bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy of chemoradiation therapy in HIV seropositive patients with squamous cell carcinoma of the anus
Authors: Efron J. E. , Pikarsky A. J. , Gervaz P. , Locker G. , Weiss E. G. , Wexner S. D. , Nogueras J. J.
Published: March 2003

Objective

The aim was to assess the efficacy of chemoradiation therapy for squamous cell carcinoma of the anal canal in HIV seropositive patients.

Patients and methods

A retrospective review of all patients with squamous cell carcinoma of the anus treated primarily with combined chemotherapy (5‐fluorouracil and mitomycin) and radiotherapy or local excision was undertaken comparing HIV seropositive to HIV seronegative patients.

Results

Thirteen HIV seronegative patients were compared with 6 HIV seropositive patients. The HIV positive group included a higher proportion of males and a significantly greater history of prior treatment for condyloma. There was no difference in the median radiation dose (5020 cGy vs 4500 cGy, P=0.10). There was a trend towards higher local tumour recurrence in the HIV seropositive patients although this was not statistically significant (30% vs 66%). The CD4 count of HIV positive patients did not correlate either with their ability to complete the prescribed treatment regimen or with subsequent recurrence.

Conclusion

Combined chemoradiation is feasible in HIV positive patients, however, local recurrence rates in HIV positive patients may be higher. Tolerance of this therapy in HIV seropositive patients or recurrence after therapy are not related to the patient’s CD4 cell count.
A prospective audit of fistula‐in‐ano at St. Mark’s hospital
Authors: Malouf A. J. , Buchanan G. N. , Carapeti E. A. , Rao S. , Guy R. J , Westcott E. , Thomson J. P. S. , Cohen C. R. G.
Published: March 2003

Objective

To conduct a prospective audit of all patients presenting with anal fistula at St. Mark’s Hospital during one calendar year and to compare the presentation and outcome of this cohort with previous reports from this institution.

Patients and methods

All patients undergoing examination under anaesthetic (EUA) for anal fistula during 1997 were studied. All fistulae were anatomically classified and operative procedures recorded. During a mean follow‐up period of 14 months details of healing, recurrence and function were gathered.

Results

98 patients with a mean age of 43.7 years were assessed. 86 (88%) patients had fistulae of cryptoglandular (idiopathic) origin. Fistulae were superficial in 11 (11%) patients, intersphincteric in 30 (31%) patients, trans‐sphincteric in 52 (53%) patients, suprasphincteric in 3 (3%) patients and extra‐sphincteric in 2 (2%) patients. 49 (50%) fistulae were classified as complex. Eradication of fistulae with preservation of function was achieved in 89 (91%) patients. Fistula recurrence occurred in 4 (4%) cases. Ten (10%) patients had some degree of incontinence, 9 (9%) of whom had undergone previous fistula surgery. Nine (9%) patients still had setons in situ at the end of the follow‐up period.

Conclusions

A greater proportion of difficult fistulae was seen during the year compared with previous studies from St. Mark’s. Despite this a satisfactory outcome was achieved in the vast majority with a relatively low rate of disturbed function. Previous fistula surgery is a risk factor for incontinence, which can usually be managed conservatively.
Colorectal cancer in patients with chronic renal failure: the effect of dialysis or renal transplantation
Authors: Ho Hanh‐Tam , Russ G. , Stephens J. , Rieger N.
Published: March 2003

Objective

This study reports the characteristics and surgical outcome of colorectal cancer in patients with chronic renal failure treated either by renal transplantation or dialysis.

Methods

Two thousand four hundred and seventeen patients with CRF (1387 transplant and 1030 dialysis) were treated at The Queen Elizabeth Hospital, South Australia, between January 1967 and September 2000.

Results

Fourteen have developed colorectal cancer and had their clinical records reviewed. Nine patients were renal transplant recipients and 5 patients were treated with dialysis. Eight patients had surgery. Chemotherapy was given palliatively to 3 patients. One patient died in hospital postoperatively. Seven patients with a renal transplant had notes available. Six presented with late stage disease and all were dead within 9 months of presentation from their disease. In the dialysis patients, tumour stage at presentation was not so advanced and although all the patients have died, the cause of death was secondary to the colorectal cancer in only 2 patients.

Conclusions

This study highlights the poor outcome of patients who have had renal transplant and develop colorectal cancer. Immunosuppression and late diagnosis are implicated in this poor outcome.
Topical 0.2% glyceryl trinitrate ointment for anal fissures: long‐term efficacy in routine clinical practice
Authors: Jonas M. , Lund J. N. , Scholefield J. H.
Published: March 2003

Objective  Randomized controlled trials have reported fissure healing rates of 60–70% using topical 0.2% GTN ointment, but the effectiveness of this therapy in routine clinical practice, particularly in the long term, is uncertain. This study aimed to evaluate the efficacy of topical GTN for anal fissures in an outpatient setting.

Patients and methods  A case note review and postal questionnaire survey were undertaken for patients with a diagnosis of anal fissure dispensed 0.2% GTN ointment from one hospital pharmacy over a two year period (June 1996–May 1998).

Results  Ninety‐three patients (53 male) applied 0.2% GTN ointment twice daily to the anoderm for anal fissure. They were reviewed on average 8 (2–16), weeks later, by which time 57 (61%) fissures had healed, 33 persisted and 3 patients were lost to follow up. Seventy‐two patients (41male), median age 42 (22–83) years, returned completed questionnaires (77% response rate). Forty‐nine (68%) had healed with GTN, but 25 had recurrent symptoms after a median of 6 (1–18) months. Sixteen of those patients reporting symptomatic recurrence were prescribed further GTN for a recurrent fissure: 14 (88%) healed, but 2 persisted, and had surgery. In the other nine patients symptoms resolved spontaneously. Thirty‐five (49%) experienced headaches, 3 (4%) discontinuing treatment as a result. The median follow up was 25 (13–36) months.

