Perioperative Management of Gastric Cancer Patients Treated With (Sub)Total Gastrectomy, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Lessons Learned.

BACKGROUND: The PERISCOPE I study was designed to assess the safety and feasibility of (sub)total gastrectomy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin and docetaxel for gastric cancer patients who have limited peritoneal dissemination. The current analysis investigated changes in perioperative management together with their impact on postoperative outcomes. METHODS: Patients with resectable gastric cancer and limited peritoneal dissemination were administered (sub)total gastrectomy, CRS, and HIPEC with oxaliplatin (460 mg/m2) and docetaxel (escalating scheme: 0, 50, 75 mg/m2). Of the 25 patients who completed the study protocol, 14 were treated in the dose-escalation cohort and 11 were treated in the expansion cohort (to optimize perioperative management). RESULTS: A significant proportion of the patients in the dose-escalation cohort (n = 7, 50%) had ileus-related complications. In this cohort, enteral nutrition was started immediately after surgery at 20 ml/h, which was increased on day 1 to meet nutritional needs. In the expansion cohort, enteral nutrition was administered at 10 ml/h until day 3, then restricted to 20 ml/h until day 6, supplemented with total parenteral nutrition to meet nutritional needs. Ileus-related complications occurred for two patients (18%) of the expansion cohort. The intensive care unit (ICU) readmission rate decreased from 50 (n = 7) to 9% (n = 1; p = 0.04). CONCLUSION: The implementation of a strict nutritional protocol during the PERISCOPE I study was associated with a decrease in postoperative complications. Based on these results, a perioperative care path was described for the gastric cancer HIPEC patients in the PERISCOPE II study.

Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial.

BACKGROUND: This multicentre, randomised, double-blinded, placebo-controlled, phase II/III trial aimed to evaluate an oral THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract for prevention of refractory chemotherapy-induced nausea and vomiting (CINV). Here we report the phase II component results. PATIENTS AND METHODS: Eligible patients experienced CINV during moderate-to-high emetogenic intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Study treatment consisted of one cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) three times daily, from days -1 to 5, and 1 cycle of matching placebo in a crossover design, then blinded patient preference for a third cycle. The primary end point was the proportion of participants with complete response during 0-120 h from chemotherapy. A total of 80 participants provided 80% power to detect a 20% absolute improvement with a two-sided P value of 0.1. RESULTS: A total of 81 participants were randomised; 72 completing two cycles were included in the efficacy analyses and 78 not withdrawing consent were included in safety analyses. Median age was 55 years (range 29-80 years); 78% were female. Complete response was improved with THC:CBD from 14% to 25% (relative risk 1.77, 90% confidence interval 1.12-2.79, P = 0.041), with similar effects on absence of emesis, use of rescue medications, absence of significant nausea, and summary scores for the Functional Living Index-Emesis (FLIE). Thirty-one percent experienced moderate or severe cannabinoid-related adverse events such as sedation, dizziness, or disorientation, but 83% of participants preferred cannabis to placebo. No serious adverse events were attributed to THC:CBD. CONCLUSION: The addition of oral THC:CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC:CBD to placebo. Based on these promising results, we plan to recruit an additional 170 participants to complete accrual for the definitive, phase III, parallel group analysis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001036404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370473&isReview=true.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus palliative systemic chemotherapy in stomach cancer patients with peritoneal dissemination, the study protocol of a multicentre randomised controlled trial (PERISCOPE II).

BACKGROUND: At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. METHODS: In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3-4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. DISCUSSION: The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. TRIAL REGISTRATION: clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

Utilidad del Video EEG en un hospital pediátrico de nivel terciario durante el año 2015 / Utility Of Video EEG In A Pediatric Tertiary Hospital During 2015

