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Biomedical subjects

J Humphrey

Publications and source records attributed to J Humphrey.

At least 19 recordsLinked to original sources
PubMed2005

What are the beliefs and attitudes of paramedics to prehospital thrombolysis? A questionnaire study.

BACKGROUND: The Ambulance Services have a critical role in the management of acute myocardial infarction (AMI). Paramedic delivered prehospital thrombolysis (PHT) has been proposed. To the authors' knowledge there has been no research carried out to ascertain the views of paramedics. METHODS: The authors conducted a postal questionnaire study of 250 paramedics in the West Yorkshire Metropolitan Ambulance Service (WYMAS). This included the knowledge of risks and benefits of AMI treatments, and their views on possible paramedic delivered PHT. RESULTS: 193 paramedics replied (77%); of these 83% felt paramedics could deliver PHT, 67% felt thrombolysis was safe, and only 12% felt that paramedics should not carry out PHT. There was a similar preference towards autonomous PHT (42%) and telemetry with physician directed PHT (46%). 96% wanted a nationally recognised certificate. There were concerns regarding the risks of AMI treatment, with underestimates of the benefits of aspirin, and overestimates of the benefits of thrombolysis. They also greatly overestimated the risks of thrombolysis in terms of extra deaths (71%), and bleeding (90%). CONCLUSION: The majority of paramedics in WYMAS responding to the questionnaire supported the principle of PHT. Concerns included the risks of thrombolytic treatment, training, and the medico-legal implications for them as individual paramedics. Models for paramedic thrombolysis for each ambulance service should include the views of paramedics.

Ambulances↗
PubMed2001

Is breast not best? Feeding babies born to HIV-positive mothers: bringing balance to a complex issue.

Breastfeeding prevents millions of infant deaths each year throughout the world but causes at least one-third of all pediatric HIV infections. The first randomized trial of breastfeeding versus formula feeding, reported from Nairobi in March 2000, demonstrated an improved outcome for babies of highly selected HIV-positive mothers assigned to formula feed. However, several conditions must be in place and accepted before such replacement feeding can increase HIV-free survival. The proportion of sub-Saharan African women who have access to and will accept these conditions is small. In the short term, efforts to make breastfeeding safer will probably benefit a greater number of African babies.

Africa↗
PubMed2000

Cholesterol modulates vascular reactivity to endothelin-1 by stimulating a pro-inflammatory pathway.

Hypercholesterolemia (HC) is associated with coronary endothelial dysfunction and increased circulating levels of endothelin-1. We show that pre-treatment of intact rat aortic rings with cholesterol synergistically enhances the vasoconstriction induced by endothelin-1 suggesting that elevated levels of cholesterol may predispose to hypertension by modulating the vascular reactivity to endogenous vasoconstrictors. Moreover, we report that SB202190, a selective inhibitor of p38 MAPK, and PD98059 an inhibitor of MEK1/2 are able to abolish the vasoactive properties of cholesterol. MK-886, an inhibitor of 5-lipoxygenase is inefficient at blocking the vasoactive properties of cholesterol whereas NS-398, a selective inhibitor of cyclooxygenase-2 (COX-2) completely abolishes cholesterol-induced vasoconstriction. In intact rat aortae, cholesterol stimulates prostaglandin E(2) and prostaglandin F(2 alpha) production, an effect that can be completely prevented by inhibiting p38 MAPK, or COX-2. In vitro, cholesterol appears to stimulate a similar pro-inflammatory pathway in human cerebrovascular smooth muscle cells. Disruption of the MAPK/COX-2 pathway may represent a valuable therapy to block the hypertension associated with HC, as well as the development of atherosclerosis.

Animals↗
PubMed2000

24-hour history is more closely associated with vitamin A status and provides a better estimate of dietary vitamin A intake of deficient Indonesian preschool children than a food frequency method.

