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Biomedical subjects

W Clark

Publications and source records attributed to W Clark.

At least 37 records · Page 2Linked to original sources
PubMed2000

Changes in QT dispersion during adenosine infusion.

BACKGROUND: QT dispersion (QTd) measurement during treadmill stress testing has been to shown to improve the accuracy of exercise electrocardiogram (ECG) in the detection of significant coronary artery disease (CAD). HYPOTHESIS: The aim of this study was to determine whether adenosine-induced changes in QTd could predict significant CAD and to assess its efficacy as a diagnostic index in patients undergoing adenosine stress test. METHODS: QT interval measurements were made in 57 consecutive patients undergoing adenosine sestamibi stress test. Patients with an abnormal stress test underwent coronary angiography. Patients with significant disease by coronary angiography (> 70% stenosis) were classified as having CAD (Group 1), and those with normal stress images and/or normal coronaries by angiography were classified as having no CAD (Group 2). RESULTS: QT dispersion increased from 28.2 +/- 4.5 to 43.8 +/- 4.5 ms with a delta QTd of 15.53 +/- 3.68 in Group 1 (p = 0.001) and from 28.4 +/- 2.6 to 34.8 +/- 2.8 ms with a delta QTd of 6.58 +/- 2.21 ms in Group 2 (p = 0.006). Patients in Group 1 had a significantly higher increase in QTd (delta QTd) than the patients in Group 2 (p < 0.03). Addition of delta QTd (> 10 ms) to the ST depression during adenosine infusion would increase the sensitivity of the ECG from 23 to 65% and decrease the specificity from 91 to 70% for diagnosis of significant CAD. CONCLUSIONS: delta QTd is significantly more prolonged in patients with CAD during adenosine infusion. It increases the sensitivity of the stress ECG in diagnosis of CAD during adenosine infusion when used as an adjuvant index.

Adenosine↗
PubMed2000

v-Jun overrides the mitogen dependence of S-phase entry by deregulating retinoblastoma protein phosphorylation and E2F-pocket protein interactions as a consequence of enhanced cyclin E-cdk2 catalytic activity.

v-Jun accelerates G(1) progression and shares the capacity of the Myc, E2F, and E1A oncoproteins to sustain S-phase entry in the absence of mitogens; however, how it does so is unknown. To gain insight into the mechanism, we investigated how v-Jun affects mitogen-dependent processes which control the G(1)/S transition. We show that v-Jun enables cells to express cyclin A and cyclin A-cdk2 kinase activity in the absence of growth factors and that deregulation of cdk2 is required for S-phase entry. Cyclin A expression is repressed in quiescent cells by E2F acting in conjunction with its pocket protein partners Rb, p107, and p130; however, v-Jun overrides this control, causing phosphorylated Rb and proliferation-specific E2F-p107 complexes to persist after mitogen withdrawal. Dephosphorylation of Rb and destruction of cyclin A nevertheless occur normally at mitosis, indicating that v-Jun enables cells to rephosphorylate Rb and reaccumulate cyclin A without exogenous mitogenic stimulation each time the mitotic "clock" is reset. D-cyclin-cdk activity is required for Rb phosphorylation in v-Jun-transformed cells, since ectopic expression of the cdk4- and cdk6-specific inhibitor p16(INK4A) inhibits both DNA synthesis and cell proliferation. Despite this, v-Jun does not stimulate D-cyclin-cdk activity but does induce a marked deregulation of cyclin E-cdk2. In particular, hormonal activation of a conditional v-Jun-estrogen receptor fusion protein in quiescent, growth factor-deprived cells stimulates cyclin E-cdk2 activity and triggers Rb phosphorylation and DNA synthesis. Thus, v-Jun overrides the mitogen dependence of S-phase entry by deregulating Rb phosphorylation, E2F-pocket protein interactions, and ultimately cyclin A-cdk2 activity. This is the first report, however, that cyclin E-cdk2, rather than D-cyclin-cdk, is likely to be the critical Rb kinase target of v-Jun.

Animals↗
PubMed1999

Engagement in a non-escape (displacement) behavior elicits a selective and lateralized suppression of frontal cortical dopaminergic utilization in stress.

