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Biomedical subjects

D Walker

Publications and source records attributed to D Walker.

At least 55 records · Page 3Linked to original sources
PubMed2001

Safety of a new conjugate meningococcal C vaccine in infants.

BACKGROUND: Group C conjugate meningococcal vaccines (Men C) were introduced into the UK primary immunisation schedule in November 1999. There has been extensive professional and public interest in their efficacy and safety. AIM: To determine the occurrence of at least one uncommon adverse event in infants related to the administration of the Chiron Men C vaccine. METHODS: A total of 2796 infants aged approximately 2 months were recruited into the study from areas in and around Sheffield and from Scotland. They were vaccinated with the Chiron Men C vaccine at 2, 3, and 4 months along with routine immunisations. Data on adverse events occurring one month after each dose were collected actively and prospectively and reviewed for possible relation to the vaccine. RESULTS: There were no deaths. There were no serious adverse events considered definitely or probably caused by the vaccine. Four infants developed serious adverse events (hypotonia, screaming syndrome, maculopapular rash, and agitation, respectively) that were considered possibly related to the vaccine. All recovered completely. Adverse events were seen in 1804 children but were considered possibly related to the vaccine in only 49 (1.8%). On subsequent immunisation there were no recurrences of adverse events considered to be possibly related to the vaccine.

Female↗
PubMed2001

Effects of haloperidol pretreatment on the smoking-induced EEG/mood activation response profile.

This study examined the role of dopamine in modulating the CNS response to cigarette smoking. In a randomized, double-blind, repeated-measures design, quantitative electroencephalographic (EEG) changes and self-reports induced by the smoking of a single cigarette were assessed in 16 smokers following pretreatment with placebo and a dopamine antagonist, haloperidol (2 mg). Following placebo pretreatment, absolute (muV) and relative (%) amplitudes in slow-frequency bands (delta, theta, alpha1) were reduced and absolute and relative amplitudes in fast-frequency bands (alpha2, beta) were increased following cigarette smoking as compared to sham smoking. Haloperidol pretreatment inhibited the smoking-induced increase in absolute beta frequency. Self-ratings indicated that cigarette smoking induced increases in alertness, contentedness and calmness but not euphoria, and reduced cigarette cravings as compared to the sham smoking conditions. Smoking-induced, alpha2 increments were associated with increases in alertness and decreases in euphoria while beta increments were associated with increased calmness. Smoking-related self-ratings of mood and cigarette acceptability were not altered by haloperidol, but subjects were less content overall in the haloperidol condition as compared to placebo. Discussion of these results focuses on transmitter systems and their relationship to neuro-electric and behavioural activities associated with the smoking habit.

Adult↗
PubMed2001

Economic analysis of tuberculosis diagnostic tests in disease control: how can it be modelled and what additional information is needed?

As the goal of tuberculosis (TB) control programmes is to get as many cases as possible onto correct treatment, the critical role of diagnosis is obvious. Under-diagnosis contributes to further spread of the disease, while over-diagnosis wastes scarce resources on inappropriate treatment. Various techniques are available with which to diagnose TB, including sputum smear microscopy, chest X-ray, antibiotics and culture. While it may be possible to improve the application of these diagnostic tools, there is universal recognition of their limitations. Although new technologies have been developed, their appropriateness for use in resource-poor settings has been questioned due to concerns associated with their complexity and high cost. Given the constrained resources of most countries heavily affected by TB, economic evaluation provides a powerful tool to facilitate the prioritisation of resources. However, economic appraisals of diagnostic procedures provide several unique methodological challenges, including specification of appropriate alternatives, measuring costs, and measuring outcomes. Nevertheless, the use of decision analytic models can provide an opportunity to explore many of these issues. This paper presents key problems in the diagnostic process, reviews existing diagnostic techniques, and discusses possible improvements of these techniques and the introduction of new techniques. Next it examines the usefulness of modelling the economics of TB diagnosis, highlighting gaps in information requirements. Finally, the article identifies economic and epidemiological factors that are likely to change results in different settings.

Algorithms↗
PubMed2001

Thromboprophylaxis following caesarean section--a comparison of the antithrombotic properties of three low molecular weight heparins--dalteparin, enoxaparin and tinzaparin.