Conclusion  0.2% GTN heals 60% of fissures in the outpatient setting but half the patients develop headaches. Up to one third of healed fissures may recur within 18 months but the majority respond to further GTN. Only 4% of patients initially healed with GTN later require sphincterotomy for recurrences.
Does perifascial rectal excision (i.e. TME) when combined with the autonomic nerve‐sparing technique interfere with operative radicality?
Authors: Maeda K. , Maruta M. , Utsumi T. , Hosoda Y. , Horibe Y.
Published: March 2003

Objective  The lymphatic drainage from the rectum was studied to evaluate if the autonomic nerve sparing dissection may interfere with the operative radicality and might result in metastatic lymph nodes being overlooked and left in situ.

Patients and methods  50 consecutive patients had an extended extrafascial rectal excision resection for cancer. In 19 of the 50 patients activated carbon particles (CH40) were injected preoperatively into the rectum. The autonomic nerves with surrounding connective tissue were serially dissected from the resected specimen, carefully sliced at 5‐mm intervals and collected for histological study. Lymph nodes along the axial and lateral drainage routes were examined, and the inclusion of CH40 in the nodes was microscopically studied according to the site of CH40 injection.

Results  Lymph nodes within the connective tissue along the dissected autonomic nerves were demonstrated in 47 of the 50 cases. Two of 50 cases had positive nodes along preaortic plexus or pelvic plexus, and a case with nodal involvement along the pelvic plexus had poor prognosis in spite of nerve excision. CH40 when injected into the rectum above the peritoneal reflection was demonstrated in the vast majority of the axial nodes, while in only one lymph node along the preaortic plexus when injected in the rectum above the peritoneal reflection. On the other hand when injected in the rectum below the peritoneal reflection, CH40 was demonstrated both in axial and lateral nodes as well as in lymph nodes along bilateral pelvic plexuses, right hypogastric nerve, superior hypogastric plexus, preaortic plexus and mesenteric plexus as well.

Conclusions  When located above the peritoneal reflection a rectal carcinoma will spread preferentially along the upper axial route, while a carcinoma located below the peritoneal reflection will also spread laterally and along the autonomic nerves. It was inferred that lymphatic flow along the autonomic nerves came up from the rectum below the peritoneal reflection mainly through a so‐called lateral ligament but its clinical significance was negligible. Therefore doing TME with autonomic nerve preservation does not imply a less radical surgery from the point of lymphatic spread.
Demonstrating the clinical and cost effectiveness of adhesion reduction strategies
Authors: Wilson M. S. , Menzies D. , Knight A. D. , Crowe A. M.
Published: March 2003

Objective  To examine the feasibility of conducting Randomized Controlled Trials (RCT) in lower abdominal surgery to demonstrate a reduction in adhesion‐related admissions following use of an adhesion reduction product, and to model the cost effectiveness of such products.

Methods  The number of patients in each limb of a RCT comparing an adhesion reduction product to a control has been estimated based on 25% and 50% reductions in adhesion‐related readmissions one year after surgery, for P = 0.05 at a power of 80% and P = 0.01 at a power of 90%. A cost effectiveness model based on the Surgical and Clinical Adhesions Research Group (SCAR) database has been developed which calculates the percentage reduction in readmissions required of an adhesion reduction product to return the cost of investment. It also estimates the cumulative costs of adhesion‐related readmissions for lower abdominal surgery and the cost savings associated with an adhesion reduction policy using a low or high cost product.

Results  7.2% of patients undergoing lower abdominal surgery will readmit due to adhesions in the first year after surgery. To demonstrate a 25% reduction in readmissions one year after surgery, it is calculated that a RCT would require between 5686 (P = 0.05, power = 80%) and 7766 (P = 0.01, power = 90%) lower abdominal surgery patients followed‐up for one year. A cost effectiveness analysis demonstrates that routine use of adhesion reduction products costing £50 per patient will payback the cost of such investment if they reduce adhesion‐related readmissions by 16% after 3 years. A product costing £200 will need to offer a 64.1% reduction in readmissions after 3 years. For the estimated 158 000 lower abdominal surgery operations conducted in the UK each year, the cumulative costs of adhesion‐related readmissions over 10 years are estimated at £569 Million.

Conclusion  Demonstrating the clinical effectiveness of adhesion reduction products in the RCT setting is unlikely to be feasible due to the large number of patients required. Products costing £200 or more are unlikely to payback their direct costs.
The role of topical diltiazem in the treatment of chronic anal fissures that have failed glyceryl trinitrate therapy
Authors: Griffin N. , Acheson A. G. , Jonas M. , Scholefield J. H.
Published: March 2003

Objective  The treatment of anal fissures has evolved over the last 5 years with the development of topical treatments aimed at reducing sphincter hypertonia. This is thought to improve anal mucosal blood flow and promote healing of the fissure. This study reports the use of topical diltiazem in patients with chronic anal fissures that have failed previous treatment with topical 0.2% glyceryl trinitrate (GTN).

Patients and methods  Forty‐seven patients with chronic anal fissure who had previously failed at least one course of topical GTN were recruited prospectively from a single centre. Patients were instructed to apply 2 cm (approximately 0.7 g) of 2% diltiazem cream to the anal verge twice daily for eight weeks. Symptoms of pain, bleeding and itching were recorded on a linear analogue score prior to starting the cream and then repeated at 2 weekly intervals. Patients were asked to report side‐effects throughout the study period. Healing of the fissure was assessed after 8 weeks of treatment.

