Biomedical subjects

L Whitehead

Publications and source records attributed to L Whitehead.

At least 19 recordsLinked to original sources

PubMed2006

DNA damage in outdoor workers occupationally exposed to environmental air pollutants.

BACKGROUND: Health concerns about the exposure to genotoxic and carcinogenic agents in the air are particularly significant for outdoor workers in less developed countries. AIMS: To investigate the association between personal exposure to a group of air pollutants and severity of DNA damage in outdoor workers from two Mexican cities. METHODS: DNA damage (Comet assay) and personal exposure to volatile organic compounds, PM(2.5), and ozone were investigated in 55 outdoor and indoor workers from México City and Puebla. RESULTS: In México City, outdoor workers had greater DNA damage, reflected by a longer tail length, than indoor workers (median 46.8 v 30.1 mum), and a greater percentage of highly damaged cells (cells with tail length > or =41 microm); in Puebla, outdoor and indoor workers had similar DNA damage. There were more alkali labile sites in outdoor than indoor workers. The DNA damage magnitude was positively correlated with PM(2.5) and ozone exposure. Outdoor and indoor workers with > or =60% of highly damaged cells (highly damaged workers) had significantly higher exposures to PM(2.5), ozone, and some volatile organic compounds. The main factors associated with the highly damaged workers were ozone, PM(2.5), and 1-ethyl-2-methyl benzene exposure. CONCLUSIONS: With this approach, the effects of some air pollutants could be correlated with biological endpoints from the Comet assay. It is suggested that the use of personal exposure assessment and biological endpoints evaluation could be an important tool to generate a more precise assessment of the associated potential health risks.

Adolescent↗

PubMed2006

A collaborative hit-to-lead investigation leveraging medicinal chemistry expertise with high throughput library design, synthesis and purification capabilities.

High throughput screening (HTS) campaigns, where laboratory automation is used to expose biological targets to large numbers of materials from corporate compound collections, have become commonplace within the lead generation phase of pharmaceutical discovery. Advances in genomics and related fields have afforded a wealth of targets such that screening facilities at larger organizations routinely execute over 100 hit-finding campaigns per year. Often, 10(5) or 10(6) molecules will be tested within a campaign/cycle to locate a large number of actives requiring follow-up investigation. Due to resource constraints at every organization, traditional chemistry methods for validating hits and developing structure activity relationships (SAR) become untenable when challenged with hundreds of hits in multiple chemical families per target. To compound the issue, comparison and prioritization of hits versus multiple screens, or physical chemical property criteria, is made more complex by the informatics issues associated with handling large data sets. This article describes a collaborative research project designed to simultaneously leverage the medicinal chemistry and drug development expertise of the Novartis Institutes for Biomedical Research Inc. (NIBRI) and ArQule Inc.'s high throughput library design, synthesis and purification capabilities. The work processes developed by the team to efficiently design, prepare, purify, assess and prioritize multiple chemical classes that were identified during high throughput screening, cheminformatics and molecular modeling activities will be detailed.

Chemistry, Pharmaceutical↗

PubMed2001

Epstein-Barr virus infection in paediatric liver transplant recipients: detection of the virus in post-transplant tonsillectomy specimens.

