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Biomedical subjects

A Hall

Publications and source records attributed to A Hall.

At least 73 records · Page 4Linked to original sources
PubMed2000

Functional independence of circadian clocks that regulate plant gene expression.

BACKGROUND: Circadian clocks regulate the gene expression, metabolism and behaviour of most eukaryotes, controlling an orderly succession of physiological processes that are synchronised with the environmental day/night cycle. Central circadian pacemakers that control animal behaviour are located in the brains of insects and rodents, but the location of such a pacemaker has not been determined in plants. Peripheral plant and animal tissues also maintain circadian rhythms when isolated in culture, indicating that these tissues contain circadian clocks. The degree of autonomy that the multiple, peripheral circadian clocks have in the intact organism is unclear. RESULTS: We used the bioluminescent luciferase reporter gene to monitor rhythmic expression from three promoters in transgenic Arabidopsis and tobacco plants. The rhythmic expression of a single gene could be set at up to three phases in different anatomical locations of a single plant, by applying light/dark treatments to restricted tissue areas. The initial phases were stably maintained after the entraining treatments ended, indicating that the circadian oscillators in intact plants are autonomous. This result held for all the vegetative plant organs and for promoters expressed in all major cell types. The rhythms of one organ were unaffected by entrainment of the rest of the plant, indicating that phase-resetting signals are also autonomous. CONCLUSIONS: Higher plants contain a spatial array of autonomous circadian clocks that regulate gene expression without a localised pacemaker. Circadian timing in plants might be less accurate but more flexible than the vertebrate circadian system.

Arabidopsis↗
PubMed2000

The GTPase Rap1 controls functional activation of macrophage integrin alphaMbeta2 by LPS and other inflammatory mediators.

BACKGROUND: beta2 integrins mediate many aspects of the inflammatory and immune responses, including adhesion of leukocytes to the endothelium, complement-mediated phagocytosis in macrophages and neutrophils, and antigen-specific conjugate formation between cytotoxic T cells and their targets. A variety of inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), platelet-activating factor (PAF), and lipopolysaccharide (LPS) and other bacterial products induce the functional activation of beta2 integrins, but the signaling events that link membrane receptors to integrin activation are poorly understood. RESULTS: We report here that expression of the constitutively active small GTPases Rap1 or R-ras, but not Ras or RalA, is sufficient for functional activation of alphaMbeta2, the complement receptor 3 (CR3), in macrophages, allowing phagocytosis of C3bi-opsonized targets. Inhibition of Rap1, but not other Ras-like or Rho-like small GTPases, abolishes activation of alphaMbeta2 induced by phorbol esters, LPS, TNF-alpha or PAF. Finally, Rap1 activation specifically controls the binding properties of alphaMbeta2 towards its physiological ligand, namely the complement-opsonized phagocytic targets. CONCLUSIONS: In macrophages, the Rap1 GTPase regulates activation of the alphaMbeta2 integrin in response to a wide variety of inflammatory mediators.

Animals↗
PubMed2000

Rho GTPases: molecular switches that control the organization and dynamics of the actin cytoskeleton.

The actin cytoskeleton plays a fundamental role in all eukaryotic cells it is a major determinant of cell morphology and polarity and the assembly and disassembly of filamentous actin structures provides a driving force for dynamic processes such as cell motility, phagocytosis, growth cone guidance and cytokinesis. The ability to reorganize actin filaments is a fundamental property of embryonic cells during development; the shape changes accompanying gastrulation and dorsal closure, for example, are dependent on the plasticity of the actin cytoskeleton, while the ability of cells or cell extensions, such as axons, to migrate within the developing embryo requires rapid and spatially organized changes to the actin cytoskeleton in response to the external environment. Work in mammalian cells over the last decade has demonstrated the central role played by the highly conserved Rho family of small GTPases in signal transduction pathways that link plasma membrane receptors to the organization of the actin cytoskeleton.

Actins↗
PubMed2000

Rho GTPases and their effector proteins.

Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell-cycle progression and cell adhesion. About 30 potential effector proteins have been identified that interact with members of the Rho family, but it is still unclear which of these are responsible for the diverse biological effects of Rho GTPases. This review will discuss how Rho GTPases physically interact with, and regulate the activity of, multiple effector proteins and how specific effector proteins contribute to cellular responses. To date most progress has been made in the cytoskeleton field, and several biochemical links have now been established between GTPases and the assembly of filamentous actin. The main focus of this review will be Rho, Rac and Cdc42, the three best characterized mammalian Rho GTPases, though the genetic analysis of Rho GTPases in lower eukaryotes is making increasingly important contributions to this field.

Amino Acid Sequence↗
PubMed2000

Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group.

BACKGROUND: We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensin-converting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure. METHODS: Three of the trials enrolled patients within a week after acute myocardial infarction. Data were combined by use of the Peto-Yusuf method. FINDINGS: Overall 12,763 patients were randomly assigned treatment or placebo and followed up for an average of 35 months. In the three post-infarction trials (n=5,966), mortality was lower with ACE inhibitors than with placebo (702/2995 [23.4%] vs 866/2971 [29.1%]; odds ratio 0.74 [95% CI 0.66-0-83]), as were the rates of readmission for heart failure (355 [11.9%] vs 460 [15.5%]; 0.73 [0.63-0.85]), reinfarction (324 [10.8%] vs 391 [13.2%]; 0.80 [0.69-0.94]), or the composite of these events (1049 [35.0%] vs 1244 [41.9%]; 0.75 [0.67-0.83]; all p<O.001). For all five trials the ACE inhibitor group had lower rates of death than the placebo group (1,467/6,391 [23.0%] vs 1,710/6,372 [26.8%]; 0.80 [0.74-0.87]) and lower rates of reinfarction (571 [8.9%] vs 703 [11.0%]; 0.79 [0.70-0.89]), readmission for heart failure (876 [13.7%] vs 1202 [18.9%]; 0.67 [0.61-0.74]), and the composite of these events (2161 [33.8%] vs 2610 [41.0%]; 0.72 [0.67-0.78]; all p<0.0001). The benefits were observed early after the start of therapy and persisted long term. The benefits of treatment on all outcomes were independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. Although there was a trend towards greater reduction in risk of death or readmission for heart failure in patients with lower ejection fractions, benefit was apparent over the range examined.

Aged↗
PubMed2000

Phosphatidylinositol 4,5-bisphosphate induces actin-based movement of raft-enriched vesicles through WASP-Arp2/3.

BACKGROUND: Phosphatidylinositol 4,5-bisphosphate (PIP(2)) has been implicated in the regulation of the actin cytoskeleton and vesicle trafficking. It stimulates de novo actin polymerization by activating the pathway involving the Wiskott-Aldrich syndrome protein (WASP) and the actin-related protein complex Arp2/3. Other studies show that actin polymerizes from cholesterol-sphingolipid-rich membrane microdomains called 'rafts', in a manner dependent on tyrosine phosphorylation. Although actin has been implicated in vesicle trafficking, and rafts are sites of active phosphoinositide and tyrosine kinase signaling that mediate apically directed vesicle trafficking, it is not known whether phosphoinositide regulation of actin dynamics occurs in rafts, or if it is linked to vesicle movements. RESULTS: Overexpression of type I phosphatidylinositol phosphate 5-kinase (PIP5KI), which synthesizes PIP(2), promoted actin polymerization from membrane-bound vesicles to form motile actin comets. Pervanadate (PV), a tyrosine phosphatase inhibitor, induced comets even in the absence of PIP5KI overexpression. PV increased PIP(2) levels, suggesting that it induces comets by changing PIP(2) homeostasis and by increasing tyrosine phosphorylation. Platelet-derived growth factor (PDGF) enhanced PV-induced comet formation, and these stimuli together potentiated the PIP5KI effect. The vesicles at the heads of comets were enriched in PIP5KIs and tyrosine phosphoproteins. WASP-Arp2/3 involvement was established using dominant-negative WASP constructs. Endocytic and exocytic markers identified vesicles enriched in lipid rafts as preferential sites of comet generation. Extraction of cholesterol with methyl-beta-cyclodextrin reduced comets, establishing that rafts promote comet formation. CONCLUSIONS: Sphingolipid-cholesterol rafts are preferred platforms for membrane-linked actin polymerization. This is mediated by in situ PIP(2) synthesis and tyrosine kinase signaling through the WASP-Arp2/3 pathway. Actin comets may provide a novel mechanism for raft-dependent vesicle transport and apical membrane trafficking.

