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To date, very little is known about the development of benign organic hyperinsulinism and its metastatic potential. Typical morphologic, biochemical, or genetic differentiations for benign or malign tumor course of insulinomas do not exist. As signaling pathways may affect pancreatic cancer development and the maintenance of the neoplastic phenotype, the purpose of this study was to examine the role of Notch1 expression in organic hyperinsulinism. We examined 32 well-differentiated pancreatic endocrine tumors (wd PET); 11 wd PET of unknown behavior (wd PET ub); and 15 wd pancreatic endocrine cancer (wd PEC) for Notch1 expression by immunohistochemistry. Demographic data, clinical data, and follow-up of all patients were analyzed. Islets of the Langerhans show the strongest Notch1 staining in nearly 90 %. Positive Notch1 staining was absent in the acinar of the pancreas. In patients with a wd PET more than every second tumor (56.3 %/n = 18/32) demonstrated a negative Notch1 staining. The other 14 patients were positive for Notch1. Tumors of unknown behavior (wd PET ub) and malignant insulinomas had no signs of Notch expression in contrast to benign insulinomas. Considering the clinical and histomorphological tumor behavior, no correlation between Notch1 expression and clinical data was found. The missing Notch expression in the malignant tumor course might be used as a potential predictive marker, but further studies are needed to investigate the underlying molecular mechanism.

Fragestellung: Kann die Leistung von Studierenden in der Klausur zur Hauptvorlesung durch das Angebot von CME-Fragen zu den einzelnen Themen der Veranstaltung gesteigert werden? Methodik: Fur diese prospektive randomisierte Untersuchung wurden die vier Semesterkohorten (von SoSe 2013 bis WiSe 2014/2015) jeweils in zwei Gruppen geteilt. Beide Gruppen erhielten zeitgleich Zugang zu den Folien der einzelnen Lehrveranstaltungen. Lediglich einer Gruppe wurden zusatzlich jeweils 3 CME-Fragen zu den Themen angeboten. Die Fragen konnten im Verlauf des Semesters mehrmals bearbeitet werden. Das Ergebnis der Beantwortung spielte keine Rolle fur die Benotung der Klausur. Es wurde ausgewertet, ob die Kohorte mit den CME-Fragen in der Hauptklausur besser abschnitt. Ergebnis: Die Gruppe der Studierenden mit CME-Fragen schnitt durchschnittlich um 2,2 Punkte (von moglichen 40 Punkten) besser ab. Dies stellte sich als signifikant heraus. Dieser Effekt nivellierte sich im Laufe der Semester. Schlussfolgerung: Das zusatzliche Angebot von CME-Fragen begleitend zur Hauptvorlesung in unserem Fach kann zu einer intensiveren Vorbereitung und zu einem besseren Abschneiden der Studierenden in der Klausur fuhren. Die Abflachung des Effektes uber die Semester kann eventuell durch eine Verbreitung der CME-Fragen in sozialen Netzwerken erklart werden.

Evidence exists that nutritional therapy induces favorable metabolic changes, prevents signs and symptoms of renal insufficiency, and is able to delay the need of dialysis. Currently, the main concern of the renal diets has turned from the efficacy to the feasibility in the daily clinical practice. Herewith we describe some different dietary approaches, developed in Italy in the last decades and applied in the actual clinical practice for the nutritional management of CKD patients. A step-wise approach or simplified dietary regimens are usually prescribed while taking into account not only the residual renal function and progression rate but also socio-economic, psychological and functional aspects. The application of the principles of the Mediterranean diet that covers the recommended daily allowances for nutrients and protein (0.8 g/Kg/day) exert a favorable effect at least in the early stages of CKD. Low protein (0.6 g/kg/day) regimens that include vegan diet and very low-protein (0.3-0.4 g/Kg/day) diet supplemented with essential amino acids and ketoacids, represent more opportunities that should be tailored on the single patient’s needs. Rather than a structured dietary plan, a list of basic recommendations to improve compliance with a low-sodium diet in CKD may allow patients to reach the desired salt target in the daily eating. Another approach consists of low protein diets as part of an integrated menu, in which patients can choose the “diet” that best suits their preferences and clinical needs. Lastly, in order to allow efficacy and safety, the importance of monitoring and follow up of a proper nutritional treatment in CKD patients is emphasized.

Background Dietary treatment is helpful in CKD patients, but nutritional interventions are scarcely implemented. The main concern of the renal diets is its feasibility with regards to daily clinical practice especially in the elderly and co-morbid patients. This study aimed to evaluate the effects of a pragmatic, step-wise, personalized nutritional support in the management of CKD patients on tertiary care. Methods This is a case-control study. It included 823 prevalent out-patients affected by CKD stage 3b to 5 not-in-dialysis, followed by tertiary care in nephrology clinics; 305 patients (190 males, aged 70 ± 12 years) received nutritional support (nutritional treatment Group, NTG); 518 patients (281 males, aged 73 ± 13 years) who did not receive any dietary therapy, formed the control group (CG). In the NTG patients the dietary interventions were assigned in order to prevent or correct abnormalities and to maintain a good nutritional status. They included manipulation of sodium, phosphate, energy and protein dietary intakes while paying special attention to each patient’s dietary habits. Results Phosphate and BUN levels were lower in the NTG than in the CG, especially in stage 4 and 5. The prevalence of hyperphosphatemia was lower in the NTG than in CG in stage 5 (13.3 % vs 53.3 %, p

The start of dialysis treatment is a critical step in the care management of chronic renal failure patients. When hemodialysis is performed three times a week, rapid loss of kidney function and of urine volume output generally occur and this represents an unfavorable prognostic factor. Instead, reducing frequency of hemodialysis sessions, as well as peritoneal dialysis, can contribute to a lesser decrease of residual renal function. Unfortunately, the existing protocols for an incremental hemodialysis approach are not particularly common and they are generally limited to a twice a week hemodialysis schedule. In addition to clinical and economic reasons, an incremental approach to ESRD also contributes to better social and psychological adaptation by the patients to the dramatic change in living conditions linked to the maintenance dialysis treatment. In patients who have attitude for low-protein nutritional therapy, a once weekly dialysis schedule combined with low-protein, low-phosphorus, normal to high energy diet in the remaining six days of the week can be implemented in selected patients. In our experience, this kind of program produced important clinical results and reduction in costs and hospitalization. When compared with a three times a week dialysis schedule, a greater protection of residual renal function and of urine volume output, lower increase in 2 microglobulin, better control of phosphorus and less consumption of phosphate binders and erythropoietin were observed. Careful clinical monitoring and nutrition is essential for the safety and optimization of infrequent hemodialysis. Long-term follow-up analysis shows favorable effects on the overall survival. Furthermore, twice a week hemodialysis is not the only option for an incremental approach of dialysis commencing. In patients who have a good attitude for low-protein nutritional therapy, its arrangement with a program of once weekly dialysis represents a real and effective alternative.

Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5–10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitute a large proportion of PA cases and represent a surgically correctable form of the disease. The WNT signaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling is mutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutations in a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of the tumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. All of the observed mutations altered serine/threonine residues in the GSK3β binding domain in exon 3. The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggesting activation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression and direct measurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. This report provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occur in APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway may be important in APA formation.

Reduction of intestinal load of phosphorus is important for the prevention and treatment of chronic kidney disease (CKD)-mineral and bone disorder (MBD). However, this strategy is limited by patients’ poor adherence to dietary prescription and by the existence of hidden sources of phosphorus. In addition to food containing phosphate-based additives, it was recently claimed that medications may contribute to increase the load of phosphate (P), mainly present as an excipient. To identify medications containing P as an excipient, we performed a systematic screening of medications which could potentially be prescribed for chronic oral therapies in CKD patients. We examined 311 active pharmaceutical ingredients (APIs) and 3763 branded or generic medications, identified by the anatomical therapeutic chemical (ATC) international classification system. Sixty APIs (19.3 %) included at least one medication containing P as an excipient. In total, 472 medications (12.5 %) listed P as an excipient. The prevalence of medications containing phosphate as an excipient was highest for oral antidiabetic medications (23.8 %), followed by antidepressant (19.2 %), antihypertensive (17.5 %) and gastro-intestinal tract (16.4 %) medications. All other classes showed a prevalence

Nutritional abnormalities and physical inactivity are risk factors of increased morbidity and mortality in patients with ESRD. Identify and define malnutrition, in particular protein-energy depletion (PEW), is an important task in the management of renal patients. The aim of this multicenter observational study was to implement the assessment of nutritional status and functional capacity in patients on peritoneal dialysis, including tests and validated methods which are relatively easy to apply in daily clinical practice. The study includes all the 133 prevalent patients (80 m, 53 f, age 65 14 years), in peritoneal dialysis treatment (vintage 26 19 months) in 9 centers in Tuscany. We performed anthropometry, bioimpedance (BIA), clinical biochemistry, evaluation of habitual physical activity (RAPA tests) and performance (Sit-To-Stand test), appetite-evaluation questionnaire, and indices including the Malnutrition Inflammation Score (MIS), Geriatric Nutrition Risk Index (GNRI), Charlson comorbidity index, Barthel and Karnowsky index. The latter showed a condition of dependence in 7.2% and 19.7% of cases, respectively. Poor appetite was recorded in 48.2%. The majority of patients fell within the overweight / obesity range (51%) with waist circumference values associated with increased cardiovascular risk in 51% of males and 60% of females. At the BIA analysis, a BCMI8 kg/m2 was detected in 39% of patients; an estimated protein intake1.0 g / kg/d was found in 59% of cases; 34% of patients had serum albumin3.5 g / dl; control of acidosis was good (bicarbonate 25.4 3.8 mM) but hyperphosphatemia was present in 64.6% of patients. A condition of sedentary or light physical activity was reported by 65.1% of patients, vigorous activity only by 11.9%. The 86.5% of patients able to perform the Sit-to-stand test reported a lower than the reference values for age and sex. A diagnosis of PEW was possible in 8% of our series, while a MIS score11, indicative of PEW, took place in 12.7% of cases. The values of the MIS correlated directly with age and the degree of comorbidity and inversely with the sit-to-stand test, RAPA tests and appetite level. The data in this study show that single tests indicative of malnutrition disorders are frequent to be found in our series of peritoneal dialysis patients. However, a diagnosis of PEW is quite infrequent. A large percentage of patients are overweight with increased abdominal adiposity, and reduced cell mass and protein intake below recommended levels; the level of habitual physical activity is low, and the level of physical capability is scarce. Therefore it is conceivable a nutritional counseling intervention to increase the intake of proteins, limiting the phosphorus and (when indicated) energy intake and to stimulating spontaneous physical activity or arranging assisted programs for functional rehabilitation. Close monitoring of the nutritional status and implementation of programs of adapted physical activity should have a prominent role in the clinical management of patients on peritoneal dialysis.

This is a case report on a patient with non-dialysis chronic kidney disease (CKD) in whom several nutritional issues are briefly discussed from a practical point of view. The article is accompanied by an editorial published in this Journal in relation to the 2nd International Conference of the European Renal Nutrition working group at ERA-EDTA—“Retarding CKD progression: readily available through comprehensive nutritional management?”— and focuses on several practical topics associated with the nutritional approach for the conservative treatment of non-dialysis CKD. The article is divided into 3 sections—basic nutritional assessment, nutritional targets, and nutritional follow-up in non-dialysis CKD—linked to 3 consecutive steps of the clinical follow-up of the patient and the related nutritional concerns and intervention. First visit: Baseline nutritional assessment and basic nutritional considerations in non-dialysis chronic kidney disease (CKD) • What nutritional assessment/monitoring for protein-energy wasting (PEW) should be employed? • Is a body mass index (BMI) of 21 kg/m2 adequate? • What phosphate target should be pursued? • What are the nutritional habits in patients with incident CKD? • What protein needs and amount of dietary protein should be pursued? • Does the quality of protein matter? • What amount of dietary salt should be employed? How should this be obtained? • How should normal serum phosphate be achieved? • What diet should be recommended? Is a vegetarian diet an option? Second visit: Major nutritional targets in non-dialysis CKD • Consequences of unintentional weight loss • What is the role of the renal dietitian in helping the patient adhere to a renal diet? Intermediate visits: Nutritional follow-up in non-dialysis CKD • What treatment for calcium/parathyroid hormone (PTH) will affect CKD progression? Final visits: • Would a dietary recall/intensive dietary education improve adherence with the diet? • Would a very-low-protein diet (VLPD)/ketodiet be indicated for this patient?

