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Biomedical subjects

N J Smith

Publications and source records attributed to N J Smith.

At least 19 recordsLinked to original sources
PubMed2004

Hijacking epidermal growth factor receptors by angiotensin II: new possibilities for understanding and treating cardiac hypertrophy.

Activation of the type 1 angiotensin II receptor (AT(1)R) is associated with the aetiology of left ventricular hypertrophy, although the exact intracellular signalling mechanism(s) remain unclear. Transactivation of the epidermal growth factor receptor (EGFR) has emerged as a central mechanism by which the G protein-coupled AT(1)R, which lacks intrinsic tyrosine kinase activity, can stimulate the mitogen-activated protein kinase signalling pathways thought to mediate cardiac hypertrophy. Current studies support a model whereby AT(1)R-dependent transactivation of EGFRs on cardiomyocytes involves stimulation of membrane-bound metalloproteases, which in turn cleave EGFR ligands such as heparin-binding EGF from a plasma membrane-associated precursor. Numerous aspects of the 'triple membrane-passing signalling' paradigm of AT(1)R-induced EGFR transactivation remain to be characterised, including the identity of the specific metalloproteases involved, the intracellular mechanism for their activation and the exact EGFR subtypes required. Here we examine how 'hijacking' of the EGFR might explain the ability of the AT(1)R to elicit the temporally and qualitatively diverse responses characteristic of the hypertrophic phenotype, and discuss the ramifications of delineating these pathways for the development of new therapeutic strategies to combat cardiac hypertrophy.

Angiotensin II↗
PubMed2004

When 6 is 9: 'uncoupled' AT1 receptors turn signalling on its head.

The type 1 angiotensin receptor (AT(1)) activates an array of intracellular signalling pathways that control cell and tissue responses to the peptide hormone angiotensin II (AngII). The capacity of AT(1) receptors to initiate and maintain such signals has typically been explained on the basis of conventional heterotrimeric guanine nucleotide binding protein (G protein) activation, specifically G(q/11). Accumulating evidence from studies utilising a variety of AT(1) receptor mutants and AngII analogues indicates that some important downstream effects of AT(1) receptors are independent of classical G protein coupling. Importantly, AT(1) receptor-mediated endocytosis, tyrosine phosphorylation signalling and mitogen-activated protein kinase activation as well as transactivation of the epidermal growth factor receptor can occur in G(q/11)-uncoupled receptor mutants. These observations point to a functional partitioning of AT(1) receptor signals that permits separation of short-term AngII actions (e.g., vasoconstriction) from more extended events, such as pathological cell growth in heart and blood vessels, and may open up new avenues for selective antagonism.

Animals↗
PubMed2004

Adaptive Aerosol Delivery (AAD) technology.

Jet nebulisers have, since the 1920s, been used for delivery of inhaled drugs for the treatment of asthma, chronic-obstructive pulmonary disease and pulmonary infections. During the last two decades, recognition of the shortcomings of conventional nebulisers has led to the development of new "intelligent" nebulisers such as the Adaptive Aerosol Delivery (AAD), Profile Therapeutics, a Respironics company) systems. Diseases of the airways have traditionally been logical candidates for treatment with inhaled drugs. The introduction of the "intelligent" nebulisers has, however, broadened the possibilities for inhaled treatment to include drugs targeted for systemic diseases. These nebulisers offer the possibility to deliver more precise doses of drug, maximise lung deposition, enhance adherence to treatment and compliance with the device through feedback to the patient, and last but not least, offer the possibility to reduce nebulisation times.

Administration, Inhalation↗
PubMed2002

Direct optical quantification of backflow in a 90 degrees twisted nematic cell.

Optical guided mode observations of the transient director profile (optical tensor distribution) during the relaxation of a 90 degrees twisted nematic cell directly reveals backflow. In the first 6 ms of the relaxation process, after a voltage across the cell is removed, the midplane tilt of the director increases, reaching a maximum value of 101 degrees at 1.4 ms. This increase in midplane tilt is attributed to coupling between fluid flow (backflow) and director reorientation. A 270 degrees twisted state of the opposite handedness to the 90 degrees twisted state found at equilibrium is shown to exist during the backflow period. Good fits of theoretical models with experimentally determined time dependent director profiles yield the viscosity coefficients.