Results  Forty‐six patients completed treatment; of these, 22 had healed fissures (48%). Ten of the 24 patients with persistent fissures were symptomatically improved and wished no further treatment. Of the 14 patients who remained symptomatic, one was given a repeat course of 0.2% glyceryl trinitrate with subsequent healing of the fissure, 10 were recruited into an ongoing study involving injections of botulinum toxin into the internal anal sphincter and three were referred for surgery.

Conclusion  This study shows that topical 2% diltiazem is an effective and safe treatment for chronic anal fissure in patients who have failed topical 0.2% GTN. The need for sphincterotomy can be avoided in up to 70% of cases.
Variability in serotonin and enterochromaffin cells in patients with colonic inertia and idiopathic diarrhoea as compared to normal controls
Authors: Baig M. K. , Zhao R. H. , Woodhouse S. L. , Abramson S. , Weiss J. J. Singh, E. G. , Nogueras J. J. , Wexner S. D.
Published: March 2003

Aim To evaluate differences in distribution, density and staining intensity of enterochromaffin cells (EC) and serotonin cells (SC) in the colonic mucosa of patients with colonic inertia (CI), idiopathic diarrhoea (ID) and a control group.

Methods Three groups were studied: 19 patients' colons after subtotal colectomy for CI, and 17 patients' biopsies for diarrhoea (>3 bowel movements/day) with histological findings of normal mucosa (excluding microscopic, eosinophillic and collagenous colitis). The third group included 15 patients who underwent colonoscopy and biopsy for indications other than constipation, inflammatory bowel disease, diarrhoea or neoplasm (control group). Specimen blocks were obtained in each case from the right and left colon. Immunohistochemical staining for EC and SC were done on 4 µm sections from Hollandes fixed, paraffin embedded tissues with primary rabbit antibody against chromagranin A or serotonin, and biotynylated secondary antibody and enzyme labelled streptavidin.

Results The number of EC in the mucosa of the left colon in patients with CI (16.8 ± 10.2) and ID (19.9 ± 9.7) were significantly higher than they were on the right side (CI: 9.4 ± 6.0, ID: 12.1 ± 5.3). However, there were no significant differences between the left and right sides in the control group (L: 10.3 ± 5.3; R: 13.4 ± 7.6). Although the quantity of EC in the left colon in both patients with CI (P < 0.05) and ID (P < 0.01) were significantly higher than in the controls, there was no significant difference between CI and ID. In both the right and left colon, the percentage of EC with low positive density was significantly higher (P < 0.01) while those cells with moderate or low staining intensity were significantly lower in patients with CI than in either patients with ID or control group. In patients with CI, the quantity of SC in the mucosa of the left colon (12.1 ± 6.4) was higher than in the right (CI: 7.9 ± 3.6; control 4.6 ± 3.3; ID 4.6 ± 2.9) (P = 0.0057). In contrast there was no significant difference in SC in either the ID or control groups. The quantity of SC in both sides of the colon was significantly higher both in patients with CI as compared to the control group (P < 0.01) and patients with CI vs. patients with ID (L = P < 0.01; R = P < 0.05). There was a significantly positive correlation between the numbers of EC and SC in patients with CI (L: r = 0.5425, P < 0.05; R: r = 0.745, P < 0.01).

Conclusion In patients with CI, EC increases possibly due to an increase in SC. Conversely, in patients with ID, the EC increase results from peptides other than SC. Our results suggest that different aetiological factors contribute to ID and CI.
Creation of a treatment protocol for nurse‐led management of anal fissure
Authors: Porrett T. , Knowles C. H. , Lunniss P. J.
Published: March 2003

Objective  To create a protocol for colorectal nurse‐led management of patients with idiopathic anal fissure.

Patients and methods  The outcome of 135 patients with anal fissure presenting over a 3‐year period to one (half time equivalent) Colorectal Surgeon in a District General Hospital, in whom initial management was centred on the use of 0.2% glyceryl trinitrate (GTN) was audited. Patients unavailable for complete follow‐up, those with fissures of a specific aetiology and those in whom GTN was contra‐indicated were excluded. 44% of patients were initially seen by a suitably trained and supported Nurse Practitioner (NP).

Results  Succes rates for fissure healing with 0.2% GTN were similar to those reported in other studies. There were no differences in outcome between those patients managed by the NP and those managed by the Consultant/Specialist Registrar. As a result of the audit, a treatment protocol for use by Nurse Practitioners (as well as surgical staff), a patient information leaflet, and policy documents relating to NP management of anal fissures have been developed.

Conclusion  It has been possible to construct a treatment protocol allowing rational management of patients with anal fissure by suitably trained and supported nurse specialists within their own clinic. This may be adapted to encompass future treatment developments.
Management of colorectal liver metastases
Authors: Fusai G. , Davidson B. R.
Published: March 2003

Hepatic metastases occur in 60% of patients following resection for colorectal cancer. Liver resection is the only curative option, with one third of resected patients alive at five years. In those developing recurrence in the liver following resection, further liver surgery may be curative, with similar 5 years survival rates of about 30%. Until recently surgery was feasible in only 15–25% of patients with colorectal liver metastases. New strategies, such as downstaging chemotherapy, portal vein embolization and two‐stage hepatectomy, may increase the resectability rate by 15%.

Earlier detection of liver metastases would increase resectability, although good follow‐up trials are lacking. Once suspected, colorectal liver metastases are staged by spiral CT, CT portography and MRI, which have similar overall accuracies.

Mortality following liver resection is less than 5% in major centres, with a morbidity rate of 20% to 50%. Prognostic scoring systems can be used to predict the likely cure rate with resection.