Hyperkalemia is a frequent electrolyte disturbance in patients on dialysis or non-dialysis CKD patients, including those using renin-angiotensin system inhibitor drugs. Sodium polystyrene sulfonate (SPS; Kayexalate) is a resin widely used for hyperkalemia treatment. Unfortunately, its use entails some serious unwanted gastrointestinal side effects. We report the case of a 64-year-old male diabetic patient, suffering from ESRD on hemodialysis, who was treated with 30 g of Kayexalate twice a week (long interdialytic interval). This is a quite common case in the clinical practice. The patient experienced an episode of rectal bleeding followed by the diagnosis of non-specific colitis through colonoscopy. Histological examination, showed the presence of crystals of Kayexalate in the colonic mucosa leading to the suspect of iatrogenic intestinal damage caused by Kayexalate administration. Treatment with SPS was stopped. Nevertheless crystals remain evident in the intestinal mucosa in a colonoscopy performed 14 months later due to a new episode of rectal bleeding. Two years after the first episode the patient died because of intestinal infarction. The review of the literature highlights the risk of serious side effects such as necrotizing colitis with perforation both for the drug in sodium phase and in calcium phase. New intestinal potassium-binger agents, apparently without intestinal severe side effects, are under clinical evaluation. This case does not assess if the crystals deposited in the colonic mucosa are inert or have contributed to the final event, but it shows that Kayexalate is a drug with potential harmful effect even when used orally, at very low dosage and without sorbitol. In our opinion, the SPS should be prescribed carefully, especially as chronic administration, and the prescription should be limited to real and pressing requirements.

To assess the knowledge of adult hemodialysis patients and nurses working in dialysis units, specifically with regard to knowledge of phosphorus and other nutrients related to dietary management of end-stage renal disease.Cross-sectional cohort study.Hemodialysis unit.One hundred ninety-one hemodialysis patients and 105 dialysis nurses, as well as 86 control hospital employees who are not health professionals.Nutritional knowledge was assessed by a 25-item chronic kidney disease knowledge assessment tool for nutrition, which includes 15 questions on phosphorus and 10 questions on protein, sodium, and potassium knowledge.The scores obtained by patients were much lower than those of nurses (11.6 ± 3.9 vs. 16.0 ± 2.2, P.001) but slightly higher than those of controls (10.6 ± 3.2, P.05). Patients with phosphorus serum level5.5 mg/dL showed chronic kidney disease knowledge assessment tool for nutrition scores similar to those of patients with a serum phosphorus level5.5 mg/dL. The prevalence of right answers to questions regarding knowledge of phosphorus was lower than that regarding knowledge of the other nutrients, both for patients (38.4% ± 17.8% vs. 57.3% ± 19.9%, P.001) and nurses (55.6% ± 11.1% vs. 74.8% ± 11.7%, P.001) as well as for controls (30.7% ± 14.5% vs. 60.1% ± 17.4%, P.001).Our study suggests that nutritional knowledge of hemodialysis patients, although higher than the general population, is lower for phosphorus with respect to the other nutrients, such as protein, sodium, and potassium. This occurs even in patients with hyperphosphatemia or those taking phosphate binder medications. Nurses showed the best scores; however, improvement is necessary, especially with regard to knowledge of phosphorus. Training programs on nutrition for nurses and on information for patients should be implemented. They can contribute to achievement of a more effective control of phosphate balance, reduction of costs, and improvement of the quality of care for hemodialysis patients.

The increasing detection of adrenal tumors and the availability of a more sophisticated biochemical work-up leading to rising numbers of sub-clinical Conn's and Cushing's syndromes coincide with a rising number of adrenalectomies worldwide. The aim of our study was to report a single institution's experience with adrenal surgery.We report data of 528 adrenalectomies, operated at our institution before and after the onset of minimally invasive endoscopic surgery (1986-1994, 1995-2008). Gender, age, indication, imaging, surgical approach, operating time, histology, tumor size, hospital stay, and complications were analyzed retrospectively.A total of 478 patients underwent adrenal surgery during the time observed. The average number of yearly adrenalectomies increased from 14 to 21 (p = 0.001) after the onset of laparoscopic surgery. Imaging techniques showed a significant shift towards magnetic resonance imaging (p 0.001) and preoperative assessment of tumor size was significantly correlated to malignancy: 10.8 % (11/102) and 42 % (21/50) of tumors measuring 4-6 cm and ≥6 cm, respectively, were malignant in the final histology report (p 0.001). Patients operated by minimally invasive endoscopy were significantly younger (mean 49.4 years, p = 0.046), had significantly shorter operating times (mean 118 min, p 0.001), had shorter hospital stays (mean 7.1 days, p 0.001), and had less complications (6.9 %, p = 0.004) compared to patients resected through open procedures.Although adrenalectomy rates increased and minimally invasive endoscopic surgery reduced hospital stay and complications at our institution, the yearly number of procedures was still low with often high surgical complexity. We therefore believe that adrenal surgery remains a highly specialized procedure that should preferably be performed at endocrine surgery centers.

This cross-sectional case-control study evaluated upper limb muscle strength and shoulder mobility in hemodialysis (HD) patients with arteriovenous fistula or graft. Twenty-five adult patients on thrice-a-week HD treatment for 6 months at least, were selected for the study. In all the patients and control subjects, handgrip tests and tests of range of motion in the upper extremities were evaluated by physiotherapy tests. Patients on HD showed lower muscle strength than age and sex matched subjects without severe chronic kidney disease (right: 30.1 ± 11.6 vs 40.5 ± 15.1 kg, P < 0.001; left 29.1 ± 12.9 vs 40.7 ± 11.1 kg, P < 0.01), and a reduced range of shoulder mobility. The presence of fistula or graft was associated with a greater limitation of both active (74.0 ± 18.3 vs 85.2 ± 8.8 °, P < 0.01) and passive (82.2 ± 9.9 vs 87.2 ± 6.6 °, P < 0.05) extra-rotation than the contralateral limb, with a higher prevalence of impingement (72 vs 36%, P < 0.05). Muscle strength was related to albumin and inversely to age; whereas β2-microglobulin and CRP serum levels were associated with impairment of passive and active extra-rotation of the shoulder that was free from the fistula or graft. In summary, patients on HD have a reduced range of shoulder mobility and marked reduction of muscle strength. The abnormalities are more prevalent in upper limbs with fistula or grafts. The arteriovenous fistula or graft may worsen the disability of the patient's upper limbs presumably due to the obligate position required during the HD sessions. Proper pre- and post-dialysis exercise programs should be implemented to maintain mobility and strength of the upper limbs.

