Substance P (SP) induces expression of functional corticotropin-releasing hormone receptor-1 (CRHR-1) in human mast cells

Corticotropin-releasing hormone (CRH) is secreted under stress and regulates the hypothalamic-pituitary-adrenal axis. However, CRH is also secreted outside the brain where it exerts proinflammatory effects through activation of mast cells, which are increasingly implicated in immunity and inflammation. Substance P (SP) is also involved in inflammatory diseases. Human LAD2 leukemic mast cells express only CRHR-1 mRNA weakly. Treatment of LAD2 cells with SP (0.5-2?μM) for 6?hours significantly increases corticotropin-releasing hormone receptor-1 (CRHR-1) mRNA and protein expression. Addition of CRH (1?μM) to LAD2 cells, which are "primed" with SP for 48?hours and then washed, induces synthesis and release of IL-8, tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) 24?hours later. These effects are blocked by pretreatment with an NK-1 receptor antagonist. Treatment of LAD2 cells with CRH (1?μM) for 6?hours induces gene expression of NK-1 as compared with controls. However, repeated stimulation of mast cells with CRH (1?μM) leads to downregulation of CRHR-1 and upregulation in NK-1 gene expression. These results indicate that SP can stimulate mast cells and also increase expression of functional CRHR-1, whereas CRH induces NK-1 gene expression. These results may explain CRHR-1 and NK-1 expression in lesional skin of psoriatic patients.     

Mitochondrial dysfunction in affected skin and increased mitochondrial DNA in serum from patients with psoriasis

Psoriasis is characterized by keratinocyte proliferation and chronic inflammation, but the pathogenesis is still unclear. Dysregulated mitochondria (mt) could lead to reduced apoptosis and extracellular secretion of mtDNA, acting as “innate pathogen” triggering inflammation. Serum was obtained from healthy volunteers and psoriatic patients. Mitochondrial DNA was extracted from the serum and amplified with quantitative PCR (qPCR). Punch biopsies were obtained from lesional and non‐lesional psoriatic skin (10 cm apart) and from healthy volunteers, were placed in RNA later and were stored at ?80°C until RNA was extracted and cDNA was synthesized; gene expression of uncoupling protein 2 (UCP2), Dynamin‐related protein 1 (Drp1) and calcineurin, involved in the regulation of mitochondria function, was detected with qPCR. Mitochondrial DNA was significantly increased (7s, P = 0.0496 and Cytochrome B, CytB, P = 0.0403) in the serum of psoriatic patients (n = 63) as compared to controls (n = 27). Gene expression was significantly reduced for UCP2 (P = 0.0218), Drp1 (P = 0.0001) and calcineurin (P = 0.0001) in lesional psoriatic skin, as compared to non‐lesional or control skin. Increased serum extracellular mtDNA in psoriatic patients and decreased expression of mitochondrial regulatory proteins in psoriatic skin suggest increased inflammation and reduced keratinocyte apoptosis, respectively. Inhibitors of mtDNA secretion and/or UCP2 stimulants may be potential treatment options.     

Cost effectiveness of vildagliptin versus glimepiride as add-on treatment to metformin for the treatment of diabetes mellitus type 2 patients in Greece

Objectives

This study was designed to assess the cost-effectiveness of vildagliptin versus glimepiride as add-on to metformin in the management of type 2 diabetes mellitus (T2DM) patients in the Greek healthcare setting.

Methods

A cost-effectiveness model was designed, using MS Excel, to compare two treatment strategies. Strategy 1 consisted of first-line metformin, followed by metformin + vildagliptin in second-line, while strategy 2 consisted of first line metformin, followed by metformin + glimepiride in second line. Subsequent lines were the same in both strategies and consisted of metformin + basal insulin and metformin + basal + rapid insulin. Clinical data and utility decrements relating to diabetes complications were taken from the published literature. Only direct medical costs were included in the analysis (cost base year 2014), and consisted of drug, adverse events and comorbidity costs (taken from local officially published sources and the literature). The perspective adopted was that of the Social Insurance Fund. The time horizon was lifetime, and future costs and outcomes were discounted at 3.5% per annum.

Results

Adding vildagliptin to metformin increased drug costs compared with adding glimepiride to metformin (€2853 vs. €2427, respectively). However, this increase was offset by a decrease in the costs of associated comorbidities (€4393 vs. €4539) and adverse events (€2757 vs. €3111), resulting in a lower total cost of €74 in strategy 1 compared with strategy 2. Comorbidities were the largest cost component in both strategies, accounting for 43.9 and 45.0% in strategies 1 and 2, respectively. Strategy 1 was also associated with increased life-years (LYs, 0.11) and quality-adjusted life-years (QALYs, 0.11) compared with strategy 2. Strategy 1 is therefore dominant, as it is associated with both lower overall costs and increased effectiveness.

Conclusions

Vildagliptin as add-on treatment to metformin in the management of T2DM in Greece appears to be dominant versus. glimepiride in terms of both cost per LY and cost per QALY gained.

