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Biomedical subjects

J Chan

Publications and source records attributed to J Chan.

At least 73 records · Page 4Linked to original sources
PubMed2000

Acidosis induces necrosis and apoptosis of cultured hippocampal neurons.

Acidosis, hypoxia, and hypoglycemia rapidly and transiently appear after reduction of cerebral blood flow. Acidosis also accompanies head trauma and subarachnoid hemorrhage. These insults result in necrotic and apoptotic loss of neurons. We previously demonstrated that transient acidification of intracellular pH from 7.3 to 6.5 induces delayed neuronal loss in cultured hippocampal slices (49). We now report that acidosis induced both necrotic and apoptotic loss of neurons. Necrosis and apoptosis were distinguished temporally and pharmacologically. Necrosis appeared rapidly and was dose dependent with the duration of the acidosis treatment. Apoptosis was delayed with maximal number of apoptotic cells seen with a 30-min acidosis treatment. Apoptotic neuronal loss was accompanied by DNA fragmentation and was blocked by inhibitors of protein and RNA synthesis, ectopic expression of the anti-apoptotic gene bcl-2, or an inhibitor of caspases, proteases known to be activated during apoptosis. Necrotic neuronal loss was unaffected by these treatments. Hypothermia, a treatment known to attenuate neuronal loss following a variety of insults, blocked both acidosis-induced necrosis and apoptosis. These results indicate that acidosis is neurotoxic in vitro and suggest that acidosis contributes to both necrotic and apoptotic neuronal loss in vivo.

Acidosis↗
PubMed2000

Sonic hedgehog--regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system.

During development, basic helix-loop-helix (bHLH) proteins regulate formation of neurons from multipotent progenitor cells. However, bHLH factors linked to gliogenesis have not been described. We have isolated a pair of oligodendrocyte lineage genes (Olg-1 and Olg-2) that encode bHLH proteins and are tightly associated with development of oligodendrocytes in the vertebrate central nervous system (CNS). Ectopic expression of Olg-1 in rat cortical progenitor cell cultures promotes formation of oligodendrocyte precursors. In developing mouse embryos, Olg gene expression overlaps but precedes the earliest known markers of the oligodendrocyte lineage. Olg genes are expressed at the telencephalon-diencephalon border and adjacent to the floor plate, a source of the secreted signaling molecule Sonic hedgehog (Shh). Gain- and loss-of-function analyses in transgenic mice demonstrate that Shh is both necessary and sufficient for Olg gene expression in vivo.

Age Factors↗
PubMed2000

Conversational responsiveness in specific language impairment: evidence of disproportionate pragmatic difficulties in a subset of children.

Eighteen children with specific language impairment (SLI), from 6 to 8 years of age, were compared with 9 control children matched on age and nonverbal ability (CA controls) and with 9 younger control children of comparable language level (LA controls). Half of the SLI group were rated on a teacher checklist as having pragmatic difficulties: these were referred to as the pragmatic language impairment (PLI) group; the remainder were the typical (SLI-T) group. Children's responses to adult soliciting utterances were compared. All children usually responded to conversational solicitations, but children in the PLI group were more likely than control children to give no response, and they also made very little use of nonverbal responses, such as nodding. Nonverbal responding was closely related to the quality of children's responses. Children who failed to use nonverbal responses also had a relatively high level of pragmatically inappropriate responses that were not readily accounted for in terms of limited grammar or vocabulary. This study lends support to the notion that there is a subset of the language-impaired population who have broader communicative impairments, extending beyond basic difficulties in mastering language form, reflecting difficulty in responding to and expressing communicative intents. The analytic methods developed for this project have promise for the study of pragmatic difficulties in other clinical groups.

Adult↗
PubMed2000

Anatomical M-mode: A novel technique for the quantitative evaluation of regional wall motion analysis during dobutamine echocardiography.

