Fundholding and prescribing. Similar savings in non-fundholding practices are not similarly rewarded.
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Drug Costs↗
Biomedical subjects
J E Clark
Publications and source records attributed to J E Clark.
On becoming skillful: patterns and constraints.
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Child Development↗
Non-tuberculous mycobacterial lymphadenopathy.
The surgical and antimicrobial treatment of non-tuberculous mycobacterial lymphadenopathy in 17 children was reviewed. Node excision was curative, but most nodes were still incised leaving discharging lesions. Standard antituberculous treatment was unhelpful, but a new macrolide/quinolone combination appeared to be effective in three cases.
Antitubercular Agents↗
For young jumpers, differences are in the movement's control, not its coordination.
Previous research on the development of jumping has indicated that the coordination of the jump is stable from its inception, but that individual differences lie in the control of the task. The purpose of this study was to examine control in the vertical jump as performed by novice jumpers. Two groups of children who varied in their ability to regulate the takeoff angle were compared on measures of coordination and control. The children's groups were also compared to a group of skilled adults. Both children's groups demonstrated temporal coordination patterns comparable to the adult pattern, though the children were distinguished from the adults on selected spatial (control) measures. The results indicate that a mature pattern of coordination for the jump exists at the earliest stages of the behavior's appearance in the movement repertoire. The novice, however, lacks the ability to precisely control, or tune, the movement to task demands.
Child, Preschool↗
Effects of 17-octadecynoic acid, a suicide-substrate inhibitor of cytochrome P450 fatty acid omega-hydroxylase, on renal function in rats.
This study evaluated the ability of 17-octadecynoic acid (17-ODYA) to inhibit the metabolism of arachidonic acid by cytochrome P450 in renal cortical microsomes of rats, and characterized the effects of intrarenal infusion of this substance on renal hemodynamics and the excretion of water and electrolytes. 17-ODYA was a potent inhibitor (IC50 < 100 nM) of the formation of 20-hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids by rat renal cortical microsomes incubated with arachidonic acid. Infusion of 17-ODYA (16.5 nmol/min; n = 8) directly into the renal cortical interstitium of rats produced a diuresis and a natriuresis which were associated with an increase in renal papillary blood flow in the absence of changes in renal blood flow, cortical blood flow or glomerular filtration rate. 17-ODYA inhibited the omega-hydroxylation of arachidonic acid by microsomes prepared from the infused kidney by 61.3 +/- 9.2% (n = 7) relative to that observed in the contralateral kidney, whereas infusion of vehicle (n = 6) or palmitate (n = 4) had no effect on renal metabolism of arachidonic acid by cytochrome P450. Infusion of 17-ODYA (33 nmol/min) into the renal artery of rats also increased urine flow and sodium excretion, whereas renal blood flow and glomerular filtration rate were not significantly altered. Papillary blood flow increased 36% during infusion of 17-ODYA into the renal artery, and renal interstitial hydrostatic pressure increased from 8.7 +/- 1.1 to 13.8 +/- 1.5 mm Hg. These results suggest that endogenous cytochrome P450 metabolites of arachidonic acid influence renal medullary hemodynamics and the excretion of water and electrolytes.
Animals↗
Expression of rabbit cytochromes P4504A which catalyze the omega-hydroxylation of arachidonic acid, fatty acids, and prostaglandins.