Although the preferential activation of the prefrontal cortical (PFC) dopaminergic system is generally observed in stress, limited exceptions to this have been observed. Certain non-escape behaviors have been demonstrated to attenuate physiological indices of stress (e.g., coping or displacement responses). One well-characterized non-escape behavior observed in stress is chewing, or gnawing, of inedible objects. Engagement in this behavior attenuates stress-related activation of the hypothalamopituitary-adrenal axis, in a variety of species. We examined the degree to which engagement in this non-escape behavior modulates stressor-induced activation of the PFC dopamine (DA) system. Rats and mice were exposed to a brightly lit novel environment (novelty stress) in the presence or absence of inedible objects. Following novelty exposure, various dopaminergic terminal fields were collected and dopamine and its major catabolite, DOPAC, were measured using HPLC with electrochemical detection. DOPAC/DA ratios were calculated as an index of DA utilization. In some cases serotonin (5-HT) and its major catabolite, 5-HIAA, were also measured. In animals that did not chew, novelty exposure elicited significant increases in DOPAC/DA levels within PFC, nucleus accumbens (shell and core subdivisions), and striatum (relative to quiet-controls). DOPAC/DA responses were greater in the right PFC than in the left PFC. Animals that chewed displayed significantly lower DOPAC/DA responses in PFC, but not other dopaminergic terminal fields. This effect of chewing was always observed in the right PFC and less consistently in the left PFC. Chewing did not alter novelty-induced increases in PFC 5-HIAA/5-HT responses. Thus, engagement in this non-escape behavior elicits a neuroanatomically and neurochemically specific attenuation of the PFC DA response in stress. Given the pivotal role of the PFC in certain cognitive and affective processes, behavioral regulation of PFC DA utilization may modulate cognitive and/or affective function in stress.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Therapeutic advances: leukotriene antagonists for the treatment of asthma.

Asthma is the most common respiratory disease encountered in clinical practice, affecting both children and adults. It is an important cause of respiratory morbidity and mortality. Recent therapeutic developments have shown that leukotrienes are the most potent and important inflammatory mediators in the pathology of both acute and chronic asthma. They cause increased bronchoconstriction, mucous secretion, and vascular permeability. Studies using compounds that block leukotrienes (receptor antagonists - montelukast and zafirlukast and 5-lipoxygenase inhibitors - zileuton) have demonstrated improved asthma control in patients aged 12 years and older. In this article we assess the therapeutic importance of these new compounds.

Adolescent↗
PubMed1999

Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial.

BACKGROUND AND PURPOSE: The purpose of this study was to test the feasibility, efficacy, and safety of combined intravenous (IV) and local intra-arterial (IA) recombinant tissue plasminogen activator (r-TPA) therapy for stroke within 3 hours of onset of symptoms. METHODS: This was a double-blind, randomized, placebo-controlled multi-center Phase I study of IV r-TPA or IV placebo followed by immediate cerebral arteriography and local IA administration of r-TPA by means of a microcatheter. Treatment activity was assessed by improvement on the National Institutes of Health Stroke Scale Score (NIHSSS) at 7 to 10 days. The Barthel Index, modified Rankin Scale, and the Glasgow Outcome Scale measured 3-month functional outcome. Arterial recanalization rates and their relation to total r-TPA dose and time to lysis were measured. Rates of life-threatening bleeding, intracerebral hemorrhage (ICH), or other bleeding complications assessed safety. RESULTS: Thirty-five patients were randomly assigned, 17 into the IV/IA group and 18 into the placebo/IA group. There was no difference in the 7- to 10-day or the 3-month outcomes, although there were more deaths in the IV/IA group. Clot was found in 22 of 34 patients. Recanalization was better (P=0. 03) in the IV/IA group with TIMI 3 flow in 6 of 11 IV/IA patients versus 1 of 10 placebo/IA patients and correlated to the total dose of r-TPA (P=0.05). There was no difference in the median treatment intervals from time of onset to IV treatment (2.6 vs 2.7 hours), arteriography (3.3 vs 3.0 hours), or clot lysis (6.3 vs 5.7 hours) between the IV/IA and placebo/IA groups, respectively. A direct relation between NIHSSS and the likelihood of the presence of a clot was identified. Eight ICHs occurred; all were hemorrhagic infarctions. There were no parenchymal hematomas. Symptomatic ICH within 24 hours occurred in 1 placebo/IA patient only. Beyond 24 hours, symptomatic ICH occurred in 2 IV/IA patients only. Life-threatening bleeding complications occurred in 2 patients, both in the IV/IA group. Moderate to severe bleeding complications occurred in 2 IV/IA patients and 1 placebo/IA patient. CONCLUSIONS: This pilot study demonstrates combined IV/IA treatment is feasible and provides better recanalization, although it was not associated with improved clinical outcomes. The presence of thrombus on initial arteriography was directly related to the baseline NIHSSS. This approach is technically feasible. The numbers of symptomatic ICH were similar between the 2 groups, which suggests that this approach may be safe. Further study is needed to determine the safety and effectiveness of this new method of treatment. Such studies should address not only efficacy and safety but also the cost-benefit ratio and quality of life, given the major investment in time, personnel, and equipment required by combined IV and IA techniques.

