Reduced levels of active GLP-1 in patients with cystic fibrosis with and without diabetes mellitus

Glucagon like peptide 1 (GLP-1) is an incretin hormone released as a bioactive peptide from intestinal L-cells in response to eating. It acts on target cells and exerts several functions as stimulating insulin and inhibiting glucagon. It is quickly deactivated by the serine protease dipeptidyl peptidase IV (DPP-IV) as an important regulatory mechanism. GLP-1 analogues are used as antidiabetic drugs in patients with type 2 diabetes. We served patients with cystic fibrosis (CF, n=29), cystic fibrosis related diabetes (CFRD, n=19) and healthy controls (n=18) a standardized breakfast (23 g protein, 25 g fat and 76 g carbohydrates) after an overnight fasting. Blood samples were collected before meal as well as 15, 30, 45 and 60 min after the meal in tubes prefilled with a DPP-IV inhibitor. The aim of the study was to compare levels of GLP-1 in patients with CF, CFRD and in healthy controls. We found that active GLP-1 was significantly decreased in patients with CF and CFRD compared to in healthy controls (p<0.01). However, levels in patients with CFRD tended to be lower but were not significantly lower than in patients with CF without diabetes (p=0.06). Total GLP-1 did not differ between the groups, which points to that the inactive form of GLP-1 is more pronounced in CF patients. The endogenous insulin production (measured by C-peptide) was significantly lower in patients with CFRD as expected. However, levels in non-diabetic CF patients did not differ from the controls. We suggest that the decreased levels of GLP-1 could affect the progression toward CFRD and that more studies need to be performed in order to evaluate a possible treatment with GLP-1 analogues in CF-patients.     

Nutritional problems, overhydration and the association with quality of life in elderly dialysis patients

Purpose

The aim of this pilot study was to describe the hydration and nutritional status of a cohort of elderly dialysis patients and to explore the association between these parameters and the quality of life (QoL).

Methods

All patients over 75?years of age being in chronic dialysis by January 2008 at 3 dialysis units (n?=?34) were asked to participate in this pilot study, 24 patients were entered. Hydration status was assessed by bioimpedance spectroscopy (BIS) and nutritional status by the subjective global assessment (SGA), BIS, anthropometric measures and biochemical parameters. Based on these assessments the patients were classified as being cachectic or not according to newly defined criteria. QoL was measured using the SF-36.

Results

The results showed cachexia in 6 (25?%), 37.5?% had a body mass index below 24, whereas according to SGA 91?% were malnourished. BIS showed low lean tissue index in 46?% and overhydration in 35?% of the patients. Compared to non-cachectic and normohydrated, cachectic and overhydrated patients reported consistently poorer QoL. For cachectic patients, the differences were clinically significant for all SF-36. BIS was easily applicable when used before dialysis.

Conclusions

The high frequency of nutritional deficits in this study calls for more attention to nutritional status in elderly dialysis patients. There is a need for a general agreement on how nutritional status should be assessed and reported, both in clinics and in research.     

Osteonecrosis of jaw in patient with hormone-refractory prostate cancer treated with zoledronic acid

Intravenous bisphosphonates are widely used in the management of metastatic bone disease, as well as osteoporosis. Recent published reports have documented a possible link between treatment with intravenous bisphosphonates and osteonecrosis of the jaw. We report a case of osteonecrosis of the jaw in 1 patient with prostate cancer receiving both chemotherapy and intravenous zoledronic acid (Zometa). Bisphosphonates have been demonstrated to alter the normal bone microenvironment and appear to have direct effects on tumors as well. These changes may contribute to the development of osteonecrosis of the jaw, particularly after tooth extractions or other invasive dental procedures.     

Results of gastric bypass plus resection of the distal excluded gastric segment in patients with morbid obesity

Surgical treatment is the procedure of choice for morbidly obese patients. Gastric bypass with a long limb Roux-en-Y anastomosis is the "gold standard" technique for these patients. We sought to determine the early and late results of open gastric bypass with resection of the distal excluded stomach in patients with morbid obesity. We included in this prospective study 400 patients who were seen from September 1999 through August 2003 (311 women and 89 men; mean age, 38.5 years). The mean body mass index of the patients was 46 kg/m2. All underwent 95% distal gastrectomy, with resection of the bypassed stomach, leaving a small gastric pouch of 15 to 20 ml. An end-to-side gastrojejunostomy was performed with circular stapler No. 25. The length of the Roux-en-Y loop was 125 to 150 cm. In all patients, a biopsy was taken from the liver and routine cholecystectomy was performed. Follow-up was as long as 36 months. A barium study was performed in all patients at 5 days after surgery. Mortality and postoperative morbidity rates were 0.5% and 4.75%, respectively, mainly due to anastomotic leak in 10 patients (2.5%). Hospital length of stay was 7 days for 95% of the patients. Follow-up data for longer than 12 months were available in 184 patients. There was excess body weight loss of 70% at 24 and 36 months, and there was an inverse correlation among preoperative body mass index and the loss of weight. Anemia was present in 10%, and incisional hernia was present in 10.2%. At 1 year after surgery, the BAROS index demonstrated very good or excellent index in 96.6% of the patients. Gastric bypass with resection of the distal excluded segment has results very similar to those of gastric bypass alone but eliminates the potential risks of gastric bypass such as anastomotic ulcer, gastrogastric fistula, postoperative bleeding due to peptic ulcer and gastritis, and the eventual future development of gastric cancer. It is also possible to perform via laparoscopy, as we started to do recently.     

Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M3 selective receptor antagonist

AIM: To evaluate the efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist, in the subgroup of older patients from a pooled analysis of three phase III, multicentre, randomized, double-blind clinical trials in patients with overactive bladder (OAB). PATIENTS AND METHODS: 317 patients aged > or =65 years with OAB symptoms (urge incontinence, urgency and frequency) received up to 12 weeks' oral treatment with darifenacin 7.5 mg or 15 mg once daily or matching placebo. Efficacy was evaluated from daily electronic diary records. Safety endpoints included withdrawal rates and treatment-related adverse events. RESULTS: Darifenacin treatment of patients aged > or =65 years was associated with a dose-related, significant improvement of all the major symptoms of OAB. At week 12, the median reduction in incontinence episodes/week was greater with darifenacin 7.5 mg or 15 mg than in the corresponding placebo arms (66.7% vs. 34.8% and 75.9% vs. 44.8%, respectively, both p < 0.001). Both doses were also significantly superior to placebo in improving micturition frequency (both p < 0.001), bladder capacity (volume voided) (darifenacin 7.5 mg, p = 0.018, darifenacin 15 mg, p < 0.001), and the frequency of urgency episodes (both p < 0.001). Darifenacin was well tolerated. The most common treatment-related adverse events were dry mouth (7.5 mg, 20.6%; 15 mg, 30.9%; placebo, 4.5%) and constipation (7.5 mg, 18.6%; 15 mg, 23.6%; placebo, 6.4%), typically mild or moderate. Use of constipation remedies (laxatives, stool softeners or fibre supplements) was low and similar between groups (7.5 mg, 10.3%; 15 mg, 16.4%; placebo, 10.0%). There were few withdrawals due to treatment-related adverse events (7.5 mg, 1.0%; 15 mg, 9.1%; placebo, 2.7%), and no nervous system or cardiovascular safety concerns. CONCLUSIONS: The results demonstrate excellent efficacy, tolerability and safety with darifenacin 7.5 mg and 15 mg once-daily treatment for OAB in older patients.     

A comprehensive view of sex-specific issues related to cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of mortality in women. In fact, CVD is responsible for a third of all deaths of women worldwide and half of all deaths of women over 50 years of age in developing countries. The prevalence of CVD risk factor precursors is increasing in children. Retrospective analyses suggest that there are some clinically relevant differences between women and men in terms of prevalence, presentation, management and outcomes of the disease, but little is known about why CVD affects women and men differently. For instance, women with diabetes have a significantly higher CVD mortality rate than men with diabetes. Similarly, women with atrial fibrillation are at greater risk of stroke than men with atrial fibrillation. Historically, women have been underrepresented in clinical trials. The lack of good trial evidence concerning sex-specific outcomes has led to assumptions about CVD treatment in women, which in turn may have resulted in inadequate diagnoses and suboptimal management, greatly affecting outcomes. This knowledge gap may also explain why cardiovascular health in women is not improving as fast as that of men. Over the last decades, mortality rates in men have steadily declined, while those in women remained stable. It is also becoming increasingly evident that gender differences in cultural, behavioural, psychosocial and socioeconomic status are responsible, to various degrees, for the observed differences between women and men. However, the interaction between sex-and gender-related factors and CVD outcomes in women remains largely unknown.     

Antigen recognition induces phosphatidylserine exposure on the cell surface of human CD8+ T cells

In eukaryotic cells the phospholipid phosphatidylserine (PS) is restricted to the inner plasma-membrane leaflet. This lipid asymmetry, which is maintained by the concerted action of phospholipid transport proteins, is mainly lost during apoptosis. Here, we demonstrate that primary human CD8+ cytotoxic T lymphocytes (CTLs) expose PS on T-cell receptor (TCR)-mediated antigen (Ag) recognition. In contrast to PS externalization on apoptotic cells, activation-induced PS exposure is less pronounced and reversible. Fluorescence microscopic analysis revealed that PS is distributed nonhomogenously over the plasma membrane and concentrated in membrane lipid raft domains at the immunologic synapse. By studying the activity of PS transport proteins using a fluorescence-labeled PS analogue, we found that activation of CTLs inhibited the flippase-mediated inward-directed PS transport without affecting the outward transport. Shielding of exposed PS by annexin V protein during Ag recognition diminished cytokine secretion, activation, and cell-to-cell clustering of Ag-specific CTLs. In summary, our data demonstrate for the first time that externalized PS on Ag-stimulated CTLs is linked to T-cell activation and probably involved in cell-to-cell contact formation at the immunologic synapse.