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Biomedical subjects

K Young

Publications and source records attributed to K Young.

At least 19 recordsLinked to original sources

Department of Veterans Affairs Cooperative Studies Program genetic linkage study of schizophrenia: ascertainment methods and sample description.

To help clarify the genetics of schizophrenia, the Department of Veterans Affairs Cooperative Studies Program has completed data collection for a genetic linkage study of schizophrenia. This article describes the methodological details of the data collection. Subsequent articles will describe the results of our genome scan, which is now in progress. The data collection protocol included the Diagnostic Interview for Genetic Studies, the Family Interview for Genetic Studies, a review of medical records, and the collection of blood for transformation into lymphoblast cell lines. Among relatives of schizophrenic probands, we assessed auditory attention and verbal memory with neuropsychological tests. Among the 166 families ascertained for the study, 143 had a single affected sib-pair, 17 had three affected siblings, one had five affected siblings and five had two sets of affected siblings. There was a total of 216 affected sib-pairs in these families. Using the n-1 rule, these families contain 188 independent affected sib-pairs.

Adult↗

Interrelations between plasma homocysteine and intracellular S-adenosylhomocysteine.

S-Adenosylhomocysteine, a potent intracellular methylation inhibitor, is suggested as a potential mediator for hyperhomocysteinemia-related vascular changes. We investigated the effect of acute and chronic hyperhomocysteinemia on intracellular S-adenosylhomocysteine and S-adenosylmethionine in rats and humans. Elevated plasma homocysteine in rats infused with homocysteine produced an increase in S-adenosylhomocysteine (P < 0.001) but not S-adenosylmethionine levels (P > 0.05) in various rat tissues. However intraerythrocyte S-adenosylhomocysteine and S-adenosylmethionine levels were not changed in homocysteine-infused rats and human subjects with experimentally acute hyperhomocysteinemia by methionine loading test. In contrast, erythrocyte S-adenosylhomocysteine levels were significantly higher in chronic renal failure patients, who had chronically elevated plasma homocysteine levels, than in either vascular disease patients or healthy controls (P < 0.05). In conclusion, acute hyperhomocysteinemia can increase intracellular S-adenosylhomocysteine levels in tissues actively involved in homocysteine metabolism. The findings are relevant to homocysteine-related endothelial dysfunction since S-adenosylhomocysteine modulates endothelial cell apoptosis.

Adult↗

Proton NMR chemical shifts and coupling constants for brain metabolites.

Proton NMR chemical shift and J-coupling values are presented for 35 metabolites that can be detected by in vivo or in vitro NMR studies of mammalian brain. Measurements were obtained using high-field NMR spectra of metabolites in solution, under conditions typical for normal physiological temperature and pH. This information is presented with an accuracy that is suitable for computer simulation of metabolite spectra to be used as basis functions of a parametric spectral analysis procedure. This procedure is verified by the analysis of a rat brain extract spectrum, using the measured spectral parameters. In addition, the metabolite structures and example spectra are presented, and clinical applications and MR spectroscopic measurements of these metabolites are reviewed.

Acetic Acid↗

Generalising to theory: the use of a multiple case study design to investigate needs assessment and quality of care in community nursing.

This paper outlines the detail of the case study method used in a project commissioned by the English National Board for Nursing, Midwifery and Health Visiting (ENB) to investigate the changing educational needs of community nurses with regard to needs assessment and quality of care in the context of the NHS and Community Care Act, 1990. It explains the methodological procedures and analytic processes which led to integration of data across the whole study, focusing on the role of a prior theoretical framework in case study design. Recently qualified practitioners (health visitors and district nurses) were observed during a regular shift (N=134 visits), concentrating on their practice of assessing needs, and on liaison and collaboration within teams and across sectors. They were interviewed after the observation period (N=33 practitioners), to determine the extent of formality they attached to each assessment, and elicit information about aspects which may be embedded in everyday practice as well as those recorded for explicit requirements.The preliminary analysis resulted in the modification of a model for assessing service quality, and identified various points where a 'policy-practice gap' might arise between policies and practice in both the health service and education. The practicalities of operationalising a multiple case study design into research are highlighted, and the mechanism for 'generalising to theory' illustrated.

Community Health Nursing↗

Assessment of a polyester-covered nitinol stent in an atherosclerotic swine model.