Aged↗
PubMed1998

Analysis of the interaction between c-Jun and c-Jun N-terminal kinase in vivo.

Regulation of c-Jun transcriptional activity is believed to depend on a physical interaction with c-Jun N-terminal kinase (JNK) that facilitates signal-regulated phosphorylation of multiple regulatory phosphoacceptor sites within the activation domain. Here we have investigated the structural requirements and consequences of regulatory phosphorylation for the interaction between c-Jun and JNK in vivo. We show that binding of JNK to c-Jun in vivo does not require JNK catalytic activity or the presence of the potential phosphoacceptor sites within c-Jun and that JNK retains the capacity to bind to a pseudo-phosphorylated mutant of c-Jun where these sites are replaced by phospho-mimetic aspartic acid residues. The c-Jun delta region docking site is essential for interaction with JNK in vivo but is not sufficient, because a c-Jun mutant that retains this region but that lacks the C-terminal DNA-binding domain fails to interact. Experiments using purified recombinant c-Jun and JNK proteins show that the c-Jun DNA-binding domain harbors an auxiliary interaction domain that has the potential to bind to JNK independently. Our results suggest that JNK can be tethered passively to c-Jun in situ through multiple interacting regions and, when activated, can stimulate c-Jun phosphorylation without necessarily dissociating from its substrate. Auxiliary interactions mediated by the DNA-binding domain could play a role in targeting JNK preferentially to c-Jun in specific homo- or heterodimeric complexes.

Amino Acid Substitution↗
PubMed1998

Outcome of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) using human sperm prepared via a new standardized swim-up technique fit for office use.

Objective: Recent developments in the assisted reproductive technology (ART) areas necessitate the use of new and more efficient and acceptable modes of gamete in vitro manipulation techniques. As established via the use of various forms of ART, the natural process of fertilization has been largely bypassed and the gametes are obtained and manipulated outside of the normal means of conception. For the male, improvements in sperm quality have involved the use of various techniques that aim to recover a small percentage of healthy spermatozoa that can be further used for the different ART procedures. Previous IVF results showed no differences in fertilization rates between ZSC and Percoll recovered sperm (Zarmakoupis-Zavos et al. ACOG, 1997). The current study was designed to study the fertilizing capacity of ZSC recovered spermatozoa and subsequent embryonic development and pregnancy rates established via IVF and ICSI procedures.Methods: Sperm specimens (n = 30) were prepared via the use of the standardized ZSC swim-up technique, which was designed to harvest almost all overlayered media at the end of the procedure to maximize the sperm recovery. The ZSC device consists of a column with a conical cavity where the semen is placed, and from where the sperm swim-up into the overlayered media and are subsequently recovered at the end of the procedure. Semen specimens were initially assessed and then prepared (0.5 mL each) via the ZSC swim-up technique. The enhancement of the routine semen parameters was assessed and the recovered specimens were used for either conventional IVF or ICSI.Results: The results of the fertilization and pregnancy via IVF and ICSI are shown below:The generated results point out that ZSC recovered specimens yielded acceptable levels of fertilization and pregnancy rates in our IVF and ICSI program. Furthermore, the IVF inseminations yielded higher fertilization rates with a slight increase in polyspermic oocytes when compared to the ICSI inseminations.Conclusion: The data generated in this study tend to point out that the ZSC, besides being a simple one-step standardized system, can also be effectively employed in an ART program and can generate adequate fertilization and pregnancy rates. We have previously shown that the quality and fertilizing capacity of ZSC recovered sperm is comparable to that recovered via Percoll gradients. However, the ZSC when compared to the Percoll method was less time consuming (5 minutes of actual labor) and less tedious by eliminating the dilution and centrifugation steps of Percoll preparation, since it washes the sperm while simultaneously selecting it. The ZSC is a standardized semen preparation method and could be the method of choice in an ART program.

