bluuebunny/crossref_metadata_2025 huggingface dataset:
Reducing the risk of stroke in diabetes: what have we learned that is new?
Authors: Sacco Ralph L.
Published: March 2003

Given the significant public health impact of stroke and the identification of nonmodifiable (age, gender, race/ethnicity) and modifiable (blood pressure, diabetes, lipid profile, and lifestyle) risk factors, early prevention strategies should be initiated. When a patient suffers a stroke, the focus of care becomes prevention of future events. For the patient with diabetes, comprehensive medical management of ischaemic stroke (primary or secondary prevention) includes antihypertensive and lipid‐lowering therapy, as well as antiplatelet therapy. Despite the cerebrovascular risk reduction with these modalities, clearly new agents are needed. The Heart Outcomes Prevention Evaluation (HOPE) study provides compelling evidence that treatment with the angiotensin converting enzyme inhibitor, ramipril, can further reduce the risk of stroke in high‐risk patients by mechanisms other than lowering blood pressure. In HOPE, patients were normotensive at baseline. Therefore, for the first time, in a patient population without left ventricular dysfunction, the effects of an ACE inhibitor ramipril on reducing stroke risk were demonstrated. Ramipril 10 mg achieved a significant 33% reduction in stroke among patients with diabetes. Based on the HOPE study, the recently published American Heart Association guidelines for the primary prevention of stroke recommend ramipril to prevent stroke in high‐risk patients and in patients with diabetes and hypertension. Wide‐scale adherence to these guideline recommendations for the prevention of primary and secondary stroke would significantly benefit the public health.
Distribution of newly formed vessels in human colorectal carcinomas with microangiography
Authors: Ogawa  , Miyazaki  , Tokunaga
Published: March 2003

Objectives

 Together, tumour cells and blood vessels compose a highly integrated ecosystem. This study was designed to investigate the distribution of newly formed vessels and the relationship of tissue structure to vascularity in human colorectal carcinomas.

Subjects and methods

 Microangiography, a silicone rubber compound injection method, was used successfully to study 18 resected colon cases. Vascular densities were evaluated by soft x‐ray examination, and histological constitution was assessed by an ocular, square lattice, superimposing technique.

Results

 On average, vascular density was 1.43 times greater (range 1.02–1.80) in tumour tissue than in normal mucosa. However, the vascular density in mucinous adenocarcinomas was significantly lower than that in well and moderately differentiated adenocarcinomas. When vascular densities were compared in an upper peripheral region (UR) and a lower central region (LR) (designated as upper and lower with reference to their position in relation to the submucosal vessels), the UR showed significantly higher vascular density than the LR. Histologically, the UR had a significantly higher density of carcinoma cells than the LR.

Conclusion

 These results suggest that the vascularity of colorectal carcinomas varies with respect to their topographical position and their histological subtypes.
Rectal bleeding in general and hospital practice; ‘the tip of the iceberg’
Authors: Thompson  , Pond  , Ellis  , Beach  , Thompson
Published: March 2003

Objective

To determine the incidence of rectal bleeding and its predictive value for cancer in the general population, patient consultation rates to GPs, referral rates to hospital and the nature of rectal bleeding from benign causes.

Subjects and methods

The study was based on a postal questionnaire in the setting of three General Practices in Portsmouth and South‐east Hampshire (two in Portsmouth, one in Petersfield). There were 6000 subjects, over the age of 16 years, randomly selected from the three General Practices. The main outcome measures were incidence of rectal bleeding with respect to age and sex, the number who sought medical advice from their GPs and the numbers referred on to hospital. The frequency of dark red bleeding, of an associated change in bowel habit and the presence or absence of anal symptoms were also determined. The prevalence of colorectal cancer was determined in subjects reporting rectal bleeding in the 5‐year period after the postal survey.

Results

Six thousand questionnaires were sent and 4006 (67%) were returned. Of the respondents 18% (709/4006) reported rectal bleeding in the previous year. Four percent (175/4006) had had bleeding for the first time and 38% (1522/4006) had bled at some time in the past. Of the 709 individuals, 512 (72%) had not consulted their GPs. Of the 197 (28%) who did, 50 (1:4, 7%) were referred to hospital. Eighteen percent (125/709) described the blood as dark red, and 88% (621/709) had anal symptoms. In 56% (394/709) the rectal bleeding was associated with a change in bowel habit mostly to hard stools (n=208), fewer to loose stools (n=98). Rectal cancer was diagnosed in only one patient 4 years after the first episode of rectal bleeding, giving a predictive value of rectal bleeding for colorectal cancer in the community of 1:709.

Conclusion

Many people in the community have painless rectal bleeding, an associated change in bowel habit and dark red bleeding, factors previously thought to indicate a high risk of colorectal cancer. Rectal bleeding has however a low (1:709) predictive value for cancer. As the result of a considerable selection process, only a small number are investigated in hospital. These patients therefore represent a small proportion of all patients with this symptom. The value of the factors used to decide which patients need investigation should be re‐assessed.
Impact of surgeon organization and specialization in rectal cancer outcome
Authors: García‐Granero E. , Martí‐Obiol R. , Gómez‐Barbadillo J. , García‐Armengol J. , Esclapez P. , Espí A. , Jiménez E. , Millán M. , Lledó S.
Published: March 2003

Purpose

The present study was designed to assess the differences in the outcome of patients with rectal cancer treated by a group of surgeons before and after being organized as a Coloproctology Unit at the same University Department of Surgery.