     

Persistence of post‐operative color Doppler abnormalities is linked to reduced graft survival in pediatric patients after liver transplantation

Color Doppler US is a readily available imaging modality for the evaluation of liver transplants. The aim of our study was to evaluate the temporal course of color Doppler US findings in children after LTX and to investigate the effect of resolving and persisting abnormalities during follow‐up on long‐term outcome. All children who underwent LTX during January 2000 until December 2003 (155 LTX in 137 patients, 75 male and 62 female; mean age at LTX 4.1 ± 4.8 years; range, 0.1‐16.3 years) were retrospectively evaluated. Following a predefined ultrasound protocol with prospective documentation, intraoperative, post‐operative, and follow‐up examinations were evaluated for color Doppler abnormalities. The time of occurrence and temporal course of the findings were recorded. Graft survival rates and graft survival times were compared. Abnormal color Doppler US examinations were noted in 98 of 155 grafts during the entire observational period (63.2%). In 57 of 98 grafts (58.2%), abnormalities were limited to the perioperative period (<30 days after LTX). Survival of grafts with transient perioperative abnormalities was similar to transplantations with regular color Doppler US examinations (graft survival rates, 80.7% vs 84.2%, P = .622; mean graft survival time, 2596.92 vs 2511.40 days, P = .67). Grafts with persisting color Doppler US abnormalities in the follow‐up period (>30 days after LTX; 37/98 LTX, 37.8%) showed reduced survival compared with regular courses (graft survival rate 62.2% vs 80.7%, P = .047), indicating underlying organ‐specific alterations. Standardized longitudinal evaluation during the perioperative and the follow‐up period can enhance the prognostic capabilities of color Doppler US in children following LTX.     

Rituximab-Based Treatments in Waldenström's Macroglobulinemia

The anti-CD20 monoclonal antibody rituximab has shown activity in approximately one third of patients with Waldenström's Macroglobulinemia (WM). Because this agents is nonmyelosuppressive, several studies have assessed its combination with chemotherapeutic agents such as fludarabine, cladribine, cyclophosphamide, and doxorubicin. These regimens induce at least partial response in > 70% of previously untreated patients. Recent data suggest that prolonged exposure to nucleoside-containing regimens should be avoided because of concerns of myelodysplasia and disease transformation. Rituximab has also been combined with thalidomide, which is an active and nonmyelosuppressive regimen. The rituximab-based combination represents today the most commonly used primary treatment for WM.     

Nurses' ethical decision-making role in artificial nutritional support

This study provides an insight into the process of ethical decision-making regarding the initiation or withdrawal of artificial nutritional support of seriously ill patients and explores the nursing involvement in it. Fifteen health carers were recruited from a clinical nutrition unit in the UK and qualitative research methods were used to gather data. The findings of the study indicate that nursing contribution to decision-making appeared to be in the 'back room' as the nurses feel that the decisions about difficult ethical dilemmas are 'out of their hands' because of lack of knowledge, experience and confidence. The medical staff and the clinical nurse specialist appear to be primarily responsible for making important decisions. It is clear from the study that to become more effective in the process, nurses need to enhance their knowledge in nutritional support and to develop their practical skills in ethical decision-making through experience and research.     

The effect of intraventricularly administered GnRH on plasma beta-endorphin levels of the rat.

This study investigates the effects of intraventricularly administered gonadotropin-releasing hormone (GnRH) on plasma beta-endorphin levels in female proestrous rats. Adult female Wistar rats (220-250 g) were implanted with an indwelling cannula in the third ventricle. Approximately 20 days later, the animals which had established a regular 4-day cycle were implanted with two indwelling catheters, one intracarotid and one intrajugular, on the morning of proestrus. A single injection of 100 ng GnRH dissolved in 5 microliters distilled water or 5 microliters of saline (control) was infused slowly through the cannula in the third ventricle. Blood was withdrawn via the intracarotid catheter just before the infusion (12.30 h) and at 14.00, 15.30, 16.30 and 17.30 h for the determination of plasma beta-endorphin levels. The results indicated that intracerebroventricular infusion of GnRH causes a significant decline of plasma beta-endorphin levels at all time points. It is postulated that GnRH possibly causes desensitization of GnRH receptors, due to the continuous GnRH supply to the pituitary via the blood circulation.     

G gamma-196 C-->T, A gamma-201 C-->T: two novel mutations in the promoter region of the gamma-globin genes associated with nondeletional hereditary persistence of fetal hemoglobin in Greece

The increased level of fetal hemoglobin in nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH) is associated with several single base substitutions in the promoter region of either the ^Gγ- or the ^Aγ-globin genes. In this study, we report two new forms of nd-HPFH found in two unrelated Greek adults with high HbF production (8.6% and 10.2% respectively) and positive for the ^Gγ-158 C→T substitution. Scanning by DGGE analysis and direct sequencing of the γ-globin gene 5′ promoter region revealed the presence of a ^Gγ-196 C→T in the first case and an ^Aγ-201 C→T in the second. These mutations seem to reactivate γ-genes and cause their high expression in the adult period.