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J Webber

Publications and source records attributed to J Webber.

At least 19 recordsLinked to original sources
PubMed2006

Diabetic control after total pancreatectomy.

BACKGROUND: Diabetes after total pancreatectomy is commonly described as 'brittle' with most series reporting outcomes after resection for pancreatitis alone. The aim of this study was to determine glycaemic control in patients resected for benign and malignant disease. METHODS: A retrospective analysis of all patients undergoing total pancreatectomy (1989-2003) from a single institution was done. Data of diabetic control were obtained from case notes, general practitioners and telephonic consultation. Comparison was made against a matched type 1 diabetic population. RESULTS: Forty-seven patients with a median age of 59 years (range 17-85 years) and median follow-up of 50 months (range 5-136 months) were identified. Thirty-five underwent primary resection with 11 receiving completion procedures. Thirty were for malignancy (19 deceased) and 17 for benign/indeterminate histology (2 deceased). Thirty-three patients were available for detailed follow-up. There was no significant difference between median HbA(1c) of the study group and the control (8.2% versus 8.1%). The majority of patients reported diabetic control and daily performance as excellent or good. Resection for pancreatitis gave poorer subjective control (p < 0.05) than those resected for malignancy. Two patients required in-patient treatment for diabetic complications, with no deaths related to diabetes observed. CONCLUSION: Diabetes after total pancreatectomy is not necessarily associated with poor glycaemic control and in the majority results in equivalent biochemical control compared to a normal type 1 diabetic population.

Adolescent↗
PubMed2000

Photodynamic treatment of neoplastic lesions of the gastrointestinal tract. Recent advances in techniques and results.

Photodynamic therapy (PDT) is a form of cancer treatment based on the selective accumulation of a photosensitizer (by exogenous or endogenous means) in neoplastic tissue. Subsequent activation of the photosensitizer by a specific wavelength of light results in tumor cell death. Activation of a photosensitizer to the appropriate energy state results in the production of singlet oxygen, a powerful oxidizing agent. PDT can kill cells by three mechanisms: direct cell death by photooxidation, apoptosis, or as a consequence of vascular shutdown. The toxicity of PDT is site specific and dependent on the organ being irradiated and the selectivity of the photosensitizer for target tissue over normal tissue. However, there are also reactions related to the sensitizer per se that are independent of those related to the treatment site. Such reactions include cutaneous photosensitization, nausea, vomiting, hypotension, and altered liver 'function' tests. Excitation of photosensitizer by an incident photon produces reemission of a fluorescent photon, which can be used to detect a tumor that is not ordinarily evident. The major limiting factor in using PDT is the depth of tumor kill. The majority of clinical experience involving PDT of the gastrointestinal tract involves patients who are considered to be poor operative risks, and reported follow-ups after treatment are not only limited but also variable.

Cell Survival↗
PubMed2000

Signalling in body-weight homeostasis: neuroendocrine efferent signals.

Whilst a number of neuroendocrine afferent signals are implicated in body-weight homeostasis, the major efferent pathway is the sympathetic nervous system (SNS), which affects both energy expenditure and substrate utilization. Thyroid hormones and their interactions with the SNS may also have a role to play. Some of the variability in resting energy expenditure can be explained by differences in SNS activity, and beta-blockade can reduce energy expenditure and diet-induced thermogenesis in Caucasians. Excess energy intake leads to SNS activation and increased diet-induced thermogenesis. A relationship has also been demonstrated between spontaneous physical activity and SNS activity. In many animal models the SNS activates brown adipose tissue thermogenesis, hence increasing diet-induced thermogenesis and dissipating excess energy as heat. This effect is mediated via beta3-adrenoceptors and activation of an uncoupling protein unique to brown adipose tissue. Homologous proteins have been identified in human tissues and may play a role in human energy expenditure. How the SNS is implicated in this process is unclear at present. beta3-Adrenoceptor polymorphism has been associated both with lower resting energy expenditure in some populations and with reduced autonomic nervous system activity. SNS effects on substrate cycling may also play a role. In the development of obesity the effects of the SNS in promoting lipolysis and fat oxidation are likely to be at least as important as its effects on thermogenesis. beta-Blockade has relatively small effects on energy expenditure, but more pronounced effects on reducing lipid oxidation, so tending to favour fat storage and weight gain. Low lipid oxidation is a risk factor for weight gain, and there is some evidence that low basal sympathetic nerve activity in muscle is associated with this process. Overall, the relationship between SNS activity and obesity is complex, with evidence of low SNS activity occurring in some, but not all, studies.

Animals↗
PubMed1999

Aortic thrombosis associated with cocaine use: report of two cases.