OBJECTIVES: To determine if the Simplified Dietary Assessment to Identify Groups at Risk of Inadequate Intake of Vitamin A developed by the International Vitamin A Consultative Group (IVACG) correctly classified a group of vitamin A-deficient children as being at risk, and to see if a food frequency questionnaire (FFQ) or 24-hour history (24HH) yielded estimated dietary vitamin A intakes most closely associated with vitamin A status. DESIGN: Forty-seven foods were identified as contributing most of the vitamin A to the diet of the study population. For each food, usual portion sizes were determined during a pilot study. Intake was calculated from data collected by FFQ and 24HH. Four modifications of the 24HH analysis were made to determine if this method of analysis could be simplified. SUBJECTS/SETTING: Subjects were 265 Indonesian children with or at high risk of developing xerophthalmia. RESULTS: Mean and median intakes of vitamin A based on the 24HH analysis were 50% and 27% of the US Recommended Dietary Allowance, respectively, which accurately identified the study sample as being at risk. Dietary intake based on the 24HH was significantly associated with serum retinol concentration (P = .01, trend test). Eliciting portion sizes during the 24HH was not necessary once the usual portion sizes consumed by the population were estimated in the pilot study. Mean and median intakes of vitamin A based on the FFQ were 150% and 118% of the Recommended Dietary Allowance, respectively, which suggests that the FFQ overestimated intake. Intake based on the FFQ was not correlated with serum retinol concentration. CONCLUSIONS: Our findings do not support the IVACG recommendation that the FFQ be regarded as more reliable than the 24HH when the 2 methods produce different conclusions, nor the recommendation of some users of the method that the 24HH be dropped from the assessment method.

Child Nutrition Disorders↗
PubMed2000

Responsiveness of dark-adaptation threshold to vitamin A and beta-carotene supplementation in pregnant and lactating women in Nepal.

BACKGROUND: Impaired dark adaptation occurs commonly in vitamin A deficiency. OBJECTIVE: We sought to examine the responsiveness of dark-adaptation threshold to vitamin A and beta-carotene supplementation in Nepali women. DESIGN: The dark-adapted pupillary response was tested in 298 pregnant women aged 15-45 y in a placebo-controlled trial of vitamin A and beta-carotene; 131 of these women were also tested at 3 mo postpartum. Results were compared with those for 100 nonpregnant US women of similar age. The amount of light required for pupillary constriction was recorded after bleaching and dark adaptation. RESULTS: Pregnant women receiving vitamin A had better dark-adaptation thresholds (-1.24 log cd/m(2)) than did those receiving placebo (-1.11 log cd/m(2); P: = 0. 03) or beta-carotene (-1.13 log cd/m(2); P: = 0.05) (t tests with Bonferroni correction). Dark-adaptation threshold was associated with serum retinol concentration in pregnant women receiving placebo (P: = 0.001) and in those receiving beta-carotene (P: = 0.003) but not in those receiving vitamin A. Among women receiving placebo, mean dark-adaptation thresholds were better during the first trimester (-1.23 log cd/m(2)) than during the second and third trimesters (-1.03 log cd/m(2); P: = 0.02, t test). The mean threshold of nonpregnant US women (-1.35 log cd/m(2)) was better than that of all 3 Nepali groups (P: < 0.001, t test, for all 3 groups). CONCLUSIONS: During pregnancy, pupillary dark adaptation was strongly associated with serum retinol concentration and improved significantly in response to vitamin A supplementation. This noninvasive testing technique is a valid indicator of population vitamin A status in women of reproductive age.

Adolescent↗
PubMed2000

A beta vasoactivity: an inflammatory reaction.