Resumen Objetivo: Evaluar la utilidad del V-EEG en el diagnóstico diferencial de la epilepsia en un hospital pediátrico de nivel terciario durante el año 2015 Materiales y Métodos: Se realizó un estudio descriptivo sobre 90 pacientes evaluados en esta unidad durante el año 2015. Se recogieron datos de variables relacionadas con la indicación y los resultados del V-EEG, los cuales fueron analizados usando medidas de estadística descriptiva. Resultados: El 53,3% de los pacientes fueron masculinos. El promedio de edad es de 7,7 años con una desviación estándar de 4,7 años. El tiempo que transcurre desde la primera crisis hasta que el paciente acude a realizarse el V-EEG presenta una media de 4,3 años. 72 pacientes (80%) presentaron crisis epilépticas, 12 pacientes (13,3%) presentaron trastornos paroxísticos no epilépticos, mientras 6 niños (6,7%) no presentaron crisis durante el monitoreo. En el 93,3% de los casos el estudio fue exitoso. Conclusiones: Se demuestra la utilidad del monitoreo V-EEG para el diagnóstico diferencial de epilepsia.

Summary Objective: The aim was to evaluate the V-EEG usefulness in the differential diagnosis of epilepsy in a Third Level Children's Hospital during 2015. Materials and Methods: A descriptive study was performed over 90 patients in this unit during 2015. The data was obtained from variables related to indications and results of V-EEG, which were analyzed using descriptive statistics. Results: Fifty three percent of the patients were male. The mean age was 7.7 years (SD ± 4.7 years). The time measured between the first seizure and the V-EEG recording was 4,3 years. Seventy two patients (80%) had epileptic seizures, 12 patients (13,3%) had nonepileptic seizures, while six children (6.7%) had no seizures during the V-EEG monitoring. Ninety three percent of all recordings were successful. Conclusions: It was demonstrated the usefulness of V-EEG monitoring for the differential diagnosis of epilepsy.

Neuronavegación En La Planificacion Prequirúrgica Y En La Cirugia De La Epilepsia Refractaria / Neuronavigation In Pre Surgical Planning And Surgery Of Refractory Epilepsy

RESUMEN Introducción: La epilepsia es una de las patologías neurológicas crónicas más frecuentes, con una incidencia de 50/100.000/año y una prevalencia entre 0,5 y 2% a nivel mundial. Un tercio de estos pacientes son resistentes al tratamiento con fármacos antiepilépticos, lo que se conoce como epilepsia refractaria. La mayoría de estos pacientes sufren de epilepsias focales secundarias a lesiones epileptogénicas evidenciadas cada vez más frecuentemente en correlación directa con las nuevas técnicas de neuroimagen cerebral. La cirugía de la epilepsia es el único tratamiento que podría curar la epilepsia de los pacientes con epilepsia refractaria. El objetivo de la cirugía de la epilepsia es remover la zona epileptogénica con preservación de las áreas elocuentes, y aquí la experiencia quirúrgica y la tecnología de neuroimagen juegan un papel capital. Objetivos: Demostrar la utilidad de la neuronavegación en la planificación prequirúrgica y en la cirugía de la epilepsia refractaria. Método: Estudio descriptivo transversal y analítico, en base a 47 cirugías realizadas (12 resectivas, 32 paliativas y 3 diagnósticas) en pacientes con epilepsia refractaria y edad media de 9,93 años (SD 4,1). En 27 pacientes (57.44%) se utilizó el neuronavegador. En el grupo de pacientes operados con neuronavegación disminuyó el tiempo quirúrgico en 47.17 minutos (p = 0,022), la cantidad de hemorragia en 111.41 mililitros (p = 0,011) y los días de hospitalización en 6.68 días (p = 0,005), en comparación con el grupo intervenido sin neuronavegación. Las complicaciones en el grupo con neuronavegación fueron del 29,63% en comparación con 65% en el grupo intervenido sin neuronavegación (p = 0,034). Conclusiones: En nuestra serie, el uso del neuronavegador en la planificación y desarrollo de la cirugía tuvo un impacto significativo al reducir la cantidad de hemorragia perdida, el tiempo quirúrgico, los días de hospitalización, y las complicaciones postquirúrgicas.