3T3 Cells↗
PubMed2000

Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue.

FGD1 gene mutations result in faciogenital dysplasia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adversely affects the formation of multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42. By way of Cdc42, FGD1 regulates the actin cytoskeleton and activates the c-Jun N-terminal kinase signaling cascade to regulate cell growth and differentiation. Previous work shows that FGD1 is the founding member of a family of related genes including the mouse Fgd2 gene and the rat Frabin gene. Here, we report on the isolation, characterization, and mapping of the mouse Fgd3 gene, a new and novel member of the FGD1 gene family. Fgd3 cDNA encodes a 733-amino-acid protein with a predicted mass of 81 kDa. Fgd3 and FGD1 share a high degree of sequence identity that spans >560 contiguous amino acid residues. Like FGD1, Fgd3 contains adjacent RhoGEF and pleckstrin homology (PH) domains, a second carboxy-terminal PH domain, and a distinctive FYVE domain. Together, these domains appear to form a canonical core structure for FGD1 family members. In addition, compared to other FGD1 family members, Fgd3 contains different structural regions that may be involved in distinct signaling interactions. Microinjection studies show that Fgd3 stimulates fibroblasts to form filopodia, actin microspikes formed upon the stimulation of Cdc42. Fgd3 transcripts are present in several diverse tissues and during mouse embryogenesis, suggesting a developmentally regulated pattern of expression and a potential role in embryonic development. Genetic linkage and radiation hybrid mapping data show that Fgd3 and the human FGD3 ortholog map to syntenic regions of murine chromosome 13 and human chromosome 9q22, respectively. We conclude that Fgd3 is a new and novel member of the FGD1 family of RhoGEF proteins.

3T3 Cells↗
PubMed2000

Oligodendrocyte lineage and the motor neuron connection.

One of the more surprising recent discoveries in glial biology has been that oligodendrocytes (OLs) originate from very restricted regions of the embryonic neural tube. This was surprising because myelinating OLs are widespread in the mature central nervous system, so there was no reason to suspect that their precursors should be restricted. What we now know about early OL development suggests that they might have as much (or more) in common with ventral neurons-specifically motor neurons (MNs)-as with other types of glia. This has implications for the way we think about glial development, function, and evolution. In this article we review the evidence for a shared MN-OL lineage and debate whether this is the only lineage that generates OLs. We decide in favour of a single embryonic lineage with regional variations along the anterior-posterior neuraxis.

Animals↗
PubMed2000

Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) can persist through adolescence and adulthood, resulting in significant disability. The use of low-dose oral methotrexate (MTX) for persistent polyarthritis has been shown to be effective by the USA/USSR collaborative study group. However, 2 of the most disabling subgroups of JIA, systemic and extended oligoarthritis, were underrepresented in that study. The present study was therefore conducted to investigate the efficacy of MTX in these 2 subgroups. METHODS: Patients under the age of 16 years who fulfilled the International League of Associations for Rheumatology criteria for systemic or extended oligoarticular arthritis were eligible for this multicenter, double-blind, placebo-controlled crossover trial. Forty-five patients with systemic and 43 with extended oligoarticular arthritis were enrolled. The dosage of MTX or placebo was 15 mg/m2, which could be increased to 20 mg/m2 after 2 months. Core outcome variables were considered as primary measures, giving a final score of "improved" or "not improved." Secondary measures included scores of systemic features and biochemical laboratory measures. Assessment of function was not included since there were no validated functional measures at the start of this trial in 1991. RESULTS: In the extended oligoarticular arthritis group, MTX treatment produced significant improvement in 3 of 5 core variables (erythrocyte sedimentation rate, physician's global assessment of disease activity, and parent's global assessment of disease activity). By the primary improvement criteria, there was significant overall improvement during MTX treatment. In the systemic arthritis group, only 2 of 5 core variables were significantly improved (physician's and parent's global assessment of disease activity). Systemic features were not part of the core variables, but the systemic feature score was not significantly different between MTX and placebo treatment. There was no significant overall improvement in this group during MTX treatment. However, no significant interaction between disease subgroup and treatment effect was demonstrated. When the data from both disease subgroups were combined, there was significant clinical improvement during MTX treatment (P = 0.006). CONCLUSION: MTX 15-20 mg/m2 given orally once a week was found to be an effective treatment for both extended oligoarticular and systemic JIA in this shortterm trial. Long-term efficacy needs to be addressed in future studies.