The omega-hydroxylation product of arachidonic acid is thought to be a potent vasoconstrictor or a precursor thereof in kidney. In this report, we have measured the capacity of four rabbit CYP4A enzymes, each expressed in COS-1 cells, to catalyze the omega-hydroxylation of arachidonic acid. These rates were compared to those obtained for other substrates such as lauric acid, palmitic acid, and prostaglandins PGE1 and PGA1. With the exception of P4504A5, all of the enzymes tested exhibited relatively high rates for the omega-hydroxylation of arachidonic acid. P4504A5 showed very little activity toward arachidonic or palmitic acids as compared to that toward lauric acid (< 10%). In contrast, P4504A6 and P4504A7 catalyzed the omega-hydroxylation of arachidonic acid at rates that were roughly 50% of that observed for lauric acid. P4504A4 was not active toward lauric acid, but it also catalyzed the omega-hydroxylation of arachidonic acid at a rate that was roughly 20% of that exhibited for PGE1. Thus, each enzyme exhibits a distinct substrate specificity profile across this panel of substrates. A sensitive RNase protection assay was used to provide a more quantitative estimate of the relative abundance of mRNAs encoding P4504A5, P4504A6, and P4504A7 in liver and kidney from control, pregnant, and clofibrate-treated animals. CYP4A5 is the most abundant of the mRNAs, but it was not induced in kidney and only moderately (2-fold) in liver by clofibric acid. CYP4A7 exhibits a similar pattern of induction by clofibrate. In contrast, CYP4A6 is induced 12-fold in liver and 6-fold in kidney. The higher induction ratio largely reflects a lower basal level of expression for CYP4A6 than for CYP4A7 and CYP4A5. Following treatment with clofibrate, the amount of CYP4A6 mRNA is similar to those of CYP4A5 and CYP4A7. Pregnancy did not affect the expression of CYP4A5, CYP4A6, or CYP4A7, although it induced the expression of CYP4A4 to detectable levels in the liver and kidney, where it is not normally found in nonpregnant animals. Our results indicate that the enzyme whose mRNA is most highly induced by clofibric acid (P4504A6) and the enzyme selectively elevated during pregnancy (P4504A4) both exhibit relatively high rates for the omega-hydroxylation of arachidonic acid.
Animals↗
Cytochrome P450 4A4: expression in Escherichia coli, purification, and characterization of catalytic properties.
Rabbit lung prostaglandin omega-hydroxylase (P450 4A4) was expressed in Escherichia coli using the isopropyl beta-D-thiogalactopyranoside (IPTG) inducible expression vector pCWori+, containing the full-length cDNA encoding the P450 4A4. The first seven codons were changed to reflect E. coli codon bias [a modification of the method of Barnes et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 5597-5601]; only the second residue of P450 4A4 was altered (Ser to Ala), while the remaining mutations were silent. This strategy was adopted in order to minimize changes in the structure of the expressed enzyme. Induction by IPTG of the apoprotein peaked after 6 h, and by including the heme precursor delta-aminolevulinic acid, enzymatic activity peaked 12 h after addition of IPTG. The isolated membrane fraction, free of cell debris, contained 12-15 nmol of P450/L of media. The expressed enzyme was purified to electrophoretic homogeneity, and kinetic and spectrophotometric data indicate that this expressed, purified enzyme is equivalent to the enzyme purified from rabbit lung. The Km for PGE1 was determined to be 3.0 microM, which is the same as that obtained for the enzyme purified from lung [Williams et al. (1984) J. Biol. Chem. 259, 14600-14608]. The CO-reduced difference spectrum of purified P450 4A4 exhibited a lambda max at 450 nm, and the absolute absorbance spectrum of the pyridine hemochromogen revealed a typical b type heme. To characterize P450 4A4 further, the catalytic activities with prostaglandin E1 (PGE1), arachidonate, 15-hydroxyeicosatetraenoic acid (15-HETE), and palmitate were investigated.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminolevulinic Acid↗
Characterization of a cDNA encoding a human kidney, cytochrome P-450 4A fatty acid omega-hydroxylase and the cognate enzyme expressed in Escherichia coli.
A cDNA encoding a cytochrome P-450 4A (CYP4AII) was cloned from a human kidney cDNA library. Northern blot analysis and RNase protection assays indicate that related mRNAs occur in kidney and liver with the highest abundance found in kidney. The enzyme was expressed from its cDNA in Escherichia coli. A solubilized preparation of the enzyme reconstituted with cytochrome P-450 reductase catalyzed the omega-hydroxylation of lauric acid, palmitic acid, and arachidonic acid with turnover numbers of 9.8, 2.2 and 0.55 min-1, respectively. Little or no activity was detected toward prostaglandins A1 and E1.
Amino Acid Sequence↗
Induction of flavin-containing monooxygenase (FMO B) in rabbit lung and kidney by sex steroids and glucocorticoids.
Modulation of lung and kidney levels of flavin-containing monooxygenase (FMO) isoform B following sc administration of dexamethasone, progesterone, beta-estradiol, aldosterone, or beta-estradiol plus progesterone was examined in male rabbits. Both dexamethasone and progesterone increased FMO B protein levels in lung. N-Oxygenation of N,N'-dimethylaniline (DMA) was significantly induced in lung microsomes from rabbits treated with progesterone. In kidney, only dexamethasone was effective in inducing FMO B protein levels and DMA N-oxygenation. Surgical implantation of osmotic pumps containing beta-estradiol or progesterone into non-pregnant female rabbits resulted in elevated plasma levels of these steroids after 4-5 days at which point the lung levels of FMO B were induced by 35 and 82% for beta-estradiol and progesterone, respectively. The responsiveness of FMO B in lung to both progesterone and glucocorticoids and in kidney to only the latter is consistent with the developmental pattern of both maternal FMO B and peak plasma levels of these steroids during pregnancy.
Aldosterone↗
20-Hydroxyeicosatetraenoic acid is an endogenous vasoconstrictor of canine renal arcuate arteries.
Recent studies have indicated that renal arteries can produce 20-hydroxyeicosatetraenoic acid (20-HETE) and suggest the potential involvement of a P450 metabolite of arachidonic acid in the myogenic activation of canine renal arteries. In the present study, the effects of 20-HETE on isolated canine renal arcuate arteries were studied. Administration of 20-HETE to the bath or the lumen at concentrations of 0.01-1 microM produced a graded reduction in the diameter of these vessels. In contrast, 19(R)-HETE was a vasodilator, whereas 19(S)-HETE was relatively inactive. The vasoconstrictor response to 20-HETE was not altered by the cyclooxygenase inhibitor indomethacin, endoperoxide/thromboxane receptor antagonist SQ29548, or combined blockade of the cyclooxygenase, lipoxygenase, and P450 pathways using indomethacin, baicalein, and 7-ethoxyresorufin. The response to 20-HETE was associated with depolarization and a sustained increase in the intracellular calcium concentration in renal vascular smooth muscle cells. Patch-clamp studies indicated that 20-HETE significantly reduced mean open time, the open-state probability, and the frequency of opening of a 117-pS K+ channel recorded from renal vascular smooth muscle cells in the cell-attached mode. Microsomes prepared from the renal cortex of dogs produced 20-HETE and 20-carboxyarachidonic acid when incubated with [14C]arachidonic acid. These results indicate that 20-HETE is an endogenous constrictor of canine renal arcuate arteries. The vasoconstrictor response to 20-HETE resembles the myogenic activation of these vessels after elevations in transmural pressure and suggests a potential role for this substance in the regulation of renal vascular tone.
Animals↗
Strategies for improving maintenance of weight loss. Toward a continuous care model of obesity management.
The management of obesity represents an important objective in the care of many NIDDM patients. In recent years, progress has been made in increasing initial weight reductions, but poor long-term maintenance of weight loss remains a vital clinical concern. This article reviews the challenge of weight-loss maintenance and recommends the adoption of a continuous care model of obesity management. Strategies to improve the long-term maintenance of weight loss are described, and empirical tests of their effectiveness are reviewed. Collectively, the findings suggest that, after treatment for obesity, multifaceted programs comprised of continued professional contact, skills training, social support, and exercise, can enhance the long-term maintenance of weight loss.
Continuity of Patient Care↗
Anger and sports participation.
This study investigated differences between 19 varsity and 20 intramural male football players in trait anger, anger expression, and sports orientation. While varsity athletes reported comparable levels of trait anger, they described significantly less internalized (anger in) and externalized anger (anger out) than intramural athletes. Also, the varsity athletes reported significantly less anger control. Significant differences were also found for competitiveness and goal orientation, but not win orientation, such that the varsity athletes were more competitive and goal-oriented than the intramural athletes. The implications of these findings are discussed in terms of several alternative hypotheses.
Adolescent↗
A longitudinal study of intralimb coordination in the first year of independent walking: a dynamical systems analysis.
