Search PubMed⌕ Search

Biomedical subjects

W Clark

Publications and source records attributed to W Clark.

At least 19 recordsLinked to original sources
PubMed2001

Transient hyperinsulinism in an asphyxiated newborn infant with hypoglycemia.

We describe a case of transient hyperinsulinism in an asphyxiated newborn infant with hypoglycemia. Although hypoglycemia in birth asphyxiated infants is generally attributed to depletion of glycogen stores, we observed severe hyperinsulinism associated with the hypoglycemia. The hypoglycemia was refractory to high glucose delivery rates (25 mg/kg/min), but responded to a combination of octreotide and diazoxide. At 3 weeks of age, the medications were discontinued and infant was normoglycemic on glucose infusion rates of 5-8 mg/kg/min. Subsequent insulin studies were within normal limits. Transient hyperinsulinism should be considered in asphyxiated infants with protracted hypoglycemia and medications designed to suppress insulin secretion may be useful in refractory cases.

Asphyxia Neonatorum↗
PubMed2001

Outcome of stroke patients without angiographically revealed arterial occlusion within four hours of symptom onset.

BACKGROUND AND PURPOSE: Follow-up imaging data from stroke patients without angiographically apparent arterial occlusions at symptom onset are lacking. We reviewed our Emergency Management of Stroke (EMS) trial experience to determine the clinical and imaging outcomes of patients with ischemic stroke who showed no arterial occlusion on angiograms obtained within 4 hours of symptom onset. METHODS: All patients in this report were participants in the EMS trial that was designed to address the safety and potential efficacy of combined IV and intraarterial thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke. RESULTS: Thirty-five patients were randomized to receive either IV rt-PA (n = 17) or placebo (n = 18), followed by cerebral angiography. No symptomatic arterial occlusion was evident in 10 (29%) of the 34 patients. Eight (80%) of 10 patients without angiographically apparent clot within 4 hours of symptom onset had a new cerebral infarction confirmed on follow-up brain imaging. The median 72-hour infarction volume was 2.4 cc (range, 1-30 cc). Four of the 10 "no-clot" patients had a favorable 3-month outcome as assessed by Barthel Index (score, 95 or 100) and modified Rankin Scale (score, 0 or 1). The six remaining patients had 3-month Rankin Scale scores of 1 (Barthel of 90), 2, 3, 4, or 5. CONCLUSION: Acute ischemic stroke patients with a neurologic deficit but a negative angiogram during the first 4 hours after symptom onset usually develop image-documented cerebral infarction, and approximately half suffer from long-term functional disability. The two most likely explanations for negative angiograms are very early irreversible ischemic damage despite recanalization or ongoing ischemia secondary to clot in non-visible penetrating arterioles or in the microvasculature.

Aged↗
PubMed2001

Systematic review of randomised controlled trials of sildenafil (Viagra) in the treatment of male erectile dysfunction.

BACKGROUND: Sildenafil (Viagra), a new oral drug for the treatment of erectile dysfunction, was licensed for use across Europe in 1998. AIM: To examine the effectiveness and safety of sildenafil as an oral treatment for erectile dysfunction. DESIGN OF STUDY: Systematic review and meta-analysis. SETTING: All published or unpublished randomised controlled trials comparing sildenafil with a placebo or alternative therapies. METHOD: Published studies were sought by computerised searches of electronic databases using the keywords 'sildenafil' and 'Viagra'. A hand search was also done of the British Medical Journal, Lancet, Journal of the American Medical Association, New England Journal of Medicine, British journal of General Practice, Drug, Inpharma and Scrip. An assessment of quality of all identified studies and data extraction was undertaken independently by two researchers. Results were combined in a meta-analysis where appropriate, using RevMan version 3. RESULTS: Twenty-one trials were identified. All trials showed a statistically significant improvement in erectile or sexual function in patients using sildenafil compared with a placebo. A meta-analysis of 16 trials reporting a global efficacy response showed that men were 3.57 (95% CI = 2.93-4.43) times as likely to have improved erections on sildenafil compared with those on a placebo. The number needed to treat to have one man with improved erections was two. The drug has a relatively safe side-effect profile. CONCLUSIONS: Available research shows that sildenafil is an effective treatment for male erectile dysfunction. Many trial participants had some baseline erectile function and it is probable that in clinical practice, where the erectile function tends to be more impaired, the number needed to treat may be higher.

Adult↗
PubMed2001

Uremic toxicity: present state of the art.

The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest.

Cardiovascular Diseases↗
PubMed2001

An update of neuroprotectants in clinical development for acute stroke.

Neuroprotectants are drugs designed to treat stroke by preserving ischemic neurons in the penumbra. Despite numerous studies over the past ten years, no such drug has yet shown clinical efficacy. This article reviews those trials completed since 1999, including assessments of drugs that modify receptors or ion flow, block leukocyte adhesion receptors or stabilize membranes. In addition, ongoing trials and early trials using novel mechanisms of action, such as hypothermia and antioxidants, are discussed.

Acute Disease↗
PubMed2000

Preincubation with endothelial cell monolayers increases gene transfer efficiency into human bone marrow CD34(+)CD38(-) progenitor cells.

