Oxidized lipids in atherogenesis: formation, destruction and action.
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Animals↗
Biomedical subjects
A Watson
Publications and source records attributed to A Watson.
Surgical management of gastro-oesophageal reflux disease.
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Fundoplication↗
Differential protection of primary rat cardiocytes by transfection of specific heat stress proteins.
The aim of this study was to examine the individual contribution of specific heat stress proteins in primary rat cardiocytes to any protection observed following lethal heat stress or simulated lethal ischaemia. cDNAs for the inducible heat stress protein 70, for heat stress proteins 90 or 60, or a control plasmid were contransfected with a detectable marker, alkaline phosphatase, into cardiocytes. Survival assays were performed after the lethal stress. Transfection of the inducible heat stress protein 70 was found to increase survival following a lethal heat stress by 2.45-fold (P < 0.01) and against lethal ischaemia by 2.71-fold (P < 0.01). Transfection of heat stress protein 90 improved survival against heat by 2.55-fold (P < 0.05) but failed to have any effect on survival against lethal ischaemia. Transfection of heat stress protein 60 offered no protection against either stress.
Alkaline Phosphatase↗
Gene Delivery into Neuronal Cells by Calcium Phosphate-Mediated Transfection
This paper describes a method for introducing DNA constructs into primary adult dorsal root ganglion (DRG) neuron cultures. The method uses a modified calcium phosphate technique and enables relatively small numbers of cells to be used. We have used this method to study the promoter sequences responsible for mediating gene activity and nerve growth factor responsiveness in DRG neurons. It can also be used, however, for other purposes such as testing the effect on neuronal function of overexpressing a specific gene product.
Journal Article↗
Diarrhea and quality of life in ambulatory HIV-infected patients.
Our objectives were to determine HIV-infected patients' awareness and recognition of diarrheal symptoms; and to assess the impact of diarrhea on quality of life. The design was a cross-sectional study utilizing a structured telephone interview. The setting was the HIV/AIDS outpatient clinic of a tertiary referral hospital. HIV-infected patients who attended the clinic in 1994 were interviewed. The main outcome measure was the quality-of-life score (QLS). Fifty percent of patients acknowledged having diarrhea in the previous month. All four categories of diarrhea (self-reported or elicited, within the preceding week or month) were significantly associated with decreased QLS. Patients with diarrhea who did not recognize their symptoms as diarrhea also had significantly lower QLS than patients without diarrhea. Diarrhea in all categories was independently predictive of decreased QLS by multivariable analysis. Chronic diarrhea (symptoms for more than one month) was significantly associated with decreased QLS in patients with high as well as low CD4 cell counts. Lack of recognition of diarrhea may result in significant underreporting of diarrhea by patients to physicians. Diarrhea is highly prevalent in the HIV-infected population and is strongly associated with diminished quality of life.
Acquired Immunodeficiency Syndrome↗
Passive immune globulin therapy in the SIV/macaque model: early intervention can alter disease profile.
One of the major questions in AIDS is the role that the host immune system and the virus play in the dynamics of infection and the development of AIDS in an infected individual. In order to test the role of antibody in controlling viral infection, high-dose SIV-immune globulin was passively transferred to infected macaques early in infection. Immune globulin purified from the plasma of an SIV-infected long-term non-progressor macaque (SIVIG) or a pool of normal immune globulin (normal Ig) was infused into SIVsmE660-infected macaques (170 mg/kg) at one and fourteen days post infection. Animals were monitored for SIV-specific antibodies, viremia, plasma antigenemia, and clinical course. All animals were infected by SIV. At 16 months post infection, five macaques in the combined control groups have been euthanized, one as a rapid progressor with debilitating disease at 20 weeks post infection. Four macaques from the comparison groups have signs of AIDS, accompanied by high and increasing levels of virus and p27 antigenemia. One of the ten control animals had a very low virus load in plasma and peripheral blood and lymph node mononuclear cells at all times tested and has remained disease-free. In the SIVIG treatment group, two macaques were euthanized at 18-20 weeks due to AIDS, rapid progressors to disease. Three macaques in the SIVIG group had an initial high level of virus in plasma, peripheral blood mononuclear cells (PBMC), and lymph node mononuclear cells (LNMC), which dropped to baseline at 6 weeks post infection and has remained very low or negative for 16 months, a disease profile which has not been observed in untreated animals in this model to date. These macaques have remained clinically healthy. The sixth treated animal is also healthy, with very low virus burden that is detectable only by nested set polymerase chain reaction (PCR). All SIVIG-treated macaques had no detectable p27 plasma antigenemia for the first 10 weeks of infection, demonstrating that the IgG effectively complexed with the virus. The immunological correlates in the treated animals include development of de novo virus-specific antibodies and/or cytotoxic T cell (CTL), both of which are hallmarks of long term non-progressors. The two SIVIG-treated macaques that progress to disease rapidly had no detectable de novo humoral immune responses, as is often seen in rapid HIV disease in humans. Envelope-specific and virus neutralizing antibodies alone were not sufficient to prevent disease progression, as the plasma of both non-progressors as well as progressors had high titers of envelope-specific and neutralizing antibodies against SIVsmE660. Poor clinical prognosis was associated with moderate to high and increasing virus loads in plasma, PBMC, and lymph nodes. Good clinical prognosis correlated with low or undetectable post acute viremia in the peripheral blood and lymph nodes. We hypothesize that SIVIG reduced the spread of virus by eliminating or reducing plasma virus through immune complexes during the first four to 8 weeks of infection and then maintaining this low level of viremia until the host immune response was capable of virus control. Reduction of virus burden early in infection by passive IgG can alter disease outcome in SIV infection of macaques. Modifications of this strategy may lead to effective early treatment of HIV-1 infection in humans.
Animals↗
The differing effects of regional and general anaesthesia on cerebral metabolism during carotid endarterectomy.
OBJECTIVES: To examine the effects of either regional (RA) or general (GA) anaesthesia upon parameters of cerebral metabolism (near infrared spectroscopy, continuous jugular venous oximetry) during carotid endarterectomy. DESIGN: Prospective, non-randomised, observational study. MATERIALS: Sixty-five consecutive patients (33 RA; 32 GA) undergoing carotid endarterectomy. METHODS: (i) Near infrared spectroscopy: measurement of concentrations of cerebral oxyhaemoglobin (HbO2), deoxyhaemoglobin (HHb) and oxidised cytochrome oxidase (caa3). (ii) Continuous jugular venous oximetry: O2 saturation of jugular venous blood (SJvO2). (iii) Stump pressure in internal carotid artery. RESULTS: A reduction in SJvO2 (RA: 13% (95% CI-3 to 29%) GA: 9% (95% CI-2 to 20%), p < 0.08) and a fall in caa3 levels (RA vs. GA: 25/31 vs. 19/31, p = 0.2) was more likely in patients given a RA following application of the carotid clamps. When HbO2 and caa3 did fall however spontaneous recovery occurred more often (RA vs. GA; caa3: 18/25 vs. 5/19, p < 0.005; HbO2: 30/31 vs. 4/28, p < 0.001). CONCLUSIONS: Although GA may offer a degree of cerebral protection by reducing cerebral metabolic rate (lower falls in SJvO2 and caa3) RA preserved cerebral autoregulation as judged by the spontaneous recovery in caa3 and HbO2 levels.
Aged↗
A study of ovarian cancer patients treated with dose-intensive chemotherapy supported with peripheral blood progenitor cells mobilised by filgrastim and cyclophosphamide.
We have shown that large numbers of haemopoietic progenitor cells are mobilised into the blood after filgrastim [granulocyte colony-stimulating factor (G-CSF)] alone and filgrastim following cyclophosphamide chemotherapy in previously untreated patients with ovarian cancer. These cells may be used to provide safe and effective haemopoietic rescue following dose-intensive chemotherapy. Using filgrastim alone (10 micrograms kg-1), the apheresis harvest contained a median CFU-GM count of 45 x 10(4) kg-1 and 2 x 10(6) kg-1 CD34+ cells. Treatment with filgrastim (5 micrograms kg-1) following cyclophosphamide (3 g m-2) resulted in a harvest containing 66 x 10(4) kg-1 CFU-GM and 2.4 x 10(6) kg-1 CD34+ cells. There was no statistically significant difference between these two mobilising regimens. We have also demonstrated that dose-intensive carboplatin and cyclophosphamide chemotherapy can be delivered safely to patients with ovarian cancer when supported by peripheral blood progenitor cells and filgrastim. Carboplatin (AUC 7.5) and cyclophosphamide (900 mg m-2) given at 3 weekly intervals with progenitor cell and growth factor support was well tolerated in terms of haematological and systemic side-effects. Double the dose intensity of chemotherapy was delivered compared with our standard dose regimen when the treatment was given at 3 weekly intervals. Median dose intensity could be further escalated to 2.33 compared with our standard regimen by decreasing the interval between treatment cycles to 2 weeks. However, at this dose intensity less than a third of patients received their planned treatment on time. All the delays were due to thrombocytopenia.
Adult↗
Lamotrigine-induced toxic epidermal necrolysis treated with intravenous cyclosporin: a discussion of pathogenesis and immunosuppressive management.
There is growing evidence that the final common pathway of toxic epidermal necrolysis (TEN) is mediated by the cellular immune system which targets drug altered epithelial antigens. This provides a rationale for immunosuppressive therapy. The ideal regimen for quickly turning off epidermal damage in TEN has not yet been determined and the use or benefit of routine immunosuppression remains highly controversial. This article reviews recent advances in the pathogenesis of TEN along with the theoretical benefits of early immunosuppressive treatment in severe cases, specifically utilizing cyclosporin. We describe a 29-year-old woman with TEN due to the anticonvulsant lamotrigine whose successful management included intravenous cyclosporin. The extension of her lesions ceased within 24 hours of initiating cyclosporin (day 7 of her admission). Complications included: scarring alopecia; Enterococcus faecalis septicaemia due to an infected central line; and ulceration and squamous metaplasia of conjunctivae. The potential role of lamotrigine as a cause of TEN is discussed.
Adult↗
Development of a chronically catheterized maternal-fetal macaque model to study in utero mother-to-fetus HIV transmission: a preliminary report.
The lack of a representative animal model that permits frequent in utero fetal blood sampling is a major limiting factor for the study of maternal-fetal HIV transmission. Therefore, we have developed a maternal-fetal virus infection model using chronically catheterized macaques to simultaneously study the time-course of viral infection in the mother and the response of the fetus to maternal HIV infection. Pregnant macaques were infected with 10(3) infectious units of HIV-2(287); every 3 days blood samples from both the mother and the fetus as well as amniotic fluid samples were collected. We found a varying degree of peak and time-to-peak virus load, virus-infected PBMCs, and free virus (determined by QC-RNA-PCR method) in maternal blood. Two of the three mothers with more than 10(8) copies of viral RNA/ml of plasma at peak viremia transmitted the virus to their fetuses at about 14 days post-infection. As observed with HIV-2(287) infected mothers, virus-infected fetuses also produced a rapid rate of CD4+ cell decline in utero.
Animals↗
Compliance with treatment in adult patients with cystic fibrosis.
BACKGROUND: Patients with chronic disease comply with about 50% of their treatment. The complex and time consuming daily drug regimens needed in the care of adult patients with cystic fibrosis encourage non-compliance with prescribed treatments. Understanding the reasons for, and the extent of, non-compliance is essential for a realistic appraisal of the patient's condition and sensible planning of future treatment programmes. METHODS: Patients were invited to complete a questionnaire which asked about their compliance with daily treatment. The data were used to calculate a compliance score, the percentage of prescribed treatment taken, and to examine patient attitudes to each individual prescription. An assessment score derived from consultant, cystic fibrosis research fellow, specialist nurse, and physiotherapist ratings of patient compliance was compared with the compliance score. Both scores were correlated with patient characteristics and disease severity, and the compliance score was also correlated with the patient's knowledge of cystic fibrosis. RESULTS: More than half the patients claimed to take more than 80% of their treatments. Compliance with individual treatments varied according to their perceived unpleasantness and degree of infringement on daily activities. The most common reason given for omitting treatment was forgetfulness. Professional carers were poor judges of patient compliance. There was no correlation between compliance and patients' sociodemographic characteristics or their knowledge about cystic fibrosis. CONCLUSIONS: Non-compliance is universal and should be recognised as normal behaviour. There are no reliable criteria for predicting any patient's level of compliance. Treatment protocols should be planned around individual patient's requirements, modifying treatment ideals where necessary according to the exigency and pattern of that patient's lifestyle.
Adolescent↗
Knowledge of adult patients with cystic fibrosis about their illness.
BACKGROUND: Adult patients need to understand their illness if the locus of control is to move from doctor to patient. Previous studies have shown important misconceptions and gaps in patients' knowledge about cystic fibrosis. METHODS: Patients were invited to complete a multiple choice questionnaire covering all major aspects of cystic fibrosis. The questionnaire score was compared with a predicted score derived from the consultant, cystic fibrosis fellow, nurse, and physiotherapist ratings of patient knowledge. Data were obtained to provide a comprehensive patient profile and disease severity score. Both scores were tested for any associations with patient characteristics. RESULTS: Although patients had good general knowledge about the aspects of cystic fibrosis that impacted most on their daily lives--that is, respiratory and gastrointestinal problems--important gaps and misconceptions in these areas were still present. Knowledge and understanding of genetic and reproductive issues and the less common complications of cystic fibrosis were only moderate. Older more severely affected patients, and those who had more contact with the hospital caring team, had better multiple choice questionnaire knowledge scores. Professional carers were poor judges of the knowledge of individual patients. CONCLUSIONS: Important gaps persist into adult life in the knowledge patients with cystic fibrosis have about their illness. Objective assessment of these deficits is required so that each patient can be counselled according to his or her needs.
Adolescent↗
Renal biopsy as a day case procedure.
