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Biomedical subjects

Mark A Williams

Publications and source records attributed to Mark A Williams.

At least 19 recordsLinked to original sources
PubMed2006

Marijuana as a trigger of cardiovascular events: speculation or scientific certainty?

Marijuana is the most widely used illicit substance in the United States. Cardiovascular complications in association with marijuana use have been reported during the past three decades. In view of the elevated public interest in this drug's role in pharmacotherapy in the recent years and the aging population of long-term marijuana users from the late 1960s, encounters with marijuana-related cardiovascular adversities may be silently on the rise. The purpose of this article is to increase awareness of the potential of marijuana to lead to cardiovascular disease. Here, we will discuss the physiologic effects of marijuana and include a comprehensive review of the studies and case reports that provide supportive evidence for marijuana as a trigger of adverse cardiovascular events, including tachyarrhythmias, acute coronary syndrome, vascular complications, and even congenital heart defects.

Adult↗
PubMed2006

Neural correlates of imagined and synaesthetic colours.

The experience of colour is a core element of human vision. Colours provide important symbolic and contextual information not conveyed by form alone. Moreover, the experience of colour can arise without external stimulation. For many people, visual memories are rich with colour imagery. In the unusual phenomenon of grapheme-colour synaesthesia, achromatic forms such as letters, words and numbers elicit vivid experiences of colour. Few studies, however, have examined the neural correlates of such internally generated colour experiences. We used functional magnetic resonance imaging (fMRI) to compare patterns of cortical activity for the perception of external coloured stimuli and internally generated colours in a group of grapheme-colour synaesthetes and matched non-synaesthetic controls. In a voluntary colour imagery task, both synaesthetes and non-synaesthetes made colour judgements on objects presented as grey scale photographs. In a synaesthetic colour task, we presented letters that elicited synaesthetic colours, and asked participants to perform a localisation task. We assessed the neural activity underpinning these two different forms of colour experience that occur in the absence of chromatic sensory input. In both synaesthetes and non-synaesthetes, voluntary colour imagery activated the colour-selective area, V4, in the right hemisphere. In contrast, the synaesthetic colour task resulted in unique activity for synaesthetes in the left medial lingual gyrus, an area previously implicated in tasks involving colour knowledge. Our data suggest that internally generated colour experiences recruit brain regions specialised for colour perception, with striking differences between voluntary colour imagery and synaesthetically induced colours.

Adolescent↗
PubMed2006

Clinical evidence for a health benefit from cardiac rehabilitation: an update.

The recent decision by the Centers for Medicare and Medicaid Services to expand the indications for cardiac rehabilitation (CR) provides an opportunity to review the clinical evidence of the efficacy of exercise in the CR setting for patients who have experienced an acute myocardial infarction, coronary artery bypass graft surgery, stable angina, percutaneous coronary intervention, chronic heart failure, cardiac transplant, or cardiac valve repair/replacement. Evidence shows that physician-directed, exercise-based CR positively affects the basic pathophysiology of coronary artery disease, the extent of disability and level of quality of life, and the ability to potentially impact events of both morbidity and mortality. The role of CR, including regular exercise, lifestyle modification, and appropriate medical therapy, is effective in younger and older men and women with cardiac diagnoses. The efficacy of this important therapeutic modality warrants its more widespread application.

Angina Pectoris↗
PubMed2006

Conformational diversity in the TPR domain-mediated interaction of protein phosphatase 5 with Hsp90.

Protein phosphatase 5 (Ppp5) is one of several proteins that bind to the Hsp90 chaperone via a tetratricopeptide repeat (TPR) domain. We report the solution structure of a complex of the TPR domain of Ppp5 with the C-terminal pentapeptide of Hsp90. This structure has the "two-carboxylate clamp" mechanism of peptide binding first seen in the Hop-TPR domain complexes with Hsp90 and Hsp70 peptides. However, NMR data reveal that the Ppp5 clamp is highly dynamic, and that there are multiple modes of peptide binding and mobility throughout the complex. Although this interaction is of very high affinity, relatively few persistent contacts are found between the peptide and the Ppp5-TPR domain, thus explaining its promiscuity in binding both Hsp70 and Hsp90 in vivo. We consider the possible implications of this dynamic structure for the mechanism of relief of autoinhibition in Ppp5 and for the mechanisms of TPR-mediated recognition of Hsp90 by other proteins.