Methods

Comparison of two periods of rectal cancer surgery: I (1986–91) and II (1992–95). Period I: 94 patients were operated on by 14 general surgeons. Period II: 108 patients were operated on by only 4 surgeons of the same group organized as a Colorectal Surgery Unit after visiting referral centres abroad, adopting techniques such as total mesorectal excision (TME) for middle and low rectal cancer and washout of rectal stump. Mean follow‐up during periods I and II was 69.1 and 42.0 months, respectively. A prospective data base analysis was used. Survival and local recurrence rates were calculated by the actuarial method. For comparison between groups the log rank method was used.

Results

The two groups were comparable with respect to mean age, gender, TNM and rectal tumour location. A significant increase in radical resectability and a decrease of the Abdominoperineal resection (APR)/Low anterior resection (LAR) ratio were observed in the second period. The overall pelvic recurrence rate was 25% in the first period and 11 in the second (P < 0.01). Significant differences were also found when the patients with LAR were compared between both periods, 30% vs 9% (P < 0.01) and specially when the 10 cm anal verge distance was considered to divide the LAR groups. No differences were found regarding the APR procedures in both periods. There was improved cancer‐specific survival for the LAR group in the second period (P=0.03).

Conclusion

Specialization and centralization influence the quality of rectal cancer surgery, mainly local recurrence rates and survival after low anterior resection.
Primary adenosquamous carcinoma of the rectum. Report of 4 cases and review of the literature
Authors: Schlegel R. D. , Dehni N. , Cravino A. T. , Tiret E. , Prevot S. , Waisman H. J. , Parc R.
Published: March 2003

Objective

To review the experience of two referral centres in the management of an infrequent condition: primary adenosquamous carcinoma of the rectum, a rare disease.

Materials and methods

Four cases of primary adenosquamous carcinomas of the rectum are reported with a review of the literature. No preoperative diagnosis of adenosquamous carcinoma was established. All tumours were located in the rectum. Two patients presented with liver metastasis. No preoperative therapies were indicated. All patients underwent surgery.

Results

Patients underwent anterior resections (n=2), recto‐sigmoid resection (n=1) and abdomino‐perineal excision (n=1). All resected specimens had positive lymph nodes and metastatic liver disease was confirmed in the two cases. No adjuvant therapy was carried out after surgery and patients died within 8 months after surgical treatment.

Conclusions

Adenosquamous carcinoma of the rectum is a rare and aggressive tumour characterized by coexisting of malignant glandular and squamous components. Presentation is usually at an advanced stage. The tumour is aggressive and metastatic disease at the time of diagnosis is common. Surgery is the treatment of choice. Adjuvant therapy is difficult to evaluate prospectively due to the rarity of the condition. Survival is less than 50% than that for adenocarcinoma.
Preliminary evaluation of United Kingdom National Referral Guidelines for lower gastrointestinal tract cancer
Authors: Mahon C. C. W. , Vaizey C. J. , Taylor I. , Boulos P. B.
Published: March 2003

Objective

To evaluate the efficiency of the criteria proposed by the National Referral Guidelines at selecting patients with lower gastrointestinal tract cancer for urgent outpatient assessment when compared with the standard method for prioritization.

Patients and methods

Consecutive patients aged 50 and over referred to a colorectal unit were offered urgent or non‐urgent outpatient appointments on the basis of the contents of the referral letter. Clinical information obtained during the outpatient consultation was used to identify those patients that satisfied the guideline criteria for urgent referral. Patients were investigated and the findings recorded.

Results

Of 247 patients who completed their investigations 18 were found to have lower gastrointestinal tract cancer. Urgent outpatient appointments were offered to 115 patients of whom 14 had cancer (P = 0.0067, sensitivity=78%). A total of 119 patients satisfied the guideline criteria for urgent referral, including 17 of the patients who were found to have cancer (P < 0.0001, sensitivity=94%).

Conclusion

The criteria used in the guidelines provide an effective method for selecting patients with cancer for urgent assessment. Application of the guidelines by general practitioners can be recommended.
Flexible sigmoidoscopy in general practice
Authors: Vellacott K. D. , Clarke D. , Beech C. , Joshi H.
Published: March 2003

Objective

Flexible sigmoidoscopy (FS) is increasingly being accepted as the method of choice for initial investigation of rectal bleeding and other lower gastrointestinal symptoms. The aim of this study was to assess the feasibility of FS in general practice and to compare the yield, cost and efficiency of a service provided by a consultant surgeon and a General Practitioner (GP).

Subjects and methods

A prospective study of FS was undertaken on 430 unsedated patients with symptoms suggestive of lower bowel disease in two general practices.

Results

The yield was comparable to hospital based data. Fifteen (3.5%) cancers were detected, of which 40% were Dukes A, and 46 (10.7%) adenomatous polyps. Cost per patient examination by a GP including capital costs, depreciation of equipment, and training was calculated to be cheaper or at least equivalent to a hospital‐based service but inefficient due to the low numbers examined per month. There were no complications and no missed cancers after a minimum follow up of 2 years.

Conclusions

The results suggest that FS can be safely performed by a suitably trained GP in health centres, but better utilization of equipment and value for money would be obtained by providing the service for a group of practices rather than a single practice as in this study.
Early cellular events in colorectal carcinogenesis
Authors: Renehan A. G. , O'Dwyer S. T. , Haboubi N. J. , Potten C. S.
Published: March 2003

Colorectal cancer develops through a multistage process recognizable at a histopathological level by progression from normal mucosa to invasive carcinoma (the adenoma‐carcinoma sequence). For many years, it has been hypothesized that increased cell proliferation in the colonic crypt represents the earliest recognizable stage in this sequence. This perspective is now changing. While several human studies have reported increased crypt cell proliferation in samples from at‐risk patients, there are many inconsistencies and paradoxes in their conclusions. In addition, it is appreciated that the process of apoptosis (programmed cell death) is vital for normal crypt homeostasis and its impairment may be an early event in the neoplastic process. It is now believed that aberrant crypt foci (ACFs) represent the earliest step in colorectal carcinogenesis. Two ACF types are identifiable: hypercellular and dysplastic. Increased proliferative activity may be seen in both, but the dysplastic entity is most relevant to carcinogenesis. Animal and human studies support the notion that ACFs grow by crypt fission leading to the formation of microadenomas. Adenomas are monoclonal expansions of an altered cell, but very early lesions may be polyclonal. There are outward and inward theories of polypoid growth, and evidence to support both mechanisms. The ACF assay has become a useful tool to detect carcinogens in animal studies but has been less frequently used in human studies. For future cancer chemopreventive and risk assessment studies in humans, the identification and quantification of ACFs should be considered a more effective intermediate marker of risk than the determination of crypt cell proliferation alone.
Does sentinel lymph node biopsy have a role in colorectal cancer?
Authors: Tsavellas G. , Huang A. , Allen‐Mersh T. G.
Published: March 2003

Sentinel lymph node (SLN) biopsy in colorectal cancer is feasible, and may offer a means of reducing histopathology workload while maintaining staging accuracy. Although SLN biopsy allows use of sensitive molecular markers that can identify isolated tumour cells and micrometastases, these findings require more extensive clinical evaluation before they can be used to guide patient management. The application of molecular markers to identification of minimal residual disease after primary tumour resection, shows promise as a means of indicating patients requiring chemotherapy.
The sentinel lymph node in colorectal cancer – of clinical value?
Authors: Prabhudesai A. G. , Kumar D.
Published: March 2003

Lymph node involvement is an important prognostic factor in colorectal cancer. Sentinel node status has a significant impact on the management of breast cancer and melanoma. A `sentinel lymph node' (SLN) is defined as the first regional lymph node to receive lymph flow from the primary tumour site. An electronic literature search was performed for all articles using key words: sentinel + lymph node + colorectal + cancer. The review indicated that the sentinel node model may help understanding different aspects of tumour biology in colorectal cancer. It will provide important information about variations in lymphatic pathways and skip metastases. It may alter the management if sentinel lymph node can be assessed preoperatively with radioisotope techniques by identifying patients with micrometastases who may benefit from adjuvant therapy. Although the sentinel lymph node concept has only recently been applied to colorectal cancer, it has a great potential for management.
Histopathology of stapled haemorrhoidectomy specimens: a cautionary note
Authors: George B. D. , Shetty D. , Lindsey I. , Mortensen N. J. Mc. C. , Warren B. F.
Published: March 2003

Objective  Stapled haemorrhoidectomy is a new technique with encouraging early results. The aim of this study was to examine the tissue removed during stapled haemorrhoidectomy, in particular to check on the presence or absence of transitional or squamous anal canal mucosa and internal anal sphincter muscle.

Methods  Twenty‐six consecutive patients undergoing stapled haemorrhoidectomy were studied. Resected tissue was examined histologically according to a standardized histological protocol.

Results  All 26 specimens contained columnar mucosa. Twelve specimens also contained anal transitional and stratified squamous epithelium. Two specimens contained columnar and transitional mucosa. Twenty‐two of 26 specimens contained smooth muscle as well as mucosa (median maximum diameter 7.5 mm, range 2–20 mm). In 11 specimens this was circular muscle only; in 11 circular and longitudinal smooth muscle were present. In 10 specimens smooth muscle was seen to be lying beneath stratified squamous or transitional epithelium, suggesting that it was from the internal anal sphincter.

Conclusions  Stapled haemorrhoidectomy results in resection of stratified squamous mucosa or part of the internal anal sphincter in a significant proportion of patients. Surgeons should be aware that this technique may result in damage to the internal anal sphincter.
Formaldehyde application for haemorrhagic radiation‐induced proctitis: a clinical and histological study
Authors: Chautems R. C. , Delgadillo X. , Rubbia‐Brandt L. , Deleaval J. P. , Marti M. ‐CL. , Roche B.
Published: March 2003

Objectives  Haemorrhagic radiation‐induced proctitis is a serious complication of radiotherapy of pelvic organs. In severe cases, massive haemorrhage may necessitate hospitalization and repeated transfusions. Application of formaldehyde under direct vision is one of the most efficient treatments. The aim of this study was to evaluate the results of this treatment as well as the histological changes induced by formaldehyde on the rectal mucosa.

Material and methods  From January 1991 to September 2001, 13 patients who presented a haemorrhagic radiation‐induced proctitis have been treated in our outpatient clinic with 4% formaldehyde cotton soaked applications. They were followed up to one year after the treatment. Endoscopic biopsies were performed before, immediately after the application, 1 month later, as well as at the one‐year follow‐up.

Results  In eight cases bleeding stopped after the first application. In two patients a second application was necessary to control the haemorrhage and in two other patients bleeding ceased definitively after the fourth application. Follow‐up evaluation at 12 months showed no sign of acute proctitis or rebleeding. One asymptomatic patient had a mild stenosis of the rectum. Baseline biopsies showed signs of acute inflammation. Those performed after the application of formaldehyde showed fresh thromboses of the vessels of the mucosa. Biopsies at 1 month and 1 year showed only chronic changes secondary to the radiotherapy.

Conclusion  Local application of 4% formaldehyde for the treatment of haemorrhagic radiation‐induced proctitis gives good results, is well tolerated and easy to perform. Formaldehyde applied selectively causes thromboses of the bleeding vessels, without deep lesions or extended necrosis.
Clustering of cardiovascular risk factors in type 2 diabetes mellitus: prognostic significance and tracking
Authors: Kaukua J. , Turpeinen A. , Uusitupa M. , Niskanen L.
Published: March 2003

Summary

Aim

Little attention has been paid to the prognostic significance and tracking effect of risk factor clusters characteristic of type 2 diabetes mellitus. We studied the clustering of eight cardiovascular risk factors (smoking, high body mass index, elevated systolic blood pressure, high serum, low density lipoprotein (LDL) cholesterol, high serum LDL triglycerides, low serum, high density lipoprotein (HDL) cholesterol, high fasting blood glucose and high plasma insulin concentration) and their effect on the prognosis and the tracking effect.

Methods

This study is a population‐based prospective follow‐up of newly diagnosed type 2 diabetic subjects (n = 133, aged 45–64 years) in Eastern Finland. The following end points were used: all‐cause mortality, cardiovascular mortality, and incidences of first myocardial infarction and first stroke. Furthermore, we studied the ‘tracking effect’ of the risk factor clusters during the 10‐year follow‐up period.

Results

When the clustering of risk factors typical of type 2 diabetes mellitus was taken into account, all‐cause mortality increased from 28.6% to 50.0% (p < 0.05) and cardiovascular disease mortality increased from 14.3% to 50.0% (p < 0.01) depending on the number of risk factors present. The incidence of first myocardial infarction increased from 0% to 40.0% (p < 0.05) as the number of risk factors increased from 0 to 5. In survivors, the proportion of individuals with no risk factors decreased and the proportion on individuals with three to four risk factors increased during the 10‐year follow‐up period despite the high mortality among the group with many risk factors.

Conclusions

The risk factor clusters among type 2 diabetic subjects are of great predictive value and when not aggressively treated, show a relentless increase despite selective mortality.
Effects of granulocyte‐colony stimulating factor in the treatment of diabetic foot infection
Authors: Yönem A. , Çakir B. , Güler S. , Azal Ö. , Çorakçi A.
Published: March 2003

SUMMARY

Aims  Foot infections and the subsequent amputation of a lower extremity are the most common cause of hospitalization among patients with diabetes mellitus. Although there are several reasons for susceptibility to infection in diabetic patients, white blood cell dysfunction is considered to be an important cause for this tendency. Granulocyte‐colony stimulating factor (G‐CSF) increases the release of neutrophils from the bone marrow and improves neutrophil functions. Based on this knowledge, the aim of the present study was to investigate the effects of addition of G‐CSF to the treatment of foot infections in diabetic patients.

Methods  Thirty diabetic patients with foot infection were included in the study. Fifteen of the patients received standard treatment consisting of local wound care and antibiotics (standard goup), and the other 15 patients received G‐CSF besides standard treatment (G‐CSF group). The objectives of this study were to determine the time to resolution of infection, time to hospital discharge, need for surgical intervention, and the effects of G‐CSF on phagocytosis and respiratory burst of neutrophils.

Results  Treatment with G‐CSF led to significantly higher neutrophil counts on the 5th and 10th days, and at the end of treatment in the G‐CSF treated group compared to the standard group. Respiratory burst of neutrophils increased significantly in both the G‐CSF group (from 1.6 ± 0.3 to 2.3 ± 0.5, p = 0.001) and the standard group (from 2.0 ± 0.4 to 2.3 ± 0.4, p = 0.02) with treatment. But, while phagocytosis of neutrophils increased significantly in the G‐CSF group (from 70.4 ± 2.0 to 74.5 ± 1.9, p = 0.004), it did not change significantly in the standard group (from 68.1 ± 0.2 to 69.4 ± 1.9, p = 0.3) with treatment. Duration of hospitalization (26.9 ± 2.0 vs. 28.3 days, p < 0.05), duration of parenteral antibiotic administration (22.9 ± 2.0 vs. 23.3 ± 1.9 days, p < 0.05), time to resolution of infection (23.6 ± 1.8 vs. 22.3 ± 1.7 days, p < 0.05), and need for amputation (13.3% vs. 20%, p > 0.05) were similar between the G‐CSF and the standard groups.

Conclusions  Although G‐CSF improves neutrophil function as well as increasing the absolute numbers, this improvement is not associated with shortening of duration of antibiotic administration, duration of hospital stay or need for amputation in diabetic foot infection.
Oral gavage of oleoyl‐oestrone has a stronger effect on body weight in male Zucker obese rats than in female
Authors: Grasa M. M. , Esteve M. , Masanés R. M. , Yubero P. , Blay M. , López‐Martí J. , Cabot C. , Vilà R. , Fernández‐López J. A. , Remesar X. , Alemany M.
Published: March 2003

This study was carried out to determine the effect of sex and oral administration of oleoyl‐oestrone on body weight of 12‐week‐old female and male Zucker obese (fa/fa) rats initially weighing 350–380 g and 405–420 g, respectively. The rats were maintained in standard conditions and given a daily oral gavage of 0.2 ml oleoyl‐oestrone dissolved in sunflower oil at a dose of 10 μmol/kg/day for 10 days, and their body weight and food intake was monitored. They were then killed, and their carcass composition (water, lipid, protein and total energy), liver lipids and glycogen and plasma chemistry, insulin, free and total oestrone were measured. Oral administration of oleoyl‐oestrone via gavage resulted in significant losses of fat, energy and–ultimately–weight. Treatment with oleoyl‐oestrone decreased food intake; the energy expenditure was kept close to that of controls at the expense of internal fat stores. Nevertheless, body protein and plasma metabolite homeostasis were preserved. The slimming effects were more marked in males than in females. Treatment increased circulating acyl‐oestrone and reduced to normal levels the high insulin observed in controls. Treatment of genetically obese rats with a daily oral gavage of oleoyl‐oestrone resulted in the loss of fat reserves with little modification of other metabolic parameters, except for lower plasma glucose and insulin levels. The results suggest that oleoyl‐oestrone, in addition to its slimming effects may be effective as an antidiabetic agent in type 2 diabetes.
Overexpression of the A1 adenosine receptor in adipose tissue protects mice from obesity‐related insulin resistance
Authors: Dong Q. , Ginsberg H. N. , Erlanger B. F.
Published: March 2003

In‐vitro studies have implicated the A1 adenosine receptor (A1AR) of adipocytes in inhibition of lipolysis, stimulation of lipogenesis and enhancement of the action of insulin on glucose metabolism. To determine whether any of these activities were physiologically relevant in an intact animal, A1AR was overexpressed in adipose tissue of transgenic mice. Lower plasma free fatty acid (FFA) levels were observed in the transgenic mice relative to the litter‐matched controls, supporting a significant physiological role for adipocyte A1AR in the control of lipolysis. However, no differences were observed in body weights or body composition. On a high fat diet, both the transgenic mice and the litter matched controls, male and female, became equally obese. Unlike the control mice, however, the transgenic mice did not develop insulin resistance, as demonstrated by serum glucose and insulin levels and glucose and insulin tolerance tests. These findings demonstrate that adipocyte A1AR plays an important physiological role in the control of insulin sensitivity in an intact animal and therefore should be considered to be a potential therapeutic target for the treatment of obesity‐related insulin resistance and type 2 diabetes.
Long‐term glycaemic improvement after addition of metformin to insulin in insulin‐treated obese type 2 diabetes patients
Authors: Hermann L. S. , Kalén J. , Katzman P. , Lager I. , Nilsson A. , Norrhamn O. , Sartor G. , Ugander L.
Published: March 2003

SUMMARY

Aim   To assess the adjunct effect of metformin to insulin in type 2 diabetes.

Methods   Obese and overweight type 2 diabetes patients treated with insulin for at least 1 year, and with poor glycaemic control (HbA1c > upper reference level + 2%), were included in a randomised, double‐blind, placebo‐controlled study. Patients were treated for 12 months with either metformin (850 mg b.i.d.) or placebo added to their usual insulin, which was stabilized during a 3‐month placebo run‐in period, but thereafter attempted to be unchanged.

Results   Thirty‐seven patients were included. Two patients dropped out during run‐in. There were no differences between the metformin (n = 16) and placebo (n = 19) group at baseline. Most patients received multiple insulin injections. Metabolic control was improved by addition of metformin. Mean change in HbA1c from baseline showed highly significant difference between groups at 3, 6, 9 and 12 months. Mean change (percentage units ± s.d.) at 12 months was −1.1 ± 0.7% vs. + 0.3 ± 0.8% (p < 0.001) for HbA1c and −1.4 ± 2.1 mmol/l vs. + 0.6 ± 2.2 mmol/l (p = 0.025) for fasting blood glucose. Mean low density lipoprotein (LDL) cholesterol change differed slightly at 6 months, but not at 12 months. There were no changes in insulin dose, blood pressure, body weight, triglycerides, total‐ and high density lipoprotein (HDL) cholesterol, fibrinogen, C‐peptide and laboratory safety variables, including serum B12. Combination therapy was well‐tolerated with the same adverse event rate as insulin alone, but more patients with diarrhoea.

Conclusion   Addition of metformin to insulin induced and maintained clinically significant and consistent long‐term reduction of hyperglycaemia in obese, insulin‐treated type 2 diabetes patients.
The NEPI Antidiabetes Study (NANSY). 1: Short‐term dose–effect relations of glimepiride in subjects with impaired fasting glucose*
Authors: Lindblad U. , Lindwall K. , Sjöstrand Å. , Ranstam J. , Melander And A.
Published: March 2003

SUMMARY

Aim  NANSY is a randomised, placebo‐controlled Swedish‐Norwegian study which aims to include 2 × 1112 male and female subjects with impaired fasting glucose (IFG), to assess whether conversion to type 2 diabetes can be delayed by addition of sulphonylurea to dietary regulation and increased exercise. This pilot study was conducted to find the optimum dose of glimepiride in NANSY.

Methods  In a double blind trial in primary care 25 IFG subjects were in random order exposed to single doses and one‐week treatments with 0 (placebo), 0.5, 1.0 and 2.0 mg glimepiride once daily. The optimum dose was assessed by measuring blood glucose during oral 75 g glucose tolerance test (OGTT), comparing fasting blood glucose, and the area under the blood glucose curve (AUC), and by monitoring hypoglycaemic events.

Results  With single doses, there was a clear dose–response relationship for the reduction in AUC, with a statistically significant difference only between placebo (mean 1981, 95% confidence intervals (CI) 1883–2078) and 2 mg glimepiride (mean 1763, 95% CI 1665–1861). However, following 1‐week treatments, the only significant difference was between placebo (mean 1934, 95% CI 1856–2012) and 1 mg glimepiride (mean 1714, 95% CI 1637–1792). Correspondingly, the only statistically significant difference in fasting blood glucose day 7 was between placebo (5.87 mmol/l, 95% CI 5.68–6.05 mmol/l) and 1 mg glimepiride (5.42 mmol/l, 95% CI 5.21–5.62 mmol/l). Chemical hypoglycaemia was common but hypoglycaemic symptoms were rare and similar between the active doses, and easily countered by the subjects.

Conclusions  The sulphonylurea dose–effect curve may be bell‐shaped, perhaps due to down regulation of sulphonylurea receptors during chronic exposure. Alternatively, the finding could be a rebound phenomenon, secondary to preceding hypoglycaemia. The optimum dose for NANSY was found to be 1 mg glimepiride.
Losartan modifies glomerular hyperfiltration and insulin sensitivity in type 1 diabetes
Authors: Nielsen S. , Hove K. Y. , Dollerup J. , Poulsen P. L. , Christiansen J. S. , Schmitz O. , Mogensen C. E.
Published: March 2003

Aim: The effect of the angiotensin II receptor antagonist losartan on renal haemodynamics and insulin‐mediated glucose disposal was examined in normotensive, normoalbuminuric type 1 diabetic patients using a double‐blind, placebo‐controlled, cross‐over design.

Methods: Diurnal blood pressure, glomerular filtration rate (GFR, determined using [125I]‐iothalamate), renal plasma flow (RPF, determined using [131I]‐hippuran) and urinary albumin excretion rate (UAE) were measured, and a hyperinsulinaemic, euglycaemic clamp with indirect calorimetry was performed in nine patients (age 30 ± 7 years (mean ± s.d.), HbA1c 8.1 ± 1.1%) following 6 weeks' administration of either losartan 50 mg/day or placebo.

Results: Diurnal blood pressure was significantly reduced after losartan compared with placebo (122/70 ± 11/8 vs. 130/76 ± 12/6 mmHg, p < 0.05). A significant decline in GFR (133 ± 23 vs. 140 ± 22 ml/min, p < 0.05) and filtration fraction (FF; GFR/RPF) (24.6 ± 3.5 vs. 26.2 ± 3.6%, p < 0.05) was observed in the losartan vs. placebo groups. RPF and UAE did not change. Isotopically determined glucose disposal rates were similar after losartan and placebo in the basal (2.61 ± 0.53 vs. 2.98 ± 0.93 mg/kg/min) and insulin‐stimulated states (6.84 ± 2.52 vs. 6.97 ± 3.11 mg/kg/min). However, the glucose oxidation rate increased significantly after losartan vs. placebo in the basal state (1.72 ± 0.34 vs. 1.33 ± 0.18, mg/kg/min, p < 0.01) and during insulin stimulation (2.89 ± 0.75 vs. 2.40 ± 0.62 mg/kg/min, p < 0.03). Basal and insulin‐stimulated non‐oxidative glucose disposal tended to decrease after losartan; however, this was not significant. Endogenous glucose production and lipid oxidation were unchanged after treatment and similarly suppressed during hyperinsulinaemia. Glycaemic control, total cholesterol, high‐density lipoprotein (HDL)‐cholesterol and triglycerides were stable in both losartan and placebo groups.

Conclusions: Losartan reduces blood pressure, glomerular hyperfiltration and FF, and improves basal and insulin‐stimulated glucose oxidation in normotensive, normoalbuminuric type 1 diabetic patients.
Lipoic acid increases glucose uptake by skeletal muscles of obese‐diabetic ob/ob mice
Authors: Eason R. C. , Archer H. E. , Akhtar S. , Bailey C. J.
Published: March 2003

Aim: Alpha‐lipoic acid has been reported to increase glucose disposal in diabetic states. This study has examined the effect of α‐lipoic acid on glucose uptake by cultured L6 muscle cells and different types of skeletal muscles in normal lean (+/+) and severely insulin‐resistant, obese‐diabetic (ob/ob) mice.

Methods: Glucose uptake was measured in L6 muscle cells using the non‐metabolized glucose analogue 2‐deoxy‐d‐glucose (2DG), and in isolated muscles by glucose disappearance from the incubation medium.

Results: In L6 muscle cells, short‐term incubations (2–12 h) with 10−3 mα‐lipoic acid increased glucose uptake by 40–80%, approximately the same extent as 10−6 m insulin. Combination of the two agents produced a slightly greater increase (120% at 12 h) than either alone. Red quadriceps (mainly type 1 fibres), diaphragm (similar proportions of type 1 and 2 fibres) and abdominal muscle (mainly type 2 fibres) from normal mice incubated with 10−3 mα‐lipoic acid showed increased glucose uptake to a similar extent as 10−6 m insulin in each of the three muscles. Muscles from ob/ob mice, which showed little response to insulin, showed a substantial increase (approximately 300%, p < 0.05–0.01) in glucose uptake when 10−3 mα‐lipoic acid was added in the presence of insulin. The α‐lipoic acid also increased glucose uptake in red quadriceps (approximately 300%, p < 0.01) from ob/ob mice without added insulin.

Conclusion: The results suggest that α‐lipoic acid can increase glucose uptake by a range of normal muscle types and improve the response to insulin by insulin‐resistant skeletal muscles of ob/ob mice.
Evaluation of the safety and efficacy of sibutramine, orlistat and metformin in the treatment of obesity
Authors: Gokcel A. , Gumurdulu Y. , Karakose H. , Melek Ertorer E. , Tanaci N. , Bascil Tutuncu N. , Guvener N.
Published: March 2003

Aim: Some of our obese patients who were receiving 10 mg/day sibutramine reported feeling hunger at night. To address this, we designed a randomized, prospective clinical trial to study the efficacy and safety of 10 mg sibutramine twice daily (bid), and compare this treatment with 120 mg orlistat three times daily (tid) and 850 mg metformin (bid).

Methods: A total of 150 female patients with body mass index (b.m.i.) > 30 kg/m2 were included. The subjects were all out‐patients at the Başkent University Endocrinology and Metabolism Clinic. Each individual was assigned randomly to receive 10 mg sibutramine bid (group 1; n = 50; mean age 42.27 ± 1.40 years), 120 mg orlistat tid (group 2; n = 50; mean age 42.13 ± 1.32 years) or 850 mg metformin bid (group 3; n = 50; mean age 43.58 ± 1.40 years). All patients took the medications for 6 months. Two patients from the sibutramine group and two from the orlistat group were withdrawn from the study because of side‐effects.

Results: After 6 months of treatment, the sibutramine, orlistat, and metformin groups all showed significantly reduced b.m.i. (13.57%, 9.06% and 9.90% respectively); waist circumference (10.43%, 6.64%, and 8.10% respectively); fasting and postprandial blood glucose levels; insulin resistance as assessed by the homeostasis model for assessment of insulin resistance (HOMA)(38.63%, 32.73% and 39.28%, respectively); levels of total cholesterol, low‐density lipoprotein (LDLC) cholesterol, very low‐density lipoprotein (VLDLC) cholesterol, triglyceride, lipoprotein (a), and apolipoprotein B; uric acid level; pulse rate; and systolic and diastolic blood pressure. None of the groups showed any significant changes in levels of high‐density lipoprotein (HDLC) cholesterol, or apolipoprotein A1. There was a significantly greater fall in b.m.i. in the sibutramine group than in either of the other groups (p < 0.0001).

Conclusions: The results of this study confirm that sibutramine, orlistat and metformin are all effective and safe medications that reduce cardiovascular risk and can decrease the risk of type 2 diabetes mellitus in obese females. Overall, treatment with 10 mg sibutramine bid is more effective than orlistat or metformin therapy in terms of weight reduction.
Diabetic ketoacidosis associated with Metabolife: a report of two cases
Authors: Case C. C. , Maldonado M.
Published: March 2003

Aim: To describe two cases of diabetic ketoacidosis in newly diagnosed type 1‐ and type‐2‐diabetic individuals associated with Metabolife‐356®.

Methods: We report the acute hospitalizations and clinical courses of two individuals with diabetic ketoacidosis taking Metabolife‐356®.

Results: Both patients presented without a previous diagnosis of diabetes mellitus. One patient clinically has type 1 diabetes (positive islet cell antibodies and subnormal pancreatic beta cell function to glucagon stimulation) and is treated with insulin. The second patient, after 5 days of treatment with intravenous insulin of up to 25 units per hour, is now treated with oral medications. Several possible mechanisms may exist, including the increases in catecholamines and in blood glucose after ingestion of the ingredients of these supplements. Recent clinical trial data shows an increase in blood glucose (in non‐diabetics) with these supplements despite significant weight loss at 8 weeks, although no association with diabetes mellitus has been shown in these closely monitored studies.

Conclusions: Although no precipitating factor of diabetic ketoacidosis was found in these individuals, the dietary supplement Metabolife cannot be established as a precipitant. However, patients with diabetes should take this supplement only after consultation with their health care provider, as stated on the product label. Most individuals using this supplement meet the current criteria for screening to detect undiagnosed diabetes mellitus and should consider these tests.
Brain‐derived neurotrophic factor modulates glucagon secretion from pancreatic alpha cells: its contribution to glucose metabolism
Authors: Hanyu O. , Yamatani K. , Ikarashi T. , Soda S. , Maruyama S. , Kamimura T. , Kaneko S. , Hirayama S. , Suzuki K. , Nakagawa O. , Nawa H. , Aizawa Y.
Published: March 2003

Aim: Brain‐derived neurotrophic factor (BDNF) reduces plasma glucose levels in obese db/db diabetic mice and is speculated to produce its effects via the hypothalamus, the regulatory centre of satiety and the autonomic nervous system. The potential effect of BDNF directly on peripheral endocrine organs, however, remains to be clarified. Here we report the effects of BDNF on hormonal secretion from pancreatic islets of Langerhans using their isolated culture.

Methods and results: In an immunohistochemical study, mouse pancreatic alpha cells were stained specifically with the anti‐TrkB (a specific receptor for BDNF) antibody. After 7 days culture of isolated islets of the normal mouse pancreas, 10 ng/ml BDNF decreased the secretion of glucagon per 6 h significantly less than that of the control (p = 0.016). In contrast, there were no significant changes in insulin secretion or glucagon and insulin contents in the islets cultured under the same conditions. In vivo administration of BDNF (10 mg/kg/day) to normal mice for 7 days significantly decreased their food consumption (p < 0.05). The fasting plasma glucose levels were decreased on day 7 compared with day 1 more significantly in BDNF‐treated mice (p = 0.043) than in pair‐fed control mice (p = 0.14). In newborn BDNF‐knockout mice, fasting plasma glucose levels increased in the order of homozygote, heterozygote and wild type (p = 0.033). No apparent immunohistochemical abnormality was observed for pancreatic glucagon in the BDNF‐knockout mice.

Conclusion: These data suggest that BDNF affects glucose metabolism not only with its anorectic effect but also with modulated glucagon secretion from pancreatic alpha cells.
Structure and ultrastructure of the spermatozoa ofTrichogramma pretiosumRiley andTrichogramma atopoviriliaOatman and Platner (Hymenoptera: Trichogrammatidae)
Authors: Lino‐Neto José , Báo Sônia N. , Dolder Heidi
Published: March 2003

Lino‐Neto, J., Báo, S. N. and Dolder, H. 2000. Structure and Ultrastructure of the Spermatozoa ofTrichogramma pretiosumRiley andTrichogramma atopoviriliaOatman and Platner (Hymenoptera: Trichogrammatidae). —Acta Zoologica(Stockholm)81: 205–211

