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Biomedical subjects

P Watkins

Publications and source records attributed to P Watkins.

At least 19 recordsLinked to original sources
PubMed2001

Extracorporeal photopheresis in Sézary syndrome: hematologic parameters as predictors of response.

Data were analyzed from 23 patients with Sézary syndrome (defined by erythroderma, more than 10% circulating atypical mononuclear cells, and peripheral blood T-cell clone) undergoing monthly extracorporeal photopheresis as the sole therapy for up to 1 year. The cohort showed a significant reduction of skin scores during treatment (P =.001). Thirteen patients (57%) achieved a reduction in skin score greater than 25% from baseline at 3, 6, 9, or 12 months (responders). Reduction in skin score correlated with reduction in the Sézary cell count as a percentage of total white cell count (P =.03). Responders and nonresponders were compared. None of the measured parameters was significantly different between the 2 groups. It was assessed whether any of the baseline parameters predicted outcome. A higher baseline lymphocyte count was significantly associated with a decrease in skin score at 6 months (P <.05). A higher baseline Sézary cell count as a percentage of total white cell count predicted a subject was more likely to be a responder after 6 months of treatment (P =.021). No other parameters predicted responder status. These data show that the modest falls in CD4, CD8, and Sézary cell counts were seen in all patients and might have resulted from lymphocyte apoptosis. This mechanism could explain the more favorable response seen in patients with higher percentages of Sézary cells in the peripheral blood. Alternatively, minimum tumor burden might be required for the induction of a cytotoxic response. Analysis of tumor-specific cytotoxic T cells is needed to investigate these possibilities further.

Adult↗
PubMed2000

Development of proliferative retinopathy in patients with long-standing insulin-dependent diabetes mellitus.

PURPOSE AND METHOD: Some patients with long-standing insulin-dependent diabetes mellitus (IDDM) develop little or no retinopathy. Using a clinic-based questionnaire and examination, we investigated a group of patients with over 40 years or more of IDDM who had been followed up at the King's Diabetes Centre for an average of 40 years. We compared those who had developed proliferative diabetic retinopathy during their disease with those with minimal or no retinopathy. RESULTS: The study did not find any statistically significant differences between the two groups to suggest why some long-term insulin-dependent diabetics develop little retinopathy. Those who developed sight-threatening retinal complications did so at an average of 35 years after diagnosis and it resulted in little visual disablement. Very few patients in either group had developed other significant complications. CONCLUSIONS: This study details an interesting group of patients with long-term IDDM mellitus with a mean follow-up period of 40 years. Some patients with long-standing IDDM develop little or no retinopathy. With the advent of community ophthalmic screening, these patients are now rarely seen in the eye clinic. Those who did develop retinal complications and required treatment have remarkably little visual disablement. However, these complications developed late in the history of their disease, emphasising the need for continued screening.

Aged↗
PubMed2000

COMT inhibitors and liver toxicity.

This paper reviews the issue of hepatotoxicity with the use of the catechol-O-methly transferase (COMT) inhibitors tolcapone and entacapone. Neither drug caused hepatotoxicity in preclinical toxicity testing. However, in clinical trials of tolcapone, liver chemistry tests were elevated more than 3 times above the upper limit of normal in approximately 1% of patients who took the 100 mg dose and in approximately 3% of patients who took the 200 mg dose. These observations led to the recommendation that periodic monitoring of liver function be performed. Post-marketing surveillance studies noted 3 instances of acute liver failure with death after 60,000 patients had received tolcapone for a total of 40,000 patient-years. For this reason, the drug was withdrawn from the market in Europe and Canada, and a black box warning issued in the United States. In contrast, clinical trials with entacapone demonstrated no increase in liver enzymes above those observed with placebo. Further, no instances of acute liver failure or death attributed to the drug have been observed in post-marketing surveillance studies. Consequently, liver monitoring is not required with this agent. These data demonstrate that tolcapone is associated with a risk of hepatotoxicity but that no such risk has been detected with entacapone.

