Biomedical subjects
Publications and source records attributed to A Holmes.
The paper describes the use of monopolar thermocoagulation in the treatment of acardiac twinning. The technique and outcomes of a series of 12 pregnancies which have presented for treatment at the Fetal Medicine Unit of University College London are presented.
OBJECTIVES: To determine the natural history of Anderson-Fabry disease (AFD) as a baseline for efficacy assessment of potentially therapeutic drugs. DESIGN: The first large cross sectional study of a patient cohort from the AFD clinical and genetic register (UK), maintained for the last 15 years. MEASURES: Prevalence, mortality, frequency of AFD manifestations, and impact of disease on patient lives, assessed from the AFD register and the disease specific questionnaire. RESULTS: The median cumulative survival was 50 years (n=51), which represents an approximately 20 year reduction of life span. Neuropathic pain was present in 77% (n=93) with mean pain score of 5 (scale 0-10) despite treatment with anticonvulsants and opiates. Pain stopped in only 11%. Cerebrovascular complications developed in 24.2% and renal failure in 30%. The onset and progression of serious AFD manifestations was highly variable. The relationship of gastrointestinal manifestations on weight, using body mass index (BMI), was significant (p=0.01). High frequency sensorineural deafness was confirmed in 78% of audiograms. Neuropathic pain and angiokeratoma were absent in five adult males (approximately 5%). Median age at diagnosis of AFD was 21.9 years (n=64). IMPACT OF DISEASE: Attendance at school, sports, and social activity were significantly affected by AFD. Only 56.6% (n=46) of patients were employed. Psychosexual effects of genital angiokeratoma, genital pain, and impotence were not previously recognised. CONCLUSION: The majority of males experience multiple disease manifestations and the duration of neuropathic pain was lifelong. The AFD register proved useful for the determination of baseline disease parameters in this cohort.
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OBJECTIVES: To verify the applicability and validity of time-frequency analysis (TFA) of evoked potential (EP) signals in detecting the integrity of spinal cord function and preventing spinal cord injury. METHODS: The spinal cord was simulated during surgery in 20 mature rats by mechanically damaging the spinal cord. Cortical somatosensory evoked potential (CSEP), spinal somatosensory evoked potential (SSEP), cortical motor evoked potential (CMEP), and spinal cord evoked potential (SCEP) were used to monitor spinal cord function. Short time Fourier transform (STFT) was applied to the CSEP signal, and cone shaped distribution (CSD) was used as the TFA algorithm for SSEP, CMEP, and SCEP signals. The changes in the latency and amplitude of EP signals were measured in the time domain, and peak time, peak frequency, and peak power were measured in the time-frequency distribution (TFD). RESULTS: The TFDs of EPs were found to concentrate in a certain location under normal conditions. When injury occurred, the energy decreased in peak power, and there was a greater dispersion of energy across the time-frequency range. Strong relations were found between latency and peak time, and amplitude and peak power. However, the change in peak power after injury was significantly larger than the corresponding change in amplitude (p<0.001 by ANOVA). CONCLUSIONS: It was found that TFA of EPs provided an earlier and more sensitive indication of injury than time domain monitoring alone. It is suggested that TFA of EP signals should therefore be useful in preventing spinal cord injury during surgery.
Although the role of transforming growth factor beta (TGFbeta) in initiating fibrosis is well established, the role that TGFbeta plays in maintaining fibrosis is unclear. The gene encoding connective tissue growth factor (ccn2; ctgf), which promotes fibrosis, is not normally expressed in dermal fibroblasts unless TGFbeta is present. However, in dermal fibroblasts cultured from lesional areas of scleroderma, ccn2 (ctgf) is expressed constitutively. The contribution of several elements in the ccn2 (ctgf) promoter to basal and TGFbeta induced ccn2 (ctgf) expression in normal and scleroderma fibroblasts has been investigated. A functional SMAD binding site in the ccn2 (ctgf) promoter that is necessary for the TGFbeta mediated induction of this gene has been identified. The previously termed TGFbeta responsive enhancer (TGFbetaRE) in the ccn2 (ctgf) promoter has been found to be necessary for basal promoter activity in normal fibroblasts. The SMAD element is not necessary for the high ccn2 (ctgf) promoter activity seen in scleroderma fibroblasts. However, mutation of the previously termed TGFbetaRE reduces ccn2 (ctgf) promoter activity in scleroderma fibroblasts to that seen in normal fibroblasts. Thus, the maintenance of the scleroderma phenotype, as assessed by a high degree of ccn2 (ctgf) promoter activity, appears to be relatively independent of SMAD action and seems to reflect increased basal promoter activity.