Pulmonary metastases occur in 10–25% of patients with resected colorectal cancer, but are limited to the lung in only 2% of cases. In these selected cases surgery provides long‐term survival in 20–40%, and repeat lung resection has shown similar rates.

For patients with unresectable disease, chemotherapy and ablation techniques have been demonstrated to prolong survival, although chemotherapy alone has been shown to improve quality of life.
Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve‐week, randomized, placebo‐controlled study
Authors: Patel J. , Anderson R. J. , Rappaport E. B.
Published: March 2003

Aim: Rosiglitazone is the most potent of the thiazolidinediones, a novel class of oral antidiabetic agents that reduce blood glucose levels by sensitizing peripheral tissues to insulin. This study was designed to identify doses of rosiglitazone that would lower fasting plasma glucose (FPG) in patients with type 2 diabetes.

Methods: In this 12‐week, double‐blind, multicentre study, 380 patients with FPG values ≥7.8 mmol/L (140 mg/dL) and ≤13.3 mmol/L (240 mg/dL) were randomly assigned to receive treatment with placebo or rosiglitazone, 0.05, 0.25, 1.0, or 2.0 mg twice daily. The primary efficacy parameter was changed in FPG from baseline after 12 weeks of treatment. Secondary endpoints were changes in HbA1c, fructosamine, C peptide, insulin, lipid levels, and body weight (b.w.). Safety monitoring included clinical laboratory evaluations, electrocardiography, and echocardiography.

Results: Rosiglitazone 1.0 and 2.0 mg b.i.d. produced significant decreases in FPG (p=0.0001). Fructosamine also decreased in patients treated with these two dosages (p=0.003 in the 2.0 mg b.i.d. group). Rosiglitazone 2.0 mg b.i.d. significantly reduced plasma insulin levels (p=0.0044) and free fatty acids (p=0.0014) compared with placebo. Total cholesterol (p=0.0001), HDL (p=0.0009), and LDL (p=0.0001) increased in the rosiglitazone 2.0 mg b.i.d. group, but there was no significant change in the total cholesterol/HDL ratio or triglyceride levels in any rosiglitazone treatment group. Clinically insignificant dose‐dependent increases in b.w. were observed in the rosiglitazone 1.0 and 2.0 mg b.i.d. treatment groups.

Conclusions: Twelve weeks of treatment with rosiglitazone 2.0 mg b.i.d. significantly decreases fasting plasma glucose, fructosamine, plasma insulin, and free fatty acids in patients with type 2 diabetes. Longer studies using higher doses will be needed to assess the efficacy and safety of rosiglitazone in patients with type 2 diabetes mellitus.
Effect of food deprivation on rat plasma estrone fatty acid esters
Authors: Vilà R. , Adán C. , Grasa M. M. , Masanés R. M. , Esteve M. , Cabot C. , Fernández‐López J. A. , Remesar X. , Alemany M.
Published: March 2003

The present study was devised to determine whether the circulating levels of estrone fatty esters are modified by 6–48 h starvation in the rat, in parallel to changes in fat reserves, as a test to check the plausibility of its function as a ponderostat signal in the mammal. Food deprivation resulted in a decrease in glucose and triacylglycerols, rapid disappearance of liver glycogen and increases in fatty acids and, especially, 3‐hydroxybutyrate. Insulin and leptin decreased, corticosterone and free estrone increased from 6 h onwards and total estrone levels were maintained. Starvation reduced the lipid content of the rat by 25.6%. Plasma esterified estrone levels decreased more slowly, by 13% in 48 h, but its circulating mass decreased in the same proportion as the total lipid content of the rat. The small change in circulating estrone fatty esters is consistent with the postulated role of oleoyl‐estrone as a medium‐term ponderostat signal.
Effects of current therapeutic interventions on insulin resistance
Authors: Kobayashi M.
Published: March 2003

Summary.Although diet and exercise remain the cornerstones of type 2 diabetes therapy, attempts at lifestyle changes seldom result in the achievement of glycaemic control. As a result, the addition of pharmacological agents is usually necessary. Currently available treatment options improve glycaemic control in the short term; however, maintaining long‐term glycaemic control, halting disease progression, and preventing the complications of type 2 diabetes have all proven to be elusive therapeutic goals.

For more than 30 years, sulphonylureas (SUs) have been first‐line therapy for the management of type 2 diabetes. These compounds control hyperglycaemia by stimulating insulin release from pancreatic β cells, and thus their benefits are limited to patients with preserved β‐cell function. Despite historic reliance on these agents to treat type 2 diabetes, long‐term use of SUs may desensitize β cells. The meglitinides (e.g. repaglinide) are a new class of non‐sulphonylurea secretagogues that bind to a different receptor on the β cell. Repaglinide has a short duration of action and may be useful for the treatment of postprandial hyperglycaemia. The biguanides (e.g. metformin) represent another class of antidiabetic agents and improve glycaemic control primarily by decreasing hepatic glucose output. Metformin and SUs provide similar glucose‐lowering effects, and, in combination, may provide additional benefits in some patients. Reducing the rate of glucose absorption with α‐glucosidase inhibitors (e.g. acarbose) has been explored as an alternative approach to the management of postprandial hyperglycaemia, but these agents do not address the primary defect in type 2 diabetes. Eventually, prolonged overproduction of insulin to compensate for hyperglycaemia leads to dramatically reduced β‐cell function, and exogenous insulin therapy is required.
Risk factors for vascular disease in patients with diabetes
Authors: Brown W. Virgil
Published: March 2003

The risks of cardiovascular and cerebrovascular disease in patients with diabetes are greater than those in persons without diabetes. This is due, in part, to the metabolic effects of insulin resistance. Other contributing factors include hyperglycaemia, dyslipidaemia, hypertension, hypercoagulability, homocysteinaemia, smoking, and obesity. Risk factor modification, where possible, can reduce the risk of complications of diabetes and macrovascular disease.
Differences in pharmacotherapy and in glucose control of type 2 diabetes patients in two neighbouring towns: a longitudinal population‐based study
Authors: Olsson J. , Lindberg G. , Gottsäter M. , Lindwall K. , Sjöstrand Å. , Tisell A. , Melander A.
Published: March 2003

SUMMARY

Aim  To compare prescribing, dosage and blood glucose levels in patients with type 2 diabetes in two communities with differences in anti‐hyperglycaemic drug utilization.