Abstract Introduction: Epilepsy is one of the more frequent neurologic disorders, with an incidence of 50/100,000/year and prevalence between 0.5 and 2% worldwide. A third of these patients suffer focal epilepsy due to epileptogenic lesions evident by Neuroimaging new techniques. Epilepsy surgery is the only treatment that can cure refractory epilepsy. Its goal is to remove the epileptogenic lesion with preservation of eloquent areas, and in this case both surgical experience and neuroimaging technology play a pivotal role. Objective: To demonstrate utility of neuronavigation in presurgical planning and surgery of refractory epilepsy. Method: Descriptive, cross sectional and analytic study of 47 performed surgeries (12 resective, 12 palliative and 3 diagnostic) in patients with refractory epilepsy with an average age of 9.93 years (SD 4.1). In 27 patients (57.44%) neuronavigation was used. In patients operated with assistance of neuronavigation, surgical time diminished in 47.17 minutes (p=0.022), hemorrhage in 111.41 ml (p=0.011) and days of hospitalization in 6.68 days (p=0.005) comparing with group without neuronavigation. Complications in the group with neuronavigation were 29.63% compared with 65% in the group without it. (P=0,034). Conclusions: In this study, using neuronavigation in planning and performing surgery in reducing the amount of blood loss, surgical time, days of hospitalization and post surgical complications.

Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes.

Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.

A four-gene LincRNA expression signature predicts risk in multiple cohorts of acute myeloid leukemia patients.

Prognostic gene expression signatures have been proposed as clinical tools to clarify therapeutic options in acute myeloid leukemia (AML). However, these signatures rely on measuring large numbers of genes and often perform poorly when applied to independent cohorts or those with older patients. Long intergenic non-coding RNAs (lincRNAs) are emerging as important regulators of cell identity and oncogenesis, but knowledge of their utility as prognostic markers in AML is limited. Here we analyze transcriptomic data from multiple cohorts of clinically annotated AML patients and report that (i) microarrays designed for coding gene expression can be repurposed to yield robust lincRNA expression data, (ii) some lincRNA genes are located in close proximity to hematopoietic coding genes and show strong expression correlations in AML, (iii) lincRNA gene expression patterns distinguish cytogenetic and molecular subtypes of AML, (iv) lincRNA signatures composed of three or four genes are independent predictors of clinical outcome and further dichotomize survival in European Leukemia Net (ELN) risk groups and (v) an analytical tool based on logistic regression analysis of quantitative PCR measurement of four lincRNA genes (LINC4) can be used to determine risk in AML.

A modification of the Bohr method to determine airways deadspace for non-uniform inspired gas tensions.

BACKGROUND: The Bohr method is a technique to determine airways deadspace using a tracer gas such as carbon dioxide or nitrogen. It is based on the assumption that the inspired concentration of the tracer gas is constant throughout inspiration. However, in some lung function measurement techniques where inspired concentration of the tracer gas may be required to vary, or where rapid injection of the tracer gas is made in real time, uniform inspired concentration is difficult or impossible to achieve, which leads to inaccurate estimation of deadspace using the Bohr equation. One such lung function measurement technique is the inspired sinewave technique. OBJECTIVE: In this paper, we proposed a modification of the Bohr method, relaxing the requirement of absolute uniformity of tracer concentration in the inspired breath. METHOD: The new method used integration of flow and concentration. A computer algorithm sought an appropriate value of deadspace to satisfy the mass balance equation for each breath. A modern gas mixing apparatus with rapid mass flow controllers was used to verify the procedure. RESULT: Experiments on a tidally ventilated bench lung showed that the new method estimated dead space within 10% of the actual values whereas the traditional Bohr deadspace gave more than 50% error. CONCLUSION: The new method improved the accuracy of deadspace estimation when the inspired concentration is not uniform. This improvement would lead to more accurate diagnosis and more accurate estimations of other lung parameters such as functional residual capacity and pulmonary blood flow.

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm.

We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFRC329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2V617F-positive clone in this PV patient harbors EGFRC329R, thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2V617F disease clone in MPN.

Tumours in white suckers from Lake Michigan tributaries: pathology and prevalence.

