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Biomedical subjects

A Hill

Publications and source records attributed to A Hill.

At least 91 records · Page 5Linked to original sources
PubMed1999

Fatal familial insomnia: a new Austrian family.

We present clinical, pathological and molecular features of the first Austrian family with fatal familial insomnia. Detailed clinical data are available in five patients and autopsy in four patients. Age at onset of disease ranged between 20 and 60 years, and disease duration between 8 and 20 months. Severe loss of weight was an early symptom in all five patients. Four patients developed insomnia and/or autonomic dysfunction, and all five patients developed motor abnormalities. Analysis of the prion protein (PrP) gene revealed the codon 178 point mutation and methionine homozygosity at position 129. In all brains, neuropathology showed widespread cortical astrogliosis, widespread brainstem nuclei and tract degeneration, and olivary 'pseudohypertrophy' with vacuolated neurons, in addition to neuropathological features described previously, such as thalamic and olivary degeneration. Western blotting of one brain and immunocytochemistry in four brains revealed quantitative and regional dissociation between PrP(res)(the protease resistant form of PrP) deposition and histopathology. In the cerebellar cortex of one patient, PrP(res) deposits were prominent in the molecular layer and displayed a peculiar patchy and strip-like pattern with perpendicular orientation to the surface. In another patient, a single vacuolated neuron in the inferior olivary nuclei contained prominent intravacuolar granular PrP(res) deposits, resembling changes of brainstem neurons in bovine spongiform encephalopathy.

Adult↗
PubMed1999

Reversal of human neutrophil survival by leukotriene B(4) receptor blockade and 5-lipoxygenase and 5-lipoxygenase activating protein inhibitors.

Persistent neutrophilia is a feature of chronic obstructive pulmonary disease (COPD). Leukotriene synthesis inhibitors and cysteinyl leukotriene receptor antagonists have shown efficacy in the treatment of asthma. Antagonism of leukotriene (LT)B(4) receptors is being considered as a mode of treating COPD. We examined the capacity for inhibition of leukotriene synthesis and LTB(4) receptor antagonism to reduce survival of neutrophils from patients with COPD and those from normal subjects. The basal apoptosis level of these cells was 55.4 +/- 2.4% (mean +/- SEM) of total cells. Separate exposure to lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor (GM-CSF), dexamethasone (DEX), and LTB(4) increased neutrophil survival (p < 0. 001). The LTB(4) receptor antagonist SB201146 abolished LPS-induced survival in a concentration-dependent manner (10 pmol to 0.1 microM), with an IC(50) of 1.9 nM. Combined exposure to SB201146 and to the cysteinyl leukotriene antagonist SKF104353 did not have a greater effect on survival than did exposure to SB201146 alone. Inhibition of 5-lipoxygenase (5-LO) with BWA4C and of 5-LO-activating protein (FLAP) with MK886 abolished GM-CSF- and DEX-induced neutrophil survival. BWA4C and MK886 abolished GM-CSF- induced neotrophil survival in a concentration-dependent manner (1 nM to 10 microM), with IC(50) values of 182.0 nM and 63.1 nM, respectively. These findings demonstrate reversal of LPS-, GM-CSF-, and DEX-induced neutrophil survival by LTB(4) receptor antagonism and inhibitors of 5-LO and FLAP. They also suggest a potential additional antiinflammatory mode of action of these compounds through reduction of cell survival.

5-Lipoxygenase-Activating Proteins↗
PubMed1998

The use of out of hours health services: a cross sectional survey.

OBJECTIVES: To determine the use and costs of the principal out of hours health services in Buckinghamshire. DESIGN: Prospective cross sectional survey and cost description of patient contacts with out of hours services. SETTING: Buckinghamshire during March and April 1995. SUBJECTS: General practices, accident and emergency departments, ambulance services, and community nursing services. MAIN OUTCOME MEASURE: Contacts with patients and cost of out of hours services. RESULTS: 438 patient contacts/1000 population/year were recorded at an annual incremental cost of between 4.6 m Pounds and 7.2 m Pounds (depending on the costing of general practitioner services), for a population of 660,000. Of these contacts, 21,649 (45%) were with general practitioners. Night time contacts with all services diminished sharply after 10 pm. General practitioners considered that 40% of contacts were unnecessary or could have waited until morning. Over 70% of contacts were for upper respiratory tract infections, earache, gastroenteritis, and other minor ailments. Nursing care was predominantly for elderly people, and 33% of nursing contacts were to supervise medication. Accident and emergency care was predominantely for young adults, especially men, and 41% of attendances were for medical conditions. CONCLUSIONS: New models such as multidisciplinary primary care centres with telephone advice lines and triaging are required to ensure high quality, cost effective care that is responsive to the needs of both consumers and professionals.