Retroviral gene transfer studies targeting bone marrow CD34(+)CD38(-) stem cells have been disappointing because of the rarity of these cells, their G(0) cell cycle status, and their low or absent expression of surface retroviral receptors. In this study, we examined whether preincubation of bone marrow CD34(+)CD38(-) stem cells with a hematopoietically supportive porcine microvascular endothelial cell line (PMVECs) could impact the cell cycle status and expression of retroviral receptors in pluripotent CD34+CD38- cells and the efficiency of gene transfer into these primitive target cells. PMVEC coculture supplemented with GM-CSF + IL-3 + IL-6 + SCF + Flt-3 ligand induced >93% of the CD34(+)CD38(-) population to enter the G(1) or G(2)/S/M phase while increasing this population from 1.4% on day 0 to 6.5% of the total population by day 5. Liquid cultures supplemented with the identical cytokines induced 73% of the CD34(+)CD38(-) population into cell cycle but did not maintain cells with the CD34(+)CD38(-) phenotype over time. We found no significant increase in the levels of AmphoR or GaLVR mRNA in PMVEC-expanded CD34(+)CD38(-) cells after coculture. Despite this, the efficiency of gene transfer using either amphotropic vector (PA317) or GaLV vector (PG13) was significantly greater in PMVEC-expanded CD34(+)CD38(-) cells (11.4 +/- 5.6 and 10.9 +/- 5.2%, respectively) than in either steady state bone marrow CD34(+)CD38(-) cells (0.6 +/- 1.7 and 0.2 +/- 0.6%, respectively; p < 0.01 and p < 0.01) or liquid culture-expanded CD34(+)CD38(-) cells (1.4 +/- 3.5 and 0.0%, respectively; p < 0.01 and p < 0.01). Since PMVEC coculture induces a high level of cell cycling in human bone marrow CD34(+)CD38(-) cells and expands hematopoietic cells capable of in vivo repopulation, this system offers potential advantages for application in clinical gene therapy protocols.

ADP-ribosyl Cyclase↗
PubMed2000

v-Jun sensitizes cells to apoptosis by a mechanism involving mitochondrial cytochrome C release.

v-Jun shares the ability of the Myc, E1A, and E2F oncogenes to both sustain cell cycle progression and promote apoptosis in the absence of mitogenic stimulation. To gain an insight into the mechanism of apoptosis sensitization, we examined the possible involvement of key regulatory proteins previously implicated in oncogene-induced cell death during v-Jun-induced apoptosis triggered by serum withdrawal. We observed that ectopic expression of the anti-apoptotic Bcl-2 protein, or of two downstream effectors of growth factor signalling, v-PI 3-Kinase and v-Src, partially or completely suppressed apoptosis. Apoptosis was also observed in the presence of serum growth factors when endogenous PI3K activity was blocked using the synthetic inhibitor LY294002, further suggesting an important role for PI3-K in cell survival. Cytochrome C was released into the cytosol of apoptotic v-Jun expressing cells, and this release was inhibited by Bcl-2, suggesting an important role for mitochondrial dysfunction in v-Jun induced apoptosis. In contrast, inhibition of Fas signalling using dominant negative FADD did not inhibit apoptosis, nor was there any evidence for accumulation or activation of p53 in v-Jun transformed cells. Consistent with this latter observation, inhibition of p53 function by HPV16 E6 protein had no effect on v-Jun induced cell death. Taken together, these results suggest that mitochondrial dysfunction is an important component of the mechanism through which v-Jun sensitizes cells to apoptosis, but that the apoptotic signals elicited by v-Jun upstream of the mitochondria do not depend on increased levels of p53 activity or Fas signalling.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Transient deactivation of ERK signalling is sufficient for stable entry into G0 in primary avian fibroblasts.

Re-entry into the cell cycle from quiescence requires the activation of mitogen-activated protein (MAP) kinases of the extracellular-signal-regulated kinase (ERK) family [1,2]. The relationship between ERK and cell-cycle control is, however, complex, as ERK activation can also lead to terminal differentiation [3] or a senescence-like growth arrest [4]. Here, we report that reversible cell-cycle exit induced by serum withdrawal in primary avian fibroblasts is associated with rapid deactivation of ERK, but ERK activity is subsequently regenerated and sustained at high levels in fully quiescent (G0) cells. As in proliferating cells, ERK activation during G0 required the MAPkinase kinase MEK and was partially dependent on cell adhesion. Active, phosphorylated ERK was concentrated in the nucleus in cycling cells, but was largely confined to the cytoplasm during G0. This was unexpected, as activatory phosphorylation mediated by MEK is thought to play an important role in promoting nuclear translocation [5,6]. These results indicate that transient deactivation of ERK signalling can be sufficient for stable cell-cycle exit, and that MEK-mediated phosphorylation is not sufficient for nuclear translocation of active ERK in G0. Cytoplasmic sequestration may prevent active ERK from accessing critical nuclear cell-cycle targets, thus allowing quiescent or post-mitotic cells to retain ERK activity for other physiological functions.

3T3 Cells↗
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↗