Journal Article↗
PubMed1998

An oncogenic mutation uncouples the v-Jun oncoprotein from positive regulation by the SAPK/JNK pathway in vivo.

Stimulation of c-Jun transcriptional activity via phosphorylation mediated by the stress-activated or c-Jun amino-terminal (SAPK/JNK) subgroup of mitogen-activated protein kinases (MAP kinases) is thought to depend on a kinase-docking site (the delta region) within the amino-terminal activation domain, which is deleted from the oncogenic derivative, v-Jun [1] [2] [3]. This mutation markedly enhances v-Jun oncogenicity [4] [5]; however, its transcriptional consequences have not been resolved. In part, this reflects uncertainty as to whether binding of SAPK/JNK inhibits c-Jun function directly [6] [7] or, alternatively, serves to facilitate and maintain the specificity of positive regulatory phosphorylation [8]. Using a two-hybrid approach, we show that SAPK/JNK stimulates c-Jun transactivation in yeast and that this depends on both catalytic activity and physical interaction between the kinase and its substrate. Furthermore, c-Jun is active when tethered to DNA via SAPK/JNK, demonstrating that kinase binding does not preclude transactivation. Taken together, these results suggest that SAPK/JNK acts primarily as a positive regulator of c-Jun transactivation in situ, and that loss of the docking site physically uncouples v-Jun from this control. This loss-of-function model accounts for the deficit of v-Jun regulatory phosphorylation and repression of TPA response element (TRE)-dependent transcription observed in v-Jun-transformed cells and predicts that an important property of the oncoprotein is to antagonise SAPK/JNK-dependent gene expression.

Animals↗
PubMed1998

Drug abuse day treatment: a randomized clinical trial comparing day and residential treatment programs.

Clients entering a therapeutic community (TC)-oriented drug treatment program were randomly assigned to day or residential conditions and interviewed at 2 weeks and 6 months after admission. Outcomes included Addiction Severity Index composite scores and summary scores for the Beck Depression Inventory, Symptom Checklist-90-R, and a social support scale. Only clients who remained in treatment for at least 2 weeks were included. The mean age of the sample (N = 261) was 32.9 (SD = 6.7 years) and the mean education level was 12.1 years (SD = 1.9 years); 30% were women. Comparison of outcome scores at 6 months between groups, while controlling for baseline values, indicated greater improvement for residential clients on social problems and psychiatric symptoms. The groups were similar on the 8 remaining outcomes, including measures of alcohol and drug problems. Overall, the level of improvement among day treatment clients was not significantly different from that of residential clients.

Adult↗
PubMed1998

Citicoline treatment for experimental intracerebral hemorrhage in mice.

BACKGROUND AND PURPOSE: Citicoline sodium (cytidine-5'-diphosphocholine) has been shown previously to reduce ischemic injury in focal central nervous system models. Intracerebral hemorrhage (ICH) appears to be associated with an area of edema and ischemic injury surrounding the hematoma that may be reduced by neuroprotective therapy. The present study was designed to test whether treatment with citicoline reduces ischemic injury and improves functional neurological outcome in an experimental model of ICH. METHODS: In 68 Swiss albino mice (26 to 36 g), ICH was induced by collagenase injection into the caudate nucleus. Animals were randomized to receive either: citicoline 500 mg/kg or saline IP prior to collagenase and at 24 and 48 hours. Animals were rated on a 28-point neurological scale and sacrificed at 54 hours. The brains were sectioned, and the volume of hematoma, total lesion, and surrounding ischemic injury was determined. RESULTS: In terms of functional outcome, animals treated with citicoline had improved neurological outcome scores compared with placebo-treated animals: 10.4+/-2.0 versus 12.1+/-2.4 (P<0.01). Regarding ischemic injury, although there was no difference in the underlying hematoma volumes, animals treated with citicoline had a smaller surrounding volume of ischemic injury than placebo-treated animals: citicoline, 13.8+/-5.8 mm3 (10.8+/-4.3% of hemisphere); placebo, 17.0+/-7.1 mm3 (13.3+/-5. 1%) (P<0.05). CONCLUSIONS: In this animal model of ICH, treatment with citicoline significantly improved functional outcome and reduced the volume of ischemic injury surrounding the hematoma. This study supports a potential role for citicoline in clinical ICH treatment.