The prevalence and histopathology of neoplastic lesions were assessed in white sucker Catostomus commersonii captured at two Lake Michigan Areas of Concern (AOCs), the Sheboygan River and Milwaukee Estuary. Findings were compared to those observed at two non-AOC sites, the Root and Kewaunee rivers. At each site, approximately 200 adult suckers were collected during their spawning migration. Raised skin lesions were observed at all sites and included discrete white spots, mucoid plaques on the body surface and fins and large papillomatous lesions on lips and body. Microscopically, hyperplasia, papilloma and squamous cell carcinoma were documented. Liver neoplasms were also observed at all sites and included both hepatocellular and biliary tumours. Based on land use, the Kewaunee River was the site least impacted by human activities previously associated with fish tumours and had significantly fewer liver neoplasms when compared to the other sites. The proportion of white suckers with liver tumours followed the same patterns as the proportion of urban land use in the watershed: the Milwaukee Estuary had the highest prevalence, followed by the Root, Sheboygan and Kewaunee rivers. The overall skin neoplasm (papilloma and carcinoma) prevalence did not follow the same pattern, although the percentage of white suckers with squamous cell carcinoma exhibited a similar relationship to land use. Testicular tumours (seminoma) were observed at both AOC sites but not at the non-AOC sites. Both skin and liver tumours were significantly and positively associated with age but not sex.

CdTe Timepix detectors for single-photon spectroscopy and linear polarimetry of high-flux hard x-ray radiation.

Single-photon spectroscopy of pulsed, high-intensity sources of hard X-rays - such as laser-generated plasmas - is often hampered by the pileup of several photons absorbed by the unsegmented, large-volume sensors routinely used for the detection of high-energy radiation. Detectors based on the Timepix chip, with a segmentation pitch of 55 µm and the possibility to be equipped with high-Z sensor chips, constitute an attractive alternative to commonly used passive solutions such as image plates. In this report, we present energy calibration and characterization measurements of such devices. The achievable energy resolution is comparable to that of scintillators for γ spectroscopy. Moreover, we also introduce a simple two-detector Compton polarimeter setup with a polarimeter quality of (98 ± 1)%. Finally, a proof-of-principle polarimetry experiment is discussed, where we studied the linear polarization of bremsstrahlung emitted by a laser-driven plasma and found an indication of the X-ray polarization direction depending on the polarization state of the incident laser pulse.

NUT Carcinoma of the Sublingual Gland.

NUT carcinoma (NC) is a recently described, rare and extremely aggressive cancer primarily located to supradiaphragmatic structures and affecting young individuals. NC is characterized by translocations involving the NUT gene on 15q14 with the most common translocation partner gene being BRD4 on 19p13, resulting in the t(15;19)(q14;p13) karyotype. NC is poorly differentiated and is likely to be overlooked and misdiagnosed as poorly differentiated squamous cell carcinoma (SCC) when immunohistochemical evaluation of NUT protein expression is omitted. Previously, NC has been found in the parotid and submandibular glands and we present the first case in the sublingual gland arising in a 40-year-old woman. We discuss the diagnostic considerations for poorly differentiated carcinomas of the salivary glands and advocate the inclusion of NUT immunohistochemistry in this setting. Not only does the NC diagnosis confer a grave prognosis when treated as SCC as illustrated by the present case, but is important for the inclusion of patients in ongoing clinical trials.

Evidence of estrogenic endocrine disruption in smallmouth and largemouth bass inhabiting Northeast U.S. national wildlife refuge waters: A reconnaissance study.

Intersex as the manifestation of testicular oocytes (TO) in male gonochoristic fishes has been used as an indicator of estrogenic exposure. Here we evaluated largemouth bass (Micropterus salmoides) or smallmouth bass (Micropterus dolomieu) form 19 National Wildlife Refuges (NWRs) in the Northeast U.S. inhabiting waters on or near NWR lands for evidence of estrogenic endocrine disruption. Waterbodies sampled included rivers, lakes, impoundments, ponds, and reservoirs. Here we focus on evidence of endocrine disruption in male bass evidenced by gonad histopathology including intersex or abnormal plasma vitellogenin (Vtg) concentrations. During the fall seasons of 2008-2010, we collected male smallmouth bass (n=118) from 12 sites and largemouth bass (n=173) from 27 sites. Intersex in male smallmouth bass was observed at all sites and ranged from 60% to 100%; in male largemouth bass the range was 0-100%. Estrogenicity, as measured using a bioluminescent yeast reporter, was detected above the probable no effects concentration (0.73ng/L) in ambient water samples from 79% of the NWR sites. Additionally, the presence of androgen receptor and glucocorticoid receptor ligands were noted as measured via novel nuclear receptor translocation assays. Mean plasma Vtg was elevated (>0.2mg/ml) in male smallmouth bass at four sites and in male largemouth bass at one site. This is the first reconnaissance survey of this scope conducted on US National Wildlife Refuges. The baseline data collected here provide a necessary benchmark for future monitoring and justify more comprehensive NWR-specific studies.