Journal Article↗
PubMed2002

Nerve conduction studies for carpal tunnel syndrome: essential prelude to surgery or unnecessary luxury?

Although carpal tunnel syndrome is a relatively trivial condition, controversy surrounds the use of nerve conduction studies, and whether they are essential to make the diagnosis, or as a prelude to surgery. This is partly due to the lack of a generally agreed definition of the condition, and failure to recognize that the patient's first priority is rapid relief of symptoms. If nerve conduction studies do not contribute to achieving that aim it would be better not to do them. Supporters of routine preoperative nerve conduction studies ignore their shortcomings, which include lack of standardization, absence of population-based reference intervals, and lack of sensitivity and specificity. Only a controlled trial, in which patients are randomized to receive treatment either with or without nerve conduction studies, will determine whether they improve the outcome in patients with a firm clinical diagnosis of carpal tunnel syndrome.

Carpal Tunnel Syndrome↗
PubMed2002

Evaluation of the Digene Hybrid Capture II Assay with the Rapid Capture System for detection of Chlamydia trachomatis and Neisseria gonorrhoeae.

Screening for chlamydial and gonococcal infection has been strongly recommended for all sexually active women under the age of 26. Advances in the ability to detect infection by nucleic acid detection techniques have improved access to screening methods in routine clinical practices. To meet the increasing demand for testing, a high-throughput system is desirable. We evaluated the performance of the Hybrid Capture 2 CT/GC (HC2) assay with the Digene Rapid Capture System (HC2-RCS). The results of HC2-RCS for endocervical samples from 330 women were compared to those of culture and the COBAS Amplicor PCR. For detection of chlamydial infection, HC2-RCS had a sensitivity and a specificity similar to those of PCR (P > 0.5) and an improved sensitivity compared to that of culture (P = 0.007). For identification of gonococcal infections, all assays performed similarly (P > 0.5). The performance of HC2-RCS was also compared to that of the manual HC2 format (HC2-M) with these samples and with 911 endocervical samples collected previously. The performance of HC2-RCS was equivalent to that of HC2-M; the overall concordance rates for the detection of chlamydia and gonorrhea were 99.7% (kappa = 0.97) and 99.8% (kappa = 0.97), respectively. When the HC2 assay was performed with a semiautomated system application designed for high throughput, it demonstrated high sensitivity and a high specificity for detection of both Chlamydia trachomatis and Neisseria gonorrhoeae.

Chlamydia Infections↗
PubMed2001

A new statistical method for haplotype reconstruction from population data.

Current routine genotyping methods typically do not provide haplotype information, which is essential for many analyses of fine-scale molecular-genetics data. Haplotypes can be obtained, at considerable cost, experimentally or (partially) through genotyping of additional family members. Alternatively, a statistical method can be used to infer phase and to reconstruct haplotypes. We present a new statistical method, applicable to genotype data at linked loci from a population sample, that improves substantially on current algorithms; often, error rates are reduced by > 50%, relative to its nearest competitor. Furthermore, our algorithm performs well in absolute terms, suggesting that reconstructing haplotypes experimentally or by genotyping additional family members may be an inefficient use of resources.

Algorithms↗
PubMed2001

Time trends in autism and in MMR immunization coverage in California.

CONTEXT: Considerable concern has been generated in the lay and medical communities by a theory that increased measles-mumps-rubella (MMR) immunization among young children may be the cause of an apparent marked increase in autism occurrence. OBJECTIVE: To determine if a correlation exists in secular trends of MMR immunization coverage among young children and autism occurrence. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analyses of MMR immunization coverage rates among children born in 1980-1994 who were enrolled in California kindergartens (survey samples of 600-1900 children each year) and whose school immunization records were reviewed to retrospectively determine the age at which they first received MMR immunization; and of autism caseloads among children born in these years who were diagnosed with autism and were enrolled in the California Department of Developmental Services regional service center system. MAIN OUTCOME MEASURES: Measles-mumps-rubella immunization coverage rates as of ages 17 months and 24 months and numbers of Department of Developmental Services system enrollees diagnosed with autism, grouped by year of birth. RESULTS: Essentially no correlation was observed between the secular trend of early childhood MMR immunization rates in California and the secular trend in numbers of children with autism enrolled in California's regional service center system. For the 1980-1994 birth cohorts, a marked, sustained increase in autism case numbers was noted, from 44 cases per 100 000 live births in the 1980 cohort to 208 cases per 100 000 live births in the 1994 cohort (a 373% relative increase), but changes in early childhood MMR immunization coverage over the same time period were much smaller and of shorter duration. Immunization coverage by the age of 24 months increased from 72% to 82%, a relative increase of only 14%, over the same time period. CONCLUSIONS: These data do not suggest an association between MMR immunization among young children and an increase in autism occurrence.