Benzophenones↗
PubMed1999

6',7'-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein.

BACKGROUND: 6',7'-Dihydroxybergamottin is a furanocoumarin that inhibits CYP3A4 and is found in grapefruit juice and Seville orange juice. Grapefruit juice increases the oral bioavailability of many CYP3A4 substrates, including cyclosporine (INN, ciclosporin), but intestinal P-glycoprotein may be a more important determinant of cyclosporine availability. OBJECTIVES: To evaluate the contribution of 6',7'-dihydroxybergamottin to the effects of grapefruit juice on cyclosporine disposition and to assess the role of CYP3A4 versus P-glycoprotein in this interaction. METHODS: The disposition of oral cyclosporine was compared in healthy subjects after ingestion of water, grapefruit juice, and Seville orange juice. Enterocyte concentrations of CYP3A4 were measured in 2 individuals before and after treatment with Seville orange juice. The effect of 6',7'-dihydroxybergamottin on P-glycoprotein was assessed in vitro. RESULTS: Area under the whole blood concentration-time curve and peak concentration of cyclosporine were increased by 55% and 35%, respectively, with grapefruit juice (P < .05). Seville orange juice had no influence on cyclosporine disposition but reduced enterocyte concentrations of CYP3A4 by an average of 40%. 6',7'-Dihydroxybergamottin did not inhibit P-glycoprotein at concentrations up to 50 micromol/L. CONCLUSIONS: 6',7'-Dihydroxybergamottin is not responsible for the effects of grapefruit juice on cyclosporine. Because the interaction did not occur with Seville orange juice despite reduced enterocyte concentrations of CYP3A4, inhibition of P-glycoprotein activity by other compounds in grapefruit juice may be responsible. Reduced enterocyte CYP3A4 by 6',7'-dihydroxybergamottin could be important for other drugs whose bioavailability is less dependent on P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Extracorporeal photopheresis (ECP) in the treatment of chronic graft-versus-host disease (GVHD)

The aim of our study was to assess the efficacy of extracorporeal photopheresis (ECP) in chronic graft-versus-host disease (GVHD). Eleven patients with chronic cutaneous GVHD were studied. Four had mucosal involvement and five had pulmonary involvement. All had failed to improve on first- and second-line therapy. Three patients received ECP alone; the remainder continued to receive steroids and/or immunosuppressive therapy. Patients received ECP twice monthly for 4 months and then once monthly for 3 months. They were evaluated by serial skin scores, mucosal and skin photography, pulmonary function tests, biochemical and haematological parameters. Nine patients showed objective evidence of cutaneous improvement with a mean reduction in skin score of 48% overall. In the 10th patient, skin scores and oral involvement improved on twice monthly ECP but deteriorated when reduced to once monthly. The final patient died from renal failure secondary to cyclosporin toxicity. Two out of five patients with lung involvement showed a mild improvement in pulmonary function tests. Liver function tests were abnormal in five patients; they improved in one and deteriorated in three. All patients receiving concomitant immunosuppressive/steroid therapy were able to reduce drug dosages by trial completion. Our results indicate that ECP can benefit patients with cutaneous and mucosal chronic GVHD who have failed on first- and second-line therapies. The effect on the systemic manifestations of GVHD is less consistent.

Adolescent↗
PubMed1997

Does phenylethylamine have a role in schizophrenia?: LSD and PCP up-regulate aromatic L-amino acid decarboxylase mRNA levels.