Mounting evidence from in vitro and in vivo studies in transgenic mice overproducing beta-amyloid peptides (A beta) suggests that A beta can induce vasoconstriction and decrease cerebral blood flow. In this report, we describe the vasoactive properties of A beta, in particular the enhancement of endothelin-1-induced vasoconstriction and A beta's induction of a long-lasting vasoconstrictive event. Furthermore, we show that low doses (as low as 50 nM) of freshly solubilized A beta similar to those observed in the plasma of patients suffering from Alzheimer's disease are vasoactive. By using various inhibitors and activators of the phospholipase A2 (PLA2)/arachidonic acid (AA) cascade, we demonstrate that A beta vasoactivity is dependent on activation of this intracellular signaling pathway, resulting in stimulation of downstream cyclooxygenase-2 and 5-lipoxygenase, which mediate production of proinflammatory eicosanoids. Taken together, our data show that A beta directly activates an intracellular proinflammatory pathway, which is responsible for its vasoactive properties.

Alzheimer Disease↗
PubMed2000

A beta vasoactivity in vivo.

Bilateral temporoparietal hypoperfusion has been frequently observed early in the Alzheimer's disease (AD) process. The beta-amyloid (A beta) peptide is believed to play a central role in the pathogenesis of AD. In vitro experiments have shown that freshly solubilized A beta enhances constriction of cerebral and peripheral vessels. We proposed that in vivo, A beta would also have vasoactive properties. To test this hypothesis, we intraarterially infused freshly solubilized A beta 1-40 in rats and observed changes in peripheral blood pressure, cerebral blood flow, and cerebrovascular resistance. We found that infusion of A beta in vivo significantly increased the blood pressure in hypotensive rats but not in normotensive and hypertensive rats. Moreover, A beta infusion also resulted in a decreased blood flow and increased vascular resistance specifically in cerebral cortex but not in heart or kidneys. These data suggest that A beta has a direct and specific constrictive effect on cerebral vessels in vivo, which may contribute to the cerebral hypoperfusion observed early in the AD process.

Amyloid↗
PubMed1999

Induction of CD40 on human endothelial cells by Alzheimer's beta-amyloid peptides.

Growing evidence suggests that beta-amyloid (Abeta) peptides play a central role in mediating vascular endothelium dysfunction, but the extent to which immune mechanisms are involved in this process remains unclear. To explore such mechanisms, we incubated cultured human aortic endothelial cells (HAEC) with freshly solublized Abeta and examined expression of a central immunoregulatory molecule, CD40, in these cells using reverse transcriptase-polymerase chain reaction, Western immunoblotting, and Flow cytometry. Our results show that treatment of endothelial cells with Abeta1-40, Abeta1-42 or gamma interferon (IFN-gamma) results in a dose-dependent induction of endothelial CD40 expression. Furthermore, ligation of endothelial CD40 and simultaneous treatment of human endothelial cells with IFN-gamma or Abeta peptides leads to a significant release of interleukin-1beta (IL-1beta), a marker for endothelial cell activation. Since IL-1beta is an important inflammatory response mediator, these findings suggest that the functional role of Abeta-induced endothelial CD40 may be promotion of the inflammatory cascade in vascular endothelial cells.

Alzheimer Disease↗
PubMed1999

Activation of microglial cells by the CD40 pathway: relevance to multiple sclerosis.

It is well known that microglial cells perform a key role in mediating inflammatory processes, which are associated with neurodegenerative diseases such as multiple sclerosis (MS). In this study, we report that CD40 expression on microglia is greatly enhanced by a low dose (10 U/ml) of IFN-gamma. We also find that ligation of microglial CD40 by CD40L triggers a significant production of TNF-alpha. Activation of microglia by ligation of CD40 in the presence of IFN-gamma results in cultured cortical neuronal injury, which is markedly attenuated by blockade of the CD40 pathway or neutralization of TNF-alpha. Finally, we find significant levels of IFN-gamma and TNF-alpha in the medium of co-cultured activated CD4+ T cells and microglial cells, showing that microglia can supply the CD40 receptor to activated CD4+ T cells and suggesting that this cellular interaction is a key event in MS pathophysiology.