Recognition of abnormal wall motion during dobutamine echocardiography requires an expert observer. Anatomical M-mode echocardiography may offer a novel quantitative approach to interpretation, amenable to less expert readers. We studied the application of this new modality to 124 patients (80 with known coronary anatomy and 44 patients at low probability of coronary disease) who underwent dobutamine echocardiography, using a standard protocol. Wall motion was interpreted by an experienced reader, using digitally stored 2-dimensional echocardiographic images at rest and peak stress. Percentage of systolic thickening was measured offline using anatomical M-mode echocardiography in the basal and mid segments at rest and peak dose, and compared with wall motion scores and coronary angiography. Of 729 segments, wall motion was identified as normal in 449, ischemic or viable in 171 and showed resting WM abnormalities only in 109 segments. After exclusion of the apex, anatomical M-mode measurements were feasible in 729 of 960 possible basal- and mid-zone segments (76%). Measurement of systolic thickening at peak dose was reproducible within (r2 = 0.83) and between observers (r2 = 0.93). Systolic thickening was significantly greater in segments with normal wall motion (37 +/- 2%) compared with ischemic or viable segments (30 +/- 2%, p < 0.001), and scar segments (23 +/- 3%, p < 0.001). There was an increment of thickening from rest to stress in normal and viable segments, no change in scar, and a decrement in ischemic segments. Significant coronary artery disease (defined by stenoses >70% diameter) was present in 59 patients. Systolic thickening showed significant variation between segments interpreted by wall motion scoring and angiography as true and false positive and true and false negative (p < 0.05). Measurement of systolic thickening using anatomical M-mode echocardiography offers an objective method to quantify systolic thickening at dobutamine echocardiography but has limited clinical feasibility.

Aged↗
PubMed2000

The two thyroid hormone receptor genes have opposite effects on estrogen-stimulated sex behaviors.

The two genes coding for thyroid hormone receptors (TR) alpha 1 and beta have opposite effects on female sex behaviors. Deletion of TRalpha 1 reduced them, whereas deletion of TRbeta actually increased them. These results could not be attributed to altered levels of hormones in the blood, general alterations in estrogen responsiveness or altered general activity. Instead, they indicate a previously unknown molecular mechanism upon which the two TR genes exert opposite influences.

Animals↗
PubMed2000

Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice.

Members of the Mycobacterium tuberculosis group synthesize a family of long-chain fatty acids, mycolic acids, which are located in the cell envelope. These include the non-oxygenated alpha-mycolic acid and the oxygenated keto- and methoxymycolic acids. The function in bacterial virulence, if any, of these various types of mycolic acids is unknown. We have constructed a mutant strain of M. tuberculosis with an inactivated hma (cmaA, mma4) gene; this mutant strain no longer synthesizes oxygenated mycolic acids, has profound alterations in its envelope permeability and is attenuated in mice.

Animals↗
PubMed2000

Two kinesin-related proteins associated with the cold-stable cytoskeleton of carrot cells: characterization of a novel kinesin, DcKRP120-2.

We have previously described the biochemical isolation of 65 kDa and 120 kDa microtubule-associated proteins from carrot cytoskeletons. The 65 kDa MAPs have subsequently been shown to be structural MAPs that reconstitute 30 nm cross-bridges of the kind that maintain cortical microtubules in parallel groups. By exploiting its avid binding to microtubules, we have now devised a method for isolating MAP120 from protoplast extracts, and shown that it has properties of a kinesin-related protein. MAP120 segregates with the cold stable pool of microtubules in carrot cytoskeletons, whilst the 65 kDa MAPs are also associated with the cold-sensitive microtubules. On gradient gels, MAP120 resolves as two kinesin-like bands. We report the isolation of a carrot cDNA, DcKRP120-2, corresponding to a novel kinesin of the BimC class known to move to the plus ends of microtubules. Antibodies raised against specific expressed sequences recognize the upper band, while the lower band is recognized by antibodies to the tobacco kinesin-related protein, TKRP125. We have also isolated a partial genomic carrot DNA, DcKRP120-1, homologous to the motor region of tobacco TKRP125. Immunofluorescence of the two proteins produces different staining patterns. Anti-TKRP125 labels the cortical microtubules and the pre-prophase band, but anti-DcKRP120-2 does so only weakly. Both clearly stain the spindle and the phragmoplast, but in a proportion of cells anti-DcKRP120-2 strongly decorates the phragmoplast mid-line where the plus ends of the microtubules overlap. We discuss the potential roles of these proteins during the microtubule cycle.

Amino Acid Sequence↗
PubMed2000

The influence of the composition of the nursing staff on primary bloodstream infection rates in a surgical intensive care unit.

