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Biomedical subjects

S Nicholson

Publications and source records attributed to S Nicholson.

At least 19 recordsLinked to original sources
PubMed2003

Lysosomal membrane stability, phagocytosis and tolerance to emersion in the mussel Perna viridis (Bivalvia: Mytilidae) following exposure to acute, sublethal, copper.

The mytilid mussel Perna viridis is distributed throughout the Indo-Pacific region and is potentially a suitable candidate for biological effects (biomarker) monitoring in the subtropics. A suite of cytological and physiological responses to acute (48-72 h) copper exposures of 50-200 microgl(-1) were assessed in order to determine the suitability of P. viridis for marine pollution monitoring. Copper elicited significant destabilisation of the haemocyte lysosomal membranes and also impaired phagocytosis. Survival during emersion following exposure to copper was not related to the experimental copper exposures suggesting that higher metal concentrations may be required to interfere with anaerobic enzymes responsible for suppression of metabolism. Based on this preliminary study, cytological biomarkers evaluated in the haemocytes extracted from P. viridis should prove an effective non-destructive means of assessing metal pollution throughout the mussels subtropical range.

Animals↗
PubMed2003

A randomized phase II trial of SRL172 (Mycobacterium vaccae) +/- low-dose interleukin-2 in the treatment of metastatic malignant melanoma.

We conducted a randomized phase II trial of SRL172 (Mycobacterium vaccae) +/- low-dose interleukin-2 (IL-2) as treatment for stage IV malignant melanoma. The objectives were to establish the safety and efficacy of SRL172 with and without IL-2. All patients had measurable metastatic disease and none received concurrent chemotherapy, radiotherapy, corticosteroids or any other investigational agent. Sixteen patients were randomized into each arm of the trial prior to closure. The trial was halted prematurely when no responses were seen in the first 16 patients receiving SRL172 alone, predicting a response rate of less than 20%. Three partial remissions were seen in the 16 patients receiving SRL172 + IL-2. These patients remained on monthly SRL172 + IL-2, with disease progression at 12, 15 and 23 months. They continued on the trial regimen following surgical management of their disease progression. This trial provides preliminary evidence of a new, non-toxic, immunotherapeutic regimen in the management of malignant melanoma. Further trials are required to establish a definitive response rate and to compare the combination regimen with the regimen of low-dose IL-2 used in this trial. A biological basis for the responses seen in the SRL172 + IL-2 arm also needs to be established.

Adjuvants, Immunologic↗
PubMed2002

Allogeneic whole-cell vaccine: a phase I/II study in men with hormone-refractory prostate cancer.

OBJECTIVE: To establish the safety and toxicity of an allogeneic human tumour cell vaccine in patients with hormone-refractory prostate cancer, and to determine any biochemical, immunological or clinical response to vaccination. PATIENTS AND METHODS: Sixty patients with hormone-refractory prostate cancer were recruited and randomly allocated into four equal groups. Three cell lines (from a bank of four) were administered initially every 2 weeks and then monthly, in conjunction with the immunostimulant Mycobacterium vaccae (SRL-172), each group receiving a different combination of the four cell lines. The patients' serum prostate-specific antigen (PSA) levels were monitored regularly, and the immune response to the vaccine measured using nonspecific intracellular cytokines and specific humoral and cell-mediated assays. RESULTS: The vaccine was safe and well tolerated with no major side-effects. Whilst several patients had a decline in PSA from the entry level, there was no significant decrease that could be attributed solely to the vaccine. However, the immunological data were more encouraging, with several patients from each arm of the trial having an increase in cytokine production, increases in specific antibodies and evidence of T-cell proliferation in response to the vaccinations. CONCLUSION: The failure of the vaccine to produce a PSA response in the patients in the trial is not surprising considering the stage of the disease. The high PSA levels on entry indicate that the burden of disease was probably high and thus this was an extremely challenging group of patients in which to try and elicit a response through immunotherapy. However, the immunological evidence of a response to the vaccine was encouraging and suggests that further exploration of immunotherapy in less advanced disease may yield more encouraging clinical responses.

Aged↗
PubMed2001

Ecocytological and toxicological responses to copper in Perna viridis (L.) (Bivalvia: Mytilidae) haemocyte lysosomal membranes.