Animals↗
PubMed1999

Inhibition of Alzheimer's beta-amyloid induced vasoactivity and proinflammatory response in microglia by a cGMP-dependent mechanism.

beta-amyloid (Abeta) peptides are the major protein components of senile plaques in Alzheimer's disease (AD) brains. Vascular damage and reactive gliosis are found colocalized with amyloid deposits in AD brains, suggesting that the vasculature may be a clinically significant site of AD pathology. Our results show that freshly solubilized Abeta1-40 enhances the vasoconstriction induced by endothelin-1 (ET-1) and increases resistance to relaxation triggered by nitric oxide (NO), suggesting that Abeta may oppose the NO/cGMP pathway. Using specific inhibitors and activators of the NO/cGMP pathway, we show that Abeta vasoactivity is not due to a modulation of nitric oxide synthase (NOS) or soluble guanylyl cyclase (sGC). However, we find that a selective cGMP phosphodiesterase (cGMP-PDE) inhibitor (dipyridamole) is able to interactively block the enhanced vasoconstriction as well as the opposition to relaxation induced by Abeta, suggesting that Abeta could effect the activity of this enzyme. Cyclic GMP levels, but not cAMP concentrations, are reduced after Abeta treatment of rat aortic rings, further substantiating this hypothesis. Moreover, in examination of this pathway in another cell type pertinent to AD, we find that Abeta induces a proinflammatory response in microglia as evidenced by increased leukotriene B4 release. We show that both dipyridamole and compounds which increase cGMP levels prevent Abeta-induced microglial inflammation. Our results suggest that therapeutic intervention aimed at reduction of microglial-mediated inflammation via inhibition of cGMP-PDE or elevation of cGMP may be beneficial in the treatment of AD.

Alzheimer Disease↗
PubMed1999

Evaluation of the prototype Roche DNA amplification kit incorporating the new SSK145 and SKCC1B primers in detection of human immunodeficiency virus type 1 DNA in Zimbabwe.

We assessed the sensitivity and specificity of a newly developed DNA PCR kit (Roche Diagnostic Corporation, Indianapolis, Ind.) that incorporates primers for all the group M viruses for the detection of human immunodeficiency virus (HIV) type 1 (HIV-1) infection in Zimbabwe. A total of 202 whole-blood samples from adults whose HIV status was known were studied. This included 100 HIV-1-positive and 102 HIV-1-negative samples selected on the basis of concordant results obtained with two enzyme-linked immunosorbent assay kits. The prototype Roche DNA PCR assay had a 100% sensitivity for the detection of HIV-1 DNA and a specificity of 100%. We conclude that the new Roche DNA PCR kit is accurate for the detection of HIV DNA in Zimbabwean samples, in which HIV-1 subtype C dominates.

Adult↗
PubMed1998

Soluble Alzheimers beta-amyloid constricts the cerebral vasculature in vivo.

Bilateral temporoparietal hypoperfusion has been frequently observed early in the Alzheimer's disease (AD) process. An increased beta-amyloid (Abeta) peptide is believed to play a central role in the pathogenesis of AD. In vitro experiments have shown that freshly solubilized Abeta enhances constriction of cerebral and peripheral vessels. We propose that in vivo the Abeta vasoactive property may contribute to cerebral hypoperfusion of AD patients. To test this hypothesis, we intra-arterially infused freshly solubilized Abeta -40 in rats and observed changes in cerebral blood flow and cerebrovascular resistance using fluorescent microspheres. We found that infusion of Abeta in vivo resulted in a decreased blood flow and increased vascular resistance specifically in cerebral cortex but not in heart or kidneys. These data suggest that Abeta has a direct and specific constrictive effect on cerebral vessels in vivo, which may contribute to the cerebral hypoperfusion observed early in the AD process.

Alzheimer Disease↗
PubMed1998

Isoform-specific vasoconstriction induced by apolipoprotein E and modulation of this effect by Alzheimer's beta-amyloid peptide.