OBJECTIVES: To determine the risk factors for acquisition of nosocomial primary bloodstream infections (BSIs), including the effect of nursing-staff levels, in surgical intensive care unit (SICU) patients. DESIGN: A nested case-control study. SETTING: A 20-bed SICU in a 1,000-bed inner-city public hospital. PATIENTS: 28 patients with BSI (case-patients) were compared to 99 randomly selected patients (controls) hospitalized > or =3 days in the same unit. RESULTS: Case- and control-patients were similar in age, severity of illness, and type of central venous catheter (CVC) used. Case-patients were significantly more likely than controls to be hospitalized during a 5-month period that had lower regular-nurse-to-patient and higher pool-nurse-to-patient ratios than during an 8-month reference period; to be in the SICU for a longer period of time; to be mechanically ventilated longer; to receive more antimicrobials and total parenteral nutrition; to have more CVC days; or to die. Case-patients had significantly lower regular-nurse-to-patient and higher pool-nurse-to-patient ratios for the 3 days before BSI than controls. In multivariate analyses, admission during a period of higher pool-nurse-to-patient ratio (odds ratio [OR]=3.8), total parenteral nutrition (OR=1.3), and CVC days (OR=1.1) remained independent BSI risk factors. CONCLUSIONS: Our data suggest that, in addition to other factors, nurse staffing composition (ie, pool-nurse-to-patient ratio) may be related to primary BSI risk. Patterns in intensive care unit nurse staffing should be monitored to assess their impact on nosocomial infection rates. This may be particularly important in an era of cost containment and healthcare reform.

Case-Control Studies↗
PubMed2000

Predictors of lead absorption in children of lead workers.

OBJECTIVES: This study was conducted to determine whether children of lead workers are at a higher risk of lead absorption and if so, to identify risk factors for absorption, including lifestyle, household, environmental and parental work practices with lead. METHODS: This cross-sectional study recruited 17 'lead worker' and 13 comparison 'non-lead worker' households. Companies and eligible employees were contacted using mail-out packs. Children were aged between 12 and 72 months. Data collection involved administration of a questionnaire and collection of dust, soil, water, paint-scraping samples, and blood from the children for the determination of lead and ferritin levels. Statistical analysis was performed using SPSS. RESULTS: Participants included seven of 29 eligible employees from 14 'scheduled' lead workplaces and 12 of 19 eligible employees from 19 'leadlighter' workplaces identified. The average lead level for workers was 13.9 micrograms/dl, children of lead workers 6.93 micrograms/dl (n = 22) and comparison group 3.93 micrograms/dl (n = 16). Water lead levels were all < 2.5 ppm. The lead content of three soil samples and nine dust samples was above suggested guideline levels. Lead levels were significantly higher in children of lead workers but all were within recommended levels. Inadequate practice of lead work hygiene measures, such as inadequate use of protective equipment and taking work clothes home, was a common factor in lead worker households that were found to have elevated soil and dust lead levels. The differences in lead levels between groups did not change significantly when adjustment was made for the clustering effect of more than one child per household. CONCLUSIONS: Children of lead workers are at higher risk of lead absorption. Poor work hygiene practices of lead workers suggest an association with elevated lead levels in their children. A number of other predictors were suggested by this study but the small numbers of participants made it difficult to detect statistically significant differences between subgroups.

Adult↗
PubMed2000

Trypanosoma cruzi infection (Chagas' disease) of mice causes activation of the mitogen-activated protein kinase cascade and expression of endothelin-1 in the myocardium.

Chagas' disease, caused by the parasite Trypanosoma cruzi, is an important cause of heart disease. Previous studies from this laboratory revealed that microvascular spasm and myocardial ischemia were observed in infected mice. Infection of endothelial cells with this parasite increased the synthesis of biologically active endothelin-1 (ET-1). Therefore. in the myocardium of T. cruzi-infected mice, we examined ET-1 expression and the p42/44-mitogen activated protein kinase (MAPK)-AP-1 pathway that regulates the expression of ET-1. There was parasitism and myonecrosis in the myocardium of infected C57BL/6 mice. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed elevated mRNA expression of transcription factor AP-1 (c-jun and c-fos) and increased AP-1 DNA binding activity as determined by electrophoretic mobility shift assay (EMSA). Western blot analysis demonstrated an increase in the phosphorylated forms of extracellular signal-regulated kinase (ERK1/2). ET-1 mRNA was upregulated in the myocardium of infected mice. Immunohistochemical and immunoelectron microscopy using anti-ET-1 antibody detected increased expression in cardiac myocytes and endothelium of these mice. These data suggest that ET-1 contributes to chagasic cardiomyopathy and that the mechanism of the increased expression of ET-1 is a result of the activation of the MAPK pathway by T. cruzi infection.

Animals↗
PubMed2000

Attenuation of and protection induced by a leucine auxotroph of Mycobacterium tuberculosis.

