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Biomedical subjects

H Allen

Publications and source records attributed to H Allen.

At least 19 recordsLinked to original sources
PubMed2001

Direct phosphorylation of NF-kappaB1 p105 by the IkappaB kinase complex on serine 927 is essential for signal-induced p105 proteolysis.

The p105 precursor protein of NF-kappaB1 acts as an NF-kappaB inhibitory protein, retaining associated Rel subunits in the cytoplasm of unstimulated cells. Tumor necrosis factor alpha (TNFalpha) and interleukin-1alpha (IL-1alpha) stimulate p105 degradation, releasing associated Rel subunits to translocate into the nucleus. By using knockout embryonic fibroblasts, it was first established that the IkappaB kinase (IKK) complex is essential for these pro-inflammatory cytokines to trigger efficiently p105 degradation. The p105 PEST domain contains a motif (Asp-Ser(927)-Gly-Val-Glu-Thr), related to the IKK target sequence in IkappaBalpha, which is conserved between human, mouse, rat, and chicken p105. Analysis of a panel of human p105 mutants in which serine/threonine residues within and adjacent to this motif were individually changed to alanine established that only serine 927 is essential for p105 proteolysis triggered by IKK2 overexpression. This residue is also required for TNFalpha and IL-1alpha to stimulate p105 degradation. By using a specific anti-phosphopeptide antibody, it was confirmed that IKK2 overexpression induces serine 927 phosphorylation of co-transfected p105 and that endogenous p105 is also rapidly phosphorylated on this residue after TNFalpha or IL-1alpha stimulation. In vitro kinase assays with purified proteins demonstrated that both IKK1 and IKK2 can directly phosphorylate p105 on serine 927. Together these experiments indicate that the IKK complex regulates the signal-induced proteolysis of NF-kappaB1 p105 by direct phosphorylation of serine 927 in its PEST domain.

Amino Acid Sequence↗
PubMed1999

Anti-dementia drugs.

Explore the source record for details and available documents.

Activities of Daily Living↗
PubMed1999

Neurological correlates of depressive symptoms in Alzheimer's disease and vascular dementia.

BACKGROUND: Organic brain disease such as dementia or stroke is associated with depression. In dementia, depressive symptoms are common where there is evidence of vascular disease and in Alzheimer's disease they often coexist with extrapyramidal signs. METHOD: In a study of 60 patients with Alzheimer's disease and 39 patients with vascular dementia, depressive symptoms were rated using the Cornell Scale for Depression in Dementia. Neurological signs were assessed and severity of cognitive impairment was measured with the Mini-Mental State Examination. RESULTS: Depressive symptoms were more severe in vascular dementia. Pyramidal tract signs had no relationship to depression in either type of dementia. In vascular dementia, extrapyramidal and grasp reflexes were strongly related to the severity of depression, and were associated with neurovegetative features. In Alzheimer's disease, extrapyramidal signs were the strongest independent predictor of the severity of depression. CONCLUSION: Depressive symptoms are more severe in vascular dementia compared to Alzheimer's disease and were related to neurological abnormalities.

Aged↗
PubMed1999

Children's fractures: a population based study.

OBJECTIVE: To measure the incidence of childhood fractures in a defined population. SETTING: Accident and emergency (A&E) departments covering the Swansea and Neath Port Talbot areas of South Wales in 1996. METHODS: Linkage of data from A&E departments with population data to produce fracture incidence rates by anatomical site and cause in children aged 0-14 years. RESULTS: During 1996, 2463 new fractures occurred in 2399 residents yielding a fracture rate of 36.1/1000 children. Fractures were more common in boys than girls and increased with age in both groups. Sports and leisure activities accounted for 36% of fractures, assaults for 3.5%, and road traffic accidents 1.4%. Fractures of the radius/ulna were most frequent (36%). CONCLUSIONS: The fracture rate in South Wales children is twice the rate reported in previous studies. Further research is required to elucidate the reasons behind this high rate. Many fractures could be prevented by the use of safer surfaces in school playgrounds, and wrist protection in in-line skaters and possibly in soccer players.

Adolescent↗
PubMed1999

Depressive symptoms and plan switching under managed care.