Spermatozoa of theTrichogramma pretiosumandT. atopoviriliaare very slender and long, about 0.35 µm in diameter and 283 µm and 106 µm in length, respectively. Under light microscopy, they appear wavy along their entire length. The head contains a small acrosome which, together with the initial nuclear region is surrounded by an ‘extracellular sheath’, from which innumerable filaments irradiate. The nucleus is filled with homogeneous, compact chromatin and is attached to the flagellum by an electron dense centriolar adjunct, which extends anteriorly from the nuclear base. The flagellum consists of an axoneme with the 9 + 9 + 2 microtubule arrangement pitched in a long helix, as well as a pair of spiralling mitochondrial derivatives which coil around the axoneme. Based on these characteristics, the sperm of theseTrichogrammaare very similar to the chalcidoids studied to date and differ from non‐chalcidoid Hymenoptera. They differ widely from the sperm ofT. dendrolimiandT. ostriniaestudied, where no helically twisted structure is shown. However, based on these results we argue that the spiralling of the flagellar structures is a synapomorphy for Trichogrammatidae as well as for Eulophidae + Eurytomidae + Pteromalidae.
Proboscis musculature in the butterfly Vanessa cardui (Nymphalidae, Lepidoptera): settling the proboscis recoiling controversy
Authors: Krenn Harald W.
Published: March 2003

Krenn, H. W. 2000. Proboscis musculature in the butterfly Vanessa cardui (Nymphalidae, Lepidoptera): settling the proboscis recoiling controversy. —Acta Zoologica (Stockholm) 81: 259–266

The proboscis of Vanessa cardui (Nymphalidae) contains two basal galeal muscles and two different series of numerous oblique muscles. Both muscle series extend from the proximal region up to the tip‐region; the individual muscles of each series run a constant course throughout the proboscis. In contrast to other butterflies, the knee bend region does not have additional types of muscles. The analysis of shock‐frozen proboscises reveals that the dorsal wall is arched outwardly in the uncoiled, feeding position whereas in the coiled, resting position the dorsal proboscis wall is flat or concave. This results in a significantly greater cross‐sectional area due to the significantly greater dorso‐ventral diameter in uncoiled proboscises. After freezing the proboscis in its distal region, it can still be uncoiled, however, it cannot be fully recoiled. These morphometric and experimental results indicate that the oblique proboscis muscles are responsible for recoiling the proboscis to the resting position.
Dark hair cells in the inner ear of the rainbow trout. A study of the influence of different fixation methods
Authors: Jensen Jan Christian , Jørgensen Jørgen Mørup
Published: March 2003

The occurrence of dark staining cells in different tissues has been suggested to be artefactual and caused during the fixation process. In inner ear sensory epithelia, dark hair cells (DHC) have been suggested to be apoptotic cells. We have examined whether dark cells represent dying cells or whether they are the results of fixation artefacts. The effects of buffer osmolarity and different fixation methods on the incidence of dark hair cells in the inner ear macula sacculi of the rainbow trout (Oncorhynchus mykiss) were investigated by light and electron microscopy. Glutaraldehyde in phosphate buffer with osmolarities of 0, 135, 225, 425, and 560 mosmol were used for fixation by immersion. For comparison, fixation by vascular perfusion as well as the effects of mechanical injury and delayed fixation were studied. DHC were found in all examined saccular maculae except for the delayed fixation protocol where almost all the sensory cells were lost. The number of DHC accounted for 2.5–12.9‰ of the sensory cells. Neither the buffer osmolarity nor the fixation method had significant effects on the frequencies of DHC. Mitotic cell division events were seen exclusively in the apical cell strata of the sensory epithelium. The DHC are suggested to be associated with apoptosis rather than fixation artefacts.
The foreguts of the primitive families of the Mysida (Crustacea, Peracarida): a transitional link between those of the Lophogastrida (Crustacea, Mysidacea) and the most evolved Mysida
Authors: De Jong‐Moreau L. , Casanova J.‐P.
Published: March 2003

De Jong‐Moreau, L. and Casanova, J.‐P. 2001. The foreguts of the primitive families of the Mysida (Crustacea, Peracarida): a transitional link between those of the Lophogastrida (Crustacea, Mysidacea) and the most evolved Mysida. —Acta Zoologica (Stockholm) 82: 137–147

The morphology of the foregut, which is a good indicator of phylogenetic relationships, has been studied within the two suborders of the Mysidacea. Special attention has been focused on rare species belonging to the Lophogastrida and the three primitive families of the Mysida, i.e. Stygiomysidae, Lepidomysidae and Petalophthalmidae. It appears that the foregut of Gnathophausia gracilis (Lophogastrida) is the most primitive in the Mysidacea, and that in the Petalophthalmidae the foregut exhibits transitional stages between that of the Lophogastrida and of the evolved Mysidae. Moreover, in the four families of Mysida, ancestral characteristics of the foregut remain, thus strengthening the hypothesis of the unity of this order.
Redescription of sperm structure and ultrastructure ofTrichogramma dendrolimi(Hymenoptera: Chalcidoidea: Trichogrammatidae)
Authors: Lino‐Neto José , Dolder Heidi
Published: March 2003

To verify the questionable description of sperm structure ofTrichogramma dendrolimi, in relation to Chalcidoids, a reinvestigation was undertaken. The spermatozoa appear wavy along their entire length. A small acrosome, together with the anterior nuclear region, is surrounded by an extracellular sheath, from which filaments radiate. The nucleus is helicoidal and attached to the flagellum by a centriolar adjunct. The axoneme has the 9 + 9 + 2 microtubule arrangement pitched in a long helix, with the spiralling mitochondrial derivatives coiling around it. Therefore, the spermatozoa ofT. dendrolimiare very similar to those of other chalcidoids and different from the first description. It is now possible to affirm that the helical sperm structures are an apomorphic homology for Trichogrammatidae as well as Eulophidae, Pteromalidae, Eurytomidae, Torymidae, Mymaridae and for some other chalcidoids, if not all.