Adolescent↗
PubMed1998

Perinatal hypoxic-ischemic thalamic injury: clinical features and neuroimaging.

A common pattern of hypoxic-ischemic cerebral injury in the term newborn involves predominantly cerebral cortex and subcortical white matter. We describe 20 term newborns with moderate or severe acute hypoxic-ischemic encephalopathy who exhibit a different pattern of abnormalities on computed tomography, with evidence of decreased tissue attenuation predominantly in thalami and basal ganglia and relative preservation of cerebral cortex and white matter. Profound, acute hypoxic-ischemic insult (eg, umbilical cord prolapse, uterine rupture, or massive placental abruption) was documented in 16 of 20 infants (80%). Characteristic clinical features during the newborn period included irritability, tonic posturing of limbs, and persistent lower cranial nerve dysfunction, often with prominent tongue fasciculations. This pattern of central injury appears to be highly predictive of poor outcome; 7 newborns (35%) died, and all survivors who had follow-up to 18 months of age (11) had major neurological sequelae (eg, spastic quadriplegia, choreoathetosis, and persistent feeding problems). This pattern of hypoxic-ischemic cerebral injury corresponds closely to experimental animal models of "acute total" perinatal asphyxia.

Apgar Score↗
PubMed1998

Glucose-6-phosphate dehydrogenase deficiency and malaria.

Glucose-6-phosphate dehydrogenase (G6PD) is a cytoplasmic enzyme that is essential for a cell's capacity to withstand oxidant stress. G6PD deficiency is the commonest enzymopathy of humans, affecting over 400 million persons worldwide. The geographical correlation of its distribution with the historical endemicity of malaria suggests that 66PD deficiency has risen in frequency through natural selection by malaria. This is supported by data from in vitro studies that demonstrate impaired growth of P. falciparum parasites in G6PD-deficient erythrocytes. Attempts to confirm that G6PD deficiency is protective in field studies of malaria have yielded conflicting results, but recent results from large case control studies conducted in East and West Africa provide strong evidence that the most common African G6PD deficiency variant, G6PD A-, is associated with a significant reduction in the risk of severe malaria for both G6PD female heterozygotes and male hemizygotes. The effect of female homozygotes on severe malaria remains unclear but can probably be assumed to be similar to that of comparably deficient male hemizygotes.

Disease Susceptibility↗
PubMed1998

A detailed characterization of the effects of four cannabinoid agonists on operant lever pressing.

The present experiments were conducted to investigate the effects of four cannabimimetics on detailed temporal parameters of operant responding. In this study, the behavioral output during performance of a fixed ratio 5 schedule of reinforcement was recorded by a computer program that measured the response initiation time (IT; time interval between the offset of one lever press and the onset of the next) and the response duration (the amount of time that elapses from the onset to the offset of one lever press) of each lever press. ITs were further partitioned into fast responses (IT=0.0-1.0 s), short pauses (IT= 1.0-2.5 s), and long pauses (IT>2.5 s). Four cannabimimetic agents were assessed in this study: (R)-methanandamide (AM 356), a hydrolytically stable analog of arachidonylethanolamide, an endogenous ligand for the CB1 receptor; CP-55,940, a potent non-classical synthetic ligand; (-)-delta8-tetrahydrocannabinol (delta8-THC), an isomer of the naturally occurring delta9-THC; and WIN 55,212-2, a synthetic aminoalkylindole. All four of the cannabimimetic drugs tested significantly suppressed operant lever pressing in a dose dependent manner. The rank order of potencies observed in the present study was CP-55,940>>WIN-55,212-2>delta8-THC>AM 356, which is consistent with the rank order of affinities for the CB1 receptor shown by these drugs. All of the cannabimimetics substantially increased average IT, and also increased duration time. There was a substantial increase in average length of long pauses, and statistically significant but very small changes in the local rate of responding as measured by the average length of fast ITs. Cannabinoid-treated rats were largely immobile during pauses in responding, and these animals showed several signs of ataxia and catalepsy at the doses that suppressed lever pressing. Together with other data, the present results suggest that CB1 stimulation leads to motor effects that are associated with a suppression of lever pressing.

Animals↗
PubMed1998

The effect of a lindane and mercury polluting incident on the health of a community: the Somerton Health Survey.