Adolescent↗
PubMed2000

Procedural justice in the context of civil commitment: an analogue study.

Procedural justice theory posits that the process by which disputes are resolved influences perceptions of fairness and satisfaction with outcomes, even if the outcomes are unfavorable. Within the context of civil commitment, Tyler (1992) has suggested that enhancing respondents' perceptions of procedural justice (i.e., participation, dignity, and trust) during commitment proceedings might facilitate accommodation to an adverse judicial determination (i.e., commitment) and subsequently enhance therapeutic outcomes. The study reported here used videotapes of mock commitment hearings to examine whether patients committed for involuntary treatment are sensitive to procedural justice manipulations. Results suggest that patients are sensitive to procedural justice manipulations and, further, that such manipulations are likely to influence the patients' attitude toward psychiatric care. These findings suggest that the development of strategies to enhance patients' perceptions of procedural justice in commitment hearings may indeed have positive therapeutic implications and warrants further investigation.

Adolescent↗
PubMed2000

Improving cervical cancer screening in hospital settings.

BACKGROUND: Identifying opportunities to offer cervical cancer screening to underscreened women is important for increasing early detection. Maryland law mandates offering Pap tests during hospital admissions. We examined organizational and physician attitudes and practices regarding inpatient screening, to identify mechanisms for increasing the law's effectiveness. METHODS: We analyzed state admission data, a hospital administrators telephone survey, and a mailed survey of Maryland primary and specialty care physicians, to identify overall patterns and subgroup differences regarding screening. RESULTS: Overall, we found significant concern regarding cancer, and evidence of policies and procedures for screening. However, most hospitals and providers offered screening without assessing clinical need or including persuasive recommendations. Providers with significantly less engagement in preventive assessment and screening included medical and surgical subspecialists and non-primary care providers. Providers to African-American and Medical Assistance women were also less likely to have knowledge, attitudes, and practices conducive to inpatient screening. CONCLUSIONS: Adequate support and infrastructure for preventive screening exist within hospitals. Adding clinical assessment and persuasive education could in crease the impact of these mechanisms, and improve prevention among underscreened inpatient populations.

Attitude of Health Personnel↗
PubMed2000

Geographical variation in Ascaris lumbricoides fecundity and its implications for helminth control.

The observation by microscopy of nematode eggs in human faeces is used to diagnose a helminthic infection, while the concentration of those eggs is used to estimate the number of worms in the host. Within a community, the prevalence of infection and the mean egg count provide useful information about the extent of a public health problem, and are being used to guide the growing efforts to control disease caused by helminths. Here, Andrew Hall and Celia Holland examine data on the relationship between the worm burdens of Ascaris lumbricoides and the concentration of eggs in faeces, and discuss the implications of the variation found for using such data to plan helminth control programmes.

Adolescent↗
PubMed2000

The mediating role of caspase-3 protease in the intracellular mechanism of genistein-induced apoptosis in human prostatic carcinoma cell lines, DU145 and LNCaP.