PURPOSE: To evaluate the short-term patency and healing characteristics of the Cragg EndoPro covered stent in an atherosclerotic model as one of the Food and Drug Administration requirements before possible approval of the device for human use in the United States. MATERIALS AND METHODS: Seventeen self-expanding stent-grafts were placed in the aorta and right and left iliac arteries of six Yucatan microswine exposed to a regimen of accelerated atherosclerosis. The stent-grafts were constructed from nitinol wire formed into a tubular zigzag configuration. The stent frame was covered by a thin woven polyester fabric tube, with medium permeability, available in multiple diameters and lengths. The animals were killed at 24 hours, 3 months, and 6 months. Assessment was done by angiography and histology. RESULTS: All stents were patent immediately after deployment. Two stents were occluded at follow-up, indicating an 88% patency rate. Minor lumen narrowing was found at the follow-up intervals. Histologic examination revealed a mixture of mature and immature endothelial cells lining both the native and stented regions in all vessels examined. The new endoluminal surface was composed primarily of fibrocollagen and elastic fibers and smooth muscle cells. Intimal thickness was inversely correlated to medial thickness. Medial compression with atrophy was observed routinely with rare necrosis. Complete tissue ingrowth was seen by 3 months. The degree of vascular inflammation increased over time, as well as the foreign body giant cell reaction to the polyester fabric. CONCLUSION: The patency rate does not appear to be better than that with angioplasty or noncovered stent placement in the studied time frame. The progressive vascular inflammatory changes noted should be further investigated in longer-term animal trials to ensure its safety in humans because this device is meant to be permanent.

Alloys↗

A taxonomy of needs assessment, elicited from a multiple case study of community nursing education and practice.

The role and expectations of community nurses in carrying out needs assessments changed when an internal quasi-market was introduced to the British health service under the National Health Service (NHS) & Community Care Act 1990. This paper reports on a study commissioned by the English National Board for Nursing, Midwifery and Health Visiting (ENB) to investigate the changing educational needs of community nurses with regard to needs assessment in the context of this legislation. A multiple case study design was utilized and four cases identified, incorporating the geographical variation in England. Recently qualified practitioners (health visitors and district nurses) were observed during a regular shift (n=134 visits), concentrating on their practice of assessing needs, and on liaison and collaboration within teams and across sectors. Participants were interviewed after the observation period (n=33 practitioners), to determine the extent of formality they attached to each assessment, and to elicit information about aspects which may be embedded in everyday practice. Single and multiple case analyses across the four cases used an iterative process of pattern-matching, replication logic and explanation building. The preliminary analysis yielded a descriptive 'taxonomy' which could serve as a basis for classifying the variants of needs assessment and help to clarify the whole phenomenon. When applied further to the data, this revealed the complex interactions between the different ideals (relating to policy, nursing and ascribed worth), the various types (purpose, formality/specificity and complexity) and timing (in relation to client, service and practice issues) within needs assessment.

Community Health Nursing↗

The effect of vitamin-mineral supplementation on the intelligence of American schoolchildren: a randomized, double-blind placebo-controlled trial.

CONTEXT: Many medical, nutrition, and education professionals have long suspected that poor diet impairs the academic performance of Western schoolchildren; academic performance often improves after improved diet. However, others have suggested that such academic gains may be due to psychologic effects rather than nutrition. To resolve this issue, two independent research teams conducted randomized trials in which children were given placebos or low-dose vitamin-mineral tablets designed to raise nutrient intake to the equivalent of a well-balanced diet. Both teams reported significantly greater gains in nonverbal intelligence among the supplemented groups. The findings were important because of the apparent inadequacy of diet they revealed and the magnitude of the potential for increased intelligence. However, none of the ten subsequent replications, or the two original trials, were without limitations leaving this issue in controversy. OBJECTIVES: To determine if schoolchildren who consume low-dose vitamin-mineral tablets will have a significantly larger increase in nonverbal intelligence than children who consume placebos in a study that overcomes the primary criticisms directed at the previous 12 controlled trials. DESIGN: A double-blind, placebo-controlled trial using stratified randomization within each teacher's class based on preintervention nonverbal intelligence. SETTINGS AND SUBJECTS: Two "working class," primarily Hispanic, elementary schools in Phoenix, Arizona, participated in the study. Slightly more than half the teachers in each school distributed the tablets daily to 245 schoolchildren aged 6 to 12 years. INTERVENTION: Daily vitamin-mineral supplementation at 50% of the U.S. daily recommended allowance (RDA) for 3 months versus placebo. OUTCOME MEASURES: Post-test nonverbal IQ, as measured by the Wechsler Intelligence Scale for Children-Revised (WISC-R), while controlling for pretest nonverbal IQ as a covariate. FOUR MAIN RESULTS: First, a significant difference of 2.5 IQ points (95% CI: 1.85-3.15) was found between 125 children given active tablets and 120 children given placebo tablets (p = 0.038). Second, this finding is consistent with the mean 3.2 IQ point net gain found in the 12 similar but less rigorous studies. Third, a significantly higher proportion of children in the active group gained 15 or more IQ points when compared to the placebo group (p < 0.01). Fourth, although 81 matched pairs produced no difference at all in nonverbal IQ gain, the modest 2.5 IQ point net gain for the entire sample can be explained by the remaining 24 children who took active tablets, and had a 16 point higher net gain in IQ than the remaining 19 placebo controls. CONCLUSIONS: This study confirms that vitamin-mineral supplementation modestly raised the nonverbal intelligence of some groups of Western schoolchildren by 2 to 3 points but not that of most Western schoolchildren, presumably because the majority were already adequately nourished. This study also confirms that vitamin-mineral supplementation markedly raises the non-verbal intelligence of a minority of Western schoolchildren, presumably because they were too poorly nourished before supplementation for optimal brain function. Because nonverbal intelligence is closely associated with academic performance, it follows that schools with children who consume substandard diets should find it difficult to produce academic performance equal to those schools with children who consume diets that come closer to providing the nutrients suggested in the U.S. RDA. The parents of schoolchildren whose academic performance is substandard would be well advised to seek a nutritionally oriented physician for assessment of their children's nutritional status as a possible etiology.