OBJECTIVES: This study sought to identify possible illnesses of people exposed to lindane and methyl mercury following a pollution incidence in Somerton, Somerset, UK. METHODS: A self-administered questionnaire survey was posted to 1500 residents in three selected areas of Somerton to identify symptoms of possible illness over a 3 month period. RESULTS: There was a 74% response rate. People living near the stream had higher levels of reported mental symptoms and itching skin than in controls. Poisoning as the cause of the mental symptoms was excluded as the individuals had normal blood levels of lindane or mercury. Other symptoms were no higher in one area than another or from one time period to another. CONCLUSIONS: The survey, using controls in time and space, was able to explore, the pollution incident's contribution to the toxicity of residents and how this related to mental symptoms experienced by the residents.

Air Pollutants↗
PubMed1998

Randomised controlled trial of combined diphtheria, tetanus, whole-cell pertussis vaccine administered in the same syringe and separately with Haemophilus influenzae type b vaccine at two, three and four months of age.

An open randomised controlled multicentre study compared the immunogenicity and reactogenicity of three vaccines given by injection at two, three and four months of age. Children (89) received Haemophilus influenzae type b (Hib) vaccine (SmithKline Beecham Biologicals [SB]) administered in the same syringe with combined diphtheria-tetanus-whole-cell pertussis (DTPw) vaccine (Evans); 75 received Hib vaccine (SB) administered as a separate injection with DTPw vaccine; 66 received Hib vaccine (Pasteur Merieux [PM]) administered as a separate injection with DTPw vaccine. All subjects in both groups receiving Hib (SB) vaccine had levels of antibodies to the Hib polysaccharide polyribosylribitol phosphate (PRP) greater than 0.15 microgram ml-1 as did 97% of those receiving Hib (PM) vaccine 1 month after administration of the final vaccine dose. Subjects in all three groups demonstrated an immunological response to pertussis, diphtheria and tetanus antigens. The geometric mean titres of the group given Hib (SB) and DTPw vaccine mixed in the same syringe were lower than the other groups. There were no apparent differences between the treatment groups in the incidence of local or systemic reactions, or serious adverse events. This study has confirmed that it is possible to halve the number of injections necessary to offer protection, with advantages to parents, children, doctors and nurses, using a combined DTPwHib vaccine and in accordance with the UK's accelerated primary immunisation schedule at two, three and four months of age.

Antibodies↗
PubMed1998

Intraventricular hemorrhage: emphasis on prevention.

Germinal matrix/intraventricular hemorrhage is a common type of cerebral injury in premature newborns. Based on the improved understanding of underlying pathogenetic mechanisms, numerous interventional strategies for prevention have been proposed. This article summarizes and evaluates the efficacy and safety of major interventions that are currently under consideration for the prevention of germinal matrix/intraventricular hemorrhage.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

The Royal Marsden experience of a small bowel adenocarcinoma treated with protracted venous infusion 5-fluorouracil.

The purpose of this study was to review the efficacy of a protracted venous infusion of 5-fluorouracil (PVI 5-FU)-based chemotherapy in advanced small bowel adenocarcinoma. Data on all patients with small bowel malignancy who were seen at a single institution over a 5-year period were retrieved from the gastrointestinal unit and hospital databases, and these cases were reviewed. Eight patients with advanced small bowel adenocarcinoma received PVI 5FU-based chemotherapy. The overall response rate in assessable patients was 37.5% (3/8). The median overall survival was 13 months (range 1-28), and progression-free survival was 7.8 months (range 0-15). Overall, the treatment was well tolerated and symptomatic benefit was seen. In conclusion, PVI 5-FU has activity in this disease. This should be assessed either as a single agent or as part of a combination regimen such as epirubicin/cisplatin/PVI FU (ECF) in a multicentre randomized study.

Adenocarcinoma↗
PubMed1998

Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation.

The origin of CD4+ T cells reappearing in the blood following antiretroviral therapy in human immunodeficiency virus type-1 (HIV-1) infection is still controversial. Here we show, using mathematical modeling, that redistribution of T cells to the blood can explain the striking correlation between the initial CD4+ and CD8+ memory T-cell repopulation and the observation that 3 weeks after the start of treatment memory CD4+ T-cell numbers reach a plateau. The increase in CD4+ T cells following therapy most likely is a composite of initial redistribution, accompanied by a continuous slow repopulation with newly produced naive T cells.

Anti-HIV Agents↗
PubMed1998

Reviews of units of care: combining practice, research and quality assurance.