Bivalve lysosomes are sites of intense intracellular digestion. Lysosomes accumulate many pollutants to high concentrations resulting in membrane destabilisation. Consequently, the elucidation of lysosomal membrane integrity utilising the neutral red assay has been used to good effect in pollution monitoring. Naturally occurring environmental stressors also have the potential to destabilise the membrane. Exposure to elevated copper concentrations and extremes of temperature, salinity, hypoxia, emersion and inadequate ration were investigated in haemocyte lysosomes from the tropical bivalve, Perna viridis. Elevated copper concentrations destabilised the membrane although responses were not entirely related to the exposure-concentration. Environmental stressors induced through higher thermal regimes (29 degrees C and 35 degrees C), hyposalinity (10-25/1000) and prolonged emersion elicited significant lysosomal membrane destabilisation. Hypoxia and inadequate ration did not significantly effect membrane stability. The haemocyte lysosomal membranes were generally resistant to exogenous alterations within normal ranges and only showed significant labilisation at environmental extremes. P. viridis haemocyte lysosomal membrane biomarkers should, therefore, prove robust to natural stressors when deployed in marine monitoring programmes and thus prove a valuable, rapid, cost-effective cytological marker of pollution.

Animals↗
PubMed2001

The incentive effects of the Medicare indirect medical education policy.

Medicare provided teaching hospitals with US$ 5.9 billion in supplemental graduate medical education (GME) payments in 1998. These payments distort input and output prices and provide teaching hospitals with incentives to hire residents, close beds, and admit more Medicare patients. The structure of the GME payment policy creates substantial variation in input and output prices between teaching hospitals. We examine the extent to which hospitals responded to these financial incentives using a panel data set of 3,900 hospitals, including over 900 teaching hospitals. We find that teaching hospitals did hire residents and close beds in response to the Medicare policy, but did not increase Medicare admissions or alter their use of registered nurses (RNs).

Aged↗
PubMed2001

Designing a community-based fourth-year obstetrics and gynaecology module: an example of innovative curriculum development.

INTRODUCTION: This paper describes the design and evaluation of the community-based obstetrics and gynaecology module at St Bartholomew's and the Royal London School of Medicine and Dentistry. This module sets out to comply with the General Medical Council's recommendations of encouraging students to consider the community perspective, and places less emphasis on a disease-orientated approach. OBJECTIVES: The development of the module, issues of improving student acceptance of the course, staff development and the benefits of community teaching in obstetrics and gynaecology are discussed. MODULE ORGANIZATION: The 2-week module precedes the 8-week hospital obstetrics and gynaecology firms that occur in the fourth undergraduate year. The course is organized into three components: general practice, departmental teaching, and self-directed learning. Students are allocated to general practices for their clinical teaching, for eight sessions. Seven departmental sessions are run by the Academic Department of General Practice and Primary Care. These include a review of the students' self-directed learning. EVALUATION AND CONCLUSION: Evaluation data are reported for the three components of the course. Overall the majority of students rated the module as useful, GP attachments being most favourably received. The majority of students have grasped the basic obstetric and gynaecological history and examination skills and found this useful before starting their hospital firms. Aspects of a specialist subject, such as, obstetrics and gynaecology, can be taught successfully in the community and GP tutors are, as yet, an untapped source of excellent obstetric and gynaecology teaching.

Community Medicine↗
PubMed2001

A randomized trial of treatment for multisystem Langerhans' cell histiocytosis.

OBJECTIVE: To compare 2 active agents, vinblastine and etoposide, in the treatment of multisystem Langerhans' cell histiocytosis (LCH) in an international randomized study. STUDY DESIGN: One hundred forty-three untreated patients were randomly assigned to receive 24 weeks of vinblastine (6 mg/m(2), given intravenously every week) or etoposide (150 mg/m(2)/d, given intravenously for 3 days every 3 weeks), and a single initial dose of corticosteroids. RESULTS: Vinblastine and etoposide were equivalent (P > or = .2) in all respects: response at week 6 (57% and 49%); response at the last evaluation (58% and 69%); toxicity (47% and 58%); and probability of survival (76% and 83%) [corrected], of disease reactivation (61% and 55%), and of developing permanent consequences (39% and 51%) including diabetes insipidus (22% and 23%). LCH reactivations were usually mild, as was toxicity. All children > or = 2 years old without risk organ involvement (liver, lungs, hematopoietic system, or spleen) survived. With such involvement, lack of rapid (within 6 weeks) response was identified as a new prognostic indicator, predicting a high (66%) mortality rate. CONCLUSIONS: Vinblastine and etoposide, with one dose of corticosteroids, are equally effective treatments for multisystem LCH, but patients who do not respond within 6 weeks are at increased risk for treatment failure and may require different therapy.

Adolescent↗
PubMed2001

Hemorrhage-induced alpha-adrenergic signaling results in myocardial TNF-alpha expression and contractile dysfunction.

Hemorrhagic shock (HS), secondary to major blood loss, frequently precedes multiple organ dysfunction and is accompanied by a surge in circulating catecholamine levels. Expression of the cardiodepressant cytokine, tumor necrosis factor-alpha (TNF-alpha), has been observed in the heart after HS and resuscitation (HS/R) and alpha(1)-adrenergic blockade prevented translocation of the nuclear transcription factor, NF-kappa B, to the nucleus. We hypothesized that alpha(1)-adrenergic stimulation induces myocardial TNF-alpha expression, which results in depressed cardiac function after HS/R. The role of alpha(1)-adrenergic stimulation in myocardial TNF-alpha expression and depressed cardiac function after HS/R was assessed by treatment with the alpha(1)-adrenergic inhibitor, prazosin hydrochloride (1 mg/kg ip), for 1 h before the onset of hemorrhage. In addition, TNF-alpha was neutralized with a specific antibody (600 microl/kg iv) 5 min before hemorrhage. HS was induced by the withdrawal of blood to a mean blood pressure of 50 mmHg for 1 h. Contractile function was measured with the use of a Langendorff apparatus 2 h after the end of HS. HS/R led to significant decreases in left ventricular developed tension and in the maximal rate of pressure increase over time during both contraction and relaxation. Myocardial expression of TNF-alpha measured by enzyme-linked immunosorbent assay increased significantly after 30 min of hemorrhage and peaked after 60 min of HS and 45 min of resuscitation. Depression in cardiac function after HS/R was reversed by 85% in hearts from rats treated with a TNF-alpha neutralizing antibody and by 90% in hearts from rats treated with prazosin hydrochloride. We conclude that HS activates a alpha(1)-adrenergic pathway, resulting in TNF-alpha expression in the heart and depressed myocardial contractile function.

Adrenergic alpha-Agonists↗
PubMed2000

Analysis of DNA adducts by accelerator mass spectrometry in human breast tissue after administration of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and benzo[a]pyrene.

Epidemiological evidence has suggested an association between meat consumption and the risk of breast cancer. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine found in cooked meat, has been implicated in the aetiology of breast cancer and has been shown to induce tumour formation in rodent mammary glands. In addition, polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (B[a]P) which has also been shown to induce tumour formation at a number of sites in rodents including the breast, are produced during the cooking of meat through the pyrolysis of fats. The aim of this study was to examine the bioavailability of these compounds to human breast tissue and their ability to bind to DNA to form DNA adducts. Patients undergoing breast surgery at York District Hospital were orally administered prior to surgery a capsule containing 20microg of 14C PhIP (182kBq, specific activity 2.05GBq/mmol) or 5microg of 14C B[a]P (36kBq, specific activity 1.81GBq/mmol). At surgery, normal and tumour breast tissue was resected and tissue concentrations of carcinogen measured by liquid scintillation counting and DNA adduct levels by accelerator mass spectrometry (AMS) were subsequently determined. It was found that both 14C PhIP and 14C B[a]P were able to reach the target organ where they had the ability to form DNA adducts. The level of adducts ranged from 26.22-477.35 and 6.61-208. 38 adducts/10(12) nucleotides following administration of 14C PhIP and 14C B[a]P, respectively, with no significant difference observed between levels in normal or tumour tissue. In addition, the data obtained in this study were comparable to adduct levels previously found in colon samples following administration of the same compounds to individuals undergoing colorectal surgery. This is the first report that these two carcinogens bind to human breast DNA after administration of a defined low dose.

Aged↗
PubMed2000

The Child-Friendly Healthcare Initiative (CFHI): Healthcare provision in accordance with the UN Convention on the Rights of the Child. Child Advocacy International. Department of Child and Adolescent Health and Development of the World Health Organization (WHO). Royal College of Nursing (UK). Royal College of Paediatrics and Child Health (UK). United Nations Children's Fund (UNICEF).

OBJECTIVE: Although modern medical technology and treatment regimens in well-resourced countries have improved the survival of sick or injured children, most of the world's families do not have access to adequate health care. Many hospitals in poorly resourced countries do not have basic water and sanitation, a reliable electricity supply, or even minimal security. The staff, both clinical and nonclinical, are often underpaid and sometimes undervalued by their communities. In many countries there continues to be minimal, if any, pain control, and the indiscriminate use of powerful antibiotics leads to a proliferation of multiresistant pathogens. Even in well-resourced countries, advances in health care have not always been accompanied by commensurate attention to the child's wider well-being and sufficient concerns about their anxieties, fears, and suffering. In accordance with the United Nations Convention on the Rights of the Child,(1) the proposals set out in this article aim to develop a system of care that will focus on the physical, psychological, and emotional well-being of children attending health care facilities, particularly as inpatients. DESIGN OF THE PROGRAM: To develop in consultation with local health care professionals and international organizations, globally applicable standards that will help to ensure that practices in hospitals and health centers everywhere respect children's rights, not only to survival and avoidance of morbidity, but also to their protection from unnecessary suffering and their informed participation in treatment. Child Advocacy International will liase closely with the Department of Child and Adolescent Health and Development of the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) in the implementation of the pilot scheme in 6 countries. In hospitals providing maternity and newborn infant care, the program will be closely linked with the Baby Friendly Hospital Initiative of WHO/UNICEF that aims to strengthen support for breastfeeding. United Nations Children's Fund, United Nations Convention on the Rights of the Child, child protection, breastfeeding, pain control, palliative care, child abuse.

Child↗
PubMed1999

The kinesin light chain gene: its mapping and exclusion in mouse and human forms of inherited motor neuron degeneration.

The underlying genetic cause is known for only 10-20% of familial motor neuron disease (MND). Thus the genes involved in the aetiology of 80-90% of familial MND remain to be determined, and animal models are powerful tools for undertaking this task. We have mapped a heritable form of motor neuron degeneration in the mouse to a region that has homology to human chromosome 14q32.1-qter. This region contains the kinesin light chain gene (KLC1), which is a candidate for involvement in motor neuron degeneration because of its function in the motor-protein kinesin, and its neuronal expression. To investigate the role of KLC1 in a mouse motor neuron degeneration mutant that we are studying, we have identified mouse Klc1 gene sequences and mapped them with respect to our mutant locus. We have also investigated KLC1 in human patients with familial MND. Based on recombination and the absence of mutations in the coding region of KLC1, this gene can be excluded as a candidate gene in our mouse mutation and, where we have investigated, it is normal in human familial MND.

Animals↗
PubMed1999

Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase.

The two genetically established antimicrobial mechanisms of macrophages are production of reactive oxygen intermediates by phagocyte oxidase (phox) and reactive nitrogen intermediates by inducible nitric oxide synthase (NOS2). Mice doubly deficient in both enzymes (gp91(phox-/-)/NOS2(-/-)) formed massive abscesses containing commensal organisms, mostly enteric bacteria, even when reared under specific pathogen-free conditions with antibiotics. Neither parental strain showed such infections. Thus, phox and NOS2 appear to compensate for each other's deficiency in providing resistance to indigenous bacteria, and no other pathway does so fully. Macrophages from gp91(phox-/-)/NOS2(-/-) mice could not kill virulent Listeria. Their killing of S. typhimurium, E. coli, and attenuated Listeria was markedly diminished but demonstrable, establishing the existence of a mechanism of macrophage antibacterial activity independent of phox and NOS2.

Abscess↗
PubMed1998

Use of a reduced-carbohydrate, modified-fat enteral formula for improving metabolic control and clinical outcomes in long-term care residents with type 2 diabetes: results of a pilot trial.

Physiologic responses of 30 enterally-fed long-term care residents with type 2 diabetes receiving total nutrition support via either a disease-specific (reduced-carbohydrate, modified-fat) formula or a standard high-carbohydrate formula for 3 mo were compared. Objectives of the study included evaluating metabolic response (glycemic control and lipids) and clinical outcomes. Thirty-four subjects requiring total enteral nutrition support by tube were enrolled in this prospectively randomized, double-blind, controlled, parallel group 3-mo pilot trial. Thirty were evaluable in that they completed 4 wk. Twenty-seven completed all 12 wk. The groups were well-matched for physiologic and demographic parameters at baseline. Fasting serum glucose and capillary (fingerstick) glucose values demonstrated better control in the disease-specific formula-fed group. Serum lipid profiles of this group were similar to or better than those of the standard formula-fed group. The amount of insulin administered to insulin-using subjects in the disease-specific formula-fed group was consistently less than before initiation of the formula, whereas the amount administered was consistently higher in the group fed the standard formula. Overall, subjects randomized to the disease-specific formula experienced better numerical biochemical control and better clinical outcomes when expressed on a numerical and percentage basis. These included surrogate markers of diabetes control such as serum glucose and glycohemoglobin, as well as clinical outcomes such as incidence of infections and pressure ulcers. These findings confirm that the disease-specific formula provides better glycemic control, poses no risk to lipoprotein metabolism, and provides for better clinical outcomes.

Aged↗