Biomedical subjects
Publications and source records attributed to J O'Brien.
HELLP syndrome is a form of severe pre-eclampsia with multisystem involvement. Laboratory markers include haemolysis (H), elevated liver enzymes (EL), and low platelets (LP). We present a patient to our institution with HELLP syndrome complicated by liver necrosis. The patient underwent urgent Caesarian section prior to transfer.
BACKGROUND AND OBJECTIVE: A prospective sentinel study into the population-based incidence of pertussis in adults was done between 2001 and 2004 in Rostock (former East Germany) and Krefeld (former West Germany). PATIENTS AND METHODS: 971 outpatients, who consulted general practitioners or internists, were included. Clinical inclusion criteria were coughing for one week or more and no chronic respiratory diseases. Bordetella infection was diagnosed by PCR on nasopharyngeal swabs and ELISA for serology (IgG-anti-PT, IgA-anti-PT, IgG-anti-FHA, IgA-anti-FHA). RESULTS: We found a total of 97 cases of pertussis in this cohort. The main symptom was coughing for a median of 7-8 weeks. Population-based incidence was estimated in Krefeld at 169 cases/100000 population per year, and in Rostock at 160/100000 per year. Resource use was 120 EUR of direct medical cost and 434 euro of indirect medical cost, not including hospitalization in this study. CONCLUSIONS: Pertussis is a frequent cause of longer lasting cough in German adults, and it causes significant morbidity and costs.
BACKGROUND: The objective of this comparative neuropathologic study was to determine the extent to which dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) are distinct entities or part of a continuum with respect to the duration of parkinsonism. METHODS: We evaluated the relationship between cortical alpha-synuclein pathology, plaques (Consortium to Establish a Registry for Alzheimer's Disease [CERAD]), tangles (Braak staging), and cholinergic deficits (choline acetyltransferase in temporal cortex) in 57 prospectively assessed patients (29 DLB, 28 PDD), confirmed at autopsy. The PDD group was divided according to the median duration of parkinsonism prior to dementia. RESULTS: There was an association between longer duration of parkinsonism prior to dementia and less severe cortical alpha-synuclein pathology (chi(2) 10.4, df 2, p = 0.006) and lower CERAD plaque scores (chi(2) 26.6, df 9, p = 0.002), but not Braak staging. These findings were confirmed in a further correlation analysis, which also identified an unexpected correlation between more pronounced cortical cholinergic deficits and longer duration of parkinsonism prior to dementia (R = -0.37, p = 0.04). CONCLUSION: While there is a clear relationship between the duration of Parkinson disease prior to the onset of dementia and key neuropathologic and neurochemical characteristics, there is a gradation of these differences across the dementia with Lewy bodies/Parkinson disease dementia spectrum and the findings do not support an arbitrary cut-off between the two disorders.
This study of frontotemporal dementia (FTD) was carried out to determine whether MR spectroscopy can provide an in vivo marker for the neuronal loss and gliosis that occur in this condition. We compared spectra in frontal and temporal regions known to be affected early in the course of the disease with spectra in the parietal lobe that is spared until late stages of FTD. We were interested in the relative concentrations of two compounds, NAA (a marker of neuronal integrity) and mI (a marker of gliosis), expressed as ratios to creatine (a relatively stable brain constituent). MR spectroscopy was performed on the temporal, parietal, and anterior cingulate cortices of five patients with the established semantic dementia form of FTD, two patients with the frontal form of FTD and 13 age matched controls. Structural MRI and neuropsychometry were also performed. Patients with FTD had reduced NAA/Cr in frontal and temporal, but not parietal lobes. The two patients with the frontal form of FTD had increased mI/Cr in their cingulate cortices. These data show for the first time that MR spectroscopy can reveal regionally selective abnormalities in patients with FTD. This opens up the possibility of using MR spectroscopy as a clinical tool to identify earlier presentations of the condition.
The present paper examines the particular difficulties presented by low levels of food-borne DNA-reactive genotoxic carcinogens, some of which may be difficult to eliminate completely from the diet, and proposes a structured approach for the evaluation of such compounds. While the ALARA approach is widely applicable to all substances in food that are both carcinogenic and genotoxic, it does not take carcinogenic potency into account and, therefore, does not permit prioritisation based on potential risk or concern. In the absence of carcinogenicity dose-response data, an assessment based on comparison with an appropriate threshold of toxicological concern may be possible. When carcinogenicity data from animal bioassays are available, a useful analysis is achieved by the calculation of margins of exposure (MOEs), which can be used to compare animal potency data with human exposure scenarios. Two reference points on the dose-response relationship that can be used for MOE calculation were examined; the T25 value, which is derived from linear extrapolation, and the BMDL10, which is derived from mathematical modelling of the dose-response data. The above approaches were applied to selected food-borne genotoxic carcinogens. The proposed approach is applicable to all substances in food that are DNA-reactive genotoxic carcinogens and enables the formulation of appropriate semi-quantitative advice to risk managers.
PURPOSE: Central venous cannulation via the common femoral vein is an important starting point for many interventions. The purpose of this study was to determine the optimum conditions for cannulation of the femoral vein and to compare these with the relative changes in the internal jugular vein. METHODS: High-resolution 2D ultrasound was utilised to determine variability of the calibre of the femoral and internal jugular veins in 10 healthy subjects. Venous diameter was assessed during the Valsalva manoeuvre and in different degrees of the Trendelenburg position. RESULTS: The Valsalva manoeuvre significantly increased the size of the femoral and internal jugular veins. There was a relatively greater increase in femoral vein diameter when compared with the internal jugular vein of 40 and 29%, respectively. Changes in body inclination (Trendelenburg position) did not significantly alter the luminal diameter of the femoral vein. However, it significantly increased internal jugular vein diameter. CONCLUSIONS: Femoral vein cannulation is augmented by the Valsalva manoeuvre but not significantly altered by the gravitational position of the subject.
BACKGROUND: Aspirin (acetylsalicylic acid) irreversibly inhibits platelet cyclooxygenase (COX)-1, the enzyme that converts arachidonic acid (AA) to the potent platelet agonist thromboxane (TX) A2. Despite clear benefit from aspirin in patients with cardiovascular disease (CAD), evidence of heterogeneity in the way individuals respond has given rise to the concept of 'aspirin resistance.' AIMS: To evaluate the hypothesis that incomplete suppression of platelet COX as a consequence of variation in the COX-1 gene may affect aspirin response and thus contribute to aspirin resistance. PATIENTS AND METHODS: Aspirin response, determined by serum TXB2 levels and AA-induced platelet aggregation, was prospectively studied in patients (n = 144) with stable CAD taking aspirin (75-300 mg). Patients were genotyped for five single nucleotide polymorphisms in COX-1 [A-842G, C22T (R8W), G128A (Q41Q), C644A (G213G) and C714A (L237M)]. Haplotype frequencies and effect of haplotype on two platelet phenotypes were estimated by maximum likelihood. The four most common haplotypes were considered separately and less common haplotypes pooled. RESULTS: COX-1 haplotype was significantly associated with aspirin response determined by AA-induced platelet aggregation (P = 0.004; 4 d.f.). Serum TXB2 generation was also related to genotype (P = 0.02; 4 d.f.). CONCLUSION: Genetic variability in COX-1 appears to modulate both AA-induced platelet aggregation and thromboxane generation. Heterogeneity in the way patients respond to aspirin may in part reflect variation in COX-1 genotype.
The grid has the potential to transform collaborative scientific investigations through the use of closely coupled computational and visualization resources, which may be geographically distributed, in order to harness greater power than is available at a single site. Scientific applications to benefit from the grid include visualization, computational science, environmental modelling and medical imaging. Unfortunately, the diversity, scale and location of the required resources can present a dilemma for the scientific worker because of the complexity of the underlying technology. As the scale of the scientific problem under investigation increases so does the nature of the scientist's interaction with the supporting infrastructure. The increased distribution of people and resources within a grid-based environment can make resource sharing and collaborative interaction a critical factor to their success. Unless the technological barriers affecting user accessibility are reduced, there is a danger that the only scientists to benefit will be those with reasonably high levels of computer literacy. This paper examines a number of important human factors of user interaction with the grid and expresses this in the context of the science undertaken by RealityGrid, a project funded by the UK e-Science programme. Critical user interaction issues will also be highlighted by comparing grid computational steering with supervisory control systems for local and remote access to the scientific environment. Finally, implications for future grid developers will be discussed with a particular emphasis on how to improve the scientists' access to what will be an increasingly important resource.
BACKGROUND: In 2002 diagnostic testing for West Nile Virus (WNV) infection was not ideal because commercial products were unavailable. Although testing was performed without charge by public health (PH), testing is not intended to be used for patient management and generally results are not available in a timely or reliable manner. OBJECTIVES: This study was conducted to determine the clinical impact of having WNV serology available by a diagnostic laboratory within a few days of sample collection. STUDY DESIGN: An IgM immunoassay (FT, from Focus Technologies) was performed August 13, 2003 to October 31, 2003 Monday, Wednesday and Friday in our hospital's virology laboratory with split sample testing at PH. All results (positive and negative) were called to physicians. RESULTS AND CONCLUSIONS: Turn-around time for the FT assay was within 0-3 days; for PH, it was approximately 8 days. Of 95 samples, 6 were positive and 89 negative. For the FT negative samples, all were concordant with PH, but four FT positive samples (three sera and one cerebrospinal fluid) were discrepant. After resolution of the discrepancies, the FT test had a sensitivity of 100% and a specificity of 99%. Physicians reacted positively to having results faster. Fifty-eight percent of the results had clinical impact, 22% had undetermined impact, 13% were patient requests, and 4% had no impact. Concluding, the FT assay is 100% sensitive and 99% specific and in 58% there was clinical impact for WNV reporting in a timely manner.
BACKGROUND/AIM: Ultrasound biomicroscopy (UBM) is an important tool for assessing anterior segment pathology. This study sought to evaluate UBM in the management of anterior segment tumours. METHODS: Retrospective analysis of medical records of consecutive patients referred to the ocular oncology unit, University of California San Francisco (UCSF), for suspected anterior segment tumours from 1999 to 2004. RESULTS: 132 eyes from 130 patients were evaluated, including 55 uveal melanomas (UM), 21 iris naevi, 30 iris cysts, and 26 remaining lesions. Of the melanomas, 45 were also evaluated with conventional A/B-scan. There was 29% correspondence between the anatomical structures invaded by melanoma as identified by B-scan v disease extent defined by UBM. Ciliary body and peripheral iris involvement by melanomas was significantly more frequently observed by UBM than B-scan. Seven of 30 benign cysts were diagnosed as cystic before UBM evaluation. In three cases, neuroepithelial cysts were associated with intercurrent pathology including iris naevus (n = 2) and ciliary body melanoma (n = 1). Two ciliary body melanomas showed cavitation, including one patient with a pseudocyst. Histopathological correlation was possible in six cases. CONCLUSION: UBM is an indispensable tool for the management of anterior segment tumours. This study demonstrates the superiority of UBM v conventional B-scan for the precise localisation of uveal melanoma, especially involving the ciliary body and peripheral iris.