Methods  A retrospective longitudinal (1984–1994) population‐based study in two neighbour towns in southern Sweden. The mean prescribed daily dose was expressed as a fraction of the Defined Daily Dose (DDD) for each drug.

Results  In town A, prescribing of oral agents and insulin was predominantly made by one specialized diabetes clinician, while in town B it was spread among several different general practitioners and one specialist. Altogether 44 636 medical visits by 2348 patients were identified. In each town, about 40% of the patients were treated without anti‐hyperglycaemic drugs, about 40% with oral agents and about 20% with insulin. However, there were pronounced between‐town differences in dosage and glucose control. The mean prescribed daily dose of sulphonylurea monotherapy decreased gradually from ≈ 0.7 to ≈ 0.5 DDD in town B but remained ≈ 0.8 DDD in town A. The proportion of patients on both sulphonylurea and metformin increased substantially in town A but not in town B. In these patients, the mean prescribed daily dose of sulphonylurea exceeded 1.0 DDD in both towns, although it decreased with time in town B. The mean prescribed daily dose of insulin increased from 1.05 to 1.2 DDD in town A but remained virtually unchanged at 0.95 DDD in town B. The mean fasting blood glucose was lower in town A than in town B both overall (7.7 vs. 8.8 mmol/l), in those treated without any anti‐hyperglycaemic drugs (7.2 vs. 8.1 mmol/l), in those on sulphonylurea monotherapy (8.3 vs. 9.7 mmol/l) and in those treated with insulin (8.1 vs. 10.2 mmol/l).

Conclusions  Glucose control in routine care was better when most patients were treated by a diabetes specialist and were exposed to more intense pharmacotherapy.
β3‐Adrenergic receptor gene polymorphism and type 2 diabetes in a Caucasian population
Authors: Oeveren van‐Dybicz A. M , Vonkeman H. E , Bon M. A. M , Van Den Bergh F. A. J. T. M , Vermes I
Published: March 2003

Summary

Aim

The β3‐adrenergic receptor (β3‐AR) is suspected to play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. A mutation in the β3‐AR gene (Trp64Arg) has been associated with the capacity of weight gain and with early onset of noninsulin dependent diabetes mellitus (type 2 diabetes). In this study we investigated the prevalence of the two β3‐AR alleles in a Caucasian population and studied the association between the β3‐AR genotype and metabolic disorders (obesity and type 2 diabetes).

Methods

Genomic DNA extracted from peripheral blood leucocytes of 200 Caucasian subjects (137 subjects with and 63 subjects without type 2 diabetes). The MvaI polymorphism of β3‐AR, which detects the Trp64Arg mutation, was determined by polymerase chain reaction (PCR). We studied the correlation between the Trp64Arg mutation and the body mass index (b.m.i. kg/m2).

Results

There was no significant difference between the patients with type 2 diabetes and control subjects in the frequency of the Arg64 allele (5.5% and 4.8%, respectively). Within the group of type 2 diabetes patients were 14 subjects with the Trp64Arg mutation (b.m.i., mean ± s.d.: 31 ± 8.5 kg/m2) and 123 without the mutation (b.m.i. 29 ± 4.8). There was no association between the β3‐AR gene polymorphism and sex, obesity, blood pressure, glycohaemoglobin concentration, proteinuria.

Conclusion

Our results suggest that the Trp64Arg mutation is not a major determinant of metabolic disorders (type 2 diabetes, obesity) and chronic complications of type 2 diabetes in a Dutch population.
Anomalous lipoproteins in obese Zucker rats
Authors: Blay M. , Peinado‐Onsurbe J. , Julve J. , Rodríguez V. , Fernández‐López J. A. , Remesar X. , Alemany M.
Published: March 2003

Aims  Obesity is characterized by dislipoproteinaemia with increased cholesterol and triacylglycerol levels and lower chylomicra disposal rates. We studied here whether these alterations were related to lipoprotein number and/or size and composition.

Methods  Plasma from lean and obese Zucker rats was fractionated into lipoprotein classes (chylomicra, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL)) by differential centrifugation. The apoprotein and lipid composition of each fraction were measured. Lipoprotein particle size was estimated by dynamic light scattering and used to tabulate the mean diameter and volume of lipoprotein micelles. Particle mass was calculated from the density and volume. The mass of lipids and protein in each fraction/ml of plasma allowed the estimation of mean particle concentration and then the number of molecules of lipid and protein/unit of lipoprotein micelle.