Cocaine use has been associated with many vascular complications which may involve the carotid, coronary, and renal vascular beds. Cocaine may also cause venous thrombosis. This report describes a new entity of cocaine-induced aortic thrombosis. On the basis of clinical findings and response to treatment, a therapeutic algorithm is presented.

Acute Disease↗
PubMed1999

Glucose and fatty acid metabolism in type 2 diabetes mellitus: an assessment using low-dose insulin infusion and the hyperinsulinaemic euglycaemic clamp.

AIM: To assess whether resistance to the effects of insulin on lipid metabolism in type 2 diabetes mellitus parallels that demonstrated for glucose metabolism. METHODS: Thirteen patients with type 2 diabetes were studied (mean age 56.2 years, mean body mass index (b.m.i.) 28.7 kg m(-2)). The hyperinsulinaemic euglycaemic clamp (2 mU insulin kg(-1) min(-1)) and a low-dose insulin infusion technique were used in order to assess insulin effects on both glucose and lipid metabolism. RESULTS: Using the low-dose insulin infusion there were significant correlations between measures of insulin sensitivity for glucose metabolism and those for NEFA (r = 0.82, p < 0.01) and glycerol (r = 0.73, p < 0.01). Mean clamp glucose disposal was 33.4 micromol kgb.w.(-1) min(-1). There was no correlation between clamp glucose disposal and insulin sensitivity derived from the low-dose insulin infusion. CONCLUSIONS: At low insulin concentrations, insulin's effects on glucose metabolism (mainly suppression of hepatic glucose output) mirror those on inhibition of lipolysis. At the high insulin concentrations seen during the clamp, stimulation of glucose uptake provides a measure of maximal insulin action which does not parallel its physiological effects shown at lower concentrations.

Blood Glucose↗
PubMed1999

Current concepts in gastrointestinal photodynamic therapy.

OBJECTIVE: To review current concepts of photodynamic therapy (PDT) applied to the treatment of tumors of the gastrointestinal tract. SUMMARY BACKGROUND DATA: PDT initially involves the uptake or production of a photosensitive compound by tumor cells. Subsequent activation of the photoreactive compound by a specific wavelength of light results in cell death, either directly or as a result of vascular compromise and/or apoptosis. METHODS: The authors selectively review current concepts relating to photosensitization, photoactivation, time of PDT application, tissue selectivity, sites of photodynamic action, PDT effects on normal tissue, limitations of PDT, toxicity of photosensitizers, application of principles of PDT to tumor detection, and current applications of PDT to tumors of the gastrointestinal tract. RESULTS: PDT is clearly effective for small cancers, but it is not yet clear in which cases such treatment is more effective than other currently acceptable approaches. The major side effect of PDT is cutaneous photosensitization. The major limitation of PDT is depth of tumor kill. As data from current and future clinical trials become available, a clearer perspective of where PDT fits in the treatment of cancers will be gained. Many issues regarding pharmacokinetic data of photosensitizers, newer technology involved in light sources, optimal treatment regimens that take advantage of the pharmacophysiology of photoablation, and light dosimetry still require solution. One can foresee application of differing sensitizers and light sources depending on the specific clinical situation. As technologic advances occur, interstitial PDT may have significant application. CONCLUSIONS: PDT has a potentially important role either as a primary or adjuvant mode of treatment of tumors of the gastrointestinal tract.

Gastrointestinal Neoplasms↗
PubMed1998

CD4 cell counts as a prognostic factor of major abdominal surgery in patients infected with the human immunodeficiency virus.

OBJECTIVE: To measure the prognostic utility of helper T-cell (CD4) counts in human immunodeficiency virus (HIV)-infected patients undergoing major abdominal surgery. DESIGN: Retrospective case series. SETTING: Three university-affiliated hospitals. PATIENTS: Forty-three HIV-infected patients undergoing major abdominal surgery. MAIN OUTCOME MEASURES: Morbidity and mortality rates with respect to CD4 cell counts. RESULTS: Nineteen of 32 patients who had CD4 cell counts less than 0.20 X 10(9)/L (200 cells/microL) suffered major complications compared with 2 of 11 patients who had CD4 cell counts greater than 0.20 x 10(9)/L (200 cells/microL) (P=.03). Perioperative mortality was 38% for patients with CD4 cell counts less than 0.20 x 10(9)/L, and was 9% for those with CD4 cell counts greater than 0.20 x 10(9)/L (P=.13). Six months postoperatively, mortality rates were 47% and 9%, respectively (P=.03). Of patients with septic processes perioperatively (n=12), mortality was 75%, and was 19% (P=.009) for those with nonseptic processes (n=31). Nine patients had HIV-related intra-abdominal pathologic conditions at laparotomy. Mortality was 56% perioperatively (P=.13) and 88% after 6 months (P=.001). Sixty-eight percent of patients who received blood product transfusions developed complications, whereas only 7% of those who did not receive transfusions developed complications (P<.001). Overall mortality and morbidity rates were 37% and 49%, respectively. Patients with morbidity had lower CD4 cell counts (median, 0.034 x 10(9)/L) than those without complications (median, 0.102 x 10(9)/L) (P=.02). Similarly, patients who died had lower CD4 cell counts (median, 0.031 x 10(9)/L vs 0.088 x 10(9)/L) (P=.05). CONCLUSIONS: Patients with acquired immunodeficiency syndrome-defining CD4 cell counts undergoing major abdominal surgery developed more complications and had poorer outcomes at 6-month follow-up compared with HIV-infected patients whose CD4 cell counts were greater than 0.20 x 10(9)/L (200 cells/microL). A perioperative septic process and HIV-related pathologic conditions seen at laparotomy are also associated with worse outcomes.