Arizona↗

Skeletal muscle contractile and noncontractile components in young and older women and men.

To examine the influences of age, gender, and habitual physical activity level on human skeletal muscle composition, we developed a relatively simple magnetic resonance imaging method for the quantitation of leg anterior compartment contractile and noncontractile content. We studied 23 young (11 women and 12 men, 26-44 yr old) and 21 older (10 women and 11 men, 65-83 yr old) healthy adults. Analysis was by two-factor (age, gender) ANOVA. Physical activity, quantitated by three-dimensional accelerometer worn about the waist for 1 wk, was not different between groups. Men had larger contractile and noncontractile cross-sectional areas (cm(2)) than women, with no gender effect on percent noncontractile area. Young subjects had larger contractile areas and smaller absolute (cm(2)) and relative (percent total) noncontractile areas than older subjects. There was a significant linear relationship between physical activity and percent noncontractile area in older (r = -0.68, P = 0.002) but not young subjects. These data demonstrate a more than twofold increase in the noncontractile content of locomotor muscles in older adults and provide novel support for physical activity as a modulator of this age-related change in muscle composition.

Adult↗

Dynamic cerebral autoregulation in sick newborn infants.

The sick newborn infant is vulnerable to brain injury and impaired cerebral autoregulation is thought to contribute to this. Coherent averaging is a method of measuring the dynamic cerebral autoregulatory response that is particularly suitable for neonates. We used this method in combination with a measure of the gradient of the cerebral blood flow velocity (CBFV) response following transient blood pressure (BP) peaks to study dynamic autoregulation in infants undergoing intensive care. Term and preterm infants at high risk of neurologic injury were compared with a control group of infants, also undergoing intensive care. Simultaneous video-EEG, CBFV (using transcranial Doppler), and arterial blood pressure measurements were obtained intermittently during a study period of at least 2 h. Cerebral autoregulatory response curves were constructed for high risk and control groups. Intact cerebral autoregulation produces a characteristic response consisting of a brief period when CBFV follows arterial blood pressure but quickly returns to baseline value. An impaired autoregulatory response shows CBFV mirroring the arterial blood pressure curve closely. Thirteen high-risk infants, who also had seizures (10 term and 3 preterm) and 12 control infants (6 term and 6 preterm) were studied. Autoregulation was absent in high-risk term and preterm infants. It was also absent in preterm control infants. Term, neurologically healthy infants undergoing intensive care have an intact autoregulatory response. The constant passive response seen in high-risk infants may reflect the severity of the underlying neurologic disease.

Blood Flow Velocity↗

Tacrolimus (FK 506) induced thrombotic thrombocytopenic purpura after ABO mismatched second liver transplantation: salvage with plasmapheresis and prostacyclin.

We report the course of thrombotic thrombocytopenic purpura (TTP) in a patient receiving tacrolimus (FK506) immunosuppression for an ABO mismatched second liver graft. A Chinese woman with fulminant hepatitis-B reactivation failed a living-related orthotopic liver transplantation (OLT) due to portal vein thrombosis. An ABO mismatched cadaveric OLT (group A to O) was performed, with peri-operative plasmapheresis to reduce anti-A hemagglutinin titers. On day 30, she developed fever, hemolysis, thrombocytopenia and neurologic dulling. Prominent microangiopathic features in peripheral blood film, and characteristic brain lesions on magnetic resonance imaging confirmed TTP. She responded initially to intensive plasmapheresis with cryosupernatant replacement, and withdrawal of FK506. An attempted reintroduction of FK506 for threatened rejection led to TTP exacerbation. This was controlled with prolonged plasmapheresis and a ten-day infusion of prostacyclin. Immunosuppression was changed to mycophenolate mofetil. By day 53, the peripheral film and lactate dehydrogenase level had returned to baseline and plasmapheresis was stopped.