Results  A large part of hyperlipidaemia of obese rats is due to the accumulation of chylomicra: 1.3 ± 0.2 mg/ml in lean rats [LR] (34% of all lipoproteins) and 8.2 ± 0.9 mg/ml in the obese rats [OR] (66% of all lipoproteins). Lipid percentage composition of lipoproteins was similar in both groups. The particle size of LDL and HDL was much higher in OR than in LR: LDLs weighed 31.1 ± 7.5 ag (LR) vs. 273 ± 81 ag (OR), and HDLs weighed 31.7 ± 12.6 ag (LR) and 375 ± 103 ag (OR). In chylomicra and VLDL there was a relative scarcity of apoproteins in OR compared with LR. The whole architecture of LDLs is altered in OR, with a predominance of surface lipids: phospholipid and free cholesterol, and lower amounts of core lipids: triacylglycerols and cholesterol esters, with surface/core lipids ratios of 0.74 (LR) and 1.89 (OR). The consequences of anomalous LDL and HDL composition, size and overall structure may result in magnified lipoprotein metabolism alterations that hamper their ability to transfer apolipoproteins to larger chylomicra and VLDL, and to alter cholesterol transfer and binding of their apoproteins to cell surface receptors. The smaller number of LDL and HDL particles may further compound these difficulties and thus change the free to esterified cholesterol ratios observed in OR.

Conclusions  The main conclusions of this study are the key importance of chylomicron analysis for a better understanding of the transfer of lipids, and the altered lipoprotein size and apoprotein distribution in obese rats, which seriously hamper cholesterol interchange, resulting in hypercholesterolaemia, and thus triggering even more far‐reaching consequences for the well‐being of the obese.
Do baseline serum leptin levels predict weight regain after dieting in obese women?
Authors: Mavri A. , Stegnar M. , Sabovic M.
Published: March 2003

SUMMARY

Aim  Weight loss achieved during weight reduction programme is difficult to maintain. We investigated the possible role of circulating leptin in failure or success in maintaining weight loss.

Methods  Serum leptin levels were measured in 30 healthy premenopausal obese women before and after 12 weeks of dietary intervention and after 5 months of follow‐up.

Results  After intervention body mass index (BMI) decreased from 30.6 to 25.4 kg/m2 (p < 0.01) and leptin levels decreased from 16.7 to 7.7 ng/ml (p < 0.01). After 5 months follow‐up 12 women regained reduced weight and 18 women maintained weight loss. In the regainers leptin levels increased again, but remained low in the maintainers. Baseline leptin concentrations were lower in the regainers than in the maintainers (12.1 vs. 21.2 ng/ml, p = 0.04). During intervention leptin levels decreased three times more in the maintainers than in the regainers, although weight loss was similar in both groups.

Conclusions  This study shows that obese women who regain weight after dieting have significantly lower baseline leptin levels than women who maintain weight loss. Our results suggest that differences in leptin resistance might exist in similarly obese women which could influence the success of dieting.
Effects and serum levels of glibenclamide and its active metabolites in patients with type 2 diabetes
Authors: Jönsson A. , Hallengren B. , Rydberg T. , Melander A.
Published: March 2003

SUMMARY

Objective  To study the effects and serum levels of glibenclamide (Gb) and its active metabolites in patients on chronic Gb medication on different daily doses.

Material and methods   Fifty patients with type 2 diabetes on regular Gb therapy (1.75–14.0 mg daily). Blood samples were taken immediately before and 90 min after regular Gb intake. A standardized breakfast was served 30 min after drug intake. Serum insulin and proinsulin levels were determined by ELISA methods without cross‐reactivities. Serum drug levels were determined by HPLC. Fischer's R to Z‐test (correlation coefficients) and paired Student t‐tests were used when comparing values within the entire group and unpaired non‐parametric Mann–Whitney tests were used when comparing high and low dose levels. A p‐value < 0.05 was considered significant.

Results   There were significant correlations between daily Gb dose, on the one hand, and, on the other, HbAlc (r = 0.55), Δ‐insulin (r = − 0.59) and Δ‐proinsulin (r = − 0.52) levels. Significant correlations between Gb therapy duration and insulin (r = − 0.40) and proinsulin (r = − 0.34) secretion and between Gb dose and ratio proinsulin/insulin (RPI) at both time points (r = 0.32 and 0.30) were also found. The RPI was lower after Gb intake. In patients on ≥ 10.5 mg steady state serum metabolite levels (Ml and Ml + M2) were higher (29(0–120) and 33 (0–120) ng/ml) than those of Gb itself (18(0–64) ng/ml). A great inter‐subject variability in Gb levels at both time points was seen.

Conclusions   Our results indicate that, in patients on chronic medication, Gb is capable of stimulating both insulin and proinsulin secretion; the effect on insulin release is relatively greater. The effect was more pronounced in patients on a low Gb dose, either because of less impaired β‐cells in those receiving low doses, or due to reduced sulphonylurea sensitivity in those on high dosage (down‐regulation). In patients on a daily dose of 10.5 mg or more, serum metabolite levels of clinical relevance were demonstrated; the metabolites may contribute to hypoglycaemic events.
Insulin‐like growth factor I, epidermal growth factor and transforming growth factor beta expression and their association with intrauterine fetal growth retardation, such as development during human pregnancy
Authors: Hernandez‐Valencia M. , Zarate A. , Ochoa R. , Fonseca M. E. , Amato Dante , De Jesus Ortiz M.
Published: March 2003

Aim: Fetal intrauterine growth retardation (IUGR) is one of the most common obstetric problems, with a frequency of 12% in Mexico. In the past, investigations have focused on extrinsic causes of IUGR. More recent studies have examined the intrinsic factors that cause fetal intrauterine growth. Maintenance of fetal growth has been attributed to insulin‐like growth factor (IGF), epidermal growth factor (EGF) and transforming growth factor beta (TGF‐β). The objective of this study was to assess the levels of these growth factors during pregnancy and to determine whether or not low concentrations are associated with IUGR.

Methods: Nine women whose pregnancies were complicated by IUGR and a group of nine women whose pregnancies exhibited normal fetal intrauterine growth were studied. IUGR was determined by sonography and confirmed by weight at birth. Venous blood samples were taken from both groups of pregnant women at the end of each trimester. Enzyme‐linked immunosorbent assays, immunoradiometric assays and radioimmunoassays were used to process samples, and the results were analysed by anova.

