Features of patients and fracture risk in hypoparathyroidism; a single center study.

PURPOSE: Patients with hypoparathyroidism (hypoPT) have low bone turnover and high bone mineral density (BMD). However, data on fracture risk are conflicting. The objectives of this study were: 1. To describe clinical/biochemical characteristics of hypoPT patients followed at a single medical center. 2. To identify postsurgical hypoPT patients and investigate their fracture rate compared with gender/age-matched post-surgical normocalcemic patients. METHODS: Retrospective analysis of patient's medical records treated at the tertiary medical center in 2010-2021 identified by computerized medical database search. RESULTS: The cohort included 133 patients (91% women, mean age 64 ± 13 years) of whom 105 (79%) had post-thyroidectomy hypoparathyroidism and the remainder had an autoimmune/idiopathic/other etiology. Mean follow-up time was 21 ± 12 and 27 ± 12 years, respectively. The control group included 142 post-thyroidectomy patients without hypoparathyroidism. Patients in the postsurgical hypoparathyroidism group were older and had higher calcium and PTH levels at diagnosis than the non-surgical hypoPT patients. Comparing the postsurgical hypoPT and postsurgical normocalcemic control patients revealed a significantly higher BMD in the hypoPT group. Yet, fracture rates were 31% in the postsurgical hypoparathyroidism group and 21% in the control group (P = 0.1) over a similar median follow-up period (17 and 18.4 years, respectively). In both groups the most common fracture site was the spine (50% and 70%, respectively; p = 0.33), mainly nonclinical morphometric fractures. Higher phosphorus blood level was associated with increased fracture risk. CONCLUSIONS: The relatively high BMD in patients with postsurgical hypoparathyroidism is not associated with lower fracture risk. Silent morphometric fractures are quite common in this group of patients.

Cecal Resection with Bipolar Sealing Devices in a Rat Model.

Background: Bipolar sealing devices are routinely used to seal blood vessels. The aim of the study is to evaluate the feasibility and safety of colonic sealing with the use of the bipolar energy devices in rats as model for experimental appendectomy. Methods: Seventy-five male Wistar rats underwent a cecal resection with four different bipolar sealing devices or a linear stapler. The harvesting procedure was performed immediately or at postoperative day (POD) 7. The sealing front bursting pressure (BP) was measured in both groups. At POD7, the resection line was clinically examined and the hydroxyproline (HDP) levels were determined. Hematoxylin and Eosin (H&E) staining was used for histopathological evaluation of the sealing front as well. Results: There was no mortality and no insufficiency. The BPs between the bipolar sealing devices showed no statistical differences. The early phase of the seal (POD 0) provides a low BP with an 30.8% increase until POD 7. The BPs in the stapler group showed significant better values. The hydroxyproline levels did not differ statistically between the groups. Histopathologically, there were more signs of ischemic necrosis in the stapler group than in the sealing devices groups. Conclusion: The resection and sealing of the cecum as an experimental appendectomy model with the use of bipolar energy devices proved feasible and safe in rats. The different energy devices in this study produce comparable results. To justify clinical practice in humans, several studies on the underlying mechanisms of early stage wound healing are needed.

[Colorectal tumor evolution in inflammatory bowel disease : Dynamics of genomic alterations and potential molecular markers to predict malignant progression]. / Kolorektale Tumorevolution bei chronisch-entzündlichen Darmerkrankungen : Dynamik genomischer Alterationen und mögliche molekulare Marker zur Vorhersage einer malignen Progression.

Inflammatory bowel diseases (IBDs) increase the risk for colorectal cancer (CRC). In IBD, the evolution of potential tumor clones occurs long before neoplastic lesions become evident and these clones can be undetectable by endoscopy and histology at early stages. The spectrum of genomic alterations in IBD-associated colorectal carcinogenesis is distinct from the changes observed in the sporadic adenoma-carcinoma sequence. Predominant alterations include aneuploidies and mutations of TP53, which both occur early in IBD-related tumorigenesis. In some IBD patients, genomic alterations can already be detected in colonic mucosa without any histologic signs of dysplasia. Genomic analysis of multiregional samples from colectomy specimens of IBD patients revealed distinct tumor evolutionary patterns. This suggests an increased genomic instability in the chronically inflamed bowel that enables the emergence of multiple, phylogenetically unrelated neoplastic lesions within the colorectum of a single IBD patient. This article summarizes the genomic alterations underlying IBD-associated colorectal tumorigenesis and the evolutionary patterns from inflamed, not yet dysplastic epithelium to CRC. Furthermore, it is discussed how this knowledge can eventually be exploited for early detection of malignant progression of IBD and thus help to improve the clinical management and surveillance schedule of IBD patients.

