Biomedical subjects

A Woods

Publications and source records attributed to A Woods.

At least 19 recordsLinked to original sources

PubMed2006

Intramembrane receptor-receptor interactions: a novel principle in molecular medicine.

In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and long-lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A/D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.

Animals↗

PubMed2006

Treatment of isolated severe immune hemolytic anaemia associated with systemic lupus erythematosus: 26 cases.

The aim of this study was to evaluate the response to treatment and the long-term outcome in a cohort of patients in whom severe autoimmune hemolytic anaemia (AHA) was the leading manifestation of systemic lupus erythematosus (SLE). Twenty-six women with severe isolated AHA were included. Corticosteroids were used as the initial treatment for all patients in our study. An initial response was obtained in all but one patient (96%). The overall recurrence rate was three per 100 person-years, with an expected recurrence-free proportion of 73% with a 180 months median follow-up. Seven patients (27%) experienced a relapse of AHA. We found a higher proportion of pleuritis in relapsing patients. Only three patients experienced multiple relapses despite splenectomy and several immunosuppressants. Steroid-sparing effect of hydroxychloroquine and azathioprine could not be assessed because most of the patients received these treatments for other reasons than AHA. Intravenous immunoglobulins induced transient response in three cases. Splenectomy was efficient to definitively control AHA in one patient but two patients quickly experienced relapses while one patient did not benefit. Five patients received immunosuppressants that induced only transient responses. Rituximab was long-term efficient in one case. In conclusion, severe AHA is a serious complication of SLE that warrants appropriate management. On the basis of our experience, the ideal treatment of isolated AHA should be oral corticosteroids in first-line treatment. Our study does not support an important role for splenectomy. Patients refractory to conventional therapy should be treated either with few toxic immunosuppressive drugs, danazol or rituximab.

Adolescent↗

PubMed2005

Anthrax lethal factor inhibition.

The primary virulence factor of Bacillus anthracis is a secreted zinc-dependent metalloprotease toxin known as lethal factor (LF) that is lethal to the host through disruption of signaling pathways, cell destruction, and circulatory shock. Inhibition of this proteolytic-based LF toxemia could be expected to provide therapeutic value in combination with an antibiotic during and immediately after an active anthrax infection. Herein is shown the crystal structure of an intimate complex between a hydroxamate, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, and LF at the LF-active site. Most importantly, this molecular interaction between the hydroxamate and the LF active site resulted in (i) inhibited LF protease activity in an enzyme assay and protected macrophages against recombinant LF and protective antigen in a cell-based assay, (ii) 100% protection in a lethal mouse toxemia model against recombinant LF and protective antigen, (iii) approximately 50% survival advantage to mice given a lethal challenge of B. anthracis Sterne vegetative cells and to rabbits given a lethal challenge of B. anthracis Ames spores and doubled the mean time to death in those that died in both species, and (iv) 100% protection against B. anthracis spore challenge when used in combination therapy with ciprofloxacin in a rabbit "point of no return" model for which ciprofloxacin alone provided 50% protection. These results indicate that a small molecule, hydroxamate LF inhibitor, as revealed herein, can ameliorate the toxemia characteristic of an active B. anthracis infection and could be a vital adjunct to our ability to combat anthrax.

Animals↗

PubMed2005

Interaction of bismuth subsalicylate with fruit juices, ascorbic acid, and thiol-containing substrates to produce soluble bismuth products active against Clostridium difficile.

Bismuth subsalicylate (BSS), the active ingredient of Pepto-Bismol, has been used for many years to treat various disorders of the gastrointestinal tract. Using mass spectrometry and the agar dilution method, we determined that insoluble BSS interacts with certain dietary components and organic substrates to produce water-soluble products with activity against Clostridium difficile.