Patients with scleroderma receiving Iloprost as a treatment for severe Raynaud's phenomenon report a reduction in skin tightness, suggesting that this drug inhibits skin fibrosis. Connective tissue growth factor (CTGF), a recently described profibrotic cytokine, acts downstream and in concert with TGF-beta to stimulate the fibrotic process and is involved in the fibrosis seen in scleroderma. Here we show that Iloprost, acting by elevation of cAMP, blocks the induction of CTGF and the increase in collagen synthesis in fibroblasts exposed to TGF-beta. The potency of Iloprost with respect to suppression of CTGF far exceeds that of other prostanoid receptor agonists, suggesting that its effect is mediated by the prostacyclin receptor IP. By sampling dermal interstitial fluid using a suction blister device, we show that CTGF levels are greatly elevated in the dermis of scleroderma patients compared with healthy controls and that Iloprost infusion causes a marked decrease in dermal CTGF levels. These studies suggest that Iloprost could be reducing the level of a key profibrotic cytokine in scleroderma patients and that endogenous production of eicosanoids may limit the fibrotic response to TGF-beta.
Elementary Ca(2+) signals, such as "Ca(2+) puffs", which arise from the activation of inositol 1,4,5-trisphosphate receptors, are building blocks for local and global Ca(2+) signalling. We characterized Ca(2+) puffs in six cell types that expressed differing ratios of the three inositol 1,4,5-trisphosphate receptor isoforms. The amplitudes, spatial spreads and kinetics of the events were similar in each of the cell types. The resemblance of Ca(2+) puffs in these cell types suggests that they are a generic elementary Ca(2+) signal and, furthermore, that the different inositol 1,4,5-trisphosphate isoforms are functionally redundant at the level of subcellular Ca(2+) signalling. Hormonal stimulation of SH-SY5Y neuroblastoma cells and HeLa cells for several hours downregulated inositol 1,4,5-trisphosphate expression and concomitantly altered the properties of the Ca(2+) puffs. The amplitude and duration of Ca(2+) puffs were substantially reduced. In addition, the number of Ca(2+) puff sites active during the onset of a Ca(2+) wave declined. The consequence of the changes in Ca(2+) puff properties was that cells displayed a lower propensity to trigger regenerative Ca(2+) waves. Therefore, Ca(2+) puffs underlie inositol 1,4,5-trisphosphate signalling in diverse cell types and are focal points for regulation of cellular responses.
To study behavioral functions of the D5 subtype, mice were generated with null mutations in the D5 gene. This 1st behavioral characterization of D5 null mutant mice (D5-/-) indicated normal general health, sensory abilities, and neurological reflexes. Under basal conditions, D5-/- mice were generally normal on locomotor activity, the rotarod test, acoustic startle response, prepulse inhibition, elevated plus-maze, light <--> dark exploration, Morris water maze, and cued and contextual fear conditioning. In the Porsolt forced swim test for antidepressant activity, male D5-/- mice showed lower levels of immobility. D5-/- mice showed some evidence of reduced responses to the hyperactivity-inducing effects of the D1/D5 receptor agonist SKF 81297. The ability of SKF 81297 to disrupt acoustic startle and prepulse inhibition appeared to be attenuated in D5-/- mice. These results suggest that the D5 receptor is not essential for many dopamine-mediated behaviors but may contribute to the pharmacological activation of dopaminergic pathways relevant to exploratory locomotion, startle, and prepulse inhibition.