[Crohn's disease-associated colorectal carcinogenesis : TP53 mutations and copy number gains of chromosome arm 5p as (early) markers of tumor progression]. / Morbus-Crohn-assoziierte kolorektale Karzinogenese : TP53-Mutationen und Kopienzahlzugewinne von Chromosomarm 5p als (frühe) Marker der Tumorprogression.

BACKGROUND: Patients with inflammatory bowel diseases, i. e., ulcerative colitis and Crohn's disease (CD), face an increased risk of developing colorectal cancer (CRC). Evidence, mainly from ulcerative colitis, suggests that TP53 mutations represent an initial step in the progression from inflamed colonic epithelium to CRC. OBJECTIVES: In this study, we aimed to analyze the genetic events that define CD-CRCs, in particular the dynamics of their development from histologically undetectable precursor lesions to invasive disease. MATERIALS AND METHODS: We analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions by next generation sequencing (563 gene panel) and array-based comparative genomic hybridization. The results were compared with our own data and the Cancer Genome Atlas data on sporadic CRC. RESULTS: The gain of 5p was significantly more prevalent in CD-CRCs than in sporadic CRCs, despite an overall similar chromosomal aberration pattern. CD-CRCs had a distinct mutation signature with TP53 being the most frequently mutated gene in CD-CRCs. TP53 mutations and copy number alterations were early events in CD progression and could sometimes already be detected in non-dysplastic colonic mucosa, indicating occult tumor evolution. CONCLUSIONS: Molecular profiling of CD-CRCs and precursor lesions revealed an inflammation-associated landscape of genome alterations: gains of 5p and TP53 mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predict disease progression and distinguishes CD-associated from sporadic colorectal neoplasia.

Synthesis and biological assessment of 3,7-dihydroxytropolones.

3,7-Dihydroxytropolones (3,7-dHTs) are highly oxygenated troponoids that have been identified as lead compounds for several human diseases. To date, structure-function studies on these molecules have been limited due to a scarcity of synthetic methods for their preparation. New synthetic strategies towards structurally novel 3,7-dHTs would be valuable in further studying their therapeutic potential. Here we describe the successful adaptation of a [5 + 2] oxidopyrilium cycloaddition/ring-opening for 3,7-dHT synthesis, which we apply in the synthesis of a plausible biosynthetic intermediate to the natural products puberulic and puberulonic acid. We have also tested these new compounds in several biological assays related to human immunodeficiency virus (HIV), hepatitis B virus (HBV) and herpes simplex virus (HSV) in order to gain insight into structure-functional analysis related to antiviral troponoid development.

Stem cells and bFGF in tendon healing: Effects of lentiviral gene transfer and long-term follow-up in a rat Achilles tendon defect model.

BACKGROUND: The influence of stem cells and lentiviral expression of basic fibroblastic growth factor (bFGF) on tendon healing and remodelling was investigated in an in-vivo long-term (12 weeks) rat Achilles tendon defect model. METHODS: In sixty male Lewis rats, complete tendon defects (2.4 mm) were created and either left untreated (PBS) or treated by injection of stem cells lentivirally expressing the enhanced green fluorescence marker gene eGFP (MSC-LV-eGFP) or basic fibroblast growth factor bFGF (MSC-LV-bFGF). Tendons were harvested after 12 weeks and underwent biomechanical and (immuno)-histological analysis. RESULTS: After 12 weeks the mean ultimate load to failure ratio (treated side to contralateral side) in biomechanical testing reached 97 % in the bFGF-group, 103 % in the eGFP-group and 112 % in the PBS-group. Also in the stiffness testing both MSC groups did not reach the results of the PBS group. Histologically, the MSC groups did not show better results than the control group. There were clusters of ossifications found in all groups. In immunohistology, only the staining collagen-type-I was strongly increased in both MSC groups in comparison to PBS control group. However, there were no significant differences in the (immuno)-histological results between both stem cell groups. CONCLUSION: The biomechanical and (immuno)-histological results did not show positive effects of the MSC groups on tendon remodelling in a long-term follow-up. Interestingly, in later stages stem cells had hardly any effects on biomechanical results. This study inspires a critical and reflected use of stem cells in tendon healing.