Anti-Bacterial Agents↗

PubMed2004

von Willebrand disease: laboratory aspects of diagnosis and treatment.

von Willebrand disease is the most common inherited bleeding disorder in humans. VWD can be classified into three major types, designated Types 1, 2 and 3; Type 2 can be further separated into subtypes 2A, 2B, 2M and 2N. The diagnosis of VWD requires a personal and family history of bleeding and confirmation by laboratory analysis. Although Types 2 and 3 are relatively straightforward to diagnose, there may be a risk of overdiagnosis of Type 1 because of an overlap within the normal range. We also report on the clinical profile and diagnosis of VWD in a South American cohort of patients and on the in vitro characteristics of some factor concentrates available for treatment of VWD.

Adolescent↗

PubMed2004

Injury prevention training: a cluster randomised controlled trial assessing its effect on the knowledge, attitudes, and practices of midwives and health visitors.

OBJECTIVE: To evaluate the effectiveness of injury prevention training. DESIGN: Cluster randomised controlled trial. SETTING: Primary care facilities in the East Midlands area of the United Kingdom. SUBJECTS: Midwives and health visitors. INTERVENTION: Evidence based training session on the risks associated with baby walkers. MAIN OUTCOME MEASURES: The primary outcome measures were knowledge of baby walker use and walker related injury, attitudes towards walkers and towards walker education, and practices relating to walker health education. RESULTS: Trained midwives and health visitors had greater knowledge of the risks associated with baby walkers than untrained midwives and health visitors (difference between the means 0.22; 95% confidence interval (CI) 0.12 to 0.33). Trained health visitors had more negative attitudes to baby walkers (difference between the means 0.35; 95% CI 0.10 to 0.59) and more positive attitudes towards baby walker health education (difference between the means 0.31; 95% CI 0.00 to 0.62) than untrained health visitors. Midwives who had been trained were more likely to discuss baby walkers in the antenatal period than those who were not trained (odds ratio 9.92; 95% CI 2.02 to 48.83). CONCLUSIONS: Injury prevention training was associated with increased knowledge, more negative attitudes towards walkers, and more positive attitudes towards walker education. Trained midwives were more likely to give advice antenatally. Training did not impact on other practices. Larger trials are required to assess the impact of training on parental safety behaviours, the adoption of safety practices, and injury reduction.

Attitude of Health Personnel↗

PubMed2003

Bypassing the glucose/fatty acid cycle: AMP-activated protein kinase.

The AMPK (AMP-activated protein kinase) cascade plays a key role in regulating energy metabolism. Conditions which cause a decrease in the ATP/AMP ratio lead to activation of AMPK. Once activated, AMPK initiates a series of responses that act to restore the energy balance of the cell. In skeletal muscle, activation of AMPK increases both glucose uptake and fatty acid oxidation, raising the possibility that AMPK can bypass the glucose/fatty acid cycle. This review focuses on the role of AMPK in the regulation of glucose and fatty acid metabolism in muscle. Recently, naturally occurring mutations within the gamma isoforms have been identified which lead to altered metabolic regulation in cardiac and skeletal muscle and suggest an important role for the kinase in regulating glycogen metabolism.

AMP-Activated Protein Kinases↗

PubMed2002

Home oxygen status and rehospitalisation and primary care requirements of infants with chronic lung disease.

OBJECTIVES: To determine whether the rehospitalisation and primary care requirements of infants with chronic lung disease (CLD) during the first two years after birth were influenced by a requirement for supplementary oxygen after discharge from the neonatal intensive care unit. METHODS: Review of records from both the hospital and general practitioner. PATIENTS: 235 infants, median gestational age 27 (range 22-31) weeks, 88 of whom were receiving supplementary oxygen when discharged home. RESULTS: Overall, the infants required a median of 2 (range 0-20) admissions per patient, 8 (0-41) outpatient attendances, 13 (0-76) contacts with the general practitioner, and 17 (0-169) consultations with other primary healthcare professionals. The home oxygen patients required significantly more and longer admissions (p < 0.01) and more outpatient attendances (p < 0.05). The total cost of care per infant of the home oxygen group was greater (p < 0.001); this reflected higher costs for hospital stay (p < 0.01), total inpatient care (p < 0.01), and primary care drugs (p < 0.01). CONCLUSION: Despite routine use of antenatal steroids and postnatal surfactant, certain patients with CLD, particularly those who receive home oxygen treatment, show high rates of utilisation of health service resources after discharge from the neonatal care unit.