OBJECTIVE: A central assumption underlying managed care is that plan switching is a viable option for enrollees when they are dissatisfied. The authors used a national employee survey to test the hypothesis that this mechanism is less effective for enrollees with high levels of depressive symptoms than for the remainder of the population. METHOD: The study used data from the Employee Health Care Value Survey, a 1993 survey of 20,283 employees of three major corporations. The authors used the Medical Outcomes Study 36-Item Short-Form Health Survey to identify individuals with the highest decile of depressive and physical symptoms. They examined the relationship between symptoms and dissatisfaction and, for dissatisfied individuals, how symptoms predicted plan switching. Multivariate models were used to control for potential demographic, health, and health coverage confounders. RESULTS: Depressive and physical symptoms were both associated with dissatisfaction with care. Unlike physical symptoms, depressive symptoms were associated with a significantly lower likelihood of actually disenrolling among people who were dissatisfied or who intended to disenroll. This effect was most pronounced for satisfaction with administrative aspects of care (e.g., gatekeeping, utilization review). CONCLUSIONS: People with high levels of depressive symptoms appeared to be less willing or able to act on their dissatisfaction by switching plans. In particular, they were willing to tolerate higher rates of dissatisfaction with the administrative aspects of their health coverage without disenrolling. Plan switching is an essential mechanism underpinning a health care system predicated on competition; it may be less effective for people with depressive disorders.

Attitude to Health↗
PubMed1999

Parents' judgements about young children's problems: why mothers and fathers might disagree yet still predict later outcomes.

Correlates of parents' ratings of behavioural problems were explored in a sample of 93 British families, in which mothers and fathers rated their children at the time of the fourth birthday on the Achenbach Child Behavior Checklist. As in other samples, there was moderate convergence in mothers' and fathers' total problem scores, but also signs that they were reporting different sorts of problems linked to different influences. The father's rating was primarily associated with the child's cognitive ability. The mother's rating was primarily affected by her own mental state and view of her marriage. The father's but not the mother's rating provided unique information that predicted teachers' reports of the children's problems 7 years later. In general, parents' ratings of preschool children's problems reflect particular informants' perspectives on family life.

Affective Symptoms↗
PubMed1998

Brefeldin A-mediated apoptosis requires the activation of caspases and is inhibited by Bcl-2.

Brefeldin A (BFA) has recently been shown to induce apoptosis in human tumor cells in a p53-independent fashion. In this study, BFA-induced apoptosis was analyzed in the human Jurkat T-cell line. Apoptosis occurred 8 h after treatment with BFA and at concentrations as low as 10 ng/ml and increased with the duration of BFA exposure. Forskolin, an inhibitor of BFA-induced deaggregation of the Golgi-microtubular complex in some cell lines, failed to reverse BFA-mediated apoptosis. Further study of the mechanism of BFA-induced apoptosis was conducted by using a series of peptide protease inhibitors. Complete inhibition of cell death was achieved with benzyloxycarbonyl-Val-Ala-Asp-fluromethylketone, a peptide inhibitor of the caspase protease family, and Z-Asp-Glu-Val-Asp-FMK, a specific inhibitor of caspase-3. Both Acetyl-Tyr-Val-Ala-Asp-chloromethylketone and Acetyl-Tyr-Val-Ala-Asp-aldehyde, selective caspase-1 (interleukin-1beta converting enzyme) inhibitors, exerted only partial protection of cells from apoptosis at higher concentrations. Z-Phe-Ala-FMK, a cysteine protease inhibitor lacking aspartate at the P1 position, did not have any impact on BFA-induced apoptosis. Furthermore, Jurkat cells transfected with the proto-oncoprotein Bcl-2, which is able to block various apoptotic conditions, showed remarkable resistance to the apoptotic effect of BFA. Thus, the data indicate that BFA-induced apoptosis requires caspase(s) activation, primarily the activation of caspase-3, and is inhibited by overexpression of Bcl-2.

Amino Acid Chloromethyl Ketones↗
PubMed1998

Caspase-mediated fragmentation of calpain inhibitor protein calpastatin during apoptosis.

Two cysteine protease families (caspase and calpain) participate in apoptosis. Here we report that the endogenous calpain inhibitor calpastatin is fragmented by caspase(s) to various extents during early apoptosis in two cell types. In anti-fas or staurosporine-treated Jurkat T-cells, the high-molecular-weight form (HMW) of calpastatin (apparent Mr 110 K) was extensively degraded to immunoreactive fragments of Mr 75 K and 30 K In apoptotic SH-SY5Y human neuroblastoma cells, HMW calpastatin was degraded to a major immunoreactive fragment of 75 K. In both cell types, fragmentation of HMW calpastatin was blocked by a caspase-specific inhibitor carbobenzoxy-Asp-CH2OC(O)-2,6-dichlorobenzene. In vitro translated HMW calpastatin was sensitive to proteolysis by recombinant caspase-1, -3, and -7. By contrast, in vitro translated LMW calpastatin (which lacks domains L and I) was cleaved into multiple fragments only by caspase-1 and was relatively resistant to caspase-3, -7, and other caspases tested. Consistently with that, purified erythroid LMW calpastatin was also highly susceptible to caspase-1 digestion. Recombinant human calpastatin spanning domain I through III (CAST(DI-III)) was found cleaved by caspase-1 at at least three sites, located in either the A or the C helix of domains I and III (ALDD137*L, LSSD203*F and ALAD404*S), while only a single site (ALDD137*L) was cleaved by caspase-3. These findings suggest that both HMW and LMW calpastatins are more vulnerable to caspase-1 than to caspase-3. Surprisingly, both erythroid LMW calpastatin and recombinant CAST(DI-III) fragmented by caspase-1 suffered only a less than twofold reduction of inhibitory activity toward calpain. We propose that the proteolysis of calpastatin in early apoptosis might have yet unidentified effects on the cross-talk between the two protease systems.