Abeta peptides are thought to be centrally involved in Alzheimer's disease (AD) pathogenesis, although Abeta's pathophysiological mechanisms remain to be elucidated. We previously showed that soluble beta-amyloid1-40 (Abeta) and Abeta1-42 exhibit vasoactive properties, and are able to promote vasoconstriction in rat aortae induced by an endogenous vasoconstrictor, endothelin-1. It is well established that the APOE epsilon4 allele confers risk for both familial and sporadic AD, as well as for hypertension. We now report that physiologic amounts (10 nM) of specific human recombinant apoE isoforms are vasoactive (E4 > E3, and not E2) in isolated rat aortae. In order to investigate if various apoE isoforms could modulate Abeta vasoactivity, we co-incubated Abeta1-40 with various isoforms of apoE in our tissue bath system. Our results show that, while none of the APOE isoforms are able to affect the maximum constriction induced by Abeta; the apoE E4 isoform synergistically enhances the rate of vasoconstriction induced by Abeta. Our data suggest that apoE may promote hypertension and contribute to AD pathogenesis via enhancement of vasoconstriction, and support a link between hypertension, cerebral amyloid angiopathy and AD.

Amyloid beta-Peptides↗
PubMed1998

Role of peroxynitrite in the vasoactive and cytotoxic effects of Alzheimer's beta-amyloid1-40 peptide.

Increasing evidence implicates oxidative stress as partially responsible for the neurodegenerative process of Alzheimer's disease (AD). Recent reports show an increased production of nitrotyrosine in AD brains, suggesting that peroxynitrite is produced in excess in this disease. Furthermore, incidence of cerebral amyloid angiopathy in AD cases is very frequent (83%), strongly suggesting a vascular component of AD pathogenesis. We have evaluated the hypothesis that peroxynitrite could be responsible for mediating the cytotoxicity and vasoactivity induced by the amyloid-beta1-40 (Abeta) peptide. Rat brain endothelial cells (RBE-4) appear to be sensitive to Abeta-induced toxicity but not to the cytotoxicity induced by peroxynitrite. Addition of Cu/Zn superoxide dismutase to cell culture media, which is only able to clear extracellular superoxide, was not effective in blocking Abeta-induced toxicity. However, we were able to partially block Abeta-induced cytotoxicity by using Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP) which dismutes superoxide intracellularily. Yet, MnTBAP was not able to prevent the vasoactivity triggered by Abeta. Moreover, addition of peroxynitrite to rat aortae did not modulate the vasotension induced by Abeta. We conclude that intracellular superoxide radicals may contribute to Abeta-induced cytotoxicity. Our results also indicate that peroxynitrite does not significantly contribute to Abeta-induced cytotoxicity in rat brain endothelial cells (RBE-4) or vasoactivity in rat aortae. These results suggest that therapeutic efforts aimed at removal of reactive oxygen species with SOD is unlikely to be beneficial for treatment of Abeta-induced endothelial dysfunction. However, compounds that clear free radicals intracellularly may well be beneficial.

Alzheimer Disease↗
PubMed1998

Controlling for selection bias in the evaluation of Alcoholics Anonymous as aftercare treatment.

OBJECTIVE: The purpose of this research was to control for self-selection bias in the evaluation of Alcoholics Anonymous (AA) as aftercare treatment. Observational studies of alcoholism aftercare treatment are subject to selection bias whenever the self-selection process results in important differences in unobserved casemix dimensions between treatment groups. METHOD: The sample included 118 male veterans discharged from inpatient alcohol treatment, 85% of whom were followed-up at 3 months. Drinking outcomes were measured by self-reported abstinence in the third month after discharge. The aftercare treatment effect of AA was estimated using standard logistic regression analysis and instrumental variables analysis. Instruments included the subject's ability to drive oneself to AA meetings and the presence/absence of an AA meeting in the subject's town of residence. A Hausman exogeniety test was used to determine whether the standard logistic regression results were subject to self-selection bias. RESULTS: Estimates from the standard logistic regression yielded a positive (OR = 3.7) and significant (p = .018) treatment effect for AA attendance. However, the instrumental variables analysis yielded a smaller (OR* = 1.7) and insignificant treatment effect estimate (p = .782). The Hausman exogeniety test indicated that the treatment effect estimate from the standard logistic regression was subject to significant self-selection bias (chi2 = 83.9, 1 df, p <.01). CONCLUSIONS: The AA aftercare treatment effect observed in this sample was due to differences in unobserved casemix factors between the treatment groups. Results suggest that previous AA aftercare research may have also been subject to self-selection bias. Researchers of substance abuse outcomes should consider analyzing nonexperimental data using instrumental variables methodologies.