Analysis of Variance↗

PubMed2001

PDGF-regulated rab4-dependent recycling of alphavbeta3 integrin from early endosomes is necessary for cell adhesion and spreading.

BACKGROUND: It has been postulated that the regulation of integrin vesicular traffic facilitates cell migration by internalizing integrins at the rear of the cell and transporting them forward within vesicles for exocytosis at the leading edge to form new contacts with the extracellular matrix. The rab family of GTPases control key targeting events in the endo/exocytic pathway; therefore, these GTPases may be involved in the regulation of cell-matrix contact assembly. RESULTS: The endo/exocytic cycle of alphavbeta3 and alpha5beta1 integrins was studied using mouse 3T3 fibroblast cell lines. In serum-starved cells, internalized integrins were transported through rab4-positive, early endosomes and arrived at the rab11-positive, perinuclear recycling compartment approximately 30 min after endocytosis. From the recycling compartment, integrins were recycled to the plasma membrane in a rab11-dependent fashion. Following treatment with PDGF, alphavbeta3 integrin, but not alpha5beta1, was rapidly recycled directly back to the plasma membrane from the early endosomes via a rab4-dependent mechanism without the involvement of rab11. This rapid recycling pathway directed alphavbeta3 to numerous small puncta distributed evenly across the dorsal surface of the cell, and the integrin only became localized into focal complexes at later times following PDGF addition. Interestingly, inhibition of PDGF-stimulated alphavbeta3 recycling using dominant-negative rab4 mutants compromised cell adhesion and spreading on vitronectin (a ligand for alphavbeta3), but adhesion to fibronectin (a ligand for alpha5beta1 and alphavbeta3) was unchanged. CONCLUSIONS: We propose that growth factor-regulated, rab4-dependent recycling of alphavbeta3 integrin from early endosomes to the plasma membrane is a critical upstream event in the assembly of cell-matrix contacts.

3T3 Cells↗

PubMed2001

On-ramp simulations and solitary waves of a car-following model.

An on-ramp simulation of a car-following model reveals qualitatively similar results to previous simulations of continuum models carried out by Helbing et al. [Phys. Rev. Lett. 82, 4360 (1999)] and by Lee, Lee, and Kim[Phys. Rev. E 59, 5101 (1999)]. Here, we discuss the solitary solution type in greater detail. It can be approximated by a Kortweg-de Vries equation derived from the analogous continuum version. Hence, this establishes a further link between these two traffic simulation types and supports the idea that models of either kind lead to similar results when they contain a relaxation term.

Journal Article↗

PubMed2001

Solution structure of the dimeric cytoplasmic domain of syndecan-4.

The syndecans, transmembrane proteoglycans which are involved in the organization of cytoskeleton and/or actin microfilaments, have important roles as cell surface receptors during cell-cell and/or cell-matrix interactions. Since previous studies indicate that the function of the syndecan-4 cytoplasmic domain is dependent on its oligomeric status, the conformation of the syndecan-4 cytoplasmic domain itself is important in the understanding of its biological roles. Gel filtration results show that the syndecan-4 cytoplasmic domain (4L) itself forms a dimer stabilized by ionic interactions between peptides at physiological pH. Commensurately, the NMR structures demonstrate that syndecan-4L is a compact intertwined dimer with a symmetric clamp shape in the central variable V region with a root-mean-square deviation between backbone atom coordinates of 0.95 A for residues Leu(186)-Ala(195). The molecular surface of the 4L dimer is highly positively charged. In addition, no intersubunit NOEs in membrane proximal amino acid resides (C1 region) have been observed, demonstrating that the C1 region is mostly unstructured in the syndecan-4L dimer. Interestingly, two parallel strands of 4L form a cavity in the center of the dimeric twist similar to our previously reported 4V structure. The overall topology of the central variable region within the 4L structure is very similar to that of 4V complexed with the phosphatidylinositol 4,5-bisphosphate; however, the intersubunit interaction mode is affected by the presence of C1 and C2 regions. Therefore, we propose that although the 4V region in the full cytoplasmic domain has a tendency for strong peptide--peptide interaction, it may not be enough to overcome the repulsion of the C1 regions of syndecan-4L.