Abdomen↗
PubMed1998

Hemodynamic effects of 5-aminolevulinic acid in humans.

Endogenous protoporphyrin IX (PpIX), which results from the oral administration of 5-aminolevulinic acid (ALA), is being investigated for its efficacy as a photosensitizing agent for photodynamic therapy (PDT). Clinical use of ALA has been associated with only mild gastrointestinal side effects. The hemodynamic effects of orally administered ALA in doses used for PDT are unknown. Six patients with a significant history of cardiac disease underwent Swan-Ganz catheterization prior to ALA administration and abdominal operation for PDT. Hemodynamic data collection began at least 1 h prior to ALA, and continued for at least 4 h subsequently, during which time no other medications were administered. When compared to measurements made prior to ALA administration, all patients displayed a significant decrease in systolic and diastolic blood pressures, pulmonary artery systolic and diastolic pressures as well as pulmonary vascular resistance. Five of the six patients also developed a decrease in systemic vascular resistance. No significant changes in pulmonary capillary wedge pressure, cardiac output or cardiac index was observed, but the mean pulse rate rose significantly. These findings cannot be explained on the basis of other cardiovascular depressants or to poor central volume status. Although no adverse sequela were appreciated as a result of the observed hemodynamic changes, this potential should be recognized in patients undergoing PDT using ALA.

Aminolevulinic Acid↗
PubMed1998

Abnormalities in glucose metabolism and their relevance to nutrition support in the critically ill.

This review covers the recent advances that have been made in understanding the abnormalities of glucose metabolism found in critically ill patients. The alterations in the pathways of glucose production and utilization and the hormones and cytokines responsible for these are described. Therapies that have the potential to alter abnormal glucose metabolism and improve nutritional status are discussed.

Animals↗
PubMed1997

Side effects and photosensitization of human tissues after aminolevulinic acid.

Aminolevulinic acid (ALA) is being used as a "prodrug" for photodynamic therapy. The side effects of ALA have been only anecdotally reported and these effects as well as pharmacokinetics of the photosensitizing end product of ALA, protoporphyrin IX (PpIX), in patients undergoing operation are unknown. This study systematically determines the side effects of ALA and pharmacokinetics of PpIX in patients undergoing abdominal surgery. Patients were given 30 or 60 mg/kg ALA preoperatively, kept in subdued light for 48 hr, and monitored clinically and with laboratory tests for 5 to 7 days and for at least 2 months thereafter. Periodic plasma samples and tissue biopsies were analyzed for PpIX concentrations using a photodiode array system. No patient developed symptoms of porphyria other than nausea and vomiting, which occurred in 20%. Nearly one-quarter of patients developed transient abnormal liver functions. No patient developed cutaneous phototoxicity, abnormal neurologic function, or unexpected postoperative laboratory tests. The times of peak plasma, skin, skeletal muscle, omental, mucosal, muscularis mucosal, and tumor concentrations of PpIX varied among patients. In general, PpIX concentrations were significantly greater with the higher dose of ALA. Tumor PpIX concentrations were significantly greater than in other tissues except liver. In conclusion, ALA, up to 60 mg/kg, is associated with minimal side effects in patients undergoing operation. Actual tissue concentrations of PpIX suggest that endogenous photosensitization using systemically administered ALA is a mode of PDT feasible for treatment of adenocarcinomas of the gastrointestinal tract in humans.

Adenocarcinoma↗
PubMed1997

Homology modeling with internal coordinate mechanics: deformation zone mapping and improvements of models via conformational search.