Androgen Receptor CAG Repeat Length in Relation to Phenotype Among Females with Nonclassical 21-Hydroxylase Deficiency.

Nonclassical 21-hydroxylase deficiency (NC21OHD) manifests with various degrees of post natal virilization. The length of CAG repeats of the androgen receptor gene (AR) is inversely correlated to activity of the human androgen receptor (AR) and affects phenotype of several androgen-dependent disorders. The aim of the study was to investigate the associations between CAG repeat length and the phenotype of females with NC21OHD. CAG repeat length and AR inactivation were assessed in females with NC21OHD, and related to their clinical presentation. CAG repeat length and AR inactivation were assessed in 119 females with NC21OHD. Biallelic mean (BAM) of the CAG repeat length and the weighted BAM (WBAM) were related to various clinical parameters. Age at diagnosis and age of menarche positively correlated with BAM (r=0.22, p=0.02, and r=0.23, p=0.01, respectively). A shorter (<25) BAM was associated with younger age at diagnosis (14.8 vs. 21.4 years, p<0.01), at adrenarche (8.1 vs. 10.2 years, p<0.01) and gonadarche (9.9 vs. 11.2 years, p<0.01), and higher corrected height standard deviation score at diagnosis (0.77 vs. 0.15, p=0.01). Precocious pubarche and precocious puberty were more frequent in these with the shorter BAM. Results of WBAM were similar. The CAG repeat length of the AR gene contributes to the clinical diversity of the phenotype in females with NC21OHD.

Stem cells and basic fibroblast growth factor failed to improve tendon healing: an in vivo study using lentiviral gene transfer in a rat model.

BACKGROUND: The aim of this controlled study was to investigate the influence of mesenchymal stem cells (MSCs) and lentiviral (LV) expression of basic fibroblast growth factor (bFGF) on tendon remodeling in an in vivo rat model of an Achilles tendon defect. METHODS: In eighty-four male Lewis rats, complete 2.4-mm tendon defects were created and were either left untreated (the phosphate-buffered saline solution [PBS] group) or were treated with mesenchymal stem cells expressing enhanced green fluorescent protein (the MSC-LV-eGFP group) or with mesenchymal stem cells expressing basic fibroblast growth factor lentivirally (the MSC-LV-bFGF group). After fourteen and twenty-eight days, the tendons were harvested and analyzed biomechanically and immunohistologically. RESULTS: After fourteen days, both mesenchymal stem cell groups were slightly superior in biomechanical testing. However, only the PBS control group showed a significant increase in biomechanical results over time (fourteen versus twenty-eight days; p = 0.012). Biomechanical results were better after twenty-eight days for the control group than for both MSC groups. However, the difference was significant only with regard to the stiffness results in the comparison of the PBS control and the eGFP stem cell group (p = 0.024). Histologically, the MSC groups had no better results than the control group after fourteen and twenty-eight days. In immunohistology, only labeling for type-I procollagen was strongly increased in both MSC groups in comparison with the PBS control group (p = 0.0009 for the MSC-LV-bFGF group and p = 0.0041 for the MSC-LV-eGFP group at fourteen days, and p = 0.004 and p = 0.132, respectively, at twenty-eight days). There were no significant differences in the immunohistological results between the stem cell groups. CONCLUSIONS: The biomechanical and immunohistological results showed that mesenchymal stem cells in both groups had only partially positive effects on tendon remodeling in the initial stages; however, in later stages, stem cells had potentially negative effects on biomechanical results. The additional expression of bFGF in stem cells had negligible effects on tendon remodeling. CLINICAL RELEVANCE: Preliminary studies using stem cells are partially promising; however, there are no relevant clinical data showing that stem cells are of significant benefit. The present study should lead to a more critical evaluation and thoughtful use of stem cells in humans until more clinical data are available.