Amino Acid Sequence↗

PubMed2001

Resuscitation of dormant Mycobacterium tuberculosis by phospholipids or specific peptides.

The presence of dormant tubercle bacilli presents a major problem for tuberculosis treatment. The culture supernatant of Mycobacterium tuberculosis was previously shown to resuscitate dormant bacilli in vitro. Here we report identification of active components as phospholipids and a tuberculosis protein Rv1174c. Remarkably, dormant bacilli from a one year old culture which failed to form any colonies could be resuscitated with peptides derived from Rv1174c and formed 10(5-7) colonies/ml. This finding represents the first unambiguous demonstration of resuscitation of dormant tubercle bacilli in vitro and may have implication for the study of mycobacterial dormancy and the design of novel strategies for improved treatment of tuberculosis.

Adaptation, Biological↗

PubMed2001

Rat embryo fibroblasts require both the cell-binding and the heparin-binding domains of fibronectin for survival.

Fibronectin (FN) is known to transduce signal(s) to rescue cells from detachment-induced apoptosis (anoikis) through an integrin-mediated survival pathway. However, the functions of individual FN domains have not been studied in detail. In the present study we investigated whether the interaction of the cell-binding domain of FN with integrin is sufficient to rescue rat embryo fibroblasts (REFs) from detachment-induced apoptosis. REFs attached and spread normally after plating on substrates coated with either intact FN or a FN fragment, FN120, that contains the cell-binding domain but lacks the C-terminal heparin-binding domain, HepII. REFs on FN maintained a well-spread fibroblastic shape and even proliferated in serum-free medium at 20 h after plating. In contrast, previously well-spread REFs on FN120 started losing fibroblastic shape with time and detached from FN120-coated plates after approx. 8 h. Nuclear condensation indicated apototic cell death. This was due to the decreased activity/stability of focal adhesion kinase (pp125FAK) in the absence of HepII domain. A peptide in the HepII domain [peptide V, WQPPRARI (single-letter amino acid codes)], which has previously been implicated in cytoskeletal organization, rescued apoptotic changes. Consistently, pp125FAK phosphorylation was increased, and both cleavage of pp125FAK and activation of caspase 3 on FN120 were partly blocked by peptide V. Thus the interaction of the cell-binding domain with integrin has a major role in cell survival but is itself not sufficient for cell survival. One or more additional survival signals come from the HepII domain to regulate pp125FAK activity/stability.

Amino Acid Sequence↗

PubMed2001

Traveling waves in an optimal velocity model of freeway traffic.