A series of in vitro studies were carried out to investigate genistein-induced cell death, and the nature of cell death, in two human prostate cancer cell lines (LNCaP and Du145), and the possible involvement of caspase-3 protease in genistein-induced apoptosis in the target cells. The major findings of these studies are: i) genistein inhibits growth and proliferation of both LNCaP and DU145 cells via apoptosis mainly, and necrosis at higher concentrations; ii) genistein induces activation and expression of caspase-3 (CPP32) in both target cells; iii) genistein-induced apoptosis and CPP32 activation could be significantly inhibited by the caspase-3 inhibitor, z-VAD-fmk (N-benzyloxycarbonyl-Val-Asp-fluoromethyl-ketone), thus confirming a mediator role of CPP32 in the genistein-induced apoptotic pathway in the target cells. The potency of most known chemopreventive drugs for cancer is due to induction of apoptosis in solid tumors (Thompson, Science 267 (1995) 1456; Gurney et al., Science 288 (2000) 283). Inevitably, agents that increase transcription of caspase-3 protease could reinforce cell death via CPP32-mediated apoptosis. In this regard, genistein may find an application in the treatment of human prostate carcinoma, independently of hormone sensitivity.

Amino Acid Chloromethyl Ketones↗
PubMed2000

The Medical Interaction Process System (MIPS): an instrument for analysing interviews of oncologists and patients with cancer.

The increase in communication skills training for doctors has led to the need for more effective means of evaluation. Analysis of video and audiotaped consultations using systems of interaction analysis can provide the trainee with in-depth feedback about their communication skills. Most interaction process systems were designed for use in primary care and recent research has questioned the applicability of these systems in medical specialties such as oncology. We describe the development of a new instrument, the Medical Interaction Process System (MIPS) for use in teaching communication skills and empirical research in medical encounters, particularly, between doctors and patients with cancer. A comparison of the MIPS and comparable behaviour categories of another widely used system (the Roter Interaction Analysis System) was made to test convergent validity. Pearson correlation coefficients suggested a good level of concurrence between the two systems. Intercoder reliability tests were carried out between two coders at two separate time periods. Both of these indicated good reliability for the majority of categories. The two major advantages of the MIPS over other coding systems are: (1) the system allows for sequential and parallel coding, thus avoiding major coding conflicts and (2) the design of the coding sheet results in a multidimensional view of the consultation without data loss. We believe that the MIPS yields useful information for teaching doctors communication skills and also provides an objective method for evaluating the effectiveness of communication skills courses.

Humans↗
PubMed2000

Description and evaluation of an education and communication skills training course in HIV and AIDS for dental consultants.

A 2-day course was organised for dental hospital consultants as part of a project on raising awareness of dental staff about HIV and AIDS. The course comprised an information update, practical experience in the diagnosis of oral conditions and a "hands-on" exercise in infection control. The 2nd day of the course consisted of experiential communication skills training using rôle-play with actors and video feedback. Evaluation of the course showed that the consultants perceived the course to be valuable. There was a general improvement in dentists' confidence in their knowledge, ability to communicate with HIV-positive patients and in talking to staff who are unwilling to provide treatment. These changes are statistically significant and these skills are still being utilized and maintained 2 years later. Information and training packs prepared by multidisciplinary groups using a variety of teaching methods should be made available to those involved in training dental staff.

Communication↗
PubMed2000

The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho.

Loss of the tumour-suppressor gene TSC1 is responsible for hamartoma development in tuberous sclerosis complex (TSC), which renders several organs susceptible to benign tumours. Hamartin, the protein encoded by TSC1, contains a coiled-coil domain and is expressed in most adult tissues, although its function is unknown. Here we show that hamartin interacts with the ezrin-radixin-moesin (ERM) family of actin-binding proteins. Inhibition of hamartin function in cells containing focal adhesions results in loss of adhesion to the cell substrate, whereas overexpression of hamartin in cells lacking focal adhesions results in activation of the small GTP-binding protein Rho, assembly of actin stress fibres and formation of focal adhesions. Interaction of endogenous hamartin with ERM-family proteins is required for activation of Rho by serum or by lysophosphatidic acid (LPA). Our data indicate that disruption of adhesion to the cell matrix through loss of hamartin may initiate the development of TSC hamartomas and that a Rho-mediated signalling pathway regulating cell adhesion may constitute a rate-limiting step in tumour formation.

3T3 Cells↗