ABO Blood-Group System↗

Inhibition of IMP-1 metallo-beta-lactamase and sensitization of IMP-1-producing bacteria by thioester derivatives.

IMP-1 metallo-beta-lactamase is a transferable carbapenem-hydrolyzing enzyme found in some clinical isolates of Pseudomonas aeruginosa, Serratia marcescens and Klebsiella pneumoniae. Bacteria that express IMP-1 show significantly reduced sensitivity to carbapenems and other beta-lactam antibiotics. A series of thioester derivatives has been shown to competitively inhibit purified IMP-1. As substrates for IMP-1, the thioesters yielded thiol hydrolysis products which themselves were reversible competitive inhibitors. The thioesters also increased sensitivity to the carbapenem L-742,728 in an IMP-1-producing laboratory stain of Escherichia coli, but will need further modification to improve their activity in less permeable organisms such as Pseudomonas and Serratia. Nonetheless, the thioester IMP-1 inhibitors offer an encouraging start to overcoming metallo-beta-lactamase-mediated resistance in bacteria.

Bacteria↗

Computer model for cryosurgery of the prostate.

The objective of this study was to devise an interactive tool to assist in cryoablation therapy through computer modeling, simulation, and visualization. CryoSim, a software package, accepts a set of acquired and processed three-dimensional ultrasound images, then models heat diffusion (formation of the iceball) based on numerical approximation of the heat equation and knowledge of the thermal properties of the underlying tissues. Results of cryoexperiments were found to be significantly similar to those generated by CryoSim. Therefore, CryoSim provides a viable technique for predicting the outcome of cryosurgery, and establishes a platform for future automation of cryosurgery.

Animals↗

Spectral simulations incorporating gradient coherence selection.

Computer-aided methods can considerably simplify the use of the product operator formalism for theoretical analysis of NMR phenomena, which otherwise becomes unwieldy for anything but simple spin systems and pulse sequences. In this report, two previously available programming approaches using symbolic algebra (J. Shriver, Concepts Magn. Reson. 4, 1-33, 1992) and numerical simulation using object-oriented programming (S. A. Smith, T. O. Levante, B. H. Meier, and R. R. Ernst, J. Magn. Reson. A 106, 75-105, 1994) have been extended to include the use of gradient operators for simulation of spatially localized NMR spectroscopy and gradient coherence selection. These methods are demonstrated using an analysis of the response of an AX(3) spin system to the STEAM pulse sequence and verified with experimental measurements on lactate.

Computer Simulation↗

Balanced biosynthesis of major membrane components through regulated degradation of the committed enzyme of lipid A biosynthesis by the AAA protease FtsH (HflB) in Escherichia coli.

The suppressor mutation, named sfhC21, that allows Escherichia coli ftsH null mutant cells to survive was found to be an allele of fabZ encoding R-3-hydroxyacyl-ACP dehydrase, involved in a key step of fatty acid biosynthesis, and appears to upregulate the dehydrase. The ftsH1(Ts) mutation increased the amount of lipopolysaccharide at 42 degrees C. This was accompanied by a dramatic increase in the amount of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase [the IpxC (envA) gene product] involved in the committed step of lipid A biosynthesis. Pulse-chase experiments and in vitro assays with purified components showed that FtsH, the AAA-type membrane-bound metalloprotease, degrades the deacetylase. Genetic evidence also indicated that the FtsH protease activity for the deacetylase might be affected when acyl-ACP pools were altered. The biosynthesis of phospholipids and the lipid A moiety of lipopolysaccharide, both of which derive their fatty acyl chains from the same R-3-hydroxyacyl-ACP pool, is regulated by FtsH.

ATP-Dependent Proteases↗

Mobile elements carrying ermF and tetQ genes in gram-positive and gram-negative bacteria.