Car-following models provide both a tool to describe traffic flow and algorithms for autonomous cruise control systems. Recently developed optimal velocity models contain a relaxation term that assigns a desirable speed to each headway and a response time over which drivers adjust to optimal velocity conditions. These models predict traffic breakdown phenomena analogous to real traffic instabilities. In order to deepen our understanding of these models, in this paper, we examine the transition from a linear stable stream of cars of one headway into a linear stable stream of a second headway. Numerical results of the governing equations identify a range of transition phenomena, including monotonic and oscillating travelling waves and a time- dependent dispersive adjustment wave. However, for certain conditions, we find that the adjustment takes the form of a nonlinear traveling wave from the upstream headway to a third, intermediate headway, followed by either another traveling wave or a dispersive wave further downstream matching the downstream headway. This intermediate value of the headway is selected such that the nonlinear traveling wave is the fastest stable traveling wave which is observed to develop in the numerical calculations. The development of these nonlinear waves, connecting linear stable flows of two different headways, is somewhat reminiscent of stop-start waves in congested flow on freeways. The different types of adjustments are classified in a phase diagram depending on the upstream and downstream headway and the response time of the model. The results have profound consequences for autonomous cruise control systems. For an autocade of both identical and different vehicles, the control system itself may trigger formations of nonlinear, steep wave transitions. Further information is available [Y. Sugiyama, Traffic and Granular Flow (World Scientific, Singapore, 1995), p. 137].

Journal Article↗

PubMed2001

The distribution and regulation of integrin-linked kinase in normal and diabetic kidneys.

Alteration in cell adhesion and extracellular matrix deposition is a hallmark of diabetic glomerulosclerosis. Integrin-linked kinase (ILK) is a recently identified integrin cytoplasmic-binding protein that has been implicated in the regulation of cell adhesion and extracellular matrix deposition. To begin to investigate whether ILK is involved in the pathogenesis of diabetic glomerulosclerosis, we have analyzed the distribution and regulation of ILK in normal and diabetic kidneys as well as in isolated mesangial cells. We have found that ILK is normally expressed at high concentration in visceral epithelial cells. In diabetic glomeruli, ILK expression in the mesangium is dramatically increased. The increase in ILK level is associated with diffuse mesangial expansion. In glomeruli where advanced nodular sclerosis and global sclerosis were dominant, ILK level was reduced, suggesting that the increase in ILK expression likely associates with relatively early glomerulosclerosis. Additionally, we have found that exposure of mesangial cells to high concentrations of glucose significantly increased the ILK level. Finally, we show that ILK localizes to regions of cell membranes that are in close contact with mesangial fibronectin matrix. These results suggest that ILK is likely involved in mesangial matrix expansion in response to hyperglycemia in the pathogenesis of diabetic glomerulosclerosis.

Animals↗

PubMed2001

Syndecans and cell adhesion.

Now that transmembrane signaling through primary cell-matrix receptors, integrins, is being elucidated, attention is turning to how integrin-ligand interactions can be modulated. Syndecans are transmembrane proteoglycans implicated as coreceptors in a variety of physiological processes, including cell adhesion, migration, response to growth factors, development, and tumorigenesis. This review will describe this family of proteoglycans in terms of their structures and functions and their signaling in conjunction with integrins, and indicate areas for future research.

Amino Acid Sequence↗

PubMed2001

Syndecan-4 and focal adhesion function.

Two groups have now reported the viability of mice that lack syndecan-4. These mice have wound healing/angiogenesis problems, and fibroblasts from these animals differ in adhesion and migration from normal. This is consistent with recent in vitro data indicating a need for signaling via syndecan-4 for focal adhesion formation, and reports that overexpression of proteins that bind syndecan-4 can modify cell adhesion and migration.

Animals↗

PubMed2001

A direct chemical interaction between dynorphin and excitatory amino acids.

The endogenous opioid peptide dynorphin A elicits non-opioid receptor-mediated neurotoxic effects. These effects are blocked by pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists. Herein, the mechanism for the non-opioid effects of dynorphin and related peptides was studied by matrix-assisted laser desorption ionization (MALDI) mass-spectrometry. We observed that both glutamate or aspartate bind non-covalently to dynorphin A and dynorphin 2-17. However, when dynorphin A or dynorphin 2-17 were added to an equimolar mixture of Glutamate and Aspartate, they both complexed preferentially with glutamate. These data may explain the non-opioid physiological effects of dynorphin A and related peptides and indicate that the direct chemical interaction between neurotransmitters should be monitored when studying interactions between different neurochemical systems.

Dynorphins↗