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Adolescent↗
The cyclic AMP response element in the calcitonin/calcitonin gene-related peptide gene promoter is necessary but not sufficient for its activation by nerve growth factor.
The gene encoding calcitonin gene-related peptide (CGRP) is inducible by nerve growth factor (NGF) in primary dorsal root ganglion neurons. By transfecting these primary neurons, we have defined a region of the CGRP promoter from -140 to -72 relative to the transcriptional start site which is essential for its inducibility by NGF as well as by cyclic AMP and which can confer these responses on a heterologous promoter. A cyclic AMP response element (CRE) within this region is essential for both these responses which are abolished by site-directed mutagenesis of this element. In contrast to the intact fragment the isolated CRE can confer responsiveness to cyclic AMP but not NGF on a heterologous promoter. The reasons for the different role of the CRE in the response of the CGRP promoter to cyclic AMP and NGF are discussed.
Animals↗
Treatment of chlamydial infection in developing countries.
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Amoxicillin↗
A minimal CGRP gene promoter is inducible by nerve growth factor in adult rat dorsal root ganglion neurons but not in PC12 phaeochromocytoma cells.
The calcitonin/CGRP gene is transcribed in thyroid C cells and some neuronal cells but not in other cell types. Although the promoter sequences mediating gene activity in thyroid C cells have been extensively studied, the elements responsible for promoter activity in neuronal cells and its stimulation by nerve growth factor (NGF) have not previously been defined. We report the first use of the calcium phosphate procedure to successfully transfect adult rat dorsal root ganglion neurons, which naturally express the calcitonin/calcitonin gene-related peptide (CGRP) in an NGF-inducible manner. This method was used to characterize the elements in the calcitonin/CGRP promoter which are responsible for its basal activity and NGF inducibility in DRG neurons and in PC12 cells, a neuronally derived cell line which does not naturally express the calcitonin/CGRP gene. Although the sequences required for basal activity are similar in each cell type, we show that a minimal calcitonin/CGRP promoter is NGF-responsive in dorsal root ganglion cells, but that upstream sequences are required for such inducibility in PC12 cells.
Animals↗
Laparoscopic 'physiological' antireflux procedure: preliminary results of a prospective symptomatic and objective study.
The 'physiological' antireflux procedure has been shown to be as effective as Nissen fundoplication in reflux control, but with a significant reduction in the incidence of mechanical complications. This technique was attempted laparoscopically in 26 patients in a prospective study involving independent symptomatic, manometric and pH assessment performed before operation and at a mean of 5.5 months after operation. The procedure was successfully completed laparoscopically in 23 (88 per cent) patients. Mean hospital stay was 3.8 days and mean time to return to work 1.8 weeks. There was neither mortality nor reoperation; 91 per cent of patients obtained symptomatic relief (82 per cent Visick grade 1). There was no gas-bloat or inability to belch or vomit. All 14 patients who underwent objective testing had a normal oesophageal pH profile, the mean percentage total time that pH < 4 falling from 11.0 to 1.1 (P < 0.001). Lower oesophageal sphincter characteristics, including relaxation, were similar to control values. These preliminary results suggest symptomatic and objective results comparable to those following open surgery, but with the benefits of a shorter hospital stay and time off work. In addition to a lower incidence of mechanical complications, the relative ease of performance of this procedure confers an additional advantage over Nissen fundoplication when performed laparoscopically.
Adolescent↗
Manometric assessment of the effect of the diaphragmatic crural sling in gastro-oesophageal reflux: implications for surgical management.
A manometric method to measure the effect of contraction of the crural sling of the diaphragm on intraoesophageal pressure is described. The manometric crural pressure was measured in 57 patients with gastro-oesophageal reflux disease, documented by 24-h ambulatory pH monitoring, and compared between patients with and without hiatal hernia. Repeat measurements were made in 33 patients who underwent antireflux surgery that incorporated a crural repair. Mean crural pressure in 41 patients with hiatal hernia was 5.0 mmHg, compared with 15.0 mmHg in 16 without hiatal hernia (P < 0.01). In the 33 patients undergoing antireflux surgery, mean crural pressure rose from 7.1 mmHg before operation to 11.6 mmHg afterwards (P < 0.02) overall, and from 4.7 to 10.1 mmHg (P < 0.01) in the 26 patients with hiatal hernia. These results confirm a measurable contribution of the diaphragmatic crural sling to resting pressure at the high-pressure zone. The crural pressure is deficient in patients with hiatal hernia compared with that in those with reflux but no hernia. The mean crural pressure is increased in patients by antireflux surgery, particularly in those with hiatal hernia. The results provide objective support for the role of the crural diaphragm in the antireflux mechanism and the rationale of performing crural repair during antireflux surgery, particularly in the presence of hiatal hernia.
Adolescent↗