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Biomedical subjects

B Walker

Publications and source records attributed to B Walker.

At least 55 records · Page 3Linked to original sources
PubMed2000

Streptokinase-induced platelet activation involves antistreptokinase antibodies and cleavage of protease-activated receptor-1.

Streptokinase activates platelets, limiting its effectiveness as a thrombolytic agent. The role of antistreptokinase antibodies and proteases in streptokinase-induced platelet activation was investigated. Streptokinase induced localization of human IgG to the platelet surface, platelet aggregation, and thromboxane A(2) production. These effects were inhibited by a monoclonal antibody to the platelet Fc receptor, IV.3. The platelet response to streptokinase was also blocked by an antibody directed against the cleavage site of the platelet thrombin receptor, protease-activated receptor-1 (PAR-1), but not by hirudin or an active site thrombin inhibitor, Ro46-6240. In plasma depleted of plasminogen, exogenous wild-type plasminogen, but not an inactive mutant protein, S(741)A plasminogen, supported platelet aggregation, suggesting that the protease cleaving PAR-1 was streptokinase-plasminogen. Streptokinase-plasminogen cleaved a synthetic peptide corresponding to PAR-1, resulting in generation of PAR-1 tethered ligand sequence and selectively reduced binding of a cleavage-sensitive PAR-1 antibody in intact cells. A combination of streptokinase, plasminogen, and antistreptokinase antibodies activated human erythroleukemic cells and was inhibited by pretreatment with IV.3 or pretreating the cells with the PAR-1 agonist SFLLRN, suggesting Fc receptor and PAR-1 interactions are necessary for cell activation in this system also. Streptokinase-induced platelet activation is dependent on both antistreptokinase-Fc receptor interactions and cleavage of PAR-1. (Blood. 2000;95:1301-1308)

Adenosine Diphosphate↗
PubMed2000

In vitro properties of red cells prepared from half-strength citrate CPD/RAS-2 (Erythro-sol) donations in PL-146 plastic.

Whole blood donations were collected into 0.5CPD anticoagulant in PL-146 plastic. This was shown to improve the stability of plasma FVIII levels when compared with CPD. RAS-2 was used as additive and this improved the in vitro properties of the red cells, such that post processing 2,3-DPG levels were maintained for 21 days and ATP levels were maintained for 28 days. Whether or not such improvements in red cell properties yield a benefit in clinical use remains to be established.

Anticoagulants↗
PubMed2000

Quality assurance by a commercial flow cytometry method of leucodepletion of whole blood donations: initial application of universal testing and proposals for a batch-release sampling plan.

We have used the Becton-Dickinson LeucoCOUNT test to monitor residual leucocytes in whole blood by flow cytometry following leucodepletion filtration. This test was found to be quick, robust and reliable, and allowed measurement of residual leucocytes down to 2.25 x 104 leucocytes per unit, which was found to match approximately the limit of filter proficiency. The results of testing > 1000 units showed a lognormal distribution with means between log(10) 4.864 (0.73 x 105) and log(10) 5.016 (1.04 x 105) leucocytes per unit in the three different homogeneous groups of filtered units studied. The numbers of units with residual leucocytes exceeding the 5 x 106 upper threshold were 1/577, 2/457 and 0/87 in these groups. The filtration processes were validated according to the published BEST working party guidelines and were well within the 99% confidence and 95% tolerance target for the 5 x 106 upper threshold set for the UK. A sampling plan based on British Standard BS 6001 with elimination of outliers by the extreme studentized deviate (Grubbs' test) was evaluated on random samples from these groups and has been adopted locally as a prospective batch-release criterion for release of leucodepleted blood.

Blood Donors↗
PubMed2000

Montelukast in the prophylaxis of migraine: a potential role for leukotriene modifiers.

OBJECTIVE: Clinical observation of a decrease in migraine frequency in patients with comorbid asthma taking montelukast, a specific D4 leukotriene receptor antagonist, or zafirlukast, another leukotriene receptor antagonist, prompted us to explore a possible role for leukotriene modifiers in the treatment of migraine. (A further prompt was a pharmacist colleague's observation that a number of patients on these agents reported a decreased sensitivity to perfume triggers and improvement in migraine.) BACKGROUND: Nonsteroidal anti-inflammatory agents have been used widely in the treatment of migraine. Another class of anti-inflammatory agents, known as leukotriene modifiers, have not been studied to date with regard to their possible role in the treatment of migraine. The name "leukotriene is derived both from the parent molecule, which was originally isolated from leukocytes, and from its three double-bond carbon backbone or triene structure. Both prostaglandins and leukotrienes are derived from the metabolism of arachidonic acid, with prostaglandins coming off the cyclooxygenase pathway and leukotrienes derived via the enzyme 5-lipoxygenase. Both prostaglandins and leukotrienes mediate inflammatory responses. The latter have been studied with regard to their role in the pathophysiology of asthma. METHODS: A prospective, open-label study evaluating the efficacy of montelukast, 10 mg or 20 mg, in the prophylaxis of migraine in 17 patients is presented in this paper. All 17 patients completed the study that consisted of a 2-month baseline run-in period and a 3-month treatment phase. RESULTS: Montelukast was extremely well tolerated, and no adverse events were reported by any of the patients. Fifty-three percent showed a reduction of greater than 50% (P<.025) in the frequency of severe attacks, with 41% showing a reduction of greater than 60%. Responders, including modest responders, rated the drug as excellent. CONCLUSIONS: We conclude, given the limitations of an open-label study design and the small sample size, that montelukast shows potential as an effective, well-tolerated prophylactic agent in migraine. Double-blinded, placebo-controlled studies are warranted. In addition, the leukotrienes, as suggested previously in the literature, may play a role in the pathogenesis of migraine.