Attenuated mutants of Mycobacterium tuberculosis represent potential vaccine candidates for the prevention of tuberculosis. It is known that auxotrophs of a variety of bacteria are attenuated in vivo and yet provide protection against challenge with wild-type organisms. A leucine auxotroph of M. tuberculosis was created by allelic exchange, replacing wild-type leuD (Rv2987c), encoding isopropyl malate isomerase, with a mutant copy of the gene in which 359 bp had been deleted, creating a strain requiring exogenous leucine supplementation for growth in vitro. The frequency of reversion to prototrophy was <10(-11). In contrast to wild-type M. tuberculosis, the DeltaleuD mutant was unable to replicate in macrophages in vitro. Its attenuation in vivo and safety as a vaccine were established by the fact that it caused no deaths in immunodeficient SCID mice. Complementation of the mutant with wild-type leuD abolished the requirement for leucine supplementation and restored the ability of the strain to grow both in macrophages and in SCID mice, thus confirming that the attenuated phenotype was due to the DeltaleuD mutation. As a test of the vaccine potential of the leucine auxotroph, immunocompetent BALB/c mice, susceptible to fatal infection with wild-type M. tuberculosis, were immunized with the DeltaleuD mutant and subsequently challenged with virulent M. tuberculosis by both the intravenous and aerosol routes. A comparison group of mice was immunized with conventional Mycobacterium bovis BCG vaccine. Whereas all unvaccinated mice succumbed to intravenous infection within 15 weeks, mice immunized with either BCG or the DeltaleuD mutant of M. tuberculosis exhibited enhanced and statistically equivalent survival curves. However, the leuD auxotroph was less effective than live BCG in reducing organ burdens and tissue pathology of mice challenged by either route. We conclude that attenuation and protection against M. tuberculosis challenge can be achieved with a leucine auxotroph and suggest that to induce optimal protection, attenuated strains of M. tuberculosis should persist long enough and be sufficiently metabolically active to synthesize relevant antigens for an extended period of time.

Animals↗
PubMed2000

A commercial preparation of catalase inhibits nitric oxide production by activated murine macrophages: role of arginase.

Catalase is widely used as a pharmacological probe to evaluate the role of hydrogen peroxide in antimicrobial activities of phagocytic cells. This report demonstrates that the ability of a commercial preparation of catalase to inhibit concomitantly macrophage antimycobacterial activity and production of reactive nitrogen intermediates can be attributed, at least in part, to the depletion of L-arginine by contaminating arginase. In experimental systems that employ pharmacological probes, the existence of nonspecific effects should be considered in data interpretation.

Animals↗
PubMed2000

Quality measures for mental health care: results from a national inventory.

The National Inventory of Mental Health Quality Measures was funded by the Agency for Healthcare Research and Quality to (1) inventory process measures for assessing the quality of mental health care; (2) identify clinical, administrative, and quality domains where measures have been developed; and (3) identify areas where further research and development is needed. Among the 86 measures identified, most evaluated treatment of major mental disorders, for example, schizophrenia (24 percent) and major depression (21 percent). A small proportion focused on children (8 percent) or the elderly (9 percent). Domains of quality included treatment appropriateness (65 percent), continuity (26 percent), access (26 percent), coordination (13 percent), detection (12 percent), and prevention (6 percent). Few measures were evaluated for reliability (12 percent) or validity (3 percent). Measures imposing a lower burden were more likely to be in use (chi 2 = 4.41, p = .036). Further measures are needed to assess care for several priority clinical and demographic groups. Research should focus on measure validity, reliability, and implementation costs. In order to foster quality improvement activities and use of common measures and specifications for mental health care, the inventory of quality measures will be made available at www.challiance.org/cqaimh.

Adult↗
PubMed1999

The 65-kDa carrot microtubule-associated protein forms regularly arranged filamentous cross-bridges between microtubules.

In plants, cortical microtubules (MTs) occur in characteristically parallel groups maintained up to one microtubule diameter apart by fine filamentous cross-bridges. However, none of the plant microtubule-associated proteins (MAPs) so far purified accounts for the observed separation between MTs in cells. We previously isolated from carrot cytoskeletons a MAP fraction including 120- and 65-kDa MAPs and have now separated the 65-kDa carrot MAP by sucrose density centrifugation. MAP65 does not induce tubulin polymerization but induces the formation of bundles of parallel MTs in a nucleotide-insensitive manner. The bundling effect is inhibited by porcine MAP2, but, unlike MAP2, MAP65 is heat-labile. In the electron microscope, MAP65 appears as filamentous cross-bridges, maintaining an intermicrotubule spacing of 25-30 nm. Microdensitometer-computer correlation analysis reveals that the cross-bridges are regularly spaced, showing a regular axial spacing that is compatible with a symmetrical helical superlattice for 13 protofilament MTs. Because MAP65 maintains in vitro the inter-MT spacing observed in plants and is shown to decorate cortical MTs, it is proposed that this MAP is important for the organization of the cortical array in vivo.

Cell Membrane↗