to $160. The most productive recruitment strategies tended to be mass mailings directed at a broad audience that was weighted toward, but not limited to, minority participants. DASH's African-American participants overwhelmingly (89%) cited health and dietary factors, such as learning more about blood pressure and healthy eating habits, as their primary reason for participating, while only six percent listed the financial incentives as their primary reason for participating. Eighty-eight percent of African-American respondents reported they would participate again in a similar study. The insights from DASH should help inform future efforts to recruit minority participants.

Adult↗
PubMed1997

Early postinfection antiviral treatment reduces viral load and prevents CD4+ cell decline in HIV type 2-infected macaques.

Reports of significant reductions in plasma viral load by anti-HIV drugs have raised the possibility that antiviral therapy, if initiated sufficiently early, may result in sustained control of infection and prolonged clinical benefits. We evaluated the effects of intervention coincident with infection using an antiviral nucleoside, d4T, in Macaca nemestrina infected with a highly pathogenic isolate of HIV-2 (HIV-2[287]). Infection with this virus reproducibly results in high viremia and rapid CD4+ cell depletion, allowing a sensitive measurement of the treatment effect on viral load and clinical outcome. Compared to the control group, d4T-treated macaques showed significantly lower (2-3 log10) plasma- and cell-associated viral load. No CD4+ cell decline was observed in the treatment group while on therapy with d4T whereas CD4+ cells of control macaques declined from a preinfection mean of 32% of PBMCs to below 10%. Notably, when d4T treatment was withdrawn after 16 weeks, five of the six macaques continued to control viral load and have maintained normal CD4+ cell level for more than a year. These results demonstrate that early antiviral intervention, even of a limited duration, may constitute an important strategy against lentiviral-induced disease.

Animals↗
PubMed1997

Mechanism of inhibition of protein-tyrosine phosphatases by vanadate and pervanadate.

Vanadate and pervanadate (the complexes of vanadate with hydrogen peroxide) are two commonly used general protein-tyrosine phosphatase (PTP) inhibitors. These compounds also have insulin-mimetic properties, an observation that has generated a great deal of interest and study. Since a careful kinetic study of the two inhibitors has been lacking, we sought to analyze their mechanisms of inhibition. Our results show that vanadate is a competitive inhibitor for the protein-tyrosine phosphatase PTP1B, with a Ki of 0.38+/-0.02 microM. EDTA, which is known to chelate vanadate, causes an immediate and complete reversal of the inhibition due to vanadate when added to an enzyme assay. Pervanadate, by contrast, inhibits by irreversibly oxidizing the catalytic cysteine of PTP1B, as determined by mass spectrometry. Reducing agents such as dithiothreitol that are used in PTP assays to keep the catalytic cysteine reduced and active were found to convert pervanadate rapidly to vanadate. Under certain conditions, slow time-dependent inactivation by vanadate was observed; since catalase blocked this inactivation, it was ascribed to in situ generation of hydrogen peroxide and subsequent formation of pervanadate. Implications for the use of these compounds as inhibitors and rationalization for some of their in vivo effects are considered.

Animals↗
PubMed1997

Sources of human urinary epinephrine.