Results: IGF‐I levels increased in both groups during pregnancy, but the increase was lower (p < 0.001) in the IUGR group throughout pregnancy and at delivery. EGF did not show any significant changes during pregnancy. Blood TGF‐β levels varied only during the first trimester of pregnancy. The differences were not statistically significant. However, TGF‐β concentrations were higher in the pregnancies with IUGR. Women in the IUGR group were smaller than in the control group (p < 0.05), and, using the covariance test (p < 0.05), this was found to be correlated with IGF‐I levels but not with EGF or TGF‐β levels.

Conclusions: Changes in fetal weight might be explained by the different concentrations of IGF. The structural homology between IGF‐1 and insulin could mean that the presence of higher levels of IGF would result in a increased energetic metabolism that could contribute to fetal growth. EGF levels were not related to IUGR, and TGF‐β levels increased only during the first 3 months in the IUGR group. This observation correlates with the in vitro action of TGF‐β as a negative factor of growth, but as a positive support for sustaining early pregnancy. Our data illustrates that low height represents an increased risk factor for IUGR. These data also correlate with the studies involving extrinsic factors.
Identification of two novel and potent competitive inhibitors of the glucose‐6‐phosphatase catalytic protein
Authors: Westergaard N. , Madsen P. , Lundbeck J. M. , Jakobsen P. , Varming A. , Andersen B.
Published: March 2003

Aim: In this study, we show that inhibitors of the glucose‐6‐phosphatase (G‐6‐Pase) catalytic protein could be an alternative approach to the recent G‐6‐Pase T1‐translocase inhibitors to target this enzyme for the treatment of type 2 diabetes.

Method: The active enantiomers of 4‐methoxyphenyl‐[4‐(4‐methoxyphenyl)‐4,5,6,7‐tetrahydrothieno[3,2‐c]pyridin‐5‐yl]methanone (Compound A‐1) and 4‐methoxyphenyl‐[4‐(4‐trifluoromethoxyphenyl)‐4,5,6,7‐tetrahydrothieno[3,2‐c]pyridin‐5‐yl]methanone (Compound B‐1) were characterized as inhibitors of the G‐6‐Pase catalytic protein using pig and rat liver microsomes and cultured rat hepatocytes.

Results: Both compounds were found to be potent competitive inhibitors of the G‐6‐Pase catalytic protein obtained from pig and rat liver microsomes. The Ki values (µM) were calculated to be 0.61 ± 0.02 and 0.63 ± 0.08 for compound A‐1 and B‐1 on intact pig microsomes, and 0.27 ± 0.02 and 0.29 ± 0.06 on disrupted pig microsomes. The corresponding values for rat liver microsomes were found to be 3.3 ± 0.6 and 4.0 ± 1.2 for compound A‐1 and B‐1 on intact microsomes, and 1.54 ± 0.1 and 1.21 ± 0.1 on disrupted microsomes. Compound A‐1 was also able to inhibit pyrophosphatase activities from both intact and disrupted microsomes with equal potency (IC50; 0.43–0.55 µm). Using cultured rat hepatocytes and glycerol as the substrate, these compounds were able to prevent glucose production up to 60% with a concomitant increase in the G‐6‐P content (2.3‐fold) using compound A‐1. No increase in glycogen levels was seen.

Conclusion: These data demonstrated that these compounds were more potent inhibitors on G‐6‐Pase obtained from pig microsomes and were able to penetrate the microsomal membrane. The hepatocyte data further support the kinetic data, and are also consistent with the evoked mechanism of action.
2‐[18F]fluoro‐2‐deoxy‐d‐glucose combined with microdialysis can be used for the comparison of tissue glucose metabolism in obese and lean rats
Authors: Virtanen K. A. , Haaparanta M. , Grönroos T. , Bergman J. , Solin O. , Rouru J. , Nuutila P. , Huupponen R.
Published: March 2003

Aims: Direct assessment of tissue metabolism in vivo is important to understand the pathogenesis of obesity. Labelled glucose analogues are potential candidates to be used for this purpose. The aim of this study was to compare the kinetics and metabolism of 2‐[18F]fluoro‐2‐deoxy‐d‐glucose (FDG) in obese (fa/fa) and lean (Fa/?) Zucker rat tissues with microdialysis, and the measurement of uptake and phosphorylation with or without insulin bolus injection.

Methods: Obese (n = 10) and lean (n = 11) anaesthetized rats underwent a microdialysis study after FDG‐injection either with or without insulin stimulation. Microdialysis probes were inserted in the jugular vein, quadriceps muscle and liver. After 110 min, tissue [18F]‐uptake and intracellular phosphorylation of FDG were studied in blood, liver, skeletal muscle, subcutaneous adipose tissue, intra‐abdominal adipose tissue and hypothalamus.

Results: When measured with microdialysis, insulin‐enhanced FDG disappeared from the blood pool and interstitial space of skeletal muscle and liver more effectively in lean rather than in obese animals. Insulin‐stimulated skeletal muscle and adipose tissue[18F]‐uptake was impaired in obese Zucker rats compared with lean animals. Hypothalamic FDG uptake was six to sevenfold higher than in other measured tissues, but was attenuated in obese rats. In liver and in mesenteric fat, insulin‐enhanced FDG phosphorylation in lean rats compared with obese animals.

Conclusions: Positron‐emitting glucose analogue FDG, combined with microdialysis and tissue analysis, is a feasible method in studying glucose metabolism at the cellular level in animal studies.
Effects of arachidonic acid plus zinc on glucose disposal in genetically diabetic (ob/ob) mice
Authors: Hwang I. K. , Go V. L. W. , Harris D. M. , Yip I. , Song M. K.
Published: March 2003

Aim: The present study is designed to determine whether arachidonic acid (AA) plus zinc improves clinical signs of diabetes in genetically diabetic ob/ob mice.