Bodyweight change aids prediction of survival in chronic equine grass sickness.

REASONS FOR PERFORMING STUDY: Objective criteria for predicting survival of chronic grass sickness cases are currently lacking. OBJECTIVES: To determine whether the rate and/or magnitude of bodyweight change during hospitalisation of chronic grass sickness cases can provide an objective predictor of survival to discharge from hospital. Clinicians' recorded indication(s) for euthanasia were also reviewed. STUDY DESIGN: Single centre retrospective observational study. METHODS: Case records of all horses admitted for management of chronic grass sickness to The Dick Vet Equine Hospital between 1998 and 2013 were analysed. Case background, survival to hospital discharge, indication(s) for euthanasia, disease duration at admission and bodyweight changes during the hospitalisation period were analysed, and data for survivors and nonsurvivors compared. Percentage weight change was calculated for 7 day intervals up to 28 days (0-7, 7-14, 14-21, 21-28 days) and for entire periods from the first weight recorded (0-7, 0-14, 0-21, 0-28 days). These results were used to estimate survival probability conditional on weight change. RESULTS: The study sample comprised 213 horses, with 114 survivors (53.5%) and 99 (46.5%) nonsurvivors. Compared with nonsurvivors, survivors had significantly lower median maximum bodyweight loss as a percentage of first weight (survivors 5.9%, interquartile range 1.8-13.5; nonsurvivors 12.7%, 6.4-17.3). Throughout all time periods analysed, survivors had significantly lower median bodyweight loss than nonsurvivors, but no specific time period was more predictive of survival. Highest percentages of total bodyweight loss for individual horses were comparable for survivors (36%) and nonsurvivors (37%). Survival prediction curves reporting percentage survival rates for all time periods analysed provided data to aid prediction of chronic grass sickness survival. CONCLUSIONS: Overall, nonsurvivors had greater bodyweight loss than survivors. Rapidity and magnitude of bodyweight loss were equally predictive of outcome. Percentage survival prediction curves provide objective data to aid discussion of prognosis, but greater predictive specificity with associated sensitivity is required for clinical decision making in individual cases.

Sirolimus conversion after heart transplant: risk factors for acute rejection and predictors of renal function response.

In a randomized, comparative study of cardiac transplant patients with mild-to-moderate renal insufficiency, conversion from calcineurin inhibitors (CNIs) to sirolimus improved renal function at 1 year versus continuing CNIs, with an attendant risk of biopsy-confirmed acute rejection (BCAR). Post hoc analyses were conducted to identify predictors of BCAR and GFR improvement associated with conversion. Patients with proteinuria >500 mg/day were excluded. Univariate and multivariate regression analyses tested 13 parameters for BCAR and six for GFR improvement. In 57 sirolimus-treated patients, mean daily mycophenolate mofetil (MMF) dose was lower in those with versus without BCAR (1000 vs. 1420 mg; p = 0.014). Receiver operating characteristic analysis identified MMF dose ≤1000 mg/day as the optimal cutoff to predict BCAR. Multivariate analysis confirmed low MMF dose (odds ratio: 9.94; p = 0.007) and non-white race (odds ratio: 15.3; p = 0.06) were independently associated with BCAR. GFR improvement was evaluated in intent-to-treat patients (n = 116). Significant interaction was detected between treatment effect and preexisting diabetes status (univariate p = 0.077; multivariate p = 0.022), indicating greater beneficial effect of sirolimus in those without preexisting diabetes. These findings suggest that sirolimus is more effective in improving GFