PubMed Health⌕ Search

Biomedical subjects

T Nichols

Publications and source records attributed to T Nichols.

At least 19 recordsLinked to original sources
PubMed2006

Prolonged function of macrophage, von Willebrand factor-deficient porcine pulmonary xenografts.

Porcine von Willebrand factor (vWF) activates human and primate platelets. Having determined the importance of pulmonary intravascular macrophages (PIMs) in pulmonary xenotransplantation, we evaluated whether, in the absence of PIMs, vWF might play a role in pulmonary xenograft dysfunction. Utilizing a left single-lung transplant model, baboons depleted of anti-alphaGal antibodies received lungs from either vWF-deficient (n = 2); MCP-expressing (n = 5); MCP PIM-depleted (n = 5); or vWF-deficient PIM-depleted swine (n = 3). Two out of three of the PIM-depleted, pvWF deficient grafts survived longer than any previously reported pulmonary xenografts, including PIM-depleted xenografts expressing human complement regulatory proteins. Depletion of PIM's from vWF-deficient lungs, like depletion of PIM's from hMCP lungs, resulted in abrogation of the coagulopathy associated with pulmonary xenotransplantation. Thus, in terms of pulmonary graft survival, control of adverse reactions involving pvWF appears to be equally or even more important than is complement regulation using hMCP expression. However, based on the rapid failure of PIM-sufficient, pvWF-deficient pulmonary xenografts, pVWF-deficient pulmonary xenografts appear to be particularly sensitive to macrophage-mediated damage. These data provide initial evidence that vWF plays a role in the 'delayed' (24 h) dysfunction observed in pulmonary xenotransplantation using PIM depleted hMCP organs.

Animals↗
PubMed2006

Impact of complex genetic variation in COMT on human brain function.

Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a working-memory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 3' region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association.

Adult↗
PubMed2006

Quality of in-hospital care for adults with acute bacterial meningitis: a national retrospective survey.

BACKGROUND: Most adults with bacterial meningitis and meningococcal septicaemia present to junior doctors who have limited experience of these conditions. In contrast to paediatric practice, data from industrialized countries with regard to current hospital management practice are lacking. AIM: To examine whether current practice meets recommended standards in hospital management of community-acquired bacterial meningitis and meningococcal septicaemia among adults. DESIGN: National audit of medical records. METHODS: We conducted a survey of all patients with acute bacterial meningitis and meningococcal septicaemia admitted to 18 randomly selected acute hospitals in England and Wales between 1 January 2000 and 31 December 2001. All stages of care, including pre-hospital management, initial hospital assessment, record keeping, and ongoing hospital and public health management, were assessed. RESULTS: We identified 212 cases of bacterial meningitis and meningococcal septicaemia; 190 cases remained in the final analysis. Clinical record keeping did not meet acceptable standards in 33% of cases. Parenteral antibiotics were given within 1 h of hospital arrival in 56% of cases, increasing to 79% among those with an initial differential diagnosis that included bacterial meningitis or meningococcal septicaemia. A full severity of illness assessment was made in 27%. The quality of clinical practice varied widely between hospitals. This was most pronounced in the timeliness of consultant review (p < 0.0005). DISCUSSION: The quality of adult clinical practice for bacterial meningitis and meningococcal septicaemia needs improvement. This study provides a tool for developing targeted interventions to improve quality of care and outcome among adults with life-threatening infections, both in the UK and in other countries.

Adolescent↗
PubMed2004

Health impacts of flooding in Lewes: a comparison of reported gastrointestinal and other illness and mental health in flooded and non-flooded households.

Severe flooding may become more frequent due to global warming. A historical cohort study was conducted by telephone interview for new episodes of illness in all age groups, and for psychological distress in adults, following severe river flooding on 12 October 2000 in the town of Lewes in Southern England. Two hundred and twenty-seven residents of 103 flooded households and 240 residents of 104 non-flooded households in the same postal district were recruited by random selection of addresses from a post flooding survey and a commercial database respectively. Having been flooded was associated with earache (RR 2.2 [1.1,4.1] p = 0.02), and a significant increase in risk of gastroenteritis with depth of flooding (RR 1.7 [0.9,3.0] p = 0.09, p for trend by flood depth = 0.04). Adults had a four-times higher risk of psychological distress defined as a score of > or = 4 in response to the 12-item General Health Questionnaire (GHQ-12) (RR 4.1 [2.6, 6.4] p < 0.0005, p for trend by flood depth = 0.01). Associations between flooding and new episodes of physical illness in adults diminished after adjustment for psychological distress. Flooding remained highly significantly associated with psychological distress after adjustment for physical illnesses. Psychological distress may explain some of the excess physical illness reported by flooded adults and possibly by children as well. Policies to promote population resilience to flooding where flood prevention has failed must include practical support for flood victims and provision of appropriate psychological support. Associations with physical illnesses affirm the need for advice and assistance with individual, household and environmental hygiene and access to medical services.

Adolescent↗
PubMed2003

Validity and interpretation of mortality, health service and survey data on COPD and asthma in England.

The comparability of asthma and chronic obstructive pulmonary disease (COPD) epidemiology in different English routine data sources was examined to explore their use and validity in investigating environmental influences on respiratory health. National data were obtained for mortality, emergency hospital admissions, general practitioner contacts and symptoms in the early 1990s. Age/sex patterns, seasonal variations and regional and urban/rural age/sex standardised event ratios were examined. Spearman rank correlations were used to describe consistency of regional rankings across data sets. Asthma showed inconsistent disease patterns in different data sources and weak correlations for regional rankings but COPD was notably consistent. Unmeasured confounders may partly explain the findings, but individual level adjustment for social class and smoking (possible for symptoms) only partially attenuated the higher COPD rates in northern and urban areas and did not affect findings for asthma. When epidemiological patterns are consistent across data sources as with chronic obstructive pulmonary disease in England, healthcare use is likely to reflect the underlying prevalence and severity of disease and can be used to study environmental influences. When patterns vary, as with asthma, the validity of the data in relation to its intended use must be carefully considered.

Adolescent↗
PubMed2003

Investigation of an outbreak of E. coli O157 infections associated with a trip to France of schoolchildren from Somerset, England.

A retrospective cohort study was conducted after 2 confirmed and 8 probable cases of VTEC 0157 occurred in a schoolgroup from Somerset following a trip to France. The strain of the 2 confirmed cases was vero-cytotoxin type 2, phage type 34. Despite its low statistical power due to small numbers, this study suggested the most likely vehicle of infection was cucumber salad (crude RR=4.3, 95%CI [0.6-29], adjusted OR=107, 95%CI indeterminate, p=0.08). The cucumbers were purchased from Belgium but it was not possible to trace them back to source. The international nature of this outbreak emphasises the importance of close collaboration between organisations in the management of outbreaks, of ensuring international standards in food safety, and of agreeing a common standard in VTEC typing across Europe.

Adolescent↗
PubMed2003

Laboratory diagnosis of urinary symptoms in primary care--a qualitative study.

The use of the microbiology laboratory for the investigation of urinary symptoms and the test positivity rate for the urine specimens varies considerably. We used qualitative methods to explore how and why primary care staff make diagnostic and management decisions in patients presenting with urinary symptoms. Stratified random sampling was used to include general practitioner (GP) practices that were heavy and light users of the microbiology service. The data were analysed using a modified grounded theory approach utilising the constant comparative method. Frequent users of the laboratory, with low specimen positivity, did not use near patient tests (NPTs) and sent urines from most patients with urinary symptoms to confirm their clinical diagnosis. Frequent users with high positivity advise patients with negative NPTs and send all specimens with positive NPTs for antibiotic susceptibility testing. Infrequent users did not value the laboratory for diagnosis, made great use of NPTs, and tended to prescribe empirical antibiotic treatment even in patients with minimal symptoms. Guidance on the management of urinary symptoms, the use of near patient tests and laboratory culture should form part of the ongoing education of primary care staff.

Anti-Bacterial Agents↗
PubMed2002

Workload and stress in consultant medical microbiologists and virologists: a questionnaire survey.

AIMS: To document demography, changing workload patterns, job satisfaction, morale, and prevalence of stress and psychological morbidity among UK consultant medical microbiologists and virologists. METHOD: A questionnaire survey of all identified UK practising consultant medical microbiologists and virologists (n= 464). RESULTS: Among 367 respondents (79%), there were 33 virologists and at least 89 single handed consultants. Over half the respondents (58%) were working a 1 : 1 or 1 : 2 on call rota during the week and a similar proportion (51%) at weekends. Of all consultants (including those working part time), 56% were working more than 48 hours weekly. Working more than 48 hours weekly, and being on call 1 : 1 or 1 : 2 at weekends, were both independently associated with increased psychological morbidity. Those on call 1 : 1 or 1 : 2 at weekends were also more likely to have low or very low morale. Female consultants were more likely to have higher stress scores. More than half of the respondents (208 of 363; 57%) were making active financial provision to retire early, and 198 of 363 (55%) did not intend to work beyond the age of 60. CONCLUSIONS: The long hours worked by many consultant microbiologists and virologists are in breach of the European Working Time Directive and are associated with a higher degree of psychological morbidity. For most consultants, the frequency of on call commitments is demanding and job satisfaction and morale have deteriorated. Urgent action is needed, particularly to support those working more than 48 hours each week and those on call at weekends 1 : 1 or 1 : 2. However, a major expansion of the consultant establishment cannot be achieved rapidly, and will be slowed further if early retirements become more frequent.

Adult↗
PubMed2001

Promoting sun safety among zoo visitors.

BACKGROUND: Each year, millions of children visit zoological parks, where they are exposed to long bouts of ultraviolet radiation (UVR). We conducted a study in the winter and replicated it in the summer to evaluate an intervention for reducing UVR exposure during the zoo visit. METHODS: Each study used a nonequivalent control group design: one zoological site received the intervention and a second received evaluation only. Key outcome measures consisted of observed prevalence of hat use by exiting children (N = 8,721 and 8,524, respectively, in winter and summer studies) and purchase rates of sunscreen and hats in zoo gift shops. Intervention consisted of tip sheets for parents, children's activities, prompts, and discounts off the price of sunscreen and sun-protective hats. RESULTS: In the summer study, sales of both sunscreen and target hats increased significantly at the intervention site relative to the control site, whereas in the winter study, only sunscreen sales at the intervention site had a significant (relative) increase. Children's hat use increased significantly at the intervention site, but only in the winter study. CONCLUSIONS: The multicomponent program was effective in promoting purchases of sun-safe items, but its impact on children's hat use was inconclusive.

California↗
PubMed2000

A comparison of digital nonmydriatic fundus imaging with standard 35-millimeter slides for diabetic retinopathy.

PURPOSE: The purpose of this study was to compare nonmydriatic digital images with 35-mm slide images for the detection of diabetic retinal findings. STUDY DESIGN: Comparative, observational case series. PARTICIPANTS: Twenty-two patients with diabetes. METHODS: Diabetic patients underwent digital (nonmydriatic fundus camera attached to a digital back) and standard dilated 35-mm retinal photography of three areas: posterior pole, nasal retina, and temporal retina. The images were reviewed by a single masked grader for the presence or absence of specific retinal findings. PRIMARY OUTCOME MEASURES: Presence or absence of neovascularization of the disc (NVD), neovascularization elsewhere (NVE), venous beading (VB), nerve fiber layer (NFL) hemorrhage, dot-blot hemorrhage, microaneurysm (MA), clinically significant macular edema, cotton wool spot, intraretinal microvascular anomaly (IRMA), hard exudate (HE), and retinal pigment epithelial (RPE) pigmentary changes. RESULTS: Forty eyes of 22 patients underwent both imaging procedures. The agreement between image type was highest for IRMA (97.5%) and VB (95%) and lowest for RPE pigmentary changes (65%) and MA (62.5%). Sensitivity ranged from 25% (NVD) to 100% (VB). Specificity ranged from 90% (RPE pigmentary changes) to 100% (NVD, NVE, VB, NFL hemorrhage, HE). Positive predictive value ranged from 50% (IRMA) to 100% (NVD, NVE, HE, NFL, VB). Negative predictive value ranged from 48% (MA) to 100% (IRMA). CONCLUSIONS: Nonmydriatic digital fundus imaging for detection of diabetic retionopathy has a low sensitivity rate and a high specificity rate and is less clinically useful than standard dilated 35-mm fundus slide images.

Adult↗
PubMed2000

Epidemiology of pneumothorax in England.

BACKGROUND: Little is known of the epidemiology of pneumothorax. Routinely available data on pneumothorax in England are described. METHODS: Patients consulting in primary care with a diagnosis of pneumothorax in each year from 1991 to 1995 inclusive were identified from the General Practice Research Database (GPRD). Emergency hospital admissions for pneumothorax were identified for the years 1991-4 from the Hospital Episode Statistics (HES) data. Mortality data for England & Wales were obtained for 1950-97. Analyses of pneumothorax rates by age and sex were performed for all data sources. Seasonal and geographical analyses were carried out for the HES data. RESULTS: The overall person consulting rate for pneumothorax (primary and secondary combined) in the GPRD was 24. 0/100 000 each year for men and 9.8/100 000 each year for women. Hospital admissions for pneumothorax as a primary diagnosis occurred at an overall incidence of 16.7/100 000 per year and 5.8/100 000 per year for men and women, respectively. Mortality rates were 1. 26/million per year for men and 0.62/million per year for women. The age distribution in both men and women showed a biphasic distribution for both GP consultations and hospital admissions. Deaths showed a single peak with highest rates in the elderly. There was an urban-rural trend observed for hospital admissions in the older age group (55+ years) with admission rates in the conurbations significantly higher than in the rural areas. Analysis for trends in mortality data for 1950-97 showed a striking increase in the death rate for pneumothorax in those aged 55+ years between 1960 and 1990, with a steep decline in the 1990s. Mortality in the younger age group (15-34 years) remained low and constant. CONCLUSION: There is evidence of two epidemiologically distinct forms of spontaneous pneumothorax in England. The explanation for the rise and fall in mortality for secondary pneumothorax is obscure.

Adolescent↗
PubMed1999

Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors.

Hemophilia B, or factor IX deficiency, is an X-linked recessive disorder occurring in about 1 in 25,000 males. Affected individuals are at risk for spontaneous bleeding into many organs; treatment mainly consists of the transfusion of clotting factor concentrates prepared from human blood or recombinant sources after bleeding has started. Small- and large-animal models have been developed and/or characterized that closely mimic the human disease state. As a preclinical model for gene therapy, recombinant adeno-associated viral vectors containing the human or canine factor IX cDNAs were infused into the livers of murine and canine models of hemophilia B, respectively. There was no associated toxicity with infusion in either animal model. Constitutive expression of factor IX was observed, which resulted in the correction of the bleeding disorder over a period of over 17 months in mice. Mice with a steady-state concentration of 25% of the normal human level of factor IX had normal coagulation. In hemophilic dogs, a dose of rAAV that was approximately 1/10 per body weight that given to mice resulted in 1% of normal canine factor IX levels, the absence of inhibitors, and a sustained partial correction of the coagulation defect for at least 8 months.

Animals↗
PubMed1999

Persistent expression of canine factor IX in hemophilia B canines.

We previously demonstrated that direct intramuscular injection of recombinant adeno-associated virus (rAAV) carrying the human FIX (hFIX) cDNA can safely be administered to hemophilic B canines and express human factor IX protein; however, the functional activity of the hFIX protein could not be assessed due to anti-human FIX antibody (inhibitor) formation. To test the therapeutic efficacy of rAAV in hemophilic dogs, rAAV type 2 (rAAV2) carrying canine FIX (cFIX) cDNA was injected into the skeletal muscle of two dogs at doses of 1012-13particles. Circulating cFIX protein levels were maintained for 1 year at levels of 1-2% of normal. Hemostatic correction (WBCT and APTT) paralleled plasma FIX antigen levels. Both dogs still required plasma infusion for spontaneous and traumatic bleeding events. Inhibitors to cFIX protein were not detected in either animal by Bethesda assay. Neutralizing antibodies directed against AAV-2 capsid were pronounced and persistent. Vector DNA and mRNA transcripts were detected only at the injected skeletal muscle tissue. Analysis of both high and low molecular weight DNA identified both replicative episomal and integrated AAV species. These results demonstrate that persistent secretion of the FIX transgene protein, necessary for successful gene therapy of hemophilia B, can be achieved using the parvovirus-based rAAV vector

Animals↗
PubMed1999

The contribution of 'holiday deaths' to seasonal variations in asthma mortality in England and Wales.

BACKGROUND: In younger age groups there is a summer peak in asthma deaths, but whether this is due to social or environmental factors is not known. One suggested social factor is a summer holiday away from home during which there may be a lack of compliance with medication or greater difficulty in getting medical help. In older age groups there is a winter peak in asthma deaths. OBJECTIVE: To study the contribution of 'holiday deaths' to seasonal variations in asthma mortality in England and Wales. METHODS: Routinely collected mortality statistics were used (all asthma deaths of persons dying in England and Wales, 1991-93 and 1995). Deaths occurring 40 miles or more from home were estimated using the District Health Authority in which the person was usually resident; the registration district of death; and the 'transferability code' (derived by the Office for National Statistics). RESULTS: There were 484 asthma deaths in people aged 0-34 years, and 6337 asthma deaths in people aged 35 years or more. Deaths estimated to occur 40 miles or more from home contributed little (16%) to the summer peak in asthma deaths age 0-34 years, and nothing to the winter peak in asthma deaths age 35 years or more. CONCLUSIONS: Holidays away from home do not play an important part in explaining the seasonal variation of either young or old asthma deaths. Other social or environmental factors are more important.

Adolescent↗
PubMed1999

Use of the General Practice Research Database (GPRD) for respiratory epidemiology: a comparison with the 4th Morbidity Survey in General Practice (MSGP4).

BACKGROUND: The General Practice Research Database (GPRD) covers over 6% of the population of England and Wales and holds data on diagnoses and prescribing from 1987 onwards. Most previous studies using the GPRD have concentrated on drug use and safety. A study was undertaken to assess the validity of using the GPRD for epidemiological research into respiratory diseases. METHODS: Age-specific and sex-specific rates derived from the GPRD for 11 respiratory conditions were compared with patient consultation rates from the 4th Morbidity Survey in General Practice (MSGP4). Within the GPRD comparisons were made between patient diagnosis rates, patient prescription rates, and patient "prescription plus relevant diagnosis" rates for selected treatments. RESULTS: There was good agreement between consultation rates in the MSGP4 and diagnosis or "prescription plus diagnosis" from the GPRD in terms of pattern and magnitude, except for "acute bronchitis or bronchiolitis" where the best comparison was the combination category of "chest infection" and/or "acute bronchitis or bronchiolitis". Within the GPRD, patient prescription rates for inhalers, tuberculosis or hayfever therapy showed little similarity with diagnosis only rates but a similarity was seen with the combination of "prescription plus diagnosis" which may be a better reflection of morbidity than diagnosis alone. CONCLUSIONS: The GPRD appears to be valid for primary care epidemiological studies by comparison with MSGP4 and offers advantages in terms of large size, a longer time period covered, and ability to link prescriptions with diagnoses. However, careful interpretation is needed because not all consultations are recorded and the coding system used contains terms which do not directly map to ICD codes.

Adult↗
PubMed1999

Synthetic alphaVbeta3 antagonists inhibit insulin-like growth factor-I-stimulated smooth muscle cell migration and replication.

Porcine aortic smooth cells respond to insulin-like growth factor-I (IGF-I) with increases in DNA synthesis and cell migration. Because ligand occupancy of the alphaVbeta3 integrin has been shown to be necessary for IGF-I to stimulate maximal increases in both processes, we determined whether synthetic alphaVbeta3 antagonists could inhibit IGF-I-stimulated actions on this cell type. Low-molecular-weight compounds that had been selected based on their ability to compete with vitronectin for binding to purified human alphaVbeta3 in vitro were analyzed for their ability to compete with 125I-kistrin (a known ligand for porcine alphaVbeta3) for binding to porcine alphaVbeta3. Nine compounds were screened, and five were found to be potent competitive inhibitors. The most potent compound, SC-69000, resulted in 88% competition at 10(-7) M and was nearly equipotent with echistatin. The compounds that were the most potent inhibitors of kistrin binding were tested for their capacity to inhibit the cell migration response to IGF-I. Three compounds caused between 81-88% inhibition of IGF-I-stimulated migration at 10(-7) M. To determine whether these compounds could inhibit other IGF-I-stimulated actions, their ability to inhibit IGF-I-stimulated [3H]-thymidine incorporation into DNA was analyzed. The four compounds that were the most potent inhibitors of cell migration also inhibited IGF-I-stimulated DNA replication. IGF-I stimulates the synthesis of IGF binding protein-5 by these cells. Preincubation with the four most active compounds also resulted in significant inhibition of the ability of IGF-I to stimulate IGF binding protein-5 synthesis. AlphaVbeta3 occupancy by the ligand vitronectin has been shown to enhance the capacity of IGF-I to activate its receptor tyrosine kinase. The four most active compounds were shown to inhibit IGF-I-stimulated IGF-I receptor autophosphorylation. These findings suggest that blockade of ligand occupancy of the alphaVbeta3 integrin globally inhibits several IGF-I-stimulated biologic actions and that synthetic inhibitors are very active in this regard. Because these compounds can be administered to whole animals, they should be very useful in determining whether blocking alphaVbeta3 occupancy in vivo results in alteration in responsiveness to IGF-I.

Animals↗