Acetates↗
PubMed2000

Local regulation of glucocorticoid activity in sites of inflammation. Insights from the study of tuberculosis.

In sites of inflammation there is a change in the equilibrium between the enzymes that inactivate cortisol by conversion to cortisone and those that reactivate cortisone by conversion to cortisol. Current evidence suggests that during an immune response with a Type 1 cytokine profile such as tuberculosis, there is locally enhanced reductase activity with locally increased cortisol concentrations due to recruitment of cortisone. This results in enhanced cortisol mediated feedback on the inflammatory process, and deviation of the response towards Type 2. Preliminary data suggest that eventually, in the presence of Type 2 cytokine polarization, the enzyme equilibrium may reverse again and cortisol is then locally inactivated to cortisone. Together with changes in glucocorticoid receptor expression and function this may result in local cortisol resistance and susceptibility to tissue damage mediated by proinflammatory cytokines. These observations help to explain the sequence of events in several infectious, inflammatory and autoimmune diseases.

Animals↗
PubMed2000

Natural history of haemoglobin levels in female blood donors with haemoglobin levels of 120-124 g/l at presentation.

BACKGROUND AND OBJECTIVES: In order to assess the effects of proposed changes to UK guidelines, female blood donors with venous haemoglobin (Hb) levels of 120-124 g/l were followed up over a period of 18 months in order to assess frequency of attendance and ability to donate in relation to changes in Hb and red cell indices, and to determine the effects of inter-donation interval and iron supplementation on outcomes. MATERIALS AND METHODS: Venous samples were analysed using the Haemocue haemoglobinometer at each attendance, and a donation was taken if the Hb was 120 g/l or greater. Full blood counts were done on each sample using the Coulter Model T890. A postal questionnaire was used to elicit additional information, including use of iron supplements. RESULTS: The 392 donors enrolled in the study gave 655 subsequent attendances, resulting in 468 donations (1.5 donations/donor/year). Donors who subsequently had Hb <120 g/l had a tendency to lower initial mean corpuscular volume (MCV), but MCV could not be used as an indicator of future performance. 23% of donors reported use of iron supplements, but those donating 3 times or more were no more likely to use iron supplementation (20%). No statistical relationship was found between inter-donation interval and ability to donate at subsequent attendances. CONCLUSIONS: Female donors with borderline Hb levels proved to be highly committed, with a donation rate of 1. 5/donor/year during the period of follow-up. MCV is not a useful predictor of ability to donate in the future. This subset of the donor population shows wide variation in Hb level over time, and this is largely independent of iron supplementation or inter-donation interval.

Anemia, Iron-Deficiency↗
PubMed2000

Tissue specificity of glucocorticoid sensitivity in healthy adults.

Contradicting data exist as to whether interindividual patterns in glucocorticoid (GC) sensitivity vary between different target tissues in humans. This study therefore measured GC sensitivity in 36 healthy subjects in three target tissues: the immune system; the cardiovascular system, and the hypothalamus-pituitary-adrenal axis. For this purpose, dexamethasone inhibition of lipopolysaccharide-induced interleukin-6 and tumor necrosis factor-alpha production in peripheral leukocytes, beclomethasone dipropionate-induced skin blanching, and suppression of cortisol levels after low-dose (0.5 mg) dexamethasone suppression test were determined in each subject. The results showed the expected glucocorticoid-induced suppression of interleukin-6 and tumor necrosis factor-alpha production (both P < 0.001), dose-dependent skin blanching (P < 0.001), and suppression of salivary cortisol response to awakening (P < 0.001). However, neither simple correlations nor cluster analysis revealed a significant association among the three bioassays for GC sensitivity. In contrast to the idea that interindividual variation in GC sensitivity is an intrinsic trait affecting all tissues, these results suggest that this variability is target tissue specific in healthy subjects.

Adult↗
PubMed2000

Solid-phase synthesis and biological screening of N-alpha-mercaptoamide template-based matrix metalloprotease inhibitors.

A series of N-alpha-mercaptoacetyl containing dipeptides have been prepared on solid-phase supports as putative matrix metalloprotease (MMP) inhibitors. Inhibitor design was based on a positional scanning approach of the amino acids present within a template molecule, previously shown to be an MMP inhibitor with good pharmacological characteristics. This study is the first step in a unique programme, designed to expand the repertoire of molecular templates which can be chosen as starting points for the development of more focused parallel and/or combinatorial libraries of MMP inhibitors as a means to accelerate the lead discovery process. This paper reports the success of such an approach in the development of agents with activity against a number of pathologically important MMPs. After screening of these positional scanning libraries, we have obtained important SAR information, in particular, pharmacophores with the ability to impart selectivity for particular MMP species.