Amino Acid Sequence↗
PubMed2006

Abnormal configural face perception in a patient with right anterior temporal lobe atrophy.

Face perception is a vital aspect of human social functioning and involves specialized cognitive and neural mechanisms. For example, configural face processing involves determining the relationship between the parts of the face, and this process enables us to differentiate between different faces. Here, we report an unusual case in which right anterior temporal lobe atrophy resulted in a profound deficit in the ability to recognize faces. We demonstrate that this patient is not able to process faces via configural information, raising the possibility that the right anterior temporal lobe has a role in configural face processing.

Atrophy↗
PubMed2006

Formation of focal adhesion-like structures in circulating human neutrophils after severe injury: triggering of a tissue-phase response in the vascular space.

Neutrophils play a key role in injury to the lung, kidney, liver, and gastrointestinal tract, often seen after major trauma. We evaluated the role of integrin-linked focal adhesions in the primed state, previously identified in peripheral blood neutrophils from severely injured patients. Immunoblot analysis of Triton-insoluble cell fractions revealed that total paxillin content was unchanged in comparison with that found in neutrophils from healthy volunteers, but phosphorylation of paxillin on tyrosine residue 118 was increased by more than 2-fold. Immunoprecipitation with antipaxillin and immunoblotting for proline-rich tyrosine kinase 2 (Pyk2) and for fgr showed significantly more colocalization. Densitometric analysis of total phosphotyrosine profiles also demonstrated significantly more in patient cells as compared with healthy cells. When allowed to adhere to fibronectin-coated plates, healthy and patient cells demonstrate a significant increase in tyrosine phosphorylation from that found in suspension-phase cells. Differential interference contrast microscopy of healthy neutrophils adherent to fibronectin matrices demonstrated rounded cells, without evidence of spreading; spreading was induced by addition of TNF-alpha. Patient neutrophils spread spontaneously, a response not further enhanced by TNF-alpha. Confocal imaging using anti-Pyk2 demonstrated aggregation of Pyk2 into punctate structures in patient but not in healthy cells. We conclude that neutrophils from severely injured patients are in a primed state, characterized by formation of focal adhesion-like structures. The identification of such structures in a clinical disease setting where they likely participate in unwanted consequences provides a novel area for study of regulation of neutrophil function.

Adult↗
PubMed2005

Distinct spatial and temporal distribution of ZAP70 and Lck following stimulation of interferon and T-cell receptors.

T-cell receptor (TCR) stimulation results in the recruitment and activation of the proteins ZAP70 and Lck. These two proteins have been implicated in signalling derived from interferon receptors, although their precise role in this independent pathway has not been determined fully. These observations raise a fundamental question of how a given protein in a cell can be involved in more than one signalling pathway, yet each pathway is able to produce a highly specific downstream response to its own stimulant. To maintain exclusivity of response, each pathway must isolate its component molecules chemically, spatially or dynamically from other prevailing pathways. To address this question, the proteins ZAP70 and Lck were investigated following stimulation of the interferon-alpha receptor and the TCR in T cells by two different extracellular stimulants: interferon-alpha and the anti-CD3 antibody, OKT3, respectively. We first demonstrate that ZAP70 plays a pivotal role in interferon-stimulated MAPK activation, and that the tyrosine residue at position 319 of ZAP70 is important for interferon-stimulated ERK activation. Translocation of both ZAP70 and Lck to the nucleus following interferon receptor stimulation is demonstrated for the first time. Fluorescence resonance energy transfer microscopy revealed a high degree of spatial localization of the ZAP70/Lck complex within the cell following IFNalpha stimulation, in contrast to a diffuse presence following the application of OKT3. The difference in the spatio-temporal localization of these proteins following stimulation may eliminate signal crosstalk, and could explain the differentiation of the specific downstream responses of these pathways.

Active Transport, Cell Nucleus↗
PubMed2005

Tissue levels and biomarkers of organic contaminants in feral and caged chub (Leuciscus cephalus) from rivers in the West Midlands, UK.