AIMS: Post-transplant lymphoproliferative disease (PTLD) is an important and serious complication in transplant patients. Recent studies have suggested that quantitative assessment of Epstein-Barr virus (EBV) infection in transplant patients might help to identify those at risk of developing PTLD. Therefore, tonsils from paediatric liver transplant recipients were studied for evidence of EBV infection. METHODS: Tonsils were studied by in situ hybridisation for the detection of the small EBV encoded nuclear RNAs (EBERs). The phenotype of EBV infected cells was determined by double labelling in situ hybridisation and immunohistochemistry. The expression of viral latent and lytic antigens was determined by immunohistochemistry. Tonsils from patients without known immune defects were studied as controls. RESULTS: Tonsils from transplant patients showed pronounced follicular hyperplasia and minor paracortical hyperplasia. In situ hybridisation revealed variable numbers of EBV infected B cells in the tonsils from transplant patients (range, 2-1000/0.5 cm(2); mean, 434/0.5 cm(2); median, 105/0.5 cm(2)). Lower numbers were detected in the control tonsils (range, 1-200/0.5 cm(2); mean, 47/0.5 cm(2); median, 9/0.5 cm(2)). The latent membrane protein 1 (LMP1) of EBV was not detected and there were only rare cells in two cases showing expression of the EBV encoded nuclear antigen 2 (EBNA2). There was no evidence of lytic infection. None of the patients developed PTLD within a follow up period of up to five years. CONCLUSIONS: These data indicate that tonsillar enlargement in paediatric liver transplant patients does not necessarily imply a diagnosis of PTLD. Furthermore, the presence of increased numbers of EBV infected cells in tonsils from liver transplant recipients by itself does not indicate an increased risk of developing PTLD.

Antigens, Viral↗

PubMed2000

Amoxycillin release from a floating dosage form based on alginates.

Floating alginate beads have been prepared from alginate solutions containing either dissolved or suspended amoxycillin. The beads were produced by the dropwise addition of the alginate into calcium chloride solution, followed by removal of the gel beads and freeze drying. Drug release studies showed that beads prepared with the drug in solution provided some sustained release characteristics and that these could be improved by the addition of amylose. In all cases, the drug release was consistent with release of a dissolved solute from a granular or porous matrix. The beads retained their buoyancy when amylose and amoxycillin were incorporated, exhibiting resultant weight values greater than zero after 20 h. Preparation of the beads from alginate solutions containing the drug in suspension allowed higher drug loadings, at the expense of faster release and lower buoyancy.

Alginates↗

PubMed2000

Quantitation of Epstein-Barr virus DNA in the blood of adult liver transplant recipients.

BACKGROUND: Posttransplant lymphoproliferation is most often observed in pediatric transplant recipients who experience primary Epstein-Barr virus (EBV) infection at the time of or after transplantation. Lymphoproliferation is believed to be caused by impaired control of EBV-infected cells, which may be of recipient or donor origin. Most studies of EBV infection and lymphoproliferation have focused on the pediatric age group. METHODS: We have undertaken a prospective study of EBV infection in adult liver transplant recipients. Sequentially collected peripheral blood lymphocytes were examined with a recently developed quantitative polymerase chain reaction assay. The assay quantitates EBV DNA genomic titre over a 5 log10 range. RESULTS: Compared with healthy EBV seropositive people not undergoing immunosuppressive therapy, blood EBV DNA titre is elevated in patients with liver disease before transplantation. Overall, highest titres were observed during the first posttransplant month, and in the context of antilymphocyte therapy. In one patient, lymphoproliferation was associated with high titres which fell during reduction of immunosuppressive therapy. In another patient with lymphoproliferation of donor lymphocyte origin, blood EBV DNA titre was not as high. CONCLUSIONS: EBV proliferation is seen in the context of advanced liver disease and after liver transplantation. EBV DNA quantitation is a useful tool to examine the effects of immunosuppression on EBV-associated lymphoproliferation, and may be an essential technique for programs exploring the merits of EBV adoptive immunotherapy.

Adult↗

PubMed1999

A randomized controlled trial on the effect of inhaled corticosteroids on airways inflammation in adult cigarette smokers.