In most studies, the magnitude and rate of adaptation to various night work schedules is assessed using core body temperature as the marker of circadian phase. The aim of the current study was to assess adaptation to a simulated night work schedule using salivary dim light melatonin onset (DLMO) as an alternative circadian phase marker. It was hypothesised that the night work schedule would result in a phase delay, manifest in relatively later DLMO, but that this delay would be somewhat inhibited by exposure to natural light. Participants worked seven consecutive simulated 8-hour night shifts (23:00-07:00 h). By night 7, there was a mean cumulative phase delay of 5.5 hours, equivalent to an average delay of 0.8 hours per day. This indicates that partial circadian adaptation occurred in response to the simulated night work schedule. The radioimmunoassay used in the current study provides a sensitive assessment of melatonin concentration in saliva that can be used to determine DLMO, and thus provides an alternative phase marker to core body temperature, at least in laboratory studies.
We have used representational difference analysis (RDA) to identify up-regulated genes in skin fibroblasts from fibrotic lesions obtained from patients with systemic sclerosis (scleroderma). RDA of cDNA libraries derived from fibroblasts from involved and uninvolved skin detected several differentially expressed genes. One such gene consistently up-regulated in scleroderma cells coded for human connective tissue growth factor (CTGF). Other studies described here show that the CTGF protein is readily detected in cultures of systemic sclerosis fibroblasts but was not detected in comparable normal cells. High levels of CTGF are also evident in biological fluids from patients with systemic sclerosis. TGFbeta stimulates CTGF production in both normal and systemic sclerosis fibroblasts with the latter found to be higher producers. Moreover, an analysis of constitutive and TGFbeta-induced CTGF gene activation showed altered and elevated transcriptional responses in systemic sclerosis cells compared with controls. CTGF stimulated a two- to threefold increase in proalpha1(I) collagen and fibronectin synthesis by both dermal and lung fibroblasts in culture and promoted significant matrix remodeling of fibroblast-populated three-dimensional collagen lattices. A direct relation between the overexpression of CTGF and elevated collagen synthesis was suggested by the observation that transfection of a CMV-CTGF cDNA construct and protein expression in fibroblasts increased the transcription of a Col 1alpha2 promoter-reporter construct to levels seen in systemic sclerosis fibroblasts. Using Col 1alpha2 promoter deletion constructs the CTGF responsive element was localized to the first 379 bp upstream of the transcriptional start site. These data indicate that there is an overexpression of CTGF in the systemic sclerosis cells, probably due to increased gene transcription, and suggest that the dysregulation of CTGF production is an important factor in fibroblast activation and the excessive deposition of collagen in systemic sclerosis.
We describe an e-mail health-consultation service for overseas volunteers that has been in operation for 25 months. The scheme is accessed for diverse medical concerns and is efficient and highly valued.
This study demonstrates the neural system potentially involved in the representation of, and choice between, stimulus classifications in an ambiguous, novel, decision-making task. This difficult choice behaviour is taken as an example of a basic executive processing task. Subjects heard sounds that were consonant-vowel combinations that had been distorted and were required to categorize each stimulus as speech-like or not-speech-like. Cerebral activity was measured with positron emission tomography. A neural system (thalamic and medial prefrontal cortical regions) was demonstrated; there was greater activity involved in assigning the sound to the larger class of not-speech-like sounds than to the more restricted category of speech-like sounds. We interpret this activity as reflecting process and representation in a simple central executive task.