Registered Replication Report: Schooler and Engstler-Schooler (1990).

Trying to remember something now typically improves your ability to remember it later. However, after watching a video of a simulated bank robbery, participants who verbally described the robber were 25% worse at identifying the robber in a lineup than were participants who instead listed U.S. states and capitals-this has been termed the "verbal overshadowing" effect (Schooler & Engstler-Schooler, 1990). More recent studies suggested that this effect might be substantially smaller than first reported. Given uncertainty about the effect size, the influence of this finding in the memory literature, and its practical importance for police procedures, we conducted two collections of preregistered direct replications (RRR1 and RRR2) that differed only in the order of the description task and a filler task. In RRR1, when the description task immediately followed the robbery, participants who provided a description were 4% less likely to select the robber than were those in the control condition. In RRR2, when the description was delayed by 20 min, they were 16% less likely to select the robber. These findings reveal a robust verbal overshadowing effect that is strongly influenced by the relative timing of the tasks. The discussion considers further implications of these replications for our understanding of verbal overshadowing.

The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers.

BACKGROUND: Selective metabotropic glutamate receptor 5 (mGluR5) antagonists inhibit transient lower oesophageal sphincter relaxations (TLESRs) in animals and acid reflux in humans. AIM: To assess the effect of single doses of the mGluR5 antagonist AZD2066 on TLESRs and reflux in humans. METHODS: Healthy male volunteers received AZD2066 13 mg and placebo (part A), or AZD2066 2 mg and AZD2066 6 mg and placebo (part B), in a randomised crossover study. Postprandial manometry/pH-impedance measurements were taken after each dose. RESULTS: A total of 13 individuals completed part A of the study and 19 individuals completed part B. There was a significant reduction in the geometric mean number of TLESRs (27%; P = 0.02) and the geometric mean number of reflux episodes (51%; P = 0.01) in subjects receiving AZD2066 13 mg compared with placebo. Adverse events in participants receiving AZD2066 13 mg were mostly related to the nervous system [dizziness (3/13); disturbance in attention (3/13)]. Adverse events were reversible and of mild intensity. There were no serious adverse events. The effects of AZD2066 appeared dose-dependent, with smaller reductions in TLESRs and reflux episodes (relative to placebo) and fewer adverse events observed for AZD2066 2 mg and AZD2066 6 mg compared with AZD2066 13 mg. CONCLUSION: The mGluR5-mediated inhibition of TLESRs may be a useful approach for inhibiting gastro-oesophageal reflux.

Early metabolic markers that anticipate loss of insulin independence in type 1 diabetic islet allograft recipients.

The objective of this study was to identify predictors of insulin independence and to establish the best clinical tools to follow patients after pancreatic islet transplantation (PIT). Sequential metabolic responses to intravenous (I.V.) glucose (I.V. glucose tolerance test [IVGTT]), arginine and glucose-potentiated arginine (glucose-potentiated arginine-induced insulin secretion [GPAIS]) were obtained from 30 patients. We determined the correlation between transplanted islet mass and islet engraftment and tested the ability of each assay to predict return to exogenous insulin therapy. We found transplanted islet mass within an average of 16 709 islet equivalents per kg body weight (IEQ/kg BW; range between 6602 and 29 614 IEQ/kg BW) to be a poor predictor of insulin independence at 1 year, having a poor correlation between transplanted islet mass and islet engraftment. Acute insulin response to IVGTT (AIR(GLU) ) and GPAIS (AIR(max) ) were the most accurate methods to determine suboptimal islet mass engraftment. AIR(GLU) performed 3 months after transplant also proved to be a robust early metabolic marker to predict return to insulin therapy and its value was positively correlated with duration of insulin independence. In conclusion, AIR(GLU) is an early metabolic assay capable of anticipating loss of insulin independence at 1 year in T1D patients undergoing PIT and constitutes a valuable, simple and reliable method to follow patients after transplant.