Aromatic L-amino acid decarboxylase (AADC) is rate limiting in the production of 2-phenylethylamine (2PE). AADC activity and 2PE serum concentrations have been found to be increased in schizophrenic patients. Both antipsychotic and psychotogenic drugs, including amphetamine, affect the activity and encoding mRNA levels of AADC. Amphetamine is an analogue of 2PE and has a similar physiological effect. We have looked at the effects of chronic (32 day) treatment of rats with LSD (0.12 microg/kg/day) and phencyclidine (PCP; 10 mg/kg/day) on AADC mRNA levels. Both drugs up-regulated AADC mRNA levels in striatum, nucleus accumbens, hippocampus and cerebellum by between 50% and 150%. A splicing variant of AADC, present in human brain, which lacks the 3rd exon does not appear to be present in rat brain. These results are consistent with the hypothesis that over activity of AADC leading to increased production of 2PE is involved in endogenous psychosis such as schizophrenia.

Alternative Splicing↗
PubMed1997

Biomechanical and biochemical study of a standardized wound healing model.

Standardized protocols were developed for use in a detailed investigation into the biomechanical and biochemical properties of a dermal wound healing model in the rat. The use of a rapid freezing method at -80 degrees C minimized the detrimental effects of freezing on the biomechanical properties of the tissue and also allowed for convenient inter-laboratory collaboration to be performed. The methodology described allowed for the simultaneous and reproducible measurement of tensile strength, collagen cross-linking and proteolytic enzyme activity. Increases in the tensile properties of the tissue with time were consistent with an active process of remodelling process as indicated by changes in the cross-link and enzyme profiles. Initially the granulation tissue was comparatively rich in the keto-imine cross-link hydroxylysino-keto-norleucine, which was later replaced by the aldimine cross-link dehydro-hydroxy-lysinonorleucine. The mature cross-link histidino-hydroxy-lysinonorleucine was not observed within the granulation tissue at any stage and was also absent in aged control skin. A peak of matrix metalloproteinase-9 activity was observed at early timepoints (48 hr) and then decreased rapidly to normal levels and is consistent with an acute inflammatory response. In contrast matrix metalloproteinase-2 activity peaked later (3 days) and then decreased gradually, consistent with its role as one of the predominant enzymes involved in the remodelling process. The results described validate the animal model used and emphasize its potential for use in combined biomechanical and biochemical studies of acute wound healing.

Animals↗
PubMed1997

The requirements and development of neutron beams for neutron capture therapy of brain cancer.

One of the two overriding conditions for successful BNCT is that there must be a sufficient number of thermal neutrons delivered to each of the boronated cells in the tumour bed (target volume). Despite the poor experience with BNCT in the USA some 40 years ago, the continued apparent success of BNCT in Japan since 1968, lead indirectly to the re-start of clinical trials on BNCT in 1994 at both Brookhaven and MIT. Similar trials will start soon at Petten in Europe. At other centres worldwide, many neutron beam designs are being proposed with either thermal or epithermal neutrons, emanating predominantly from nuclear research reactors. It is apparent that whilst the success of BNCT depends on a suitable neutron beam, there is a diversity in available designs, as well as each proposed type of neutron source, with consequently different characteristics of the emergent neutron beam. The paper presents the historical development of neutron beams used for BNCT, addresses the requirements on the types of beams, describes some of the existing designs and other proposals elsewhere and lastly, considers the broader requirements in designing NCT facilities. The focus of the paper is on treatment of brain cancer, neutron beam requirements for other types of cancer may vary.

Boron Neutron Capture Therapy↗
PubMed1997

The Omega-Project--a comparison of two diagnostic strategies for risk- and cost-oriented management of dyspepsia.