BACKGROUND: Tics are involuntary, brief, stereotyped motor and vocal behaviors often associated with irresistible urges. They are a defining symptom of the classic neuropsychiatric disorder, Tourette syndrome (TS), and constitute an example of disordered human volition. The neural correlates of tics are not well understood and have not been imaged selectively. METHODS: Event-related [(15)O]H(2)O positron emission tomography techniques combined with time-synchronized audio and videotaping were used to determine the duration of, frequency of, and radiotracer input during tics in each of 72 scans from 6 patients with TS. This permitted a voxel-by-voxel correlational analysis within Statistical Parametric Mapping of patterns of neural activity associated with the tics. RESULTS: Brain regions in which activity was significantly correlated with tic occurrence in the group included medial and lateral premotor cortices, anterior cingulate cortex, dorsolateral-rostral prefrontal cortex, inferior parietal cortex, putamen, and caudate, as well as primary motor cortex, the Broca's area, superior temporal gyrus, insula, and claustrum. In an individual patient with prominent coprolalia, such vocal tics were associated with activity in prerolandic and postrolandic language regions, insula, caudate, thalamus, and cerebellum, while activity in sensorimotor cortex was noted with motor tics. CONCLUSIONS: Aberrant activity in the interrelated sensorimotor, language, executive, and paralimbic circuits identified in this study may account for the initiation and execution of diverse motor and vocal behaviors that characterize tics in TS, as well as for the urges that often accompany them. Arch Gen Psychiatry. 2000;57:741-748
Systematic observations of the defensive behavior of wild rodents have greatly informed the experimental study of anxiety and its neural substrates in laboratory animals. However, as the former work has been almost exclusively carried out in rats, few data are available concerning the reactivity of wild mice to standardized tests of anxiety-related behavior. In the present experiments, we employed ethological measures to examine the behavioral responses of a wild-derived population of house mice (Mus musculus) in the elevated plus-maze. In direct comparisons with laboratory Swiss mice, male wild mice exhibited substantially elevated levels of exploratory activities and an overall "preference" for the open arms of the plus-maze. On re-exposure to the plus-maze, male wild mice showed further increases in open arm exploration, while Swiss mice showed a marked shift to the enclosed parts of the plus-maze. Tested over a single session, female wild mice also exhibited a profile of high open arm exploration, but showed levels of exploratory behaviors and locomotor activity similar to female Swiss counterparts. While exploratory patterns in wild mice show similarities to profiles seen in certain laboratory strains (e.g., BALB/c), wild mice displayed a number of additional behaviors that are unprecedented in plus-maze studies with laboratory mice. These included actual and attempted jumps from the maze, spontaneous freezing, and exploration of the upper ledges of the closed arms. Thus, while in conventional terms the behavior of wild mice was consistent with one of low anxiety-like behavior, the presence of these unique elements instead indicates a profile more accurately characterized by high reactivity and escape motivation. We discuss how the use of an ethological approach to measuring plus-maze behavior can support accurate interpretation of other exceptional profiles in this test, such as those possibly arising from phenotyping of transgenic and gene knockout mice.
BACKGROUND: Regular exercise to elicit caloric expenditure is an important component for achieving weight loss. The Healthy People 2000 objectives recommend regular sustained physical activity lasting 30 minutes, five days per week (Objective 1.3) particularly for weight loss. Moreover, this recommendation has been restated for weight loss and overall health benefits in the Centers for Disease Control and Prevention / American College of Sports Medicine (CDC/ACSM) statement and Surgeon General's Report (SGR) on Physical ActivitY and Health. Thus, we sought to identify the relative quality, and quantity of physical activity among people trying to lose weight. DESIGN: Cross-sectional self-reported data from the West Virginia Behavioral Risk Factor Surveillance System (BRFSS) were used. The BRFSS is a state-based telephone survey of adults that uses a multistage cluster design based on the Waksberg method of random-digit dialing. Data froM 2769 men and 4490 women were obtained from the 1992, 1994, and 1996 surveys. RESULTS: Half (49.6%) of individuals trying to lose weight did not engage in any physical activity. Further, only 15% of respondents trying to lose weight reported exercising regularly. Nevertheless, those trying to lose weight were more likely (OR [odds ratio] = 1.3; 95% CI [confidence interval], 1.14, 1.51, p < 0.001) to exercise regularly than those not trying to lose weight. In particular, women trying to lose weight were significantly more likely (OR = 1.45; 95% CI, 1.22,1.74, p < 0.001) to exercise regularly than women not trying to lose weight. Conversely, men trying to lose weight were no more likely to exercise regularly (p = .23) than men not trying to lose weight. Among respondents who were using exercise for weight loss, only 14.7% were expending > or =1000 kcal/week and 18.2% were expending > or =500 kcal/week. Weekly expenditure rates of > or =1000 kcal/week were more likely to occur among men (17%) than women (13.8%), in younger age groups, and among those with higher educational attainment. CONCLUSION: These data suggest that while certain individuals trying to lose weight are more likely to engage in regular physical activity, most persons trying to lose weight have not adopted regular physical activity as part of their weight loss practice. These results suggest that public health efforts to effectively integrate physical activity into weight control practices of West Virginians have been minimally successful.