Fluorometry↗
PubMed2000

Neurobehavioral toxicity.

A growing number of agents are known to perturb one or more of the interconnected processes of the central nervous system. At the same time, there is an increase in the incidence of neurobehavioral disorders that are confronting clinicians with baffling symptoms and presentations that seem uncommon. Fundamental to the assessment of the environmental-relatedness of the syndromes is a work and exposure history, including information different from that routinely obtained in the clinical setting. Exposure examples are described to suggest the scope of inquiry necessary to differentiate neurotoxic syndromes from nonneurotoxic illness.

Behavior↗
PubMed2000

Stalking as a variant of intimate violence: implications from a young adult sample.

There is a limited but growing literature which suggests that stalking is a variant of intimate violence. The purpose of this study was to examine physical, psychological, and stalking victimization and perpetration among males and females. Alcohol use was also examined. The sample was 46 male and 84 female undergraduate students who reported stalking victimization and perpetration after a difficult breakup, and psychological and physical victimization and perpetration during that specific relationship. Overall, 27% of the sample study was classified into the stalking victimization group, which is consistent with other stalking prevalence rates among college samples. For females, stalking victimization was significantly associated with physical and psychological abuse victimization. For males, stalking victimization was significantly associated with psychological abuse victimization. However, there was also a strong significant reciprocal relationship of stalking and psychological abuse victimization and perpetration, especially for males. Also, alcohol use was significantly associated with victimization and perpetration of stalking and psychological abuse for males. The data from this study contribute to the hypothesis that stalking is a variant of or extension of intimate violence, especially for females. Implications and recommendations for future research are discussed.

Adolescent↗
PubMed1999

Neo-striatal rCBF correlates of psychomotor slowing in patients with major depression.

Psychomotor slowing is a fundamental clinical feature of severe depression and is thought to reflect dysfunction within prefrontal-subcortical circuits. This study utilised a split-dose single photon emission computerised tomography (SPECT) scanning technique in association with a two-stage test of psychomotor speed. Twenty-five patients with primary depressive disorders were injected with technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) whilst performing each component of a two-stage psychomotor task. The first stage, 'simple reaction time' (RT) and the second stage, 'choice reaction time' (CRT), were each followed by 30-min SPECT scans. Regions of interest (ROIs) corresponding to the left and right neo-striatum (caudate-putamen) were drawn, and regional cerebral blood flow (rCBF) values were calculated. Importantly, the change in rCBF measure in the left neo-striatum was inversely correlated with RT (r = -0.48, P < 0.05). That is, the patients with the greatest psychomotor slowing initially showed the least increase in rCBF during the CRT condition. This effect was independent of age. The study demonstrates that a simple two-stage motor paradigm can be used to elicit rCBF correlates of psychomotor slowing in patients with primary depression. Such rCBF findings may implicate the neo-striatum in the neurobiology of major depression.

Adult↗
PubMed1999

Inhibition of prolylendopeptidase does not affect gamma-secretase processing of amyloid precursor protein in a human neuroblastoma cell line.

Abeta peptides are major components of the amyloid plaques that characterize Alzheimer's disease. The enzyme activities (beta- and gamma-secretases) involved in generating Abeta from amyloid precursor protein (APP) are unidentified. It has been suggested that prolylendopeptidase (PEP), an oligopeptidase that normally cleaves after proline residues, could also cleave after the alanine at position 42 of Abeta to generate Abeta42. We investigated whether inhibition of PEP activity in human neuroblastoma cells affected Abeta levels in cell culture media. An SH-SY5Y cell line expressing SPA4CT, encoding the C-terminal 100 residues of APP and the signal sequence, was used. Only gamma-secretase activity is required for Abeta production in this cell line. The PEP inhibitor Fmoc-AlaPro-CN (10 microM) reduced PEP activity in these cells by approximately 95% in the absence of significant toxicity, but had no effect on Abeta40 or Abeta42 levels in cell culture media. We conclude that PEP is unlikely to be involved in gamma-secretase processing of APP.

Amino Acids↗
PubMed1999

Hydroxyurea and didanosine long-term treatment prevents HIV breakthrough and normalizes immune parameters.

Hydroxyurea and didanosine treatment suppressed HIV replication for more than 2 years, in the absence of viral breakthrough, in chronically infected patients. The profile of viral load reduction was unusual for a two-drug combination, since a continuous gradual decrease in viremia persisted despite residual viral replication. The increase in CD4+ T cell counts was not robust. However, unlike those of patients treated by other therapies, CD4+ T lymphocytes were functionally competent against HIV, mediating a vigorous HIV-specific helper T cell response in half of these patients. In addition, the percentages of naive CD4+ and CD8+ T lymphocytes were not different from those in uninfected individuals. These results demonstrate that prolonged antiretroviral therapy with a simple, well-tolerated combination of two affordable drugs can lead to sustained control of HIV, normalization of immune parameters, and specific anti-HIV immune response.

Anti-HIV Agents↗