Animals↗
PubMed1998

Clopidogrel: secondary prevention of vascular ischaemic events.

Atherosclerotic disease is one of the major causes of premature death. In patients with atherosclerotic disease, antiplatelet therapy with aspirin has been shown to decrease the risk of subsequent events by about 20%. In one large randomized controlled study, clopidogrel showed a marginal benefit over aspirin in the prevention of ischaemic vascular events in high-risk patients. Clopidogrel is therefore an alternative in secondary prevention for those patients who are unable to tolerate aspirin. A literature search was performed using MEDLINE, EMBASE, and the Cochrane library, using the keyword 'clopidogrel'. One published randomized, controlled trial was found which evaluated the effects of clopidogrel in the prevention of vascular ischaemic events.

Clopidogrel↗
PubMed1997

Event-related potential evidence for frontal cortex effects of chronic cocaine dependence.

We examined the effects of cocaine dependence and cocaine and alcohol codependence on the P3A event-related potential component. Ten chronic cocaine-dependent subjects, 10 chronic cocaine and alcohol codependent subjects, and 20 controls were studied in an auditory paradigm that included target, nontarget, and novel rare nontarget conditions. Substance-dependent subjects were abstinent from cocaine and/or alcohol for 2-6 weeks. Eighteen of these subjects (4 chronic cocaine-dependent subjects, 4 chronic cocaine/alcohol codependent subjects, and 10 normal controls) were also studied in an analogous visual paradigm. In the auditory modality, the latency of the P3A response in the novel rare nontarget condition was delayed and its amplitude was reduced in both substance-dependent samples compared to controls. Comparable results were found for the smaller samples studied in the visual modality. These results suggest that chronic cocaine dependence produces deficits in frontal cortex functions.

Acoustic Stimulation↗
PubMed1997

Calibrating the physician. Personal awareness and effective patient care. Working Group on Promoting Physician Personal Awareness, American Academy on Physician and Patient.

Physicians' personal characteristics, their past experiences, values, attitudes, and biases can have important effects on communication with patients; being aware of these characteristics can enhance communication. Because medical training and continuing education programs rarely undertake an organized approach to promoting personal awareness, we propose a "curriculum" of 4 core topics for reflection and discussion. The topics are physicians' beliefs and attitudes, physicians' feelings and emotional responses in patient care, challenging clinical situations, and physician self-care. We present examples of organized activities that can promote physician personal awareness such as support groups, Balint groups, and discussions of meaningful experiences in medicine. Experience with these activities suggests that through enhancing personal awareness physicians can improve their clinical care and increase satisfaction with work, relationships, and themselves.

Attitude of Health Personnel↗
PubMed1997

Changes in HIV-related behaviors among heterosexual alcoholics following addiction treatment.

In order to measure changes in HIV-related behaviors among heterosexual alcoholics following treatment, we conducted a prospective cohort study of 700 self-identified alcoholics recruited from five public alcohol treatment centers, all of which included HIV risk-reduction counseling. Respondents underwent an HIV antibody test and interviewer-administered questionnaire at entry to alcohol treatment and after a mean of 13 months later. Compared to baseline, at follow-up there was an overall 26% reduction in having sex with an injection-drug-using partner (23% versus 32%, P < .001) and a 58% reduction in the use of injection drugs (15% versus 37%, P < .001), along with smaller improvements in other behaviors. Respondents also showed a 77% improvement in consistent condom use with multiple sexual partners (35% versus 20%, P < .01) and a 23% improvement in partner screening (71% versus 57%, P < .001). Respondents who remained abstinent showed substantially greater improvement than those who continued to drink.

Adult↗