Apoptosis↗
PubMed1998

An adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene.

Adenoviral (Ad)-mediated in vivo gene transfer and expression are limited in part by cellular immune responses to viral-encoded proteins and/or transgene immunogenicity. In an attempt to diminish the former responses, we have previously developed and described helper-dependent (HD) Ad vectors in which the viral protein coding sequences are completely eliminated. These HD vectors have up to 37 kb insert capacity, are easily propagated in a Cre recombinase-based system, and can be produced to high concentration and purity (>99.9% helper-free vector). In this study, we compared safety and efficacy of leptin gene delivery mediated by an HD vector (HD-leptin) and a first-generation E1-deleted Ad vector (Ad-leptin) in normal lean and ob/ob (leptin-deficient) mice. In contrast to evidence of liver toxicity, inflammation, and cellular infiltration observed with Ad-leptin delivery in mice, HD-leptin delivery was associated with a significant improvement in associated safety/toxicity and resulted in efficient gene delivery, prolonged elevation of serum leptin levels, and associated weight loss. The greater safety, efficient gene delivery, and increased insert capacity of HD vectors are significant improvements over current Ad vectors and represent favorable features especially for clinical gene therapy applications.

Adenoviridae↗
PubMed1998

Reduced quality of clot formation with gelatin-based plasma substitutes.

We have studied, over a wide range of dilutions using techniques of clot weight, thrombelastography and scanning electron microscopy, the physical properties of a blood clot formed in vitro when fresh blood was diluted with gelatin-based colloid solutions compared with crystalloid controls. The colloid solutions tested (3.5% polygeline (Haemaccel) and 4% succinylated gelatin (Gelofusine)) produced clots that had reduced median weight (P < 0.001 and P = 0.018, respectively) and reduced mean shear modulus (P < 0.001) compared with crystalloid controls. Scanning electron microscopy showed that the fibrin formed a less extensive mesh in the presence of the gelatin-based colloids compared with crystalloid. Reduction in clot quality with gelatin-based colloids has not been noted previously and further work is needed to ascertain if this occurs in vivo as these solutions are used frequently in patients who require full haemostatic competence.

Blood Cells↗
PubMed1998

Anticipating market demand: tracking enrollee satisfaction and health over time.

OBJECTIVE: To assess guidelines, set by the National Committee for Quality Assurance, for the Health Plan Employer Data and Information Set (HEDIS) 1999 CAHPS 2.0H Survey (formerly the HEDIS 1999 Consumer Survey) in the light of user's needs to monitor health plan performance over time, monitor sick enrollees, and prioritize determinants (drivers) of enrollee experience. DESIGN: A two-wave, cross-sectional/longitudinal panel design, consisting of national surveys mailed to employees of three major USA corporations in 1993 and 1995. STUDY PARTICIPANTS: Samples included employees selected to represent 23 major managed care and indemnity plans in five regions of the USA. In 1993, 14 587 employees responded and in 1995 9018 employees responded (response rates: 51 and 52%). The longitudinal panel sample included 5729 employees who completed both surveys and stayed in the same plan for both years. STUDY MEASURES: The main 1993 and 1995 surveys consisted of 154 and 116 items, respectively. Panel survey content assessed care delivery, plan administration, functional status, well being, and chronic disease. RESULTS: CAHPS 2.0H's point-in-time, cross-sectional design was unable to detect selection bias and led to an inaccurate view of change in performance. CAHPS 2.0H's use of aggregate samples masked key differences between healthy and sick enrollees; e.g. the sick became less satisfied over time. The association-based, statistical techniques that many survey users will employ to prioritize the 'drivers' of enrollee experience in the absence of CAHPS 2.0H guidelines yielded a less efficient account of change than the multi-method/multi-trait approach developed for this project. CONCLUSION: Consumer experience of plan performance is best understood when the separate contributions of longitudinal membership and movement in and out of plans are clarified, changes in health are identified, changes for sick and healthy enrollees are compared, and plan performance on satisfaction criteria is probed to give confirmation and detail. Changes to the CAHPS 2.0H approach in HEDIS 1999 will facilitate user application of these principles.