The Birmingham conurbation (West Midlands, UK) has traditionally been a major centre of UK industry and population and consequently has a legacy of pollution, which is reflected in the water quality of local rivers. Three of these rivers, exhibiting good, intermediate and poor overall water quality, were the subject of a study in which the effects of contamination on hepatic biomarkers and tissue contaminant loads in feral and caged chub (Leuciscus cephalus) were investigated. Muscle polychlorinated biphenyls and organochlorine pesticides (PCBs and OCPs), as well as bile pyrene and benzo[a]pyrene-like metabolite levels, were variable in both caged and feral fish, but were generally higher in tissue from the more polluted sites. OCPs were, in most cases, higher in the feral fish than in the caged fish, although the opposite was true of bile PAH metabolites, possibly due to differences in relative accumulation rates. Hepatic CYP1A activity (via ethoxyresorufin-O-deethylase (EROD) activity) in both feral and caged fish was also generally higher at the more polluted sites. EROD activity in feral and caged fish was statistically associated with polycyclic aromatic hydrocarbon (PAH) contamination and specific PCB congeners. Other biomarkers measured (reduced glutathione in liver, and serum aspartate aminotransferase) showed little consistent evidence of relationships with water quality. The assessment of these parameters during different seasons also revealed relatively little evidence of temporal variation. Overall, the caged chub appeared to reflect the pattern of general water quality more accurately than did feral fish, particularly with respect to EROD activity and to some degree bile PAH metabolites, thus supporting their use as sentinel species. However, the fact that muscle OCPs were generally higher in the feral fish suggests that the use of feral fish may be more indicative of exposure to certain classes of contaminant, and so biological monitoring programs should be designed with such considerations in mind.

Analysis of Variance↗
PubMed2005

Effectiveness of ulnar artery catheterization after failed attempt to cannulate a radial artery.

Transradial artery catheterization has become an accepted alternative approach to performing diagnostic and interventional coronary procedures. However, its usefulness can be limited by access site failure. We report on 12 patients in whom there was failure to cannulate the radial artery. Angiograms of the hand were performed on all patients through the ulnar sheath to determine the possible mechanism of failure to cannulate the radial artery and to determine the source of the blood supply to the hand. Irrespective of the mechanism of failure, each of the 12 procedures was subsequently successfully completed using the ipsilateral ulnar artery approach.

Aged↗
PubMed2005

Cardiac rehabilitation and secondary prevention of coronary heart disease: an American Heart Association scientific statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity), in collaboration with the American association of Cardiovascular and Pulmonary Rehabilitation.

This article updates the 1994 American Heart Association scientific statement on cardiac rehabilitation. It provides a review of recommended components for an effective cardiac rehabilitation/secondary prevention program, alternative ways to deliver these services, recommended future research directions, and the rationale for each component of the rehabilitation/secondary prevention program, with emphasis on the exercise training component.

Coronary Disease↗
PubMed2005

Molecular recognition via coupled folding and binding in a TPR domain.

The majority of known tetratricopeptide repeat (TPR) domains consist of three copies of the helix-turn-helix TPR motif, together with a seventh C-terminal helix. TPR domains function as protein-protein recognition modules in intracellular signalling. This function is exemplified by the TPR domain of protein phosphatase 5 (PP5), which binds to the C terminus of the chaperone protein Hsp90. Here, we report NMR and CD spectroscopic studies that reveal that this domain is largely unfolded at physiological temperatures, and that interaction with an MEEVD pentapeptide derived from Hsp90 stabilises a folded structure. This complex, coupled folding-binding mechanism is characterised further by its observed enthalpy change on binding (determined by isothermal titration calorimetry), which displays a markedly non-linear relationship with temperature. A nested Gibbs-Helmholtz model is used in a novel combined analysis of the CD and ITC data to determine separately the thermodynamic contributions of the intrinsic folding and binding events to the overall coupled process. The analysis shows that, despite the expected large entropic opposition to the folding process, a nearly equal favourable folding enthalpy means the net effect of coupled folding on the observed affinity is small across a broad range of temperature. We hypothesise that a coupled folding-binding mechanism is common in this class of domains.

Amino Acid Sequence↗
PubMed2005

Differential amygdala responses to happy and fearful facial expressions depend on selective attention.

Facial expressions of emotion elicit increased activity in the human amygdala. Such increases are particularly evident for expressions that convey potential threat to the observer, and arise even when the face is masked from awareness. We used functional magnetic resonance imaging (fMRI) to examine whether the amygdala responds differentially to threatening (fearful) versus nonthreatening (happy) facial expressions depending on whether the face is attended or actively ignored. In separate runs, participants were cued to attend to a face or a house within semitransparent, spatially overlaid composite pairs, presented either side of fixation, and were required to perform a demanding same/different judgment. We found significant attentional modulation of activity in category-specific 'face' (fusiform gyrus) and 'place' (parahippocampal gyrus) regions, with activity in each area increasing selectively when its preferred stimulus was attended versus ignored. In contrast, activity in the amygdala differed according to the valence of the facial expression and the category of the attended stimulus. For happy faces, activity in the amygdala was greater in the attend-face than in the attend-house condition, whereas for fearful faces, activity was greater in the attend-house than in the attend-face condition. We conclude that differential amygdala responses to fearful versus happy facial expressions are tuned by mechanisms of attention and that the amygdala gives preference to potentially threatening stimuli under conditions of inattention.

Adult↗
PubMed2005

Stenting of the left carotid artery to relieve anginal symptoms.

Stenting of the carotid artery is usually performed either to prevent an acute neurologic event or to treat episodes of recurrent transient ischemic attacks. Occasionally, it may be performed for other indications. We describe the case of a patient with prior coronary artery bypass grafting using a left internal mammary arterial graft, in addition to left carotid artery to left subclavian artery bypass for symptomatic left subclavian stenosis, who subsequently underwent left common carotid artery stenting to relieve anginal symptoms.

Aged↗
PubMed2005

Ultrasound screening of asymptomatic siblings of children with vesicoureteral reflux: a long-term followup study.

PURPOSE: Siblings of patients with vesicoureteral reflux (VUR) are at greater risk of having reflux than the general population, and the role of screening in this group is widely accepted. While voiding cystourethrogram (VCUG) is the gold standard for diagnosis of VUR, ultrasound (US) is often used for screening select patients. We examine the outcomes of a conventional US screening program in older asymptomatic siblings. MATERIALS AND METHODS: Between 1984 and 2003 asymptomatic siblings older than 5 years as well as children whose parents refused VCUG were screened with conventional US and urine studies. If US showed a discrepancy in renal size, renal scarring or hydronephrosis, or a change in the size of the renal pelvis during the study, then VCUG was performed. Additionally, any child with a normal US who subsequently had symptoms of urinary tract infection was then referred for VCUG. Chart review was performed and 117 siblings were identified who met these criteria (age range 2 months to 15 years). An attempt was made to contact all 117 siblings to obtain long-term followup data. RESULTS: Of the 117 siblings 11 (9.4%) were referred for VCUG secondary to abnormal US findings (9) and development of urinary tract infection (2). VCUG was negative in the 2 symptomatic children, while 5 of the 9 (55.6%) with abnormal US were found to have VUR. Telephone contact was established with 85 of the 117 (72.6%) siblings or their parents (average followup 8.3 years, range 2 months to 19 years). All 85 siblings with available followup information had normal US, and none had had symptoms or complications of VUR since screening. CONCLUSIONS: Given the lower incidence and seemingly innocuous nature of VUR in older asymptomatic siblings of known patients with reflux, observation alone in this group is an acceptable form of management. If either parental or physician anxiety exists in this approach, then conventional US offers a reliable alternative to invasive VCUG screening in this population.

Adolescent↗
PubMed2005

Interleukin 8 dimerization as a mechanism for regulation of neutrophil adherence-dependent oxidant production.

Interleukin 8 (IL-8), a member of the CXC subfamily of chemoattractant cytokines, induces a range of functional responses in human neutrophils via its interactions with two high-affinity cell-surface receptors, CXCR1 and CXCR2. Like other CXC chemokines, IL-8 forms homodimers at physiologic concentrations. Monomers and dimers bind to CXC receptors with high affinity and induce various functions. Binding to glycosaminoglycans decreases the dimerization constant, enhancing surface-bound dimer formation. However, a specific role for IL-8 dimerization has not been identified. We explored the hypothesis that certain neutrophil responses to IL-8 were induced primarily by the IL-8 dimers. To this end, two dimerization-deficient IL-8 mutant proteins, M3 and M4, were used in various functional assays. In contrast to native IL-8, these proteins existed primarily as monomers at micromolar concentrations. The mutants retained high-affinity binding to both CXC receptors and potently induced neutrophil calcium flux, chemotaxis, and elastase release. In contrast to native IL-8, neither mutant inhibited tumor necrosis factor alpha-induced oxidant production. Additionally, M4 was less effective than native IL-8 at desensitizing neutrophil migration. These data suggest that although IL-8 dimers or monomers are sufficient for several neutrophil functions, dimers may participate in suppression of specific surface-dependent neutrophil responses.

Binding, Competitive↗