In this study our objectives were to determine the incidence of postoperative cognitive dysfunction (POCD) after laparoscopic cholecystectomy under sevoflurane anesthesia in patients aged >40 and <85 yr and to examine the associations between plasma concentrations of i) S-100beta protein and ii) stable nitric oxide (NO) products and POCD in this clinical setting. Neuropsychological tests were performed on 42 ASA physical status I-II patients the day before, and 4 days and 6 wk after surgery. Patient spouses (n = 13) were studied as controls. Cognitive dysfunction was defined as deficit in one or more cognitive domain(s). Serial measurements of serum concentrations of S-100beta protein and plasma concentrations of stable NO products (nitrate/nitrite, NOx) were performed perioperatively. Four days after surgery, new cognitive deficit was present in 16 (40%) patients and in 1 (7%) control subject (P = 0.01). Six weeks postoperatively, new cognitive deficit was present in 21 (53%) patients and 3 (23%) control subjects (P = 0.03). Compared with the "no deficit" group, patients who demonstrated a new cognitive deficit 4 days postoperatively had larger plasma NOx at each perioperative time point (P < 0.05 for each time point). Serum S-100beta protein concentrations were similar in the 2 groups. In conclusion, preoperative (and postoperative) plasma concentrations of stable NO products (but not S-100beta) are associated with early POCD. The former represents a potential biochemical predictor of POCD.
OBJECTIVE: To revise the South African Guideline for the Management of Chronic Obstructive Pulmonary Disease (COPD) in the light of new insights into the disease and the value of new treatment approaches and drugs. New aspects considered include: A growing awareness of the impact of COPD in South Africa, and the urgent need for prevention strategies. The role of concurrent exposures to domestic and occupational atmospheric pollution, and previous lung infections including tuberculosis. The need to consider as goals of treatment both prevention of exacerbations and improvement of quality of life (health status) of patients with COPD. The development of both long-acting beta2-agonist and anticholinergic drugs for use in COPD. Emerging evidence on a limited role for inhaled corticosteroids in the treatment of COPD. RECOMMENDATIONS: These include primary and secondary prevention; early diagnosis; staging of severity; assessment of reversibility with bronchodilator and, in some, responsiveness to corticosteroids; use of bronchodilators and other forms of treatment; rehabilitation; and treatment of complications. Advice is provided on the management of acute exacerbations, and the approach to air travel, prescribing long-term oxygen, and lung surgery including lung volume reduction surgery. Prevention, both primary and secondary, remains the most cost-effective measure in the management of COPD, and deserves more emphasis, particularly on the part of health care professionals. Primary prevention involves reducing public exposure to cigarette and other forms of smoke, and reduction of atmospheric pollution, and secondary prevention limits exposure and resultant progression in those with established disease. Spirometry is essential for the diagnosis of COPD and in staging severity. In addition, a new classification of severity that considers other indices of functional impairment is provided. Treatment involves a progression from 'as-needed' bronchodilators, through the addition of other more effective bronchodilators, usually in combination, in more severe stages. The importance of assessing potential reversibility in every patient with persistent symptoms, and of the limited role of oral and inhaled corticosteroids (ICS), is emphasised. These approaches also reduce exacerbations and may result in cost savings and improved prognosis. A practical low-cost approach to rehabilitation is proposed. OPTIONS: Treatment recommendations are based on the following: the recommendations of the Global Obstructive Lung Disease (GOLD) initiative, which provides an evidence-based comprehensive and up-to-date review of treatment options; independent evaluation of the level of evidence in support of some of the new treatment trends; and consideration of factors that influence COPD management in South Africa, including lung co-morbidity and drug availability and cost. OUTCOMES: The use of bronchodilators is driven by the presence of symptoms, but regular assessment of benefit, based on objective criteria, is essential. Several forms of treatment reduce exacerbations, the most effective of these is smoking cessation. EVIDENCE: Working group of clinicians and clinical researchers following detailed literature review, particularly of studies performed in South Africa, and the GOLD guidelines. BENEFITS, HARMS AND COSTS: The guideline pays particular attention to cost-effectiveness in South Africa, and promotes the initial use of less costly options. It rejects empirical use of corticosteroids both oral and inhaled, and promotes smoking cessation, and selection of treatment based on objective evidence of benefit. It also rejects a nihilistic or punitive approach, even in those who are unable to break the smoking addiction. VALIDATION: The COPD Working Group comprised experienced pulmonologists representing all university departments in South Africa and some from private practice. All contributed to the development of the previous version of the South African guideline, and attend international meetings. One (JRJ) represents South Africa on the GOLD Guideline Executive. GUIDELINE SPONSOR: The meeting of the Working Group of the South African Thoracic Society was sponsored by an unrestricted educational grant from Boehringer Ingelheim (South Africa) (Pty) Ltd.