Methods: In the first study, effects of acute administration of AA plus zinc on glucose disposal were determined in ob/ob and lean mice (n = 6 each). In the second study, ob/ob and lean mice were treated with increasing doses of AA plus zinc for 2 weeks (n = 5 each). Postprandial and fasting blood glucose concentrations, three‐hour‐area‐average above fasting glucose concentration (TAFGC), water and food intake, body weight and plasma insulin concentrations were measured.

Results: Acute administration of AA plus zinc significantly increased glucose disposal in ob/ob mice. In the second study, postprandial and fasting blood glucose concentrations, TAFGC, and water and food intake in ob/ob mice treated with AA plus zinc for 2 weeks were significantly decreased compared with those in mice given no AA. Plasma insulin concentrations in both lean and ob/ob mice were not changed by AA treatment in drinking water.

Conclusions: AA plus zinc in drinking water is effective in decreasing blood glucose levels in obese mice. These results indicate that use of these compounds should be considered as a dietary supplement to control hyperglycaemia in patients with type II diabetes.
PMT13, a pyrimidone analogue of thiazolidinedione improves insulin resistance‐associated disorders in animal models of type 2 diabetes
Authors: Chakrabarti R. , Vikramadithyan R. K. , Kumar M. Prem , Kumar S. K. B. , Mamidi N. V. S. , Misra P. , Suresh J. , Hiriyan J. , Rao C. S. , Rajagopalan R.
Published: March 2003

Aim: To evaluate the antidiabetic and hypolipidaemic potential of a novel thiazolidinedione, PMT13, in different animal models of insulin resistance.

Methods: PPAR transactivation study was performed in HEK293T cells using ligand binding domains of PPARα, γ and δ. Insulin‐resistant db/db and ob/ob mice were treated orally with different doses of PMT13 at 0.3–10 mg/kg/day for 15 and 14 days respectively. Zucker fa/fa rats were treated with 3 mg/kg (p.o.) dose of the compound. Plasma glucose, triglyceride, free fatty acid and insulin levels were measured. Liver glucose 6‐phosphatase (G6‐Ptase) and adipose lipoprotein lipase activity was measured in treated mice. Isolated rat aortic preparations preconstricted with phenylephrine were used to study the vascular relaxation potential of PMT13 in presence of insulin. A 28‐day oral toxicity study was performed in Wistar rats.

Results: PMT13 showed similar PPARγ activation as rosiglitazone, but failed to show any activity against PPARα or PPARδ. In obese and diabetic db/db and ob/ob mice, PMT13 showed better reduction in plasma glucose, triglyceride and insulin levels than rosiglitazone and an improvement in glucose tolerance. In insulin‐resistant Zucker fa/fa rat model, PMT13 treatment showed better reduction in plasma triglyceride, free fatty acid and insulin levels than that of rosiglitazone. Treated mice showed decreased G6‐Ptase activity in liver. The LPL activity was increased in post‐heparin plasma and epididymal fat of treated db/db mice. In an isolated, precontracted rat aortic preparation, PMT13 treatment significantly increased insulin‐induced relaxation. A 28‐day oral toxicity study in rats showed no treatment‐related adverse effects.

Conclusion: Our studies indicate that PMT13 is a potent activator of PPARγ with antidiabetic, hypolipidaemic and insulin‐sensitizing properties. Additionally, PMT13 inhibited liver G6‐Ptase activity and increased lipoprotein lipase activity. It showed improvement in insulin‐induced vasorelaxation. The compound also showed a good safety margin. Therefore, PMT13 can be a potential drug candidate for future development.
A longitudinal magnetic resonance imaging (MRI) study of differences in abdominal fat distribution between normal mice, and lean overexpressors of mitochondrial uncoupling protein‐3 (UCP‐3)
Authors: Changani K. K. , Nicholson A. , White A. , Latcham J. K. , Reid D. G. , Clapham J. C.
Published: March 2003

Aim: To characterize evolution and distribution of abdominal adipose fat between 6 and 18 weeks of age in an animal model of energy consumption based on mice overexpressing the mitochondrial uncoupler protein 3 (UCP‐3).

Methods: T2‐weighted multislice MRI was performed six times during the 12 week study; visceral, subcutaneous and intermuscular fat depots were quantified.

Results: The overexpressor (UCP‐3tg) mice consistently have less subcutaneous, visceral, interskeletal muscle and total fat throughout the experiment. Mean (standard error) volumes (ml) of the three distinct depots change between week 6 and week 18 as follows: wild type: subcutaneous 1.93 (0.28) to 6.18 (0.47), visceral 2.15 (0.34) to 6.37 (0.64), intermuscular 0.23 (0.04) to 0.53 (0.03); UCP‐3tg: subcutaneous 1.47 (0.17) to 4.07 (0.57), visceral 1.18 (0.04) to 3.69 (0.59), intermuscular 0.23 (0.01) to 0.32 (0.04). Although they eat more (4.3 g compared with 3.4 g per day) the UCP‐3tg's always weigh less than controls. In wild‐type control animals, increases of all fat pools between week 6 and week 18 is highly significant, as it is for subcutaneous, visceral and total pools in the UCP‐3tg animals. The UCP‐3tg mice, however, show no significant absolute or relative increase in intermuscular fat; UCP‐3 is predominantly overexpressed in skeletal muscle.

Conclusion: MRI provides an excellent approach to comparative studies of fat distribution in animal models of energy expenditure such as the UCP‐3tg mouse.