STUDY OBJECTIVE: To determine whether inhaled corticosteroid treatment can reduce airways inflammation in adult cigarette smokers. DESIGN: This was a randomized, placebo-controlled, double-blinded clinical trial. SETTING: The subjects were recruited from the community by advertising. PARTICIPANTS: Seventy-one adults with a > or = 5 pack-year history who were current smokers, had a normal FEV1, and produced sputum daily. INTERVENTION: Sixty subjects were randomized to receive four puffs of placebo or beclomethasone dipropionate ([BDP]; total dosage, 1,000 microg/d) using a metered-dose aerosol inhaler with a valved holding chamber (AeroChamber; Trudell Medical; London, Ontario, Canada) for 28 days. MEASUREMENTS AND RESULTS: Eleven subjects were not randomized because of poor compliance. The primary outcome was fractional airway neutrophilia, as assessed by a differential cell count of sputum. Additional outcome measures were spirometry, measurement of airway responsiveness by methacholine challenge, and lung epithelial permeability measured by the clearance of radiolabeled diethylenetriamine pentaacetic acid. There were no significant differences between the two groups in any outcome measurement after 4 weeks of treatment. CONCLUSIONS: With normal spirometry, we found no benefit of treatment with inhaled BDP, 1,000 microg/d, on noninvasive measures of airways inflammation in adult smokers. This indicates that cigarette smoke-induced inflammation in its early stages (before a demonstrable airflow obstruction) is not steroid sensitive. This may occur because the site of involvement is not accessible to inhaled medications or because the inflammatory process is resistant to moderate doses of inhaled corticosteroids.

Administration, Inhalation↗

PubMed1999

Asthma triggers in the elementary school environment: a pilot study.

Asthma, a major cause of school absenteeism, can be triggered by allergens and irritants in the child's environment. A new measurement tool, the Environmental Observation Checklist (EOC), was developed and piloted for qualitative assessment of indoor asthma triggers (allergens and irritants), adequacy of ventilation, and existing environmental control practices. Seventy-five classrooms in 20 schools from two large urban school districts in Texas were surveyed using the EOC. A Q-TRAK Air Quality Monitor was used to assess indoor carbon dioxide, temperature, and relative humidity, concurrently. The EOC appears to be a useful screening tool for identifying schools in need of intervention.

Air Pollutants↗

PubMed1998

Floating dosage forms: an in vivo study demonstrating prolonged gastric retention.

Gastroretentive dosage forms have potential for use as controlled-release drug delivery systems. The use of floating dosage forms (FDFs) is one method to achieve prolonged gastric residence times (GRTs), providing opportunity for both local and systemic drug action. Multiple-unit systems avoid the 'all-or-nothing' gastric emptying nature of single-unit systems. A freeze-dried calcium alginate multiple-unit FDF has been developed which demonstrated favourable in vitro floating characteristics. The aim of this study was to investigate the in vivo behaviour of this system compared to a multiple-unit non-floating dosage form manufactured from identical material. The study was performed in seven healthy volunteers, who swallowed the radiolabelled formulations after a standard breakfast. Transit was monitored by gamma-scintigraphy and subjects were maintained in the fed state. Prolonged GRTs of over 5.5 h were achieved in all subjects for the floating formulations, which remained high up in the stomach for the whole of the test period. In contrast, the non-floating beads displayed short GRTs, with a mean onset emptying time of 1 h. The results of this study suggest that, in the fed state, this FDF has potential for sustained drug delivery for either local or systemic purposes.

Adult↗

PubMed1998

The use of glycopyrrolate in a case of intermediate syndrome following acute organophosphate poisoning.

PURPOSE: This report describes a case of organophosphate intoxication refractory to atropine in which glycopyrrolate was used to reduce cholinergic symptoms, and describes the development of intermediate syndrome, an uncommon subacute complication of organophosphate poisoning. CLINICAL FEATURES: A 44-yr-old woman presented in cholinergic crisis following malathion ingestion. Treatment was initiated with atropine and pralidoxime. Despite clinical signs of adequate atropinisation, the patient continued to have profuse bronchorrhoea, which resolved with glycopyrrolate. During her course in the intensive care unit, she displayed a subacute deterioration in neuromuscular and mental status with decrement-increment phenomenon on electromyography consistent with intermediate syndrome. The patient eventually made a complete recovery. CONCLUSION: This case report describes the successful use of glycopyrrolate in organophosphate intoxication and the development of the intermediate syndrome, characterised by onset of weakness of neck flexors, proximal limb muscles, and respiratory muscles within one to four days after poisoning. Recognition of the syndrome is important in light of the potential for respiratory depression requiring ventilatory support.