Autistic Disorder↗
PubMed2001

Molecular basis by which garlic suppresses atherosclerosis.

The aim of this study was to determine the mechanism by which the aged garlic extract "Kyolic" has a protective effect against atherosclerosis. Plasma cholesterol of rabbits fed a 1% cholesterol-enriched diet for 6 wk was not reduced by supplementation with 800 microL Kyolic/(kg body. d). In spite of this, Kyolic reduced by 64% (P < 0.05) the surface area of the thoracic aorta covered by fatty streaks and significantly reduced aortic arch cholesterol. Kyolic also significantly inhibited by approximately 50% the development of thickened, lipid-filled lesions in preformed neointimas produced by Fogarty 2F balloon catheter injury of the right carotid artery in cholesterol-fed rabbits. In vitro studies found that Kyolic completely prevented vascular smooth muscle phenotypic change from the contractile, high volume fraction of filament (V(v)myo) state, and inhibited proliferation of smooth muscle cells in the synthetic state with a 50% effective dose (ED(50)) of 0.2%. Kyolic also slightly inhibited the accumulation of lipid in cultured macrophages but not smooth muscle, and had no effect on the expression of adhesion molecules on the surface of the endothelium or the adherence of leukocytes. It is concluded that Kyolic exerts antiatherogenic effects through inhibition of smooth muscle phenotypic change and proliferation, and by another (unclarified) effect on lipid accumulation in the artery wall.

Animals↗
PubMed2000

Surface electrode somatosensory-evoked potentials in spinal surgery: implications for indications and practice.

STUDY DESIGN: A retrospective study of 442 major spinal operations with spinal cord monitoring performed in a University Hospital between 1982 and 1992 was performed. OBJECTIVES: To assess the reliability of the authors' method for monitoring by somatosensory-evoked potential recording, to determine criteria for intraoperative corrective action, and to redefine the need for the wake-up test. SUMMARY OF BACKGROUND DATA: The routine use of somatosensory-evoked potential monitoring in spinal surgery remains controversial. In Nottingham, the authors have used a method of recording from either scalp or high cervical electrodes. METHODS: The recordings and outcomes of all monitored spinal operations between the years 1982 and 1992 were reviewed. RESULTS: In 442 procedures, 23 technical failures (no reliable monitoring) occurred. Most technical failures were in patients with severe preoperative neurology, identifiable by somatosensory-evoked potential recording before operation. In the remaining 419 procedures, a significant intraoperative change in response occurred in 70 procedures (16.7%). Using the definitions of the American EEG Society, the authors identified 10 true-positives and 60 false-positives. There were no false-negatives. A wake-up test was performed if an amplitude drop greater than 50% from baseline value persisted after attempts to correct any possible identifiable intraoperative cause. This occurred in only 21 patients (5%). In the true-positive group, somatosensory-evoked potential recordings remained persistently abnormal despite an apparently normal subsequent wake-up test. The sensitivity of the method according to current definitions was 100% and the specificity 85.33%. CONCLUSIONS: Modified guidelines are needed for routine intraoperative use of somatosensory-evoked potential monitoring in spinal surgery. Such guidelines should avoid the term "false-positive" as currently defined and concentrate on the causative analysis of abnormal responses that warn of critical spinal cord dysfunction before that becomes irreversible and allow for appropriate action. Information from this monitoring method alerted the surgeon to the possible need for corrective action in an additional 9.78% of the reported patients, who traditionally would have been regarded as false-positives. A wake-up test still is indicated in patients with persistent suppression of their somatosensory-evoked potential despite correction of any identifiable cause and in cases of technical failure. The current method proved flexible, versatile, and reliable for future use.

Adolescent↗
PubMed2000

ICAM-1 expression by vascular smooth muscle cells is phenotype-dependent.

Atherosclerosis is an inflammatory disease characterised by increased expression of adhesion molecules for leukocytes on both the surface of dysfunctional endothelium and on smooth muscle cells (SMC) within the lesion. It is also characterised by altered SMC phenotypic expression, indicated by a decreased volume fraction of myofilaments (V(v)myo) [1,2] and changes in gene expression [3]. The present study used an in vitro model to investigate, by immunofluorescence staining and flow cytometry, the influence of phenotype on vascular SMC expression of the adhesion molecule for leukocytes, intracellular adhesion molecule-1 (ICAM-1), and the regulatory mechanisms involved in this process. Smooth muscle cells with a high V(v)myo, freshly isolated from rat aortic media, expressed little or no ICAM-1 and this could not be induced by interleukin-1beta (IL-1beta). As SMC modulated phenotype, indicated by decreasing V(v)myo over the first 5 days of culture, there was a concomitant increase in ICAM-1 expression. At day 9 of primary culture, when SMC cultures had returned to the high V(v)myo phenotype, ICAM-1 expression was markedly lower. However, these cells retained the capacity to express ICAM-1 in response to IL-1beta. After several passages in culture, cells (with a low V(v)myo) constitutively expressed ICAM-1, with levels further up-regulated in response to IL-1beta. These changes in ICAM-1 expression were not related to proliferative state, since similar results were obtained with growth arrested SMC. Investigation of signalling pathways involved in regulating ICAM-1 expression by primary vascular SMC suggested a complex regulatory mechanism. Activation of adenyl cyclase (with forskolin) caused a significant increase in cells expressing ICAM-1. Treatment with inhibitors of protein kinase C (chelerythrine chloride), protein tyrosine kinase (genistein), or the transcription factor NF-kappaB (PDTC) had no significant effect on IL-1-induced ICAM-1 expression. However, in the presence of serum, both genistein and PDTC caused a significant increase in basal expression. The results indicate that ICAM-1 expression by SMC is phenotype-dependent, with expression evident only after cells have modulated to a low V(v)myo phenotype. They also indicate the existence of complex regulatory mechanisms, possibly involving the SMC cytoskeleton.

Analysis of Variance↗
PubMed2000

The IBIS project: data collection in London. Improved Monitoring for Brain Dysfunction during Intensive Care and Surgery.

The primary aim of the Improved Monitoring for Brain Dysfunction during Intensive Care and Surgery (IBIS) project was to create a unique and comprehensively annotated data library (DL) of multiple physiological, including neurophysiological, signals. Data collection was undertaken in Kuopio, Finland and London, UK, and comparable protocols were used at all the sites. In London, 43 patients were recruited at the Royal Brompton Hospital, followed by nine at St. Bartholomew's Hospital, all of whom underwent cardiac or combined cardiac and carotid artery surgery. Thirty-seven patients underwent a single operation, while 15 underwent two procedures. The protocols and equipment used, problems specific to the electrically hostile environment and preliminary results are described, including those of clinical interest. The DL is being used for the development of clinically applicable neurophysiological monitoring tools.

Adult↗
PubMed2000

Immunization levels and risk factors for low immunization coverage among private practices.

OBJECTIVES: Previous studies have indicated that provider characteristics are an important determinant of immunization coverage. The objectives of this study were to: 1) assess immunization coverage levels among 2-year-old children receiving care in private practices in 3 California counties; and 2) evaluate practice and patient risk factors for low immunization coverage. STUDY DESIGN: Cross-sectional chart review of immunization histories and provider survey of immunization policies. SETTING: Forty-five randomly selected, private medical practices in 3 counties in California. PATIENTS: Children 12 to 35 months old, followed by the participating practices. METHODS: Providers underwent a detailed assessment of their immunization coverage and completed a questionnaire describing their immunization policies and procedures. Immunization data were abstracted from randomly selected medical charts of children 12 to 35 months old. Only patients who met the criteria for active status (>/=2 visits and >/=1 visit during the preceding 18 months) were included in analyses. Immunization coverage levels were calculated and logistic regression was used to estimate the risk of underimmunization associated with different practice and child characteristics. RESULTS: Of the 72 eligible practices that were contacted, 45 participated in the study, yielding a participation rate of 62%. The median immunization coverage of participating offices was 54% (range: 0%-91%). Multivariate analysis revealed 5 independent risk factors for underimmunization. The strongest predictors were having fewer than 50% active children in the practice and children having fewer than 8 visits to the provider. Other significant predictors were the percentage of patients in the practice on Medicaid, administering diphtheria-tetanus-pertussis 4 at a separate visit from the Haemophilus influenzae type b booster, and practice location. CONCLUSIONS: These data provide new insights into immunization practices in an important clinical setting that has been poorly characterized previously. Immunization coverage levels were found to be low and significant risk factors for underimmunization were identified. Recommendations are made for immunization policy changes and targeting of immunization improvement interventions at practices that may be at risk for low immunization coverage. immunization, vaccination, immunization programs, primary prevention, private practice, child, preschool, pediatrics, family practice.

California↗
PubMed1999

Health consequences of religious and philosophical exemptions from immunization laws: individual and societal risk of measles.

CONTEXT: All US states require proof of immunization for school entry. Exemptions are generally offered for medical, religious, or philosophical reasons, but the health consequences of claiming such exemptions are poorly documented. OBJECTIVES: To quantify the risk of contracting measles among individuals claiming religious and/or philosophical exemptions from immunization (exemptors) compared with vaccinated persons, and to examine the risk that exemptors pose to the nonexempt population. DESIGN, SETTING, AND PARTICIPANTS: Population-based, retrospective cohort study of data from 1985 through 1992, collected by the Measles Surveillance System of the Centers for Disease Control and Prevention, as well as from annual state immunization program reports on prevalence of exemptors and vaccination coverage. The study group was restricted to individuals aged 5 to 19 years. To empirically determine and quantify community risk, a mathematical model was developed that examines the spread of measles through communities with varying proportions of exemptors and vaccinated children. MAIN OUTCOME MEASURES: Relative risk of contracting measles for exemptors vs vaccinated individuals based on cohort study data. Community risk of contracting measles derived from a mathematical model. RESULTS: On average, exemptors were 35 times more likely to contract measles than were vaccinated persons (95% confidence interval, 34-37). Relative risk varied by age and year. Comparing the incidence among exemptors with that among vaccinated children and adolescents during the years 1985-1992 indicated that the 1989-1991 measles resurgence may have occurred 1 year earlier among exemptors. Mapping of exemptors by county in California indicated that exempt populations tended to be clustered in certain geographic regions. Depending on assumptions of the model about the degree of mixing between exemptors and nonexemptors, an increase or decrease in the number of exemptors would affect the incidence of measles in nonexempt populations. If the number of exemptors doubled, the incidence of measles infection in nonexempt individuals would increase by 5.5%, 18.6%, and 30.8%, respectively, for intergroup mixing ratios of 20%, 40%, and 60%. CONCLUSIONS: These data suggest the need for systematic review of vaccine-preventable incidents to examine the effect of exemptors, increased surveillance of the number of exemptors and cases among them, and research to determine the reasons why individuals claim exemptions.

Adolescent↗
PubMed1999

Resistance of ovine, caprine and bovine endothelial cells to Clostridium perfringens type D epsilon toxin in vitro.

Ovine, caprine and bovine endothelial cells were grown in vitro and challenged with Clostridium perfringens type D epsilon toxin to compare their susceptibility to this toxin. Madin Darby canine kidney (MDCK) cells, which are known to be susceptible to epsilon toxin, were used as a positive control. No morphological alterations were observed in any of the endothelial cell cultures tested, even after challenging with doses as high as 1200 MLD50/ml of epsilon toxin. MDCK cells showed contour rounding and nuclear condensation as early as 30 min after exposure to 100 MLD50/ml of epsilon toxin and after 60 min of exposure to 12.5 MLD50/ml of the same toxin. All the MDCK cells were dead after 3 h of exposure to all concentrations of epsilon toxin. The results indicate that ovine, caprine and bovine endothelial cells are not morphologically responsive to the action of epsilon toxin in vitro.

Animals↗