Adult↗
PubMed1997

Possible antioxidant effect of vitamin A supplementation in premature infants.

BACKGROUND: Increased lipid peroxidation caused by oxygen free radicals is thought to be one of the common pathogenetic mechanisms for the so-called oxygen radical diseases of prematurity. Since in vitro studies have shown that various forms of vitamin A can exert antioxidant effects that are more potent than those of vitamin E (treatment with which has been ineffective in these diseases), the purpose of this prospective, controlled study was to determine whether administration of supplemental vitamin A to premature infants deficient in this vitamin would have an antioxidant effect in vivo. METHODS: Fourteen infants (1181 +/- 35 g; gestational age 29 +/- 0.04 weeks) with a serum retinol concentration at 7 +/- 2 days of age in the deficient range, lower than 0.7 mumol/l (< 20 micrograms/dl), were enrolled in the study. Infants were randomized to receive the standard amount of vitamin A or standard plus supplemental (2.6 mumol/l [2500 IU] orally each day) vitamin A, beginning at 1 week of age. Antioxidant effects of supplementation were assessed by a decrease in lipid peroxidation, quantified by the ethane content of expired air. RESULTS: Three weeks after study enrollment, total daily vitamin A intake in the infants receiving supplements was 4.565 +/- 0.236 mumol (4354 +/- 225 IU) versus 1.879 +/- 0.317 mumol/l (1792 +/- 302 IU) in infants receiving standard amounts of the vitamin. In spite of the difference in intake of vitamin A, 3 weeks after study enrollment, serum retinol concentrations did not differ between the infants given supplements and those receiving standard amounts of vitamin A, 0.70 +/- 0.21 versus 0.66 +/- 0.07 mumol/l (20 +/- 6 micrograms/dl versus 19 +/- 2 micrograms/dl, respectively). In the infants receiving supplemental vitamin A, breath ethane values declined from baseline values. There was an inverse correlation between the number of weeks of supplementation and breath ethane values, whereas there was no significant correlation between the duration of the study and breath ethane values in the infants not given supplements. CONCLUSIONS: Our data suggest that supplementation with vitamin A in a small group of vitamin A-deficient preterm infants was associated with an antioxidant effect. Although no immediate clinical benefits were associated with supplementation, the data provide the rationale for future investigations of possible antioxidant effects of (larger amounts?) of vitamin A in higher risk premature infants born with subnormal serum retinol concentrations.

Administration, Oral↗
PubMed1997

Validation of the Panic Outcomes Module.

This article discusses the validation of a module designed to evaluate the outcomes of clinical care for panic disorder. The research utilized a longitudinal design to examine cross-sectional relationships and change over time within and between subjects. Baseline, follow-up, and test-retest data were collected on 73 patients. The initial field test indicates that the Panic Outcomes Module measures outcomes and case-mix characteristics with acceptable levels of measurement error for group data. The module's measure of change in panic severity demonstrated encouraging agreement with the structured interviewer's judgement of change. This module, completed in approximately 20 minutes, is short enough to incorporate into outpatient mental health settings. We recommend that providers and administrators interested in monitoring the outcomes of specialty care for panic disorder seek assistance from health services researchers to use the Panic outcomes module. Further research is needed to validate this module for use in primary care populations.

Adult↗