Double modulation of 5-fluorouracil with interferon alpha-2a and high-dose leucovorin in advanced neuroendocrine tumours.
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Biomedical subjects
Publications and source records attributed to P Wilson.
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The authors "examine the emerging population issues of adolescents and youth [in Sri Lanka]. The demographic pressures have resulted in the expansion of the numbers in this age category which in turn has caused problems of employment creation. The educational expansion has brought about changes in the age at marriage and life styles, which in turn has created the need for greater attention on reproductive health issues among adolescents and youth."
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.
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We have developed a capillary gas chromatography-mass spectrometry method for the quantitative analysis of individual positional isomers of monohydroxy fatty acids derived from linoleic, arachidonic, eicosapentaenoic, or docosahexaenoic acid. Peroxidation of a particular polyunsaturated fatty acid results already in a complex mixture of positional isomers of hydroperoxy and hydroxy fatty acids. Catalytic hydrogenation of lipid extracts produces stable saturated hydroxy lipids from the complex mixtures typical of oxidized biological samples, simultaneously simplifying the analytical problem and eliminating oxidation artifacts. After saponification and methylation, monohydroxy fatty acid methyl esters are purified by solid-phase extraction and partially resolved using a CP Sil 19 column following on-column derivatization of the hydroxy groups with tetramethylammonium hydroxide. The resulting methoxy fatty acid methyl esters are subjected to electron impact mass spectroscopy. Two characteristic ions are produced for each positional isomer. Quantitative measurements were achieved by using odd chain C17 and C19 monohydroxy fatty acids as internal standards. The limit of detection of individual hydroxy fatty acid isomers is dependent on the total number of ions monitored. Monitoring 11 pairs of ions simultaneously gives limits of detection of 10 ng. Sensitivity is much higher by monitoring fewer ions and as little as 0.2 ng of a single isomer can be detected. The method has been applied for the quantitative analysis of hydroxy (plus hydroperoxy) fatty acids in plasma, adipose tissue, oils, and foods. To date over 1000 samples have been analyzed using the method described in this paper.
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The kidney plays a critical role in the regulation of inorganic phosphate (Pi) homeostasis through changes in the proximal tubular apical membrane Na-dependent Pi (Na/Pi) transport activity. In response to alterations in dietary Pi intake and during the aging process, changes in renal Na/Pi transport activity are inversely correlated with apical membrane cholesterol content. Cholesterol regulates Na/Pi transport activity by fluidity-dependent and fluidity-independent mechanisms, including regulation of Na/Pi protein transcription, synthesis, and trafficking to and from the plasma membrane.
OBJECTIVES: To study the pretreatment characteristics that predispose a patient to rupture and to compare the outcome after dilatation with the outcome after surgical myotomy. DESIGN: A survey of all patients treated for achalasia at the Creighton University Medical Center, Omaha, Neb, during a 16-year period. Clinical examination and testing of consenting patients at 12 months and longer after treatment. SETTING: Tertiary referral center. PATIENTS: Of the 61 patients, 55 were treated with dilatation. Esophageal rupture developed in 8 patients (14.5%) with achalasia after pneumatic dilatation; these patients underwent surgery for the rupture. Dilatation failed in 8 other patients; these patients underwent a surgical myotomy. Six patients underwent a primary surgical myotomy. MAIN OUTCOME MEASURES: Duration of symptoms, weight loss, lower esophageal sphincter resting pressure and relaxation, amplitude and quality of distal esophageal contractions (assessed by manometry), 24-hour esophageal pH, and maximal esophageal diameter (assessed by barium swallow examination). RESULTS: Surgical myotomy at a mean (+/-SEM) of 44.9 +/- 18.6 months alleviated dysphagia in 13 (93%) of the 14 patients compared with only 12 (39%) of the 31 patients after dilatation at a mean (+/-SEM) of 55.0 +/- 11.7 months (P < .001). Of the 14 patients who underwent surgical myotomy, 13 (93%) were able to return to a normal diet compared with only 2 (7%) of the 31 patients who underwent dilatation (P < .001). Compared with patients without perforations, patients with perforations after pneumatic dilatation had pretreatment characteristics consistent with "early" disease: shorter symptom duration (20.1 +/- 5.4 vs 68.9 +/- 4.9 months, P < .001), less weight loss (4.7 +/- 1.2 vs 10.3 +/- 0.8 kg, P < .001), a less dilated esophagus (24.0 +/- 1.8 vs 45.6 +/- 3.0 mm, P < .005), lower lower esophageal sphincter resting pressures (19.3 +/- 2.6 vs 34.2 +/- 1.3 mm Hg, P < .001), a greater percentage of lower esophageal sphincter relaxation (47.6% +/- 4.9% vs 20.7% +/- 2.1%, P < .001), and a lower percentage of synchronous contractions in the distal esophageal body (66.2% +/- 4.9% vs 85.3% +/- 2.3%, P < .005). (All data given as the mean [+/-SEM].) All patients with pneumatic perforations were successfully treated by thoracotomy and surgical repair. CONCLUSIONS: Surgical myotomy provides a better long-term outcome. The early disease stage is associated with perforation after pneumatic dilatation. Surgical myotomy rather than balloon dilatation should be considered in patients with early achalasia.