In mouse retinal explants, octreotide, a somatostatin [somatotropin release-inhibiting factor (SRIF)] receptor 2 (sst(2)) agonist, prevents the hypoxia-induced vascular endothelial growth factor upregulation. In mice with oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity, either sst(2) overexpression or octreotide have been found to limit hypoxia-induced angiogenic processes. Here, we investigated whether sst(2) influences retinal degeneration in response to hypoxia in wild-type (WT), sst(1)- and sst(2)-knockout (KO) mice. In retinal explants, we determined the role of sst(2) on apoptotic signals. In control condition, caspase-3 activity and the Bax/Bcl-2 ratio were lower in sst(1)-KO than in WT, but higher in sst(2)-KO than in WT retinas. In all strains, a comparable increase in caspase-3 activity and the Bax/Bcl-2 ratio was observed after hypoxia. The hypoxia-induced increase in apoptotic signals was recovered by octreotide in both WT and sst(1)-KO retinas. To investigate the role of sst(2) on retinal function, we recorded electroretinogram (ERG) in response to light flashes in OIR mice. ERG responses did not differ between WT and KO mice with the exception of oscillatory potentials (OPs) which, in sst(1)-KO mice, displayed much larger amplitude. In all strains, hypoxia drastically reduced a-, b-waves and OPs. In both WT and sst(1)-KO mice, octreotide recovered a- and b-waves, but did not recover OPs in sst(1)-KO mice. Neither apoptotic signals nor ERG was affected by octreotide in sst(2)-KO mice. These results show that sst(2) may protect retinal cells from hypoxia, thus implementing the background to establish potential pharmacological targets based on sst(2) pharmacology.

Introduction: Weight loss amongst women with polycystic ovary syndrome (PCOS) is crucial to reduce the risk of endocrine, reproductive and metabolic complications including hirsutism, menstrual disturbances and cardiovascular disease. With approximately 50% of women with PCOS being overweight or obese, effective dietary management of weight in PCOS is essential. However, there is inconsistent evidence as to whether specifically modified diets (e.g. reduced carbohydrate diets) are more effective at achieving weight loss amongst women with PCOS than are conventional healthy hypocaloric diets. Material and Methods: A systematic review and meta-analysis of randomized controlled trials that had compared weight and BMI between women with PCOS who had undergone either a specifically modified diet or a conventional healthy hypocaloric diet were performed. Six electronic databases were searched, a manual search of the reference lists of the included studies was carried out and authors were contacted for additional information. Nine studies with a total of 395 participants (all with a body mass index [BMI] ≥30) were included in the meta-analysis. The effect size used was the mean difference in post-intervention weight and BMI between participants who had undergone a specifically modified diet and participants who had undergone a conventional healthy hypocaloric diet. Results: There were no differences between groups in post-intervention weight (mean difference 1.26, 95% confidence interval (CI) -0.92 to 3.43, p = .26; heterogeneity I2 = 50%, p = .04) or BMI (mean difference 0.15, 95% CI -0.93 to 1.23, p = 0.79; heterogeneity I2 = 44%, p = 0.10). Subgroup analyses according to the presence of a dietary run-in period (a period at the start of the study during which all participants are placed on an identical diet in order to equalize them on variables influenced by diet), intervention duration and type of diet and a sensitivity analysis according to study quality were not significant. Conclusions: Whilst the results should be interpreted in light of the moderate heterogeneity observed, they suggest that specifically modified diets offer no added benefit for weight loss in women with PCOS over conventional healthy hypocaloric diets. The findings of this meta-analysis may promote the unification of guidelines for the dietary management of PCOS and allow clinicians to be confident in prescribing conventional healthy hypocaloric diets for weight loss amongst their PCOS patients.

Oxygen-induced retinopathy (OIR) is a model for human retinopathy of prematurity. In mice with OIR, beta-adrenergic receptor (β-AR) blockade with propranolol has been shown to ameliorate different aspects of retinal dysfunction in response to hypoxia. In the present study, we used the OIR model to investigate the role of distinct β-ARs on retinal proangiogenic factors, pathogenic neovascularization and electroretinographic responses. Our results demonstrate that β(2) -AR blockade with ICI 118,551 decreases retinal levels of proangiogenic factors and reduces pathogenic neovascularization, whereas β(1) - and β(3) -AR antagonists do not. Determination of retinal protein kinase A activity is indicative of the fact that β-AR blockers are indeed effective at the receptor level. In addition, the specificity of ICI 118,551 on retinal angiogenesis has been demonstrated by the finding that in mouse retinal explants, β(2) -AR silencing prevents ICI 118,551 effects on hypoxia-induced vascular endothelial growth factor accumulation. In OIR mice, ICI 118,551 is effective in increasing electroretinographic responses suggesting that activation of β(2) -ARs constitutes an important part of the retinal response to hypoxia. Lastly, immunohistochemical studies demonstrate that β(2) -ARs are localized to several retinal cells, particularly to Muller cells suggesting the possibility that β(2) -ARs play a role in regulating vascular endothelial growth factor production by these cells. The present results suggest that pathogenic angiogenesis, a key change in many hypoxic/ischemic vision-threatening retinal diseases, depends at least in part on β(2) -AR activity and indicate that β(2) -AR blockade can be effective against retinal angiogenesis.

PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a well established tumor suppressor gene, which was cloned to chromosome 10q23. PTEN plays an important role in controlling cell growth, apoptosis, cell adhesion, and cell migration. In various studies, a genetic change as well as loss of PTEN expression by different carcinomas has been described. To date, the role of PTEN as a differentiation marker for neuroendocrine tumors (NET) and for the loss of PTEN expression is still unknown. It is assumed that loss of PTEN expression is important for tumor progression of NETs. We hypothesize that PTEN might be used as a new prognostic marker. We report 38 patients with a NET of the pancreas. Tumor tissues were surgically resected, fixed in formalin, and embedded in paraffin. PTEN expression was evaluated by immunohistochemistry and was correlated with several clinical and pathological parameters of each individual tumor. After evaluation of our immunohistochemistry data using a modified Remmele Score, a widely accepted method for categorizing staining results for reports and statistical evaluation, staining results of PTEN expression were correlated with the clinical and pathological parameters of each individual tumor. Our data demonstrates a significant difference in survival with existence of lymph node or distant metastases. Negative patients show a significant better survival compared with positive patients. Furthermore, we show a significant difference between PTEN expression and WHO or TNM classification. Taken together, our data shows a positive correlation between WHO classification and the new TNM classification of NETs, and loss of PTEN expression as well as survival. These results strongly implicate that PTEN might be helpful as a new prognostic factor.

Summary The active transport of sperm through the female genital tract is a very important factor in the fertilisation process. There is conflicting evidence as to whether seminal plasma has a positive or a negative effect on reproductive performance regarding the sperm transport in the female genital tract. In this study, we investigated if the perfused swine uterus is an appropriate model to study the effect of human seminal plasma on uterine contractility. It was found that repeated application of human seminal plasma caused a significantly higher rise in pressure and frequency of contractions in perfused swine uteri compared to buffer [a 1.8-fold and 1.5-fold pressure rise (Δt1SP, P = 0.025; Δt2SP, P = 0.004)] after the first and second application of seminal plasma respectively, and even a 2-fold pressure rise after the third application with a statistical significance of P = 0.007. The pressure rise caused by the seminal plasma over the entire period of application was calculated using a mathematical programme and was represented by the integral of the pressure curve over time. This perfusion model as well as the use of pressure-time integrals is suitable for patho-physiological studies of the uterus.

A 35-year-old woman was admitted to the Nephrology and Dialysis Unit of Pisa University for hypertension, hypokalaemia, renal impairment, proteinuria and hyperglycaemia. plasma renin activity (PRA) and plasma aldosterone were elevated, but Doppler ultrasound and angio-computed tomography (CT) of renal arteries were normal. Abdomen CT revealed only a left adrenal mass, and measurement of catecholamines suggested the diagnosis of pheochromocytoma. Biochemical findings suggestive of hyperparathyroidism were also detected, but a multiple endocrine disorder was excluded by genetic analysis. Pathology examination confirmed the pheochromocytoma and immunohistochemistry also showed positivity for parathyroid hormone. After surgery, disappearance of the symptoms and normalization of all haemodynamic and humoral parameters was observed. This is a rare case of pheochromocytoma responsible for secondary hyperaldosteronism, hyperparathyroidism, proteinuric renal disease and diabetes mellitus.

INTRODUCTION Exercise training is beneficial for hemodialysis patients, but it should be tailored to individual abilities and willingness to participate. This study evaluated the effects of different 6-month programs of physical activity in 18 patients of a single hemodialysis unit. METHODS Before and after a 12-month control period (T0), and following 3 (T3) and 6 (T6) months of training, the patients underwent the 6-minute walk test (6MWT) and constant treadmill test at 3 km/hour speed and 10% grade; spontaneous physical activity was assessed by pedometers. All patients trained for coordination, flexibility and muscular strengthening for 30 minutes within the first 2 hours of hemodialysis sessions: 9 patients underwent home exercise walking training (advised walking group [AWG]); the other 9 patients underwent the advised home training program plus an additional supervised gym training session, twice weekly (supervised walking group [SWG]). RESULTS In both AWG and SWG, no changes occurred during the control period (232 ± 204 m and 248 ± 187 m at T0). In contrast, endurance performance at treadmill increased at T3 and T6 in the AWG (377 ± 272 m and 615 ± 413 m; p

Background Adipocytes produce signalling molecules which can act on target cells including pancreatic beta-cells. In previous studies we found adipocytes to directly stimulate insulin secretion and the proliferation of pancreatic beta-cells in vitro. Rimonabant acts as an antagonist at the cannabinoid-1 (CB-1) receptor which is expressed on adipocytes. Rimonabant decreases insulin levels in vivo. This effect can either be explained by improving insulin sensitivity or by effects on beta-cells including the modulation of adipocyte - beta-cell interactions. Objectives To test how pre-treatment of primary human adipocytes with rimonabant affects the cross-talk between adipocytes and pancreatic beta-cells in vitro. Results Rimonabant had no direct effect on insulin secretion or beta-cell proliferation at a concentration range from 1 nM to 1 μM. This is in line with previous findings showing that in the murine pancreas CB-1 receptors are preferentially expressed on non-beta-cells, while rimonabant is a selective blocker of CB-1 receptors. We found fat-cell conditioned-medium without (FCCM) and after pre-treatment for 24 h with 100 nM rimonabant (FCCM-RB) to induce insulin secretion from primary murine beta-cells to a similar extent. Proliferation of a pancreatic beta-cell line was enhanced by FCCM to 219%, while FCCM-RB inhibited proliferation to 53%. As we previously found Wnt-signalling to mediate effects of adipocytes on beta-cell proliferation we tested the ability of FCCM and FCCM-RB to activate canonical Wnt-signalling in target cells. However, there was no significant difference between the groups: FCCM and FCCM-RB stimulated Wnt reporter gene activity to 181% and 179%, respectively. In addition, there was no significant difference in adiponectin levels between FCCM and FCCM-RB (56.8 vs. 58.1 ng/ml), showing that adiponectin does not mediate the differential effects on beta-cell proliferation by FCCM and FCCM-RB. Conclusion Our data show that rimonabant modulates the adipocyte - beta-cell interaction with respect to beta-cell proliferation and indicate that signalling molecules other than adiponectin and components of the Wnt pathway mediate this cross-talk.