Five models by homology containing insertions and deletions and ranging from 33% to 48% sequence identity to the known homologue, and one high sequence identity (85%) model were built for the CASP2 meeting. For all five low identity targets: (i) our starting models were improved by the Internal Coordinate Mechanics (ICM) energy optimization, (ii) the refined models were consistently better than those built with the automatic SWISS-MODEL program, and (iii) the refined models differed by less than 2% from the best model submitted, as judged by the residue contact area difference (CAD) measure [Abagyan, R.A., Totrov, M.J. Mol. Biol. 268:678-685, 1997]. The CAD measure is proposed for ranking models built by homology instead of global root-mean-square deviation, which is frequently dominated by insignificant yet large contributions from incorrectly predicted fragments or side chains. We demonstrate that the precise identification of regions of local backbone deviation is an independent and crucial step in the homology modeling procedure after alignment, since aligned fragments can strongly deviate from the template at various distances from the alignment gap or even in the ungapped parts of the alignment. We show that a local alignment score can be used as an indicator of such local deviation. While four short loops of the meeting targets were predicted by database search, the best loop 1 target T0028, for which the correct database fragment was not found, was predicted by Internal Coordinate Mechanics global energy optimization at 1.2 A accuracy. A classification scheme for errors in homology modeling is proposed.

Models, Molecular↗
PubMed1997

Plasma levels of protoporphyrin IX in humans after oral administration of 5-aminolevulinic acid.

We report on the pharmacokinetics of PP formation and elimination in 4 patients after the administration of oral ALA (60 mg kg-1). After a brief distribution phase, plasma PP levels decline (half life = 8 h) and was almost undetectable by 48 h post-administration. This confirms pharmacokinetic clinical data which show that ALA in a shortened interval of skin photosensitization compared with other sensitizers such as Photofrin and 'HPD'. A brief summary of other clinical-toxicity findings is reported.

Administration, Oral↗
PubMed1997

On-line fluorescence of human tissues after oral administration of 5-aminolevulinic acid.

It is important to have a frame of reference for the timing of photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) so that PDT can occur when the tissue levels of protoporphyrin IX (PP) are at a maximum. This study describes a non-invasive fluorescence technique for detecting tissue PP levels after systemic ALA administration in patients with gastrointestinal cancer. The data suggest that the intensity of tumor surface fluorescence correlates with the tumor PP concentration. Spectrophotofluorometric measurements of skin and buccal mucosa also offer an easily acquired and rapid means for determining changes in plasma concentrations of PP. A number of potential variables, including blood flow, affect the intensity of fluorescence. We report that fluorescence measurements in situ are best adapted to the measurement of changes in the porphyrin levels in tissues rather than the absolute concentrations.

Administration, Oral↗
PubMed1997

Effects of fractionated 5-aminolevulinic acid administration on tissue levels of protoporphyrin in vivo.

The photodynamic therapy (PDT) of malignant tissues can be achieved via the administration of 5-aminolevulinic acid (ALA), which is naturally converted to the photoreactive substance protoporphyrin IX (PP). This study compares bolus with fractionated ALA dosing in order to determine whether one of these methods results in a higher tissue concentration of PP. Mice bearing a subcutaneously implanted colon-26 tumor were treated with ALA (200 mg kg-1), given intravenously either as a single bolus or as three equally divided doses at 50 min intervals. Tissue samples of tumor, kidney, skin, liver, skeletal muscle, colon and plasma were obtained 2, 3, 4 and 6 h later for the analysis of PP concentrations. Fractionated dosing results in significantly higher concentrations of PP at 4 and 6 h for kidney, 3 and 6 h for skin, 3 h for colon and 6 h for liver. In contrast, fractionated dosing has no significant effect on the PP concentrations of muscle and plasma. Fractionated dosing results in a significantly greater PP concentration in the tumor at 3 h relative to that observed for the bolus dose. However, from a consideration of the time of PP measurement, it is concluded that fractionated dosing may not cause a significant increase in the PP concentration in colon-26 tumors relative to that observed for the bolus dose.

Aminolevulinic Acid↗
PubMed1996

Feasibility of photodynamic therapy using endogenous photosensitization for colon cancer.

A novel approach to photodynamic therapy (PDT) involves endogenous photosensitization by the oral administration of delta-aminolevulinic acid (ALA), a naturally occurring substance that is the precursor of protoporphyrin IX (PpIX). A 60-year-old man with adenocarcinoma of the sigmoid colon received ALA, 60 mg/kg by mouth. Six hours later, when the plasma level of PpIX had peaked, the tumor was exposed locally to red light at 633 nm to activate PpIX. Endoscopy and biopsy findings subsequent to this treatment showed unequivocal visible changes and necrosis. Six months later, the patient again underwent successful treatment without adverse effects. This report suggests a role for PDT using endogenous photosensitization in certain circumstances involving adenocarcinoma of the large intestine.

Adenocarcinoma↗