Using a dynamical systems approach, we examined the development of intralimb coordination over the first year of independent walking. The segmental motion of the thigh and shank and their intralimb coordinative relationship were modeled dynamically as a system of coupled limit cycles. To test the predictions of such a dynamic model in the development of intralimb coordination, 3 infants were filmed from the onset of their first upright independent walking steps, and weekly for the next month and then every month thereafter until they had been walking for 1 year. 3 adults also were included for comparison. Analysis of the kinematic data derived from the film revealed that at the emergence of walking, the limit cycle system displayed instability in several aspects. With walking experience, however, the limit cycle regime became more attractive, such that by 3 months of walking the infants appeared to have found an adult-like stable coordinative relationship between the 2 segments. This pattern of instability followed by stability is consistent with the transitional behaviors of dynamical systems. Several potential control parameters are discussed that might contribute to the stabilization of the walking behavior. The utility of employing a dynamical systems approach for understanding developing behavioral systems is discussed.
Female↗
Cloned, expressed rat cerebellar nitric oxide synthase contains stoichiometric amounts of heme, which binds carbon monoxide.
The endogenous formation of nitric oxide (NO) has become an area of intense interest as evidence for its biological functions has been obtained in three distinct tissues: circulating macrophages, in which it exerts cytotoxic effects; blood vessels, in which it has been identified as endothelium-derived relaxing factor; and neuronal cells, in which it functions as a neurotransmitter. The formation of NO in brain extracts has been shown to be catalyzed by an enzyme, termed NO synthase, which generates the NO responsible for stimulation of cGMP formation, the highest levels of which occur in the cerebellum. NO synthase catalyzes the formation of citrulline from arginine with the coincident production of NO and has been shown to be a flavoprotein, containing 1 mol each of FAD and FMN, tetrahydrobiopterin, and iron. It is also reported to contain an alpha-helical, calmodulin-binding consensus sequence consistent with its stimulation by calmodulin in the presence of Ca2+. The formation of NO requires incorporation of one of the atoms of molecular oxygen into one of the guanidinium nitrogen atoms of arginine with the coincident formation of citrulline. This communication reports that rat cerebellar NO synthase, cloned and stably expressed in human kidney 293 cells, contains heme in amounts stoichiometric with the flavins FAD and FMN as evidenced by the appearance of a pyridine hemochrome and a reduced CO difference spectrum with an absorbance maximum at approximately 445 nm. The finding of a CO-binding heme moiety explains the presence of iron in the enzyme and suggests a role for prosthetic heme as an oxygenase reaction center. This report also presents evidence for incorporation of delta-[14C]aminolevulinate specifically into immunoprecipitable NO synthase in stably transfected human kidney 293 cells but not in nontransfected cells. Simultaneously, K. A. White and M. A. Marletta [(1992) Biochemistry 31, 6627-6631] have demonstrated a CO-binding heme prosthetic group in purified murine macrophage NO synthase and have suggested the identity of these reaction centers in both the constitutive (cerebellar) and inducible (macrophage) forms of NO synthase.
Amino Acid Oxidoreductases↗
Omega- and (omega-1)-hydroxylation of eicosanoids and fatty acids by high-performance liquid chromatography.
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Animals↗
Bilateral renal hemangiopericytoma.
The first reported case of bilateral renal hemangiopericytoma is presented. The 19 previous renal hemangiopericytomas that have been reported in the world literature are reviewed. This lesion has afflicted patients ranging in age from sixteen to sixty-eight years (mean 41 years) with an equal sex distribution. Mortality from hemangiopericytoma of the kidney has been 50 percent, and the primary mode of therapy remains surgical.
Adult↗
Development of categorical identification of native and non-native bilabial stops: infants, children and adults.
Using an infant speech identification (ISI) procedure, English language environment infants, two- and six-year-old children, and adults were tested for their identification of sounds on a native (voiced/voiceless bilabial stop) and a non-native (prevoiced/voiced bilabial stop) speech continuum. Categorical perception of the two contrasts diverged as a function of age, increasing for the native contrast and decreasing for the non-native between two and six years. In Experiment 2, subjects of the same four ages were tested for their identification of a continuum of harmonic tones varying in pitch. Comparison of the results of Experiment 1 with the essentially continuous perception of this pitch continuum supports the view that the perception of the native contrast becomes more categorical with age, while perception of the non-native contrast becomes less categorical, especially at six years. Experiment 3, in which adults were tested on the three continua with a multi-trial open set procedure, demonstrated that results with the ISI procedure in Experiments 1 and 2 are comparable to results with more traditional methods. The results of the three experiments are discussed in terms of the role of specific linguistic experience in the development of categorical speech perception.
Adult↗