The kidney is a likely source for some urinary epinephrine (E) since adrenalectomized animals and humans continue to excrete urinary E and the human kidney contains E synthesizing enzymes. We studied subjects during an intravenous infusion of 3H-E to determine the fraction of urinary E derived from the kidney. Eight normal subjects (CON) and 5 older, heavier hypertensives (OHH) ate a light breakfast along with ascorbic acid supplementation and had intravenous and arterial lines placed. They received an infusion of 3H-E and had an oral water load. During the final hour of 3H-E infusion, urine and arterial blood samples were collected for 3H-E and E levels. After the 3H-E infusion was abruptly discontinued, arterial blood samples were collected to measure 3H-E kinetics. The total body clearance of 3H-E was about 2,500 ml/min from plasma and clearance of 3H-E to urine was about 170 ml/min. CON had plasma E levels of 43 +/- 4 pg/ml. Their predicted rate of clearance of E from plasma to urine of 7,471 +/- 865 pg/min was less than (P = 0.018) the actual urinary E excretion of 15,037 +/- 2,625 pg/min. Thus, 43 +/- 9% of urinary E in CON was apparently derived from renal sources and not filtered from blood. Among OHH 85 +/- 4% of urinary E was derived from the kidney, significantly (P < 0.01) different from CON. The OHH also produced much more urinary E than predicted from plasma 3H-E clearance into urine (P = 0.03). A major fraction of urinary E is not filtered from the blood stream but is apparently derived from kidney. A small fraction of urinary E may be derived from E stored in nerve endings along with norepinephrine, but this probably represents less than 2% of urinary E. Renal cleavage of E sulfate into E may be another potential source of urinary E. Some, and perhaps most, urinary E not filtered from the bloodstream is derived from renal N-methylation of norepinephrine as the human kidney has two enzymes capable of converting norepinephrine to E. In conclusion, a major portion of urinary E is derived from the kidney and not filtered from the bloodstream. This is an important factor in the interpretation of urine E levels. Renal E could alter renal blood flow, electrolyte reabsorption, and renin release prior to excretion into urine.

Adult↗
PubMed1997

Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa.

Inadequate levels of all-trans-retinol in the blood cause retinal dysfunction; hence, genes implicated in retinal vitamin-A metabolism represent candidates for inherited retinal degenerations. In the current study, molecular genetic analysis of a consanguineous pedigree segregating for non-syndromic autosomal recessive retinitis pigmentosa (arRP) indicated that the affected siblings were homozygous by descent for a G4763A nucleotide substitution in RLBP1, the gene encoding cellular retinaldehyde-binding protein (CRALBP). This substitution is predicted to replace an arginine with glutamine at residue 150. CRALBP is not expressed in photoreceptors but is abundant in the retinal pigment epithelium (RPE) and Müller cells of the neuroretina, where it carries 11-cis-retinol and 11-cis-retinaldehyde. When expressed in bacteria, recombinant CRALBP (rCRALBP) containing the R150Q substitution was less soluble than wild-type rCRALBP. Mutant rCRALBP was purified from the soluble cell lysate and the protein structure was verified by mass spectrometry. The mutant protein lacked the ability to bind 11-cis-retinaldehyde. These findings suggest that arRP in the current pedigree results from a lack of functional CRALBP, presumably leading to disruption of retinal vitamin-A metabolism.

Amino Acid Sequence↗
PubMed1997

Sleep apnea, norepinephrine-release rate, and daytime hypertension.

Patients with obstructive sleep apnea (OSA) are often hypertensive, and both apneics and hypertensives are reported to have increased sympathetic nerve activity. We measured plasma norepinephrine (NE) levels, clearance, and release rate among 65 subjects who breathed room air, a hypoxic gas mixture, and the hypoxic mixture combined with intermittent breath holding. Apneics' plasma NE across all three breathing conditions was 307 pg/ml compared with the non-apneics' level of 248 pg/ml (p = 0.017). NE clearance increased from 3.2 l/minute to 3.9 l/minute when subjects breathed a hypoxic gas mixture (p < 0.001). NE clearance was similar among normal controls, apneics, and hypertensives. The rate at which NE was released from sympathetic nerves into the bloodstream was higher among hypertensives but not among apneics while subjects breathed room air. Hypoxia increased the NE-release rate from 892 ng/minute to 1,042 ng/minute (p < 0.001) and increased the NE-release rate more among apneics than non-apneics (p < 0.001). The NE-release rate response to hypoxia and breath holding differed between hypertensives and normotensives (p < 0.001) and between apneics and non-apneics (p < 0.001). Normotensive apneics had the largest increase in NE release during hypoxia. Like other investigators, we found that plasma NE levels were increased among apneics. Calculation of NE-release rate and correction for blood pressure status revealed a more complex situation. Apneics breathing room air had a normal NE-release rate; any increase in sympathetic neuronal NE release could be attributed to apneics who were also hypertensive. However, apneics had a greater NE response to hypoxia. These results suggest that apneics are susceptible to transient increases in sympathetic nervous activity and that hypertensive apneics maintain increased sympathetic nervous release of NE in the daytime.

Adult↗