BACKGROUND: Orally administered modified release organic nitrates are used commonly in the prophylaxis of myocardial ischaemia, although little evidence indicates a clinically superior response compared with standard formulated preparations administered symmetrically. AIM: To investigate the clinical success of transfer of suitable patients from MR to SF nitrates. METHOD: Suitable candidates for therapeutic substitution, assessed by a pharmacist, completed a baseline study to estimate frequency and timing of chest pain, the number of rescue doses of sublingual nitrates required, together with an assessment of adverse effects experienced. Following substitution to an eccentric dosing schedule, a further one month's assessment of chest pain frequency, rescue nitrate use and adverse effects was recorded and compared with baseline. RESULTS: Twelve (37.5%) patients from a possible 32 candidates were invited to complete a baseline symptoms and adverse event diary. Eight patients entered the study phase (66.7% of the 12 included in the baseline phase of the study). These candidates showed no evidence of loss of control of chest pain symptoms, 3.5 +/- 1.16 (mean +/- standard error of mean) episodes/patient/28 days compared with 1.9 +/- 0.96 episodes/patient/28 days during the test phase (P > 0.05). Similarly, there was no difference in the number of doses of rescue nitrates required when the trial phase (2.6 +/- 1.63 doses/patient/28 days) was compared with the control (2.0 +/- 1.31 doses/patient/28 days, P > 0.05). There was no evidence of an increased incidence of adverse effects during the trial period of the study. CONCLUSION: This small study suggests that, if selected carefully, therapeutic substitution of MR oral nitrates can be managed successfully without apparent risk of loss of symptom control or increased incidence of adverse effects.
OBJECTIVE: To determine the perceptions of healthcare professionals and the general public about the symptoms, diagnosis and available treatment of urological cancers, and thus the perceived value of screening for their early detection. SUBJECTS AND METHODS: Two questionnaires were developed, based on semi-structured interviews, and distributed to 288 healthcare professionals, comprising 182 general practitioners (GPs), 56 practice nurses and 50 urology nurses, and to 250 members of the general public in three different socio-economic groups. The questionnaires asked about the symptoms, diagnosis and treatment of prostate, bladder and testicular cancer, and whether the respondents considered that screening for these cancers would be useful in ameliorating morbidity or death from these diseases. RESULTS: The response rate was very poor (13 of the GPs, 7%; 34 of the nurses, 32%; and 58 members of the general public, 23%). This severely limited the interpretation of the results, but the responses highlighted areas which need addressing. Obvious symptoms were well understood by all the groups but less well-known symptoms could be missed. No GP supported screening for prostate cancer and only seven of the GPs believed in teaching testicular self-examination, but practice nurses were considerably more active in all aspects of patient education. The general public felt that they needed more information to make decisions about urological cancers, although there was a general feeling that 'screening saved lives'. CONCLUSION: This survey showed that no healthcare professional seems to have a clearly defined role in informing potential patients about screening. The general public, who seem to perceive from the media that early detection is beneficial, are confused by the lack of clarity about policies for urological cancers.
Vertebral bone quality is essential in vertebral strength and the stability of spinal screw fixation. A major factor of bone quality is the density of bone mineral and its distribution throughout the bone. There have been studies regarding bone mineral density variations in the cervical and thoracolumbar spine, but bone mineral density variations in the lumbosacral spine have not been documented. The purpose of the current study was to quantify bone mineral density variations at different lumbosacral levels and within vertebra, especially along the pathways of lumbar pedicle screws. Bone mineral density variations within the vertebrae along the lumbosacral spine were measured in 13 specimens from young male cadavers using peripheral quantitative computed tomography. Measurements included bone mineral density variations at different lumbosacral levels and in transverse layers and vertical columns within each vertebral body. These original data showed that the bone mineral density increased gradually from lumbar to S1 vertebrae, possibly reflecting a caudally increasing load on different lumbosacral levels. The highest bone mineral density in the lumbosacral spine is found at the pedicles and regions closest to pedicle bases, supporting the use of pedicle screw fixation.