OBJECTIVES: In dyspepsia few data are available from the primary care setting on how selective, risk-factor-oriented endoscopy compares with mandatory endoscopy in the diagnostic outcome and in direct and secondary costs. We studied this in a two-armed multicentre trial (omega-project) with primary care physicians. MATERIAL AND METHODS: Patients were enrolled and treated by primary care physicians and referred to a gastroenterologist for upper gastrointestinal endoscopy (UGE). Patients were enrolled in the study if they had had epigastric complaints for more than 1 month and no obvious signs or history of organic disease. In the first arm of the study endoscopy was mandatory, in the second selective, i.e. according to a predefined risk profile. Patients enrolled were treated with prokinetic drugs for 2 months. A further indication for endoscopy was non-response to treatment (reduction of the initial symptoms score by less than two-thirds) in the study with selective endoscopy and relapse within the 2-month follow-up period in both studies. The direct costs from number of consultations with the primary care physician, UGEs, number of prescriptions per patient and also absenteeism in days per week were carefully registered in both groups. RESULTS: All 172 patients of the mandatory endoscopy study and 203/656 patients enrolled in the selective endoscopy study had an UGE (125 at admission, 78 in the follow-up period). Patients were treated for 4 weeks (cisapride or domperidone) and thereafter followed for 8 weeks, at the end of the observation period the response rates were 80% and 79%, respectively. The prevalence of gastric cancers was similar in both groups (> 1%) but extrapolation from the data collected with compulsory endoscopy suggests that two-fifths of the anticipated peptic lesions remained undetected by following the selective strategy. The cost analysis revealed a 31% cost reduction with the selective strategy--in the Swiss cost system--through a reduction in the number of endoscopies by 67%. CONCLUSION: Selective UGE is cheaper and appears not to compromise the response to prokinetics; however, its diagnostic power is less than with mandatory UGE.

Adult↗
PubMed1997

Response to influenza virus vaccination in vertical HIV infection.

OBJECTIVE: To assess the antibody response to influenza vaccine of children vertically infected with HIV. DESIGN: Prospective study in HIV infected children vaccinated during the winter of 1994-5. SETTING: Family HIV clinic at St Mary's Hospital, Paddington. SUBJECTS: 25 children, aged 1-11 years, vertically infected with HIV. MAIN OUTCOME MEASURES: Responses to influenza antigens (H1N1-A/Taiwan/1/86, H3N2-A/Shandong/9/93, B/Panama/45/ 90) were tested by haemagglutination inhibition. Antibody responses were assessed according to clinical symptoms and immune function, stratified according to the 1994 revised classification for HIV infection in children. RESULTS: 23 children (92%) had either very low or no detectable antibody before vaccination. New protective antibody responses were made by 10 children (40%): in seven to a single antigen, in two to two antigens, and in one to all three antigens. For each antigen there was an overall small increase in the mean geometric titre of antibody produced, but this only reached a protective level for antigen H1N1 and for children with minimal symptoms. Less symptomatic children were significantly more likely to produce a protective antibody response to influenza vaccination. No association was found between immune function, as measured by CD4 count, and vaccine response. CONCLUSIONS: Only vaccination of the least symptomatic HIV infected children against influenza is likely to be effective. This will not only protect them against influenza, but will also protect other more immunosuppressed and vulnerable members of their families.

Antibodies, Viral↗
PubMed1997

Lack of susceptibility of the cottontop tamarin to hepatitis C infection.

The only species apart from man that is known to be susceptible to HCV infection is the chimpanzee but the availability of this primate for research is strictly limited. In an attempt to find an alternative and more practical model for HCV studies three cottontop tamarins were inoculated intravenously with HCV-containing serum from patients with chronic HCV infection. The tamarins were monitored regularly for biochemical indications of hepatic inflammation and serum samples were assayed at weekly intervals for the presence of HCV-RNA and HCV antibodies. HCV-RNA was detectable at 10 minutes postinoculation in all three animals but not at any later time point over a 6 month period. No evidence of an active humoral immune response to the inoculated HCV was obtained although passively transferred anti-HCV was detectable in one animal until 1 week postinoculation. Biochemical findings did not indicate hepatic inflammation and liver histology remained normal. It is concluded on the basis of these negative findings that the cottontop tamarin is not susceptible to HCV infection.

Animals↗
PubMed1996

Virus-specific cytotoxic T cell responses are associated with immunity of the cottontop tamarin to Epstein-Barr virus (EBV).