Adult↗
PubMed1998

Evaluation of a primary care counselling service in Dorset.

BACKGROUND: Research into the effectiveness of counselling in primary care is rare. This study attempts to provide a thorough evaluation of the effects of a new counselling service introduced throughout Dorset. AIM: To evaluate the impact of counselling on client symptomatology, self-esteem, and quality of life. The effect of counselling on drug prescribing, referrals to other mental health professionals, and client and general practitioner (GP) satisfaction were also assessed. METHOD: All new clients referred for counselling were asked to complete and return questionnaires before and after counselling. A total of 385 clients took part in the study. The first and second assessments were compared statistically. Clients were ascribed a psychiatric diagnosis using a simplified version of DSM-IIIR (Diagnostic and Statistical Manual of the American Psychiatric Association). GPs' views of the service were determined using a specially designed questionnaire. Drug data were obtained from the Prescription Pricing Authority and referral statistics from Dorset HealthCare National Health Service (NHS) Trust. RESULTS: The number of psychiatric symptoms and their severity were significantly reduced by counselling. There were no significant differences in the prescription of anxiolytic/hypnotic and anti-depressant medication between matched practices with and without counsellors. The presence of a counsellor did not affect the rate of referral to other mental health professionals. Clients and GPs valued the service highly. CONCLUSIONS: The Psychology Managed Counselling Service is an effective method of running a counselling service and is well received by both clients and GPs. Counselled clients improved significantly on several measures.

Counseling↗
PubMed1997

Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production.

Interferon-gamma-inducing factor (IGIF, interleukin-18) is a recently described cytokine that shares structural features with the interleukin-1 (IL-1) family of proteins and functional properties with IL-12. Like IL-12, IGIF is a potent inducer of interferon (IFN)-gamma from T cells and natural killer cells. IGIF is synthesized as a biologically inactive precursor molecule (proIGIF). The cellular production of IL-1beta, a cytokine implicated in a variety of inflammatory diseases, requires cleavage of its precursor (proIL-1beta) at an Asp-X site by interleukin-1beta-converting enzyme (ICE, recently termed caspase-1). The Asp-X sequence at the putative processing site in proIGIF suggests that a protease such as caspase-1 might be involved in the maturation of IGIF. Here we demonstrate that caspase-1 processes proIGIF and proIL-1beta with equivalent efficiencies in vitro. A selective caspase-1 inhibitor blocks both lipopolysaccharide-induced IL-1beta and IFN-gamma production from human mononuclear cells. Furthermore, caspase-1-deficient mice are defective in lipopolysaccharide-induced IFN-gamma production. Our results thus implicate caspase-1 in the physiological production of IGIF and demonstrate that it plays a critical role in the regulation of multiple proinflammatory cytokines. Specific caspase-1 inhibitors would provide a new class of anti-inflammatory drugs with multipotent action.

Animals↗
PubMed1997

Characterization of mice deficient in interleukin-1 beta converting enzyme.

Interleukin-1 beta converting enzyme (ICE) processes the inactive prolL-1 beta to the proinflammatory mature IL-1 beta. ICE belongs to a family of cysteine proteases that have been implicated in apoptosis. To address the biological functions of ICE, we generated ICE-deficient mice through gene targeting technology. ICE-deficient mice developed normally, appeared healthy, and were fertile. Peritoneal macrophages from ICE-deficient mice underwent apoptosis normally upon ATP treatment. Thymocytes from young ICE-deficient mice also underwent apoptosis when triggered by dexamethasone, gamma irradiation, or aging. ICE-deficient mice had a major defect in the production of mature IL-1 beta and had impaired IL-1 alpha production on LPS stimulation in vitro and in vivo. ICE-deficient mice were resistant to LPS-induced endotoxic shock.

Adenosine Triphosphate↗
PubMed1997

Effects of unsaturated fatty acids on interleukin-1beta production by human monocytes.

Dihomogammalinolenic acid is derived from gammalinolenic acid, administration of which suppresses joint inflammation. It is reported here that interleukin 1beta (IL-1beta) production by human monocytes is enhanced markedly when cells are incubated 18-24 h with the polyunsaturated fatty acids dihomogammalinolenic acid (DGLA) and arachidonic acid (AA), then stimulated with lipopolysaccharide. Effects of eicosapentaenoic acid (EPA) on IL-1beta production are minimal, and palmitic acid (PA) does not influence IL-1beta production.

8,11,14-Eicosatrienoic Acid↗