Pharmacological thromboprophylaxis is increasingly being used after caesarean section to prevent venous thromboembolism. Although a variety of low molecular weight heparins (LMWH) have been used no comparative study exists on their effects on the haemostatic system in this situation. Furthermore, their antithrombotic effect may be mediated through effects other than their inhibitory effect on activated factor X. We compared the plasma anti-factor Xa activity, plasma concentration of tissue factor pathway inhibitor (TFPI) and the reduction in plasma thrombin-antithrombin (TAT) complex concentration in 30 women randomised to receive either dalteparin 5,000 IU anti-Xa once daily (n = 10), enoxaparin 4,000 IU anti-Xa once daily (n = 10) or tinzaparin 50 IU/kg anti-Xa (average dose 3,650 anti-Xa units) once daily (n = 10) following caesarean section. Sampling occurred at 0, 1, 3, 6, 12 and 24 h relative to time of dosing. All preparations produced an increase in mean anti-Xa assay (p < 0.0001), a reduction in mean TAT (p < 0.05) and an increase in mean TFPI concentration (p <0.05). Analysis of variance (ANOVA) revealed a significant difference between the LMWHs in terms of mean anti-factor Xa activity (p < 0.005) and reduction in plasma TAT concentration (p < 0.005). Post hoc analysis indicated that the anti-Xa values of the groups receiving enoxaparin and dalteparin were significantly higher than those of the group receiving tinzaparin (p < 0.05), but not significantly different from each other. Post hoc analysis of the reduction in plasma TAT concentration showed the reduction to be significantly less in the group receiving enoxaparin compared to the dalteparin and tinzaparin groups (p < 0.05), which did not differ significantly from each other. There was no significant difference between treatment groups with regard to plasma concentration of TFPI. These findings demonstrate that LMWHs differ in their effects on haemostatic parameters including thrombin generation as assessed by TAT. The increase in TFPI may be an additional mediator of LMWH's antithrombotic effects. Although these findings demonstrate that LMWHs differ in their haemostatic effects, this does not necessarily infer a clinical difference between these agents.

Adolescent↗
PubMed2001

Les Schwab tire centers leads the way in dental insurance.

A family-owned retail tire company has a successful history with direct reimbursement for dental and other health care benefits. Although there is a co-pay and some elective services are not covered, employees are not asked to fund insurance premiums and freedom of choice with regard to provider is ensured. This approach is grounded in the family orientation of the company.

Health Benefit Plans, Employee↗
PubMed2000

A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype.

Three founder transgenic mice were generated with a 108 kb human genomic fragment containing the entire autosomal dominant polycystic kidney disease (ADPKD) gene, PKD1, plus the tuberous sclerosis gene, TSC2. Two lines were established (TPK1 and TPK3) each with approximately 30 copies of the transgene. Both lines produced full-length PKD1 mRNA and polycystin-1 protein that was developmentally regulated, similar to the endogenous pattern, with expression during renal embryogenesis and neonatal life, markedly reduced at the conclusion of renal development. Tuberin expression was limited to the brain. Transgenic animals from both lines (and the TPK2 founder animal) often displayed a renal cystic phenotype, typically consisting of multiple microcysts, mainly of glomerular origin. Hepatic cysts and bile duct proliferation, characteristic of ADPKD, were also seen. All animals with two copies of the transgenic chromosome developed cysts and, in total, 48 of the 100 transgenic animals displayed a cystic phenotype. To test the functionality of the transgene, animals were bred with the Pkd1(del34) knockout mouse. Both transgenic lines rescued the embryonically lethal Pkd1(del34/del34) phenotype, demonstrating that human polycystin-1 can complement for loss of the endogenous protein. The rescued animals were viable into adulthood, although more than half developed hepatic cystic disease in later life, similar to the phenotype of older Pkd1(del34/+) animals. The TPK mice have defined a minimal area that appropriately expresses human PKD1. Furthermore, this model indicates that over-expression of normal PKD1 can elicit a disease phenotype, suggesting that the level of polycystin-1 expression may be relevant in the human disease.