That nurses should base their practice on the best available knowledge is generally accepted by the profession. However, the operationalisation of this ideal if difficult for hard pressed clinicians. We believe that responsibility for assimilating current knowledge in a practical format belongs to all nurses working in an organisation. This paper describes a project where clinicians, administrators and academics have collaborated to rewrite standards of practice in a format that includes up to date evidence and practical measures for appraising outcomes. This work is a practical example of quality assurance activities serving to create opportunities for collaboration between nurses who have chosen to practice, teach, manage and/or research nursing.

Clinical Competence↗
PubMed1998

Variability in repeated consecutive measurements of plasma human immunodeficiency virus RNA in persons receiving stable nucleoside reverse transcriptase inhibitor therapy or no treatment.

Plasma human immunodeficiency virus (HIV) RNA levels correlate closely with clinical prognosis in both treated and untreated HIV-infected persons and are widely used to guide clinical practice and as a primary end point in clinical trials. Thus, variability in these measurements may significantly affect their interpretation in clinical practice and research. The variability in consecutive measurements of plasma HIV RNA levels was studied in 387 subjects receiving either stable nucleoside reverse transcriptase inhibitor therapy or no treatment. The Pearson's correlation coefficient between baseline measures 2 weeks apart was 0.92. The mean SD in consecutive measurements 1 month apart was 0.31 log10 copies/mL with a 95% tolerance limit of 0.7 log10 copies/mL (5-fold). Two-thirds of the total variance in consecutive measures 1 month apart was due to biologic fluctuation; one-third was due to assay variance. The biologic variance increased proportionately with the number of weeks between assessments. Clinicians and investigators should be aware of the magnitude of variability in viral RNA levels in the HIV-infected population.

Analysis of Variance↗
PubMed1998

Heterogeneity of microsatellite mutations within and between loci, and implications for human demographic histories.

Microsatellites have been widely used to reconstruct human evolution. However, the efficient use of these markers relies on information regarding the process producing the observed variation. Here, we present a novel approach to the locus-by-locus characterization of this process. By analyzing somatic mutations in cancer patients, we estimated the distributions of mutation size for each of 20 loci. The same loci were then typed in three ethnically diverse population samples. The generalized stepwise mutation model was used to test the predicted relationship between population and mutation parameters under two demographic scenarios: constant population size and rapid expansion. The agreement between the observed and expected relationship between population and mutation parameters, even when the latter are estimated in cancer patients, confirms that somatic mutations may be useful for investigating the process underlying population variation. Estimated distributions of mutation size differ substantially amongst loci, and mutations of more than one repeat unit are common. A new statistic, the normalized population variance, is introduced for multilocus estimation of demographic parameters, and for testing demographic scenarios. The observed population variation is not consistent with a constant population size. Time estimates of the putative population expansion are in agreement with those obtained by other methods.

Adenocarcinoma↗
PubMed1998

Six unrelated HLA-DR-matched adults recognize identical CD4+ T cell epitopes from influenza A haemagglutinin that are not simply peptides with high HLA-DR binding affinities.

Influenza A/Beijing/32/92 (H3N2) haemagglutinin (HA)-specific short-term CD4+ T cell lines were generated from six unrelated HLA-DR0701, 1501 positive adults (aged 27-60 years) 3 months following administration of an influenza subunit vaccine containing HA A/Beijing/32/92. Epitope recognition was examined using 118 HA A/Beijing/32/92-specific 16mer peptides which overlapped by 11 residues and which spanned the entire molecule. Following influenza vaccination the donors recognized identical HA peptides. The selected peptides represented HA regions which have been free from extensive drift mutation since the emergence of human H3N2 influenza A strains. Using DAP DR7.0701 cells (a murine cell line expressing HLA-DR0701) as antigen-presenting cells the majority of CD4+ T cell responses were shown to be HLA-DR0701 restricted. The relationship between HA peptide recognition and relative strength of HA peptide-HLA-DR0701 binding was then explored in a competition assay with biotinylated CLIP peptide. Although peptides representing dominant HA epitopes bound to DR0701, the relationship between relative strength of binding and immunodominance was complex, and many strongly binding peptides, particularly those with glycosylation sites and showing inter-strain variation, were not recognized. These results illustrate the control HLA class II exerts over CD4+ T cell HA epitope selection in unrelated adult humans. Immunodominance appears not to be directly related to the relative strength of HA peptide-HLA class II binding, and thus reflects complex interactions between antigen processing, intracellular competition for HLA binding, TCR repertoires and repeated exposure to different strains of influenza A viruses.

Adult↗