Acute Disease↗

PubMed1998

Assessing the burden of cancer in Texas using vital statistics data.

BACKGROUND: Vital statistics data were used to describe the burden of cancer in Texas. METHODS: Average annual age-adjusted mortality data in Texas (1986 to 1990) for 17 cancer types were compared with the US data for whites and blacks and with California data for Hispanics. Trends were examined from 1980 to 1990 for the entire state and from 1976 to 1989 for 24 geographic regions within the state. RESULTS: Mortality excesses were detected for lung and liver cancer, and deficits for colorectal, breast, and prostate cancers. Rates were generally stable from 1980 to 1990 with several exceptions (lung, liver, colon). Six areas of Texas, including four areas along the Gulf Coast, had relatively more excesses of various cancers, without a discernible pattern by cancer type. CONCLUSIONS: Overall, Texas has fared favorably in cancer mortality when compared with the United States. Enhanced evaluation of the frequency of cancer, as well as the conduct of etiologic research, must await the availability of statewide long-term cancer incidence data.

Black or African American↗

PubMed1997

Epstein-Barr virus infection and malignant lymphomas in liver transplant recipients.

Post-transplant lymphoproliferative disease (PTLD) is a major cause of death and disease in transplant patients. We describe 4 cases with histologically confirmed malignant lymphoma arising in the Birmingham liver transplant programme between 1982 and 1995. One was an EBV-positive diffuse large B-cell lymphoma, 2 were EBV-positive Burkitt's lymphomas and the 4th was an EBV-negative Burkitt's lymphoma. Immunohistochemistry revealed expression of the EBV-encoded latent membrane protein LMP1 and of the BZLF1 trans-activator protein in 2 cases each, whereas the virus-encoded nuclear antigen EBNA2 was not detectable. All available post-transplant biopsies from the 3 patients with EBV-associated lymphoma were then studied to test whether the detection of EBV-positive cells in liver allograft biopsies could be used to identify patients at risk for the development of PTLD. Two patients showed infrequent EBV-positive cells in liver allograft biopsies up to 14 months before the occurrence of lymphoma and a marked increase in the number of such cells at the time of lymphoma diagnosis. Multiple biopsies from the 3rd patient did not reveal any EBV-carrying cells in the entire post-transplant period. Our results demonstrate a low incidence of PTLD in the Birmingham liver transplant programme. The PTLDs were morphologically high-grade malignant lymphomas. Only 3 cases were associated with EBV infection, and these showed heterogeneous patterns of EBV latent protein expression. Our results also suggest that the examination of liver allograft biopsies using EBER in situ hybridisation is not an appropriate method for identifying patients at risk of developing PTLD.

Adult↗

PubMed1997

Immunohistochemical detection of the Epstein-Barr virus-encoded latent membrane protein 2A in Hodgkin's disease and infectious mononucleosis.

We describe two new monoclonal antibodies specific for the Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) that are suitable for the immunohistochemical analysis of routinely processed paraffin sections. These antibodies were applied to the immunohistochemical detection of LMP2A in Hodgkin's disease (HD). LMP2A-specific membrane staining was seen in the Hodgkin and Reed-Sternberg (HRS) cells of 22 of 42 (52%) EBV-positive HD cases, but not in 39 EBV-negative HD cases. In lymphoid tissues from patients with acute infectious mononucleosis (IM), interfollicular immunoblasts were shown to express LMP2A. This is the first demonstration of LMP2A protein expression at the single-cell level in EBV-associated lymphoproliferations in vivo. The detection of LMP2A protein expression in HD and IM is of importance in view of the proposed role of this protein for maintaining latent EBV infection and its possible contribution for EBV-associated transformation. Because LMP2A provides target epitopes for EBV-specific cytotoxic T cells, the expression of this protein in HRS cells has implications for the immunotherapeutic approaches to the treatment of HD.

Animals↗

PubMed1997

Epstein-Barr virus (EBV) infection in infectious mononucleosis: virus latency, replication and phenotype of EBV-infected cells.

Primary Epstein-Barr virus (EBV) infection may manifest itself as a benign lymphoproliferative disorder, infections mononucleosis (IM). EBV infection has been characterized in lymphoreticular tissues from nine patients with IM using the abundantly expressed EBV-encoded nuclear RNAs (EBERs) as a marker of latent infection. Expression of the virus-encoded nuclear antigen (EBNA) 2 and of the latent membrane protein (LMP) 1 was seen in variable proportions of cells in all cases. Double labelling revealed heterogeneous expression patterns of these proteins. Thus, in addition to cells revealing phenotypes consistent with latencies I (EBNA2-/LMP1-) and III (EBNA2+/LMP1+), cells displaying a latency II pattern (EBNA2-/LMP1+) were observed. Cells expressing EBNA2 but not LMP1 were also detected; whilst this may represent a transitory phenomenon, the exact significance of this observation is at present uncertain. EBER-specific in situ hybridization in conjunction with immunohistochemistry revealed expression of the EBERs mainly in B-lymphocytes, many of which showed features of plasma cell differentiation. By contrast, convincing evidence of latent EBV infection was not found in T-cells, epithelial or endothelial cells. Double-labelling immunohistochemistry revealed expression of the replication-associated BZLF1 protein in small lymphoid cells, often showing plasmacytoid differentiation. There was no unambiguous expression of this protein in other cell types. These results suggest that B-cells are the primary target of EBV infection and that plasma cells may be a source of infectious virus found in the saliva of IM patients.

Antigens, Viral↗

PubMed1997

Cancer mortality among petroleum refinery and chemical manufacturing workers in Texas.

Epidemiologic historical cohort studies of petroleum refinery and chemical manufacturing workers in Texas were reviewed to examine their cancer mortality in comparison to the U.S. and to assess the possible impact of cancer mortality among these workers on the State of Texas as a whole. Summary standardized mortality ratios and 95% confidence intervals were calculated for 20 cancer types, taking into account the heterogeneity of individual studies. There were 4314 cancer deaths among the 92,318 workers employed in 10 independent plant populations. Overall, there was a significant deficit in cancer mortality among petrochemical workers compared with the general U.S. population (SMR = 88, 95% CI = 80 to 96). Only the summary SMRs for brain cancer (SMR = 113, 95% CI = 96 to 133) and leukemias (SMR = 112, 95% CI = 94 to 130) approached statistical significance. Lung and liver cancer mortality excesses, noted for Texas as a whole, were decreased in these workers. Additional follow-up of these cohorts, their expansion to include minority and female workers, and additional study of possible occupational contributions to leukemia and brain cancer are recommended.

Chemical Industry↗

PubMed1995

Media influence on parasuicide. A study of the effects of a television drama portrayal of paracetamol self-poisoning.

BACKGROUND: Paracetamol self-poisoning, which carries a significant risk of fatal liver damage, is increasing in the UK, especially among adolescents. There is concern that media portrayal of suicidal behaviour may influence its occurrence. We have investigated the effects of two broadcasts of a television drama showing a teenage girl's overdose of paracetamol. METHOD: Data from the Oxford Monitoring System for Attempted Suicide were used to examine changes in the number of overdoses and the use of paracetamol in the three week period before and after both broadcasts. An analysis of log-linear models was carried out, using additional data from two previous years, in order to control for the effects of gender, age group, time period, season, year and drug. A questionnaire was used to ascertain whether the programme had influenced patients' decisions to take an overdose or their choice of drug. RESULTS: An increase in paracetamol overdoses occurred following the first broadcast, but when data from the two previous years were examined and the log-linear analysis was used there was no evidence of significant effects attributable to the broadcasts. The questionnaire study revealed that very few people had seen either episode, and only two claimed that it had influenced them (one in terms of getting help). CONCLUSIONS: It is important to use sound methodology to avoid interpreting chance fluctuations as a media effect. The potential positive benefits of such programmes should also be investigated.