Two-photon excitation microscopy shows coexisting regions of different generalized polarization (GP) in phospholipid vesicles, in red blood cells, in a renal tubular cell line, and in purified renal brushborder and basolateral membranes labeled with the fluorescent probe laurdan. The GP function measures the relative water content of the membrane. In the present study we discuss images obtained with polarized laser excitation, which selects different molecular orientations of the lipid bilayer corresponding to different spatial regions. The GP distribution in the gel-phase vesicles is relatively narrow, whereas the GP distribution in the liquid-crystalline phase vesicles (DOPC and DLPC) is broad. Analysis of images obtained with polarized excitation of the liquid-crystalline phase vesicles leads to the conclusion that coexisting regions of different GP must have dimensions smaller than the microscope resolution (approximately 200 nm radially and 600 nm axially). Vesicles of an equimolar mixture of DOPC and DPPC show coexisting rigid and fluid domains (high GP and low GP), but the rigid domains, which are preferentially excited by polarized light, have GP values lower than the pure gel-phase domains. Cholesterol strongly modifies the domain morphology. In the presence of 30 mol% cholesterol, the broad GP distribution of the DOPC/DPPC equimolar sample becomes narrower. The sample is still very heterogeneous, as demonstrated by the separations of GP disjoined regions, which are the result of photoselection of regions of different lipid orientation. In intact red blood cells, microscopic regions of different GP can be resolved, whereas in the renal cells GP domains have dimensions smaller than the microscope resolution. Preparations of renal apical brush border membranes and basolateral membranes show well-resolved GP domains, which may result from a different local orientation, or the domains may reflect a real heterogeneity of these membranes.
In a cell culture model of aging we have previously shown that there is an age-related decrease in the lipid dynamics of the proerythropoetic K562 cell membranes, as determined by the generalized polarization (GP) of the phase-sensitive lipid probe 2-dimethylamino-6-lauroylnaphthalene (Laurdan) (T. Parasassi, M. Di Stefano, G. Ravagnan, O. Sapora and E. Gratton. Exp. Cell Res., 202 (1992) 432-439). In the present study we also extended our observations to the lymphoblastoid HL60 cell line. In both K562 and HL60 cells during the four days after the last cell culture medium renewal the GP Laurdan value increased in a linear fashion indicating a time-dependent decrease in lipid dynamics. The initial membrane physical properties were almost completely restored upon renewal of the cell culture medium. We measured lipid composition, including individual and total phospholipids, free and esterified cholesterol at the first ('young') and at the fourth ('aged') day after culture medium renewal. We found that the decreased membrane lipid 'fluidity' at the fourth day of cell growth was associated with a 40% increase in cholesterol concentration in both cell lines. This increase in cholesterol concentration was reversible 24 h following the culture medium change. We conclude that in K562 and HL60 cells the 'age-related' decrease in membrane lipid dynamics is mediated by an 'age-related' increase in cell cholesterol content.
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The need for flexible and well understood knowledge representations which are capable of capturing clinical guidelines and protocols for decision support systems is widely recognised. The PROforma method for specifying clinical guidelines and protocols comprises a graphical notation for their design, and a formal knowledge representation language to enable them to be executed by a computer to support the management of medical procedures and clinical decision making. PROforma technology consists of a graphical knowledge editor for the creation of guidelines, and an enactment engine for testing and executing them. This paper provides an overview of the motivation and structure of PROforma, and illustrates its use in the development of clinical applications.
The authors compared conventional and Bactec determinations of pyrazinamide susceptibility with pyrazinamidase activity determined using either standard Dubos Oleic agar or Middlebrooks 7H9 agar. Of the 26 Mycobacterium tuberculosis tested, Bactec found 16 strains susceptible and 10 resistant, conventional methods found six susceptible and 20 resistant. Dubos identified 13 and Middlebrooks 10 strains as producing pyrazinamidase (susceptible). Of the 11 strains susceptible in Bactec and resistant by conventional methods, eight produced pyrazinamidase. All mycobacteria other than tuberculosis (6) and Mycobacterium bovis (2) were resistant by all methods. Bactec results gave a better correlation with pyrazinamidase results than conventional tests.
BACKGROUND: Cytomegalovirus (CMV) disease is a major cause of morbidity in patients with HIV infection. Despite treatment, CMV retinitis causes substantial visual loss, especially in patients with CD4 cell counts below 50 x 10(6)/l. Although routine ophthalmological screening of these patients has been recommended, no controlled trials have evaluated how frequently it should be performed. The aim of this study was to assess whether CMV polymerase chain reaction (PCR) results could direct ophthalmological screening to patients at high risk of CMV retinitis. METHODS: In a prospective study of HIV-positive patients with CD4 cell counts below 50 x 10(6)/l, CMV viraemia was detected by qualitative PCR of whole blood. Patients who were CMV PCR-viraemic were allocated to monthly virological and ophthalmological follow-up; patients who were PCR-negative received 3-monthly virological and ophthalmological follow-up. CMV viral load was determined in all CMV-positive samples using a quantitative competitive PCR. RESULTS: Nineteen out of 97 patients developed CMV disease over the first 12 months of the study. Sixteen (59%) out of 27 patients who were CMV-positive developed disease compared with three (4%) out of 70 of patients who were PCR-negative (P = 0.0001). A positive CMV PCR result was significantly associated with the development of disease (P = 0.0001), with a relative hazard of 20.15 [95% confidence interval (CI), 5.80-69.98]. Median CMV viral load was significantly higher in those individuals who went on to develop CMV disease (P = 0.02). In PCR-positive patients, each 0.25 log10 increase in viral load increased the risk of disease (relative hazard, 1.37; 95% CI, 1.15-1.63; P = 0.0004). CONCLUSIONS: CMV PCR predicts the development of CMV disease and can be used to target ophthalmological resources to those patients at highest risk of retinitis. Asymptomatic patients who are PCR-positive represent a high-risk group in whom controlled trials of pre-emptive therapy could be conducted.
In a cross-sectional study we have investigated serological and T-helper (Th) cell responses to human papillomavirus type 16 (HPV-16) L1 in women with HPV-16 related diseases and related them to cervical histology and HPV DNA status. Using a virus-like particle (VLP) based ELISA to detect antibodies to the HPV-16 L1 capsid protein, 45% (33/73) of women with cervical dysplasia, 40% (2/5) of women with cervical cancer, 36% (4/11) of healthy adult female controls and 6% (2/35) of healthy children were found to be seropositive. Amongst women with cervical dysplasia, the highest levels of seropositivity were found in those who were HPV-16 DNA positive (60%, 15/25) or positive for any of the "high-risk' HPV types, 16/18/33 (58%, 18/31), when compared with those with HPV type "X' (25%, 5/20) or with healthy children (6%, 2/35; P < 0.05 for all comparisons). There was a trend for women with cervical dysplasia to show an increased level of seropositivity with increasing grade of lesion. There was no direct correlation found between seropositivity and Th cell responses in all groups studied. However, a combined analysis of each individual's Th and B cell responses suggests that a Th1 pattern of response is predominant amongst healthy adult controls (80% of responders) but reduced in women with cervical dysplasia (55% of responders). A trend towards a decrease in Th1 type responses was also noted with increasing grade of dysplastic lesion. These findings provide further evidence for the importance of the Th response in the control of genital HPV infections.
Indications for direct visualization of the bile ducts include bile duct dilatation demonstrated by ultrasound or CT scanning, where the cause of the bile duct dilatation is uncertain or where the anatomy of bile duct obstruction needs further clarification. Another indication is right upper quadrant pain, particularly in a post-cholecystectomy patient, where choledocholithiasis is suspected. A possible new indication is pre-operative evaluation prior to laparoscopic cholecystectomy. The bile ducts are usually studied by endoscopic retrograde cholangiopancreatography (ERCP), or, less commonly, trans-hepatic cholangiography. The old technique of intravenous cholangiography has fallen into disrepute because of inconsistent bile-duct opacification. The advent of spiral CT scanning has renewed interest in intravenous cholangiography. The CT technique is very sensitive to the contrast agent in the bile ducts, and angiographic and three-dimensional reconstructions of the biliary tree can readily be obtained using the CT intravenous cholangiogram technique (CT IVC). Seven patients have been studied using this CT IVC technique, between February 1995 and June 1996, and are the subject of the present report. Eight further studies have since been performed. The results suggest that CT IVC could replace ERCP as the primary means of direct cholangiography, where pancreatic duct visualization is not required.