Effect of azithromycin on acid reflux, hiatus hernia and proximal acid pocket in the postprandial period.

BACKGROUND: The risk for acidic reflux is mainly determined by the position of the gastric acid pocket. It was hypothesised that compounds affecting proximal stomach tone might reduce gastro-oesophageal reflux by changing the acid pocket position. OBJECTIVE: To study the effect of azithromycin (Azi) on acid pocket position and acid exposure in patients with gastro-oesophageal reflux disease (GORD). METHODS: Nineteen patients with GORD were included, of whom seven had a large hiatal hernia (≥3 cm) (L-HH) and 12 had a small or no hiatal hernia (S-HH). Patients were randomised to Azi 250 mg/day or placebo during 3 days in a crossover manner. On each study day, reflux episodes were detected using concurrent high-resolution manometry and pH-impedance monitoring after a standardised meal. The acid pocket was visualised using scintigraphy, and its position was determined relative to the diaphragm. RESULTS: Azi reduced the number of acid reflux events (placebo 8.0±2.2 vs Azi 5.6±1.8, p<0.01) and postprandial acid exposure (placebo 10.5±3.8% vs Azi 5.9±2.5%, p<0.05) in all patients without affecting the total number of reflux episodes. Acid reflux occurred mainly when the acid pocket was located above, or at the level of, the diaphragm, rather than below the diaphragm. Treatment with Azi reduced hiatal hernia size and resulted in a more distal position of the acid pocket compared with placebo (below the diaphragm 39% vs 29%, p=0.03). Azi reduced the rate of acid reflux episodes in patients with S-HH (38% to 17%) to a greater extent than in patients with L-HH (69% to 62%, p=0.04). CONCLUSION: Azi reduces acid reflux episodes and oesophageal acid exposure. This effect was associated with a smaller hiatal hernia size and a more distal position of the acid pocket, further indicating the importance of the acid pocket in the pathogenesis of GORD. CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1970 NTR1970.

Total versus hemithyroidectomy for microscopic papillary thyroid cancer.

BACKGROUND: No increased mortality has been reported in patients with thyroid papillary microcarcinoma (PMC); however, neck recurrences and distant metastases have been described. In this study, we compare patients' outcomes after total thyroidectomy vs hemithyroidectomy for treatment of thyroid PMC. METHODS: Two hundred and ninety-three patients from two major medical centers in Israel were included. The mean follow-up period was 7.2±6.8 yr. RESULTS: Total thyroidectomy was performed in 214 patients and hemithyroidectomy in 79 patients. Mean tumor size was 6.3±3 mm. Lymph-node (LN) metastases and extraglandular extension were more frequent in the total thyroidectomy group than in the hemithyroidectomy group, 24.8% vs 1.3% (p<0.001) and 11.7% vs 3.8% (p=0.042), respectively. The cumulative incidence of recurrence at the end of follow-up was 13.2% in the total thyroidectomy group and 14.3% in the hemithyroidectomy group (p=ns). The incidence of recurrence was higher in patients with LN involvement in both groups. Considering low risk patients only (monofocal tumors, no LN involvement, no extraglandular extension; no.=63 in the total thyroidectomy group vs no.=60 in the hemithyroidectomy group) neck recurrence was found in 10% of patients in the hemithyroidectomy group but none in the total thyroidectomy group. In the hemithyroidectomy group, all locoregional recurrences were diagnosed using ultrasonography, compared to 47.6% in the total thyroidectomy group. CONCLUSION: For patients with monofocal disease within the thyroid gland and no LN involvement, hemithyroidectomy can be considered an option, bearing in mind a higher risk for recurrence. For all other patients with PMC, we propose total thyroidectomy as initial treatment.

Prognostic value of post-thyroidectomy thyroglobulin levels in patients with differentiated thyroid cancer.

BACKGROUND: Thyroglobulin is an excellent biological marker of persistent or recurrent thyroid cancer during long-term follow-up. Most studies investigated its diagnostic value but not its prognostic value over time. We aim to study the prognostic value of thyroglobulin levels early after total thyroidectomy, before iodine ablation. METHODS: The study was based on the Rabin Medical Center registry of patients with non-medullary thyroid carcinoma. Data were collected on the clinical, laboratory, and outcome characteristics of 420 consecutive patients followed at our institution for whom early post-operative pre-ablation thyroglobulin values (baseline thyroglobulin) were available. RESULTS: Patients were classified into 4 groups by baseline thyroglobulin level: 0-2, 2-10, 10-100, and >100 ng/ml. Higher levels were associated with a shift toward male gender (p=0.01), larger tumor size (p=0.02), and a more extensive disease (p<0.0001). They were also related to disease persistence and evidence of disease at last follow-up (p<0.0001). The 10 ng/ml cut-off level identified patients with persistent disease with a sensitivity and specificity of 73%, positive predictive value of 43%, and negative predictive value of 89%. On multivariate analysis, the following variables were predictive of persistent disease: baseline thyroglobulin level, male gender, lymph-node involvement, distant metastases, higher tumor invasiveness, and larger tumor size. However, the predictive power of baseline thyroglobulin level was relatively weak (odds ratio 1.002, 95% confidence interval 1.00-1.04). CONCLUSIONS: In patients with well-differentiated thyroid cancer, a post-thyroidectomy thyroglobulin level <10 ng/ml is associated with a low probability of having persistent disease and can be used combined with other disease characteristics for decisions regarding treatment and follow-up.

High-resolution esophageal pressure topography is superior to conventional sleeve manometry for the detection of transient lower esophageal sphincter relaxations associated with a reflux event.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-esophageal reflux and are detected during manometric studies using well defined criteria. Recently, high-resolution esophageal pressure topography (HREPT) has been introduced and is now considered as the new standard to study esophageal and lower esophageal sphincter (LES) function. In this study we performed a head-to-head comparison between HREPT and conventional sleeve manometry for the detection of TLESRs. METHODS: A setup with two synchronized MMS-solar systems was used. A solid state HREPT catheter, a water-perfused sleeve catheter, and a multi intraluminal impedance pH (MII-pH) catheter were introduced in 10 healthy volunteers (M6F4, age 19-56). Subjects were studied 0.5 h before and 3 h after ingestion of a standardized meal. Tracings were blinded and analyzed by the three authors according to the TLESR criteria. KEY RESULTS: In the HREPT mode 156 TLESRs were scored, vs 143 during sleeve manometry (P = 0.10). Hundred and twenty-three TLESRs were scored by both techniques. Of all TLESRs (177), 138 were associated with reflux (78%). High-resolution esophageal pressure topography detected significantly more TLESRs associated with a reflux event (132 vs 119, P = 0.015) resulting in a sensitivity for detection of TLESRs with reflux of 96% compared to 86% respectively. Analysis of the discordant TLESRs associated with reflux showed that TLESRs were missed by sleeve manometry due to low basal LES pressure (N = 5), unstable pharyngeal signal (N = 4), and residual sleeve pressure >2 mmHg (N = 10). CONCLUSIONS & INFERENCES: The HREPT is superior to sleeve manometry for the detection of TLESRs associated with reflux. However, rigid HREPT criteria are awaited.

MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine.

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.

Correction of insulin sensitivity and glucose disposal after pancreatic islet transplantation: preliminary results.

AIMS: Pancreatic islet transplantation (PIT) represents a potential curative treatment for patients with type 1 diabetes, but only 10-15% of patients remain insulin independent 5 years post-transplant. It is not known whether intrinsic insulin resistance exacerbated by immunosuppression plays a pivotal role in low graft survival. The study objective was to understand the changes in insulin resistance, glucose effectiveness (S(g)) and free fatty acid dynamics (FFAd) before and after PIT. METHODS: Insulin sensitivity index (S(i)), S(g) and FFAd were measured before and after PIT in 10 lean patients, 8 of whom reached insulin independence. Modified Bergman minimal model of frequently sampled intravenous glucose tolerance tests were performed pretransplant and at 12 months post-transplant. Nine non-diabetic control (NDC) subjects matched by age, gender and BMI were used. RESULTS: Pretransplant S(i) and S(g) were 3.5 ± 0.8 × 10(-5)/min/(pmol/l) and 0.74 ± 0.24 × 10(-2)/min, respectively. S(i) was significantly lower than matched NDCs [10.8 ± 0.6 × 10(-5)/min/(pmol/l), p < 0.004]; S(g) did not reach statistical significance (1.27 ± 0.22 × 10(-2)/min, p = 0.25). Compared to pretransplant values, mean post-transplant S(i) and S(g) were 9.6 ± 1.3 × 10(-5)/min/(pmol/l)and 1.28 ± 0.22 ×10(-2)/min, respectively, indicating significant improvement for S(i) but not S(g) (p = 0.008 and p = 0.06). Twelve-month post-PIT compared to NDC values were not significantly different (p = 0.58 and 0.97, respectively). In addition, fractional disposal rate for FFA which directly depends on the endogenous insulin release (10-20 min) nearly normalized after PIT (p = 0.06). CONCLUSION: These preliminary findings demonstrate that PIT can restore glucose disposal and insulin sensitivity and partially correct glucose effectiveness and FFAd.

A discussion of airway and respiratory complications along with general considerations in obese patients.

Obesity is defined as the degree of excess weight associated with adverse health consequences. Within Great Britain, it is reported that a quarter of men and women are obese; these rates have trebled over the past 20 years. In 2001, it was estimated that obesity cost the National Health Service at least half a billion pounds, with a further two billion pounds lost on lower productivity and lost output. Obesity poses a significant risk factor for diseases, such as coronary heart disease, diabetes mellitus and certain forms of cancer, amongst others. Obese individuals pose significant problems to the clinician because of airway and respiratory complications. Sleep apnoea, obesity-hypoventilation syndrome, pulmonary atelectasis are associated with obesity and tracheostomy insertion is made all the more difficult in these patients. This article aims to discuss some of these issues relevant to the clinician and examine present strategies for dealing with them.

Clinically silent chromaffin-cell tumors: Tumor characteristics and long-term prognosis in patients with incidentally discovered pheochromocytomas.

BACKGROUND: Chromaffin-cell tumors (CCT), a rare group of catecholamine producing endocrine neoplasms, are traditionally suspected and diagnosed in patients presenting with episodic hypertension, together with the classic triad of headache, sweating, and tachycardia. Asymptomatic CCT are increasingly diagnosed, frequently as "incidentalomas". We have conducted a multicenter retrospective study, to assess the characteristics of a group of patients with clinically silent CCT, compared with a group of patients with typical CCT. METHODS: Forty-three consecutive patients with CCT (24 with silent and 19 with typical tumors) have been retrospectively studied for a period of up to 20 yr (between 1989 and 2009); clinical picture, biochemical tests, as well as topographic and functional assessment were analyzed at diagnosis and periodically following treatment. Surgical samples were reviewed for neuroendocrine markers and for signs of invasiveness. RESULTS: Patients with clinically silent CCT were significantly older than the typical ones (56.3±3.4 vs 48.0±4.8 yr; p<0.05); 15 of them (63%) were completely asymptomatic, and 9 patients (37%) complained of non-specific abdominal symptoms. Hypertension was present in only 6 silent CCT patients (25%), it was well controlled [mean blood pressure (BP) 134/84 mmHg], and persisted after surgery in only 2 patients. Fourteen out of twenty-four silent CCT patients (58%) were managed pre-operatively with prophylactic combination of α and ß blockade, despite normal BP values. Clinically silent CCT were larger than typical CCT (mean diameter of 5.2±2.3 cm vs 4.6±1.5 cm, p<0.05) and secreted higher a mounts of normeta neph rines. All clinically silent CCT patients were defined as "cured" after surgery. CONCLUSION: Clinically silent CCT are more prevalent than previously reported. With an adequate pre-surgical diagnosis and patient preparation, the prognosis of silent tumors is usually excellent.