Auditory afferents terminating as "large myelinated club endings" on goldfish Mauthner cells are identifiable "mixed" (electrical and chemical) synaptic terminals that offer the unique opportunity to correlate physiological properties with biochemical composition and specific ultrastructural features of individual synapses. By combining confocal microscopy and freeze-fracture replica immunogold labeling (FRIL), we demonstrate that gap junctions at these synapses contain connexin35 (Cx35). This connexin is the fish ortholog of the neuron-specific human and mouse connexin36 that is reported to be widely distributed in mammalian brain and to be responsible for electrical coupling between many types of neurons. Similarly, connexin35 was found at gap junctions between neurons in other brain regions, suggesting that connexin35-mediated electrical transmission is common in goldfish brain. Conductance of gap junction channels at large myelinated club endings is known to be dynamically modulated by the activity of their colocalized glutamatergic synapses. We show evidence by confocal microscopy for the presence of the NR1 subunit of the NMDA glutamate receptor subtype, proposed to be a key regulatory element, at these large endings. Furthermore, we also show evidence by FRIL double-immunogold labeling that the NR1 subunit of the NMDA glutamate receptor is present at postsynaptic densities closely associated with gap junction plaques containing Cx35 at mixed synapses across the goldfish hindbrain. Given the widespread distribution of electrical synapses and glutamate receptors, our results suggest that the plastic properties observed at these identifiable junctions may apply to other electrical synapses, including those in mammalian brain.
Circadian timing within the suprachiasmatic nucleus (SCN) is modelled around cell-autonomous, autoregulatory transcriptional/post-translational feedback loops, in which protein products of canonical clock genes Period and Cryptochrome periodically oppose transcription driven by CLOCK:BMAL complexes. Consistent with this model, mCLOCK is a nuclear antigen constitutively expressed in mouse SCN, whereas nuclear mPER and mCRY are expressed rhythmically. Peaking in late subjective day, mPER and mCRY form heteromeric complexes with mCLOCK, completing the negative feedback loop as levels of mPer and mCry mRNA decline. Circadian resetting by light or non-photic resetting (mediated by neuropeptide Y) involves acute up- and down-regulation of mPer mRNA, respectively. Expression of Per mRNA also peaks in subjective day in the SCN of the ground squirrel, indicating common clock and entrainment mechanisms for nocturnal and diurnal species. Oscillation within the SCN is dependent on intercellular signals, in so far as genetic ablation of the VPAC2 receptor for vasoactive intestinal polypeptide (VIP) suspends SCN circadian gene expression. The pervasive effect of the SCN on peripheral physiology is underscored by cDNA microarray analysis of the circadian gene expression in liver, which involves ca. 10% of the genome and almost all aspects of cell function. Moreover, the same molecular regulatory mechanisms driving the SCN appear also to underpin peripheral cycles.
OBJECTIVE: To assess the long-term health and economic impact of treating mild to moderate Alzheimer's disease (AD) with galantamine (16 mg or 24 mg per day) compared to no cholinesterase therapy in the UK. METHODS: The long-term costs and outcomes were assessed using a model developed from longitudinal data on a cohort of AD patients. The model predicts the time until patients require full-time care, defined as the consistent requirement for a significant amount of care and supervision each day. Efficacy data were obtained from three clinical trials comparing galantamine with placebo, forecasts were made for ten years. Costs were determined in 2001 British pounds and discounted at 6% per annum, while outcomes such as time to full-time care were discounted at 1.5%. RESULTS: Without pharmacological treatment, patients are expected to incur costs of 28,134 British pounds over ten years, 70% of costs accrue from providing full-time care. Galantamine (16 mg per day) is predicted to reduce the duration of the full-time care state by 12%; approximately five patients need to be treated to avoid one year of full-time care. The ten-year incremental costs per month of full-time care avoided average pound 192 British pounds per patient and 8,693 British pounds per QALY. Savings (1380 British pounds) are predicted for patients who continue treatment beyond six months and whose cognitive function is maintained or improved. Comparable results were estimated for the 24 mg dose. CONCLUSION: In addition to the clinical benefits associated with galantamine treatment, the savings predicted from delaying when full-time care is needed may offset the treatment costs.