Bacteroides spp. conjugative transposon Tn5030 is 150 kb which includes a 43 kb characterized region containing a number of defined genes and an open reading frame (ORF). The 43 kb region is organized with the ORF1 immediately upstream from the ermF gene, coding for an rRNA methylase, then an unknown 20 kb region downstream followed by the tetQ gene (coding for a ribosomal protection protein) then the rteA and rteB genes. The role of ORF1 is unclear; rteA is a putative sensor and rteB a regulator. Thirty-seven (62%) of 60 isolates, representing one gram-positive anaerobic and 13 gram-negative anaerobic species, co-transferred the ermFand tetQ genes to an unrelated Enterococcus faecalis recipient. We used the polymerase chain reaction to show the linkage between ORF1, ermF, tetQ, rteA and rteB. Our data suggest that the ORF1 gene product may participate in the transfer of the ermF gene with or without the ORF1-rteB region and has homology to bacterial transposases. Isolates that co-transferred the ermF and tetQ genes carried and transferred the rteB gene, suggesting that the rteB gene product may be important in transfer of the 43 kb ORF1-rteB region to E. faecalis. The rteB gene product is not required when ermF is transferred independently of tetQ.

Bacterial Proteins↗

In vitro activities of the potent, broad-spectrum carbapenem MK-0826 (L-749,345) against broad-spectrum beta-lactamase-and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli clinical isolates.

An important mechanism of bacterial resistance to beta-lactam antibiotics is inactivation by beta-lactam-hydrolyzing enzymes (beta-lactamases). The evolution of the extended-spectrum beta-lactamases (ESBLs) is associated with extensive use of beta-lactam antibiotics, particularly cephalosporins, and is a serious threat to therapeutic efficacy. ESBLs and broad-spectrum beta-lactamases (BDSBLs) are plasmid-mediated class A enzymes produced by gram-negative pathogens, principally Escherichia coli and Klebsiella pneumoniae. MK-0826 was highly potent against all ESBL- and BDSBL-producing K. pneumoniae and E. coli clinical isolates tested (MIC range, 0.008 to 0.12 microgram/ml). In E. coli, this activity was associated with high-affinity binding to penicillin-binding proteins 2 and 3. When the inoculum level was increased 10-fold, increasing the amount of beta-lactamase present, the MK-0826 MIC range increased to 0.008 to 1 microgram/ml. By comparison, similar observations were made with meropenem while imipenem MICs were usually less affected. Not surprisingly, MIC increases with noncarbapenem beta-lactams were generally substantially greater, resulting in resistance in many cases. E. coli strains that produce chromosomal (Bush group 1) beta-lactamase served as controls. All three carbapenems were subject to an inoculum effect with the majority of the BDSBL- and ESBL-producers but not the Bush group 1 strains, implying some effect of the plasmid-borne enzymes on potency. Importantly, MK-0826 MICs remained at or below 1 microgram/ml under all test conditions.

Carbapenems↗

Lysophosphatidic acid-induced calcium mobilization and proliferation in kidney proximal tubular cells.

Patients with proteinuria tend to develop progressive renal disease with proximal tubular cell atrophy and interstitial scarring. It has been suggested that the nephrotoxicity of albuminuric states may be due to the protein molecule itself or by lipids, such as lysophosphatidic acid (LPA), that albumin carries. LPA was found to cause a transient increase in intracytoplasmic free Ca2+ ([Ca2+]i) in opossum kidney proximal tubule cells (OK) that was maximal at 100 microM LPA and was dose dependent with an EC50 of 2.6 x 10(-6) M. This Ca2+ mobilization was from both internal stores and across the plasma membrane and was pertussis toxin (PTX) insensitive. Treatment of OK cells with 100 microM LPA for 5 min was found to cause a twofold increase in [3H]thymidine incorporation and a three- to fivefold increase over control after 24 h. This was highly PTX sensitive and insensitive to pretreatment with the tyrosine kinase inhibitors genistein and herbimycin A. These findings may be of significance in the progression of renal disease and indicate the potential importance of lipids in modulating proximal tubule cell function and growth.

Animals↗

Characterization of human and rat brain myristoyl-CoA:protein N-myristoyltransferase: evidence for an alternative splice variant of the enzyme.

Using 5'-rapid amplification of cDNA ends, we have identified an extended 5'-end of mRNA coding for human myristoyl-CoA:protein N-myristoyltransferase (NMT). PCR using primers based on this new 5'-sequence and reverse primers within the currently accepted coding sequence of the enzyme resulted in the identification of a novel splice variant of NMT. In vitro translation of these cDNAs resulted in the production of proteins with apparent molecular masses of 63 kDa and 48 kDa. Immunoprecipitation of NMT from human cell lines and immunoblotting of a range of rat tissues has identified proteins with molecular masses corresponding to those derived from these cDNAs, and provided evidence that their relative abundance differs among tissues. Our results provide evidence that this enzyme exists in different forms resulting from alternative splicing of the mRNA.

Acyltransferases↗