The cytotoxic responses of peripheral blood lymphocytes from cottontop tamarins to in vitro restimulation with autologous lymphoblastoid cell lines (LCL) were assayed. Lymphocytes from immune tamarins that had recovered from EBV challenge developed potent cytotoxicity for natural killer (NK) cell targets and for autologous LCL. The cytotoxicity for LCL targets was EBV-specific, as B cell blasts uninfected with EBV were not killed. The cell lines could be maintained by repeated stimulation with LCL and the addition of IL-2. Flow cytometry showed that they were T cell lines expressing CD2, CD3, CD4, CD8 and CD25. Dual-colour flow cytometry revealed two subpopulations, one CD4+ CD8+ population and the other CD4- CD8+. After separation by magnetic cell sorting both subpopulations were shown to be cytotoxic and the CD4+ CD8+ fraction was also shown to be MHC class II-restricted; the MHC restriction of the CD8+ subpopulation could not be determined. The unseparated T cells and both the subpopulations were able to inhibit LCL outgrowth in vitro. In contrast, PBL from naive tamarins stimulated by autologous LCL developed less NK cell cytotoxicity and little cytotoxicity for LCL. The cytotoxic response was enhanced at higher levels of LCL stimulation, but the cells were unable to inhibit LCL outgrowth in vitro. We conclude that cytotoxic responses capable of inhibiting LCL growth in vitro correlate with in vivo immunity in the tamarin model and provide a basis for understanding the mechanism of vaccine-induced immune protection.

Animals↗
PubMed1995

Selection of monoclonal antibodies for the identification of lymphocyte surface antigens in the New World primate Saguinus oedipus oedipus (cotton top tamarin).

32 monoclonal antibodies reactive with human CD antigens were tested against tamarin peripheral blood lymphocytes, ConA blasts and lymphoblastoid B cell lines derived from tamarin cells. Reagents that cross-react with MHC class I and II, B cells (CD20, -21 and -23), monocytes (CD14) and NK cells (CD16, -56) have been identified. In addition monoclonals that cross-react with T cells (CD2, CD3), the CD4/CD8 subsets of T cells and the IL-2 receptor (CD25) are reported. A monoclonal against the beta chain of LFA-1 (CD18) cross-reacted strongly, but there was only a very poor cross-reaction with a monoclonal against the alpha chain of CD11a. Two monoclonals tested against ICAM-1(CD54) were negative.

Animals↗
PubMed1995

Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders.

The peroxisome biogenesis disorders (PBDs) are lethal recessive diseases caused by defects in peroxisome assembly. We have isolated PXR1, a human homologue of the yeast P. pastoris PAS8 (peroxisome assembly) gene. PXR1, like PAS8, encodes a receptor for proteins with the type-1 peroxisomal targeting signal (PTS1). Mutations in PXR1 define complementation group 2 of PBDs and expression of PXR1 rescues the PTS1 import defect of fibroblasts from these patients. Based on the observation that PXR1 exists both in the cytosol and in association with peroxisomes, we propose that PXR1 protein recognizes PTS1-containing proteins in the cytosol and directs them to the peroxisome.

Amino Acid Sequence↗
PubMed1995

Doubly disabled: diabetes in combination with an eating disorder.

We present a series of patients with both an eating disorder and diabetes mellitus and compare these to a group of non-diabetic patients from the same clinic. Significantly more of the diabetic patients had previous attempts at treatment for their eating disorder. A high incidence of diabetic complications was noted with clear implications, both clinically and economically, for early intervention. The incidence of childhood trauma was lower in the diabetic than the non-diabetic group. In the majority of patients, diabetes developed before the eating disorder, suggesting that diabetes itself may provide the vulnerability and increase the risk of developing an eating disorder. Early intervention in diabetic clinics may prevent the development of serious eating disorders.

Adult↗