There is a growing interest by both consumers and industry for the development of food products with 'functional' properties, or health benefits. These products may take the form of dietary supplements or of foods. The health benefits are given by particular ingredients, and in many cases these are derived from botanicals. The variety of plants providing these functions is large, ranging from staple food sources such as cereals, fruits and vegetables, to herbals as used in traditional medicine. The food or ingredient conferring health properties may consist of the plants themselves, extracts thereof, or more purified components. The scientific literature is abundant with articles not only on the beneficial properties, but also on possible adverse health effects of plants and their components. The present report discusses the data required to determine the safe use of these types of ingredients, and provides advice on the development of risk assessment strategies consistent with due diligence under existing food regulations. Product specifications, composition and characterisation of standardised and authentic materials, documented history of use and comparison to existing products (taking into account the effect of industrial processing), description of the intended use and consequent exposure are highlighted as key background information on which to base a risk evaluation. The extent of experimental investigation required, such as in vitro, animal, and/or human studies, depends on the adequacy of this information. A decision tree is presented as an aid to determine the extent of data requirements based on product comparison. The ultimate safety in use depends on the establishment of an adequate safety margin between expected exposure and identified potential hazards. Health hazards may arise from inherent toxicities or contaminants of the plant materials, including the mechanism of the intended beneficial effect. A lower safety margin may therefore be expected than for food ingredients or additives where no physiological effects are intended. In rare cases, post launch monitoring programmes may be envisaged to confirm expected exposures and adequacy of the safety margin. This guidance document was elaborated by an expert group of the Natural Toxin Task Force of the European Branch of the International Life Sciences Institute--ILSI Europe and discussed with a wider audience of scientists at a workshop held on 13-15 May 2002 in Marseille, France.
BACKGROUND AND OBJECTIVE: Both chronic occupational exposure to volatile anaesthetic agents and acute in vitro exposure of neutrophils to isoflurane have been shown to inhibit the rate of apoptosis of human neutrophils. It is possible that inhibition of neutrophil apoptosis arises through delaying mitochondrial membrane potential collapse. We assessed mitochondrial depolarization and apoptosis in unexposed neutrophils and neutrophils exposed to sevoflurane in vivo. METHODS: A total of 20 mL venous blood was withdrawn pre- and postinduction of anaesthesia, the neutrophils isolated and maintained in culture. At 1, 12 and 24 h in culture, the percentage of neutrophil apoptosis was assessed by dual staining with annexin V-FITC and propidium iodide. Mitochondrial depolarization was measured using the dual emission styryl dye JC-1. RESULTS: Apoptosis was significantly inhibited in neutrophils exposed to sevoflurane in vivo at 24 (exposed: 38 (12)% versus control: 28 (11)%, P = 0.001), but not at 1 or 12 h, in culture. Mitochondrial depolarization was not delayed in neutrophils exposed to sevoflurane. CONCLUSIONS: The most important findings are that sevoflurane inhibits neutrophil apoptosis in vivo and that inhibition is not mediated primarily by an effect on mitochondrial depolarization.
Doctors have an ethical and legal duty to respect patient confidentiality. We consider the basis for this duty, looking particularly at the meaning and value of autonomy in health care. Enabling patients to decide how information about them is disclosed is an important element in autonomy and helps patients engage as active partners in their care. Good quality data is, however, essential for research, education, public health monitoring, and for many other activities essential to provision of health care. We discuss whether it is necessary to choose between individual rights and the wider public interest and conclude that this should only rarely be necessary. The paper makes some recommendations on practical steps which could help ensure that good quality information is available for work which benefits society and the public health, while still enabling patients' autonomy to be respected.