Objective To evaluate the impact of smoking on endocrine, metabolic, and clinical parameters in women with polycystic ovary syndrome (PCOS). Design Cohort analysis. Setting University hospital. Patient(s) 346 women with PCOS, including 98 smokers and 248 nonsmokers. Intervention(s) Screening panel, including physical examination, weight and height measurement, and ultrasound examination of the ovaries, and hormone and insulin measurements. Main Outcome Measure(s) Clinical, metabolic, and endocrine parameters, oral glucose tolerance test, calculation of insulin resistance indexes. Result(s) In women with PCOS, smoking was associated with statistically significantly increased levels of fasting insulin and calculated free testosterone (cFT) and with a raised free androgen index (FAI) score, which resulted in aggravated scores on the homeostatic model for assessment of insulin resistance (HOMA-IR). However, no differences were observed between the smoking and nonsmoking groups with regard to the clinical parameters for hirsutism, acne, ovulatory function (classified as eumenorrhea, oligomenorrhea, and amenorrhea), or polycystic ovaries using the ultrasound criteria recommended according to the Rotterdam definition. Conclusion(s) In women with PCOS, smoking is associated with increased free testosterone and fasting insulin levels, resulting in aggravated insulin resistance. However, there were no differences between smokers and nonsmokers when clinical parameters were compared.

The natural history of urolithiasis includes the risk of recurrence and of the development of chronic kidney and/or bone disease, which is why a thorough clinical and metabolic evaluation of these patients is of the utmost importance at disease onset. This paper is aimed at identifying the type of urolithiasis, the related risk factors, and the corresponding treatment options. The diagnostic and therapeutic approach described here includes 1) accurate history taking to detect secondary nephrolithiasis and screen for the main risk factors for kidney and bone disease; 2) metabolic evaluation graded according to different complexity levels based on the severity of the disease and the presence of risk factors; 3) carrying out appropriate imaging procedures. The resulting information allows to plan treatment based either on general rules of lifestyle and diet, or on selected medical intervention, if necessary. This report, which is based on current guidelines, was produced by the Gruppo Italiano di Studio Multidisciplinare per la Calcolosi Renale. It is addressed to all professionals involved in the management of patients suffering from nephrolithiasis, first of all general practitioners, who often become involved immediately at the onset of the disease.

In hemodialysis patients, sedentarism is a potentially modifiable mortality risk factor. We explored whether healthcare staff's attitude towards exercise interacts with patient-perceived barriers in modifying the level of physical activity in this population.In this prospective, cross-sectional, multicenter study we recruited 608 adult patients and 330 members of the healthcare staff in 16 hemodialysis units in Italy. We assessed patient-perceived barriers to, and healthcare staff's attitude towards, exercise by specific questionnaires. We fitted multilevel linear models to analyze the relationships of either barriers or staff's attitude, and their interaction, with a measure of patient self-reported physical activity (the Human Activity Profile-Adjusted Activity Score [HAP-AAS]), adjusting for multiple confounders. We also employed latent class analysis to dichotomize patients into those endorsing or not endorsing barriers.Most barriers were negatively associated with the HAP-AAS (adjusted change attributable to a given barrier ranging between -5.1 ["Feeling too old", 95% Confidence Interval: -9.4 to -0.8] and -15.6 ["Ulcers on legs and feet", 95%CI: -24.8 to -6.5]. We found a significant interaction between staff's attitude and barriers (adjusted P values ranging between 0.03 ["I do not believe that it is physician's or nurse's role providing advice on exercise to patients on dialysis"] and 0.001 ["I do not often ask patients about exercise"]). A beneficial effect of a proactive staff's attitude was evident only in patients not endorsing barriers.Barriers and non-proactive staff's attitude reduce physical activity in hemodialysis patients. Patients not endorsing barriers benefit the most from a proactive staff's attitude.

Forty-six consecutive patients who underwent total parathyroidectomy (tPTX) for hyperparathyroidism associated with end-stage kidney disease (CKD5) in a University Hospital from 1990 to 1999 were included in a long-term observational study. Outcome parameters included symptoms (bone pain, pruritus and muscle weakness evaluated by visual analog scales [VAS]) and laboratory data (intact parathyroid hormone [iPTH], total calcium, and alkaline phosphatase) assessed before, shortly postoperatively and then at a later time point: 40 patients were on maintenance hemodialysis and six on conservative medical therapy. Forty-four patients had four glands removed, while only three glands were found in the remaining two. Perioperative complications consisted of acute symptomatic hypocalcemia in 10 (22%) patients and non-specific complaints in three (7%). No laryngeal nerve palsies occurred. After a median follow-up of eight years, 43 subjects were evaluated: 37 (86%) were cured, three (7%) had persistent and three (7%) recurrent disease. Eleven patients underwent successful renal transplantation and 23 died during the period of observation. iPTH decreased from a mean of 1084+/-505 pg/ml to 120+/-381 pg/ml (p0.0001). No subsequent bone fractures, persistent bone pain or disability were reported; this includes patients who later received a functioning renal graft. tPTX was able to correct hyperparathyroidism in most of the patients and was associated with a low long-term relapse rate. iPTH levels remained low in 17 cases without symptoms and no clinically significant side effects. The beneficial effects of tPTX occurred in the majority of patients while renal transplantation was performed in a minority of patients. tPTX should be considered a safe and successful procedure for the treatment of severe secondary hyperparathyroidism associated with chronic kidney disease.

ObjectiveEpCAM (CD326) is overexpressed in progenitor cells of endocrine pancreatic islands of Langerhans during fetal development and was suggested to act as a morphoregulatory molecule in pancreatic island ontogeny. We tested whether EpCAM overexpression is reactivated in insulinomas, endocrine tumors arising in the pancreas.Design/methodWe used monoclonal anti-EpCAM antibody Ber-Ep4 for immunohistochemistry on formalin-fixed and paraffin-embedded tumor material. We analyzed 53 insulinomas: 40 benign (disease stageResultsIn 38% of the benign insulinomas (disease stagePConclusionThis first EpCAM expression study in benign/malignant insulinomas indicates that strong EpCAM expression could help to identify patients at risk for malignant disease and might be used as a therapeutic target for antibody-based therapies in patients with metastatic insulinoma.