Acetaminophen↗

PubMed1994

A survey of actinic keratoses among paraquat production workers and a nonexposed friend reference group.

Follow-up on two reports of an excess of keratoses among paraquat production workers was conducted to evaluate the contribution of occupational exposures to the prevalence of keratoses among workers in a paraquat production plant in Texas. A cross-sectional study design was used to compare the prevalence of keratoses among current workers to an age, race, and sex frequency-matched group of their friends who had never worked at the plant. The analysis is based on 112 workers and 232 friends. Exposure, outcome, and covariables used in the analyses were obtained from an interview questionnaire, dermatology exam, and company records. Overall, the prevalence proportion of the presence of any actinic keratoses among workers and friends was similar (0.30 and 0.28, respectively). Among high cumulative exposed workers, the prevalence of any actinic keratoses was 0.40 compared to 0.20 among low-exposed workers and 0.28 among friends. These results were further explored using a multiple logistic regression approach to adjust for known risk and possibly confounding variables. Statistically significant high risks of actinic keratoses were demonstrated for freckling before age 16 years, older age, suntanning behaviors, occupational exposure to polycyclic aromatic hydrocarbons (PAH), and Fitzpatrick skin type. There was no significant contribution of overall exposure status (worker vs. friend). Similar to the crude analysis, the odds of actinic keratoses of high-exposed workers compared to friends was 1.9 (confidence interval [CI] = 0.9-4.2) whereas the comparable odds ratio for low-exposed workers vs. friends was 0.6 (CI = 0.2-1.7). These data do not demonstrate an excess of actinic keratoses overall nor any consistent increase in the odds of keratoses with an increase in plant exposure level.

Adult↗

PubMed1990

Ecology of house dust mites in Oxfordshire.

In a survey of the mite fauna in 30 homes in Oxfordshire, Dermatophagoides pteronyssinus and Euroglyphus maynei were found to be the most abundant species but D. farinae was absent. Of a total of 14 parameters investigated for their influence on mite numbers, relative humidity was apparently the most important factor. Bedrooms with humidities above 64% contained significantly more mites in mattresses than those with lower humidities. Bedroom humidity and thus mattress mite numbers were apparently related and were influenced by the bedroom minimum temperature, the age of the house and the use of central heating. These trends were not seen in the numbers of mites found in living-room carpets. Atopic and non-atopic participants involved in this study did not differ significantly in the numbers of mites found in their homes.

Allergens↗

PubMed1987

A neurological evaluation of workers exposed to mixtures of organic solvents.

Workers with long term exposure to mixtures of organic solvents below regulatory limits have been reported to experience mild, but clinically detectable, sensory or sensorimotor polyneuropathies. In conjuction with a cross sectional study of behavioural performance a clinical neurological evaluation was conducted among printers and spray painters to examine dose response relations. All 240 subjects completed an occupational history and symptom questionnaire and underwent a clinical neurological examination. On average, subjects had been employed on their current job for six years. Classification of solvent exposure for each subject was based on exposed versus non-exposed job titles and observations during an industrial hygiene walk-through or on the measured concentration of solvents in full shift personal air samples. The average full shift solvent concentration was 302 ppm for printing plant workers and 6-13 ppm for workers at other plants. Isopropanol and hexane were the major constituents. Neurological abnormalities consistent with mild polyneuropathy were found in 16% of subjects; none was clinically significant. Exposed/non-exposed comparisons showed slightly higher frequency of symptoms in the exposed subjects which was not related to solvent level. Subjects categorised as exposed during the walk- through survey also had poorer vibratory sensation measured at the foot and diminished ankle reflexes. In multiple linear regression models, however, controlling for age, sex, alcohol intake, and examiner, no significant (p less than 0.05) relation was found between solvent concentration and poor neurological function except for two point discrimination measured at the foot. This investigation has not provided evidence for dose related adverse neurological effects from exposure to moderately low levels of solvent mixtures for a relatively short duration, although this may be due to the shortness of exposure duration, the type of solvent exposure, or to selection factors.

Adult↗