Animals↗
PubMed2000

Inhibition of a ribosome-inactivating ribonuclease: the crystal structure of the cytotoxic domain of colicin E3 in complex with its immunity protein.

BACKGROUND: The cytotoxicity of most ribonuclease E colicins towards Escherichia coli arises from their ability to specifically cleave between bases 1493 and 1494 of 16S ribosomal RNA. This activity is carried by the C-terminal domain of the colicin, an activity which if left unneutralised would lead to destruction of the producing cell. To combat this the host E. coli cell produces an inhibitor protein, the immunity protein, which forms a complex with the ribonuclease domain effectively suppressing its activity. RESULTS: We have solved the crystal structure of the cytotoxic domain of the ribonuclease colicin E3 in complex with its immunity protein, Im3. The structure of the ribonuclease domain, the first of its class, reveals a highly twisted central beta-sheet elaborated with a short N-terminal helix, the residues of which form a well-packed interface with the immunity protein. CONCLUSIONS: The structure of the ribonuclease domain of colicin E3 is novel and forms an interface with its inhibitor which is significantly different in character to that reported for the DNase colicin complexes with their immunity proteins. The structure also gives insight into the mode of action of this class of enzymatic colicins by allowing the identification of potentially catalytic residues. This in turn reveals that the inhibitor does not bind at the active site but rather at an adjacent site, leaving the catalytic centre exposed in a fashion similar to that observed for the DNase colicins. Thus, E. coli appears to have evolved similar methods for ensuring efficient inhibition of the potentially destructive effects of the two classes of enzymatic colicins.

Amino Acid Sequence↗
PubMed2000

Pollen input to, and incorporation in, two crater lakes in tropical northeast Australia.

Pollen input to the water surfaces of maar crater lakes Barrine and Eacham (1km(2) and 0.5km(2) respectively, ca. 720m a.s.l.), surrounded by rainforest in northeastern Australia, were measured in floating Tauber traps for a variety of periods spanning the years 1978 to 1985. The mean weekly total pollen catch is 75% of that estimated for the surrounding region of varied vegetation. Regardless of their sources, the influxes of pollen taxa are unevenly distributed over the lakes' surfaces. There is similar variation through time, with some indication that this might be smoothed over periods of 5years or more. There are no inflow streams and pollen input down surrounding slopes is negligible. Mean total pollen influx to seston traps close to the lakes' bottoms (1979 to 1988) is <5% of that to the Tauber traps, a discrepancy attributed to trap design. In contrast, mean annual influx measured by the Tauber traps is similar to that estimated from dated sediment samples younger than 1966 AD at Lake Barrine. The proportions of different pollen taxa are less affected by trap position or period of exposure than are their influxes; their mean percentages for Tauber traps, seston traps and sediment samples are all rather similar.The similarity between the mean contribution of exclusively rainforest pollen to the lakes' surfaces (56%) and to Oldfield traps in rainforest interiors (51%) emphasizes the importance of the rainforests, which clothe the crater walls, as sources of pollen to the lakes. The impact of pollen from other vegetation in the region, although present, is much smaller than at interfaces between rainforest and other vegetation types. All this pollen is mixed within and above the crater and delivered to the lakes' surfaces by gravity and frequent rainfall. Limnological processes redistribute it in the water body before it is incorporated into the deep-lake sediments.The value and limitations of current pollen transport and accumulation theory are noted in relation to sites with morphologies similar to these two crater lakes and to the irregular flowering and floristic inhomogeneity of tropical rainforest. The potential for the use of modern pollen input data in the interpretation of pollen analyses from the sediments of such sites is explored.

Journal Article↗
PubMed2000

Pollen fall-out from a tropical vegetation mosaic.

Pollen fall-out into 60 Oldfield traps set in 11 localities and a variety of vegetational contexts on an upland in tropical northeast Australia, range from 0.5k to 20k (mean 3.5k)grcm(-2)a(-1). The ranges attributable to the four major vegetation types in which the traps were situated overlap to such an extent as would make it virtually impossible to allocate an 'unknown' pollen count to a vegetation type on the basis of total pollen influx alone. Nevertheless, the composition of the pollen clearly differs according to the vegetation in which it is trapped and the amounts of other vegetation types within at least 100m. Substantial variations in catches from closely placed traps suggest the influence of very local site, including meteorological, conditions on the results. Pollen is carried between vegetation types, much less far from rainforest than from sclerophyll forest and woodland, regrowth scrub or herbaceous vegetation, but there is no numerically significant ubiquitous 'background' fall-out in the region. The data impose some constraints on the interpretation of fossil pollen spectra but also potentially permit a greater precision in some aspects of such applications.

Journal Article↗
PubMed2000

The plasmin system is induced by and degrades amyloid-beta aggregates.

Amyloid-beta (Abeta) appears critical to Alzheimer's disease. To clarify possible mechanisms of Abeta action, we have quantified Abeta-induced gene expression in vitro by using Abeta-treated primary cortical neuronal cultures and in vivo by using mice transgenic for the Abeta precursor (AbetaP). Here, we report that aggregated, but not nonaggregated, Abeta increases the level of the mRNAs encoding tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Moreover, tPA and uPA were also upregulated in aged AbetaP overexpressing mice. Because others have reported that Abeta aggregates can substitute for fibrin aggregates in activating tPA post-translationally, the result of tPA induction by Abeta would be cleavage of plasminogen to the active protease plasmin. To gain insights into the possible actions of plasmin, we evaluated the hypotheses that tPA and plasmin may mediate Abeta in vitro toxicity or, alternatively, that plasmin activation may lead to Abeta degradation. In evaluating these conflicting hypotheses, we found that purified plasmin degrades Abeta with physiologically relevant efficiency, i.e., approximately 1/10th the rate of plasmin on fibrin. Mass spectral analyses show that plasmin cleaves Abeta at multiple sites. Electron microscopy confirms indirect assays suggesting that plasmin degrades Abeta fibrils. Moreover, exogenously added plasmin blocks Abeta neurotoxicity. In summation, we interpret these results as consistent with the possibility that the plasmin pathway is induced by aggregated Abeta, which can lead to Abeta degradation and inhibition of Abeta actions.

Amino Acid Sequence↗
PubMed2000

Inhibition of sarcoplasmic reticulum function by polyunsaturated fatty acids in intact, isolated myocytes from rat ventricular muscle.

1. We have studied the effects of two polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on spontaneous and electrically stimulated contractions in single, isolated ventricular myocytes from rat hearts. 2. The frequency of spontaneous waves of calcium release and contraction (induced by elevation of the bathing calcium concentration) is reduced in the presence of EPA. At the same time the resting level of intracellular calcium falls, the resting cell length increases and the amplitude of shortening decreases. All these effects are reversed on removal of EPA. 3. Imaging of the waves of calcium release shows that the amplitude and the rate of propagation of the wave is increased in EPA. Consistent with the increased amplitude, integration of the caffeine-induced Na+-Ca2+ exchange current (a measure of the sarcoplasmic reticulum (SR) calcium content) is increased by both EPA and DHA. 4. EPA has a maintained negative inotropic effect on voltage clamped myocytes. This seems to be entirely due to inhibition of the L-type calcium current. Smaller depolarising pulses in control conditions that elicit the same calcium current as in EPA also activate the same level of contraction. This is in spite of the increased SR calcium content in EPA. 5. It is concluded that PUFAs have two effects on the SR; they reduce the availability of calcium for uptake and they inhibit the release mechanism. Both of these effects should lower the frequency of spontaneous waves of calcium release. As spontaneous release of calcium can initiate arrhythmias, some of the anti-arrhythmic action of PUFAs must be exerted at the level of the SR.

Action Potentials↗
PubMed2000

The glucocorticoid receptor: rapid exchange with regulatory sites in living cells.

Steroid receptors bind to site-specific response elements in chromatin and modulate gene expression in a hormone-dependent fashion. With the use of a tandem array of mouse mammary tumor virus reporter elements and a form of glucocorticoid receptor labeled with green fluorescent protein, targeting of the receptor to response elements in live mouse cells was observed. Photobleaching experiments provide direct evidence that the hormone-occupied receptor undergoes rapid exchange between chromatin and the nucleoplasmic compartment. Thus, the interaction of regulatory proteins with target sites in chromatin is a more dynamic process than previously believed.

Animals↗