Neuroendokrine Tumoren des gastroenteropankreatischen Systems (GEP-NET) sind charakterisiert durch die Expression neuroendokriner Marker sowie die Synthese, Speicherung und Sekretion von Peptidhormonen und/ oder biogenen Aminen. Es handelt sich um mehr als 50 unterschiedliche Tumorentitäten mit klinisch sehr unterschiedlichem Verlauf. Sie können sporadisch oder familiär auftreten. Die hohe biologische und klinische Vielfalt äußert sich in unterschiedlichen genetischen Profilen auf DNA- und mRNA-Ebene, welche wie folgt zusammengefasst werden können: 1. NET unterscheiden sich genetisch von den häufigen nichtneuroendokrinen Karzinomen des Verdauungstraktes. 2. Die klinisch-pathologische Heterogenität der GEP-NET spiegelt sich auch auf genetischer Ebene wider. 3. Bei pankreatischen NET finden sich deutliche genetische Unterschiede zwischen Insulinomen und anderen Entitäten. 4. Die Tumorprogression geht bei pankreatischen NET mit einer Zunahme von genetischen Veränderungen einher. 5. Pankreatische NET unterscheiden sich genetisch von gastrointestinalen NET. 6. Sporadische GEP-NET unterscheiden sich genetisch von hereditären (familiären) GEP-NET.

Introduction: The aim of this study was to evaluate long-term changes in endocrine and metabolic parameters and body mass index in women with polycystic ovary syndrome (PCOS) who were treated with metformin over 2 years without caloric restriction. Material and Methods: Twenty-six obese women with PCOS were treated with metformin over 2 years without caloric restriction. Clinical, metabolic and endocrine parameters and the body mass index were measured and an oral glucose tolerance test was carried out to calculate insulin resistance indices at the beginning and at the follow-up after 2 years. The Homeostatic Model for Assessment of Insulin Resistance (HOMA-IR) was calculated. Results: No significant changes in body mass index or HOMA-IR were observed. However, a significant decrease in fasting and 2-h insulin levels was observed. Women showed a significant increase in sex hormone-binding globulin (SHBG) levels, while total testosterone (TT) levels and the free androgen index decreased significantly. Furthermore a significant decrease in Hirsutism was observed. There was a decrease in cholesterol and an increase in high-density lipoprotein. Conclusions: Long-term treatment with metformin in women with PCOS appears to reduce androgen excess due to increased SHBG and decreased TT levels resulting in improvement of Hirsutism as a clinical sign of androgen excess. Furthermore a significant decrease in fasting and 2-h insulin levels and slightly improved insulin resistance indices were observed.

BACKGROUND: Due to limited staffing resources and the need to preserve patients' privacy, it is difficult to improve the assessed practical courses in gynecology required by law for the licensing of physicians in Germany ( ARZTLICHE APPROBATIONSORDNUNG, AAppO). A previously published project showed that including structured practical teaching (skills training) using suitable obstetric and gynecological models in courses taught by specially trained student teachers (peer teachers) represents a potential solution to the problem. However, there are as yet no data regarding the effectiveness of this approach. AIM: Aim of the study was to determine the effectiveness of a peer-assisted skills training for students as part of a gynecological and obstetric practical course for theoretical and practical examinations (objective structured clinical examination, mini-OSCE) (primary end point). How do students who have been taught in this way rate the educational quality, teaching atmosphere, personal learning progress, and this type of practical course overall (secondary end points)? METHODS: Following the implementation of a skills training section during a practical course, students (n = 139) were randomly assigned to 24 groups. Most groups consisted of six participants. Half of these groups, with a total of 71 students, received peer teaching during skills training, while the other half (n = 68) were taught by postgraduate lecturers. The rest of the one-week practical course, including the theoretical and practical examinations, was identical for all groups. The results of a theoretical and practical examination, also newly implemented (primary end point) and the results of the evaluation before (comparability of the groups) and after the practical course (secondary end points) were analyzed. RESULTS: The groups taught by postgraduate lecturers did not differ with regard to age, sex, number of completed semesters, or prior specialist training from the students who were taught by the peer teachers. In the purely practical OSCE stations, the students in the postgraduate group achieved 58.26 ± 3.2 (95 % CI, 57.5-59.5) out of a total of 62 points, while in the peer teacher group they scored 58.82 ± 2.6 (95 % CI, 58.2-59.4) (p = 0.27). In dealing with the case descriptions, for which material taught to both groups in seminars by postgraduate lecturers was relevant, the postgraduate group achieved 26.52 ± 3.2 (95 % CI, 25.7-27.3) of 30 points, while in the peer teacher group the figure was 26.29 ± 2.7 (95 % CI, 25.6-27.0) (p = 0.64). In the final evaluation regarding the motivation of the trainers, the teaching atmosphere, and the effectiveness of preparation for the practical examination, no significant differences were found. The postgraduate lecturers only had significantly better results than the peer teachers when conveying the theoretical background and responding to questions. CONCLUSIONS: To communicate the principles of basic practical medical skills in a gynecological practical course, teaching by specially trained peers is just as effective as teaching by postgraduate teachers.

Hintergrund: In der Novelle zur Arztlichen Approbationsordnung (AAppO), die am 1.10.2003 in Kraft getreten ist, wird fur die Gynakologie und Geburtshilfe ein benotetes Blockpraktikum vorgeschrieben, das auch der Forderung nach starkerer Praxisorientierung und Kleingruppenarbeit Rechnung tragen soll. Die Umsetzung dieser Forderung stost allerdings auf erhebliche Probleme, die sich u.a. aus den begrenzten personellen Ressourcen der Ausbildungskliniken sowie aus der Notwendigkeit zur Wahrung der Intimsphare der Patientinnen ergeben. Entsprechend unzufrieden ausern sich Studierende. Die Zahl der bisher existierenden Losungsvorschlage fur das Dilemma ist gering, ihre Evaluation begrenzt und ihre Reproduzierbarkeit eingeschrankt. Fragestellung: Es sollte daher untersucht werden, wie sich trotz der genannten Limitationen an einer Universitatsfrauenklinik Strukturen implementieren lassen, die den Forderungen der neuen AAppO Rechnung tragen, aktuelle medizindidaktische Erkenntnisse berucksichtigen, die Zufriedenheit der Studierenden mit der Ausbildung im Blockpraktikum erhohen sowie Fortschritte in der Beherrschung arztlicher Grundfertigkeiten im Fachgebiet messbar machen. Methoden: Zur Problemlosung wurde das von KERN inaugurierte Modell fur die Curriculumsentwicklung in der Medizin herangezogen. Dieser „Six-Step Approach“ sieht folgende Arbeitsschritte vor: Eine Problemidentifizierung mit allgemeiner Bedarfsanalyse (1), eine spezielle Bedarfsanalyse fur die Zielgruppe der Lernenden (2), die Formulierung ubergeordneter und spezifischer Lernziele (3), die Festlegung der erforderlichen Unterrichtsmethoden (4), eine Implementierungsphase (5) sowie als letzten Schritt eine Evaluations- und Feedbackphase (6). Ergebnisse: Unter den aktuellen Bedingungen erweist sich ein im Curriculum fest verankertes Training praktischer frauenarztlicher Fertigkeiten an Phantomen (Skills Training) als geeignet, bei den Studierenden die Zufriedenheit mit der praktischen Ausbildung in einem Blockpraktikum zu erhohen. Am Beispiel der Erlanger Frauenklinik wird gezeigt, wie sich dazu ubergeordnete und spezifische Lernziele formulieren lassen, welche Unterrichtsmethoden angewandt werden konnen und wie das Modell mithilfe speziell ausgebildeter Studierender (Peer Teacher) sowie einer adaquaten formativen Prufung Ressourcen sparend und effektiv implementiert werden kann.

Pheochromocytomas of the adrenal medulla may be life-threatening catecholamine-producing tumors which are malignant in about 10% of cases. Differential diagnosis between malignant and benign tumors is dependent on the development of metastasis or extensive local invasion. A number of genetic aberrations have been described in pheochromocytomas, but no marker associated to malignancy has been reported. We applied an expression microarray containing 7770 cDNA clones and analysed the expression profiles in eleven tumors compared to normal adrenal medulla. Stathmin (STMN1, Op18) was most conspiciously overexpressed among the differentially expressed genes. RT-PCR analysis further confirmed mRNA overexpression, 6 to 8-fold for benign and malignant tumors, and 16-fold for metastases. Stathmin protein overexpression was observed by immunohistochemistry, and distinct differential protein expression between benign and malignant/metastasis specimens was confirmed by Western blot analysis. The results introduce stathmin as a possible diagnostic marker for malignant pheochromocytomas, and further evaluations are warranted.

Background The aldosterone-to-renin ratio (ARR) is an established diagnostic tool in the screening for primary aldosteronism (PA). However, hormonal determinations are time consuming and expensive. Therefore, we studied the effectiveness of the serum sodium to urinary sodium to (serum potassium)2 to urinary potassium (SUSPPUP) ratio in the diagnosis of PA. Design This study included 35 patients with PA, 71 patients with essential hypertension to whom this diagnosis could be excluded, 23 normal subjects without hypertension, and 22 patients with primary adrenal insufficiency. We compared the SUSPPUP ratios with the ARR in these patient groups. Results We show that the ARR distinguished PA from essential hypertension with a sensitivity of 94·2% and a specificity of 92·1% at a cutoff of 33 (ng L−1: ng L−1). It correlated well with the SUSPPUP ratio. The sensitivity and specificity of SUSPPUP was 88·6% and 85·9% at a cutoff of 5.3 (mmol L−1)−1, respectively, and thus not as good as the ARR. Conclusions The ARR is a good parameter in the screening for PA. The SUSPPUP ratio is a cheap and rapid tool to assess the extent of mineralocorticoid excess and, therefore, can be offered to more patients. In addition, the application of the SUSPPUP ratio can be extended to patients who suffer from other forms of mineralocorticoid hypertension (e.g. with low aldosterone levels).

There is a relationship between thyroid function and insulin sensitivity and alterations in lipids and metabolic parameters. Little information is available regarding this relationship in women with polycystic ovary syndrome. However all those pathologies are also described as often affecting women with polycystic ovary syndrome. The association between thyroid-stimulating hormone2.5 mIU/l andor =2.5 mIU/l with insulin resistance and endocrine parameters in 103 women with polycystic ovary syndrome was studied. Clinical, metabolic and endocrine parameters were obtained and an oral glucose tolerance test was performed with calculation of insulin resistance indices. Women with thyroid-stimulating hormoneor =2.5 mIU/l had a significantly higher body mass index (P = 0.003), higher fasting insulin concentrations (P = 0.02) and altered insulin resistance indices (P = 0.007), higher total testosterone (P = 0.009) and free androgen indices (P = 0.001) and decreased sex hormone-binding globulin concentrations (P = 0.01) in comparison with women with thyroid-stimulating hormone2.5 mIU/l. Generally, all of these parameters correlated significantly (P0.05) with thyroid-stimulating hormone only in women with thyroid-stimulating hormoneor =2.5 mIU/l. Women with polycystic ovary syndrome and with thyroid-stimulating hormoneor =2.5 mIU/l had significantly altered endocrine and metabolic changes.

A previously reported method for the assessment of the ratio of tetrahydrocortisol (THF) + allo-tetrahydrocortisol (A-THF) to tetrahydrocortisone (THE) by HPLC-MS-MS has been significantly improved, in order to increase either ruggedness and reliability. That was achieved by the introduction of an on-line sample cleanup stage, which made use of a perfusion column as a solid phase microextraction (SPE) cartridge. The set of analytes was expanded, by introducing cortisol and cortisone, whose ratio supply additional diagnostic information. The response factors of both THF and A-THF has been checked, resulting almost identical, as well as the influence of the matrix on the calibration curves which, although different for water and urine, had similar effect on the ratios of interest. As a consequence, the calibration solutions can be prepared in pure water. The influence of several different storage procedures has also been tested, resulting in no substantial effect on the final result. Finally, the improved method has been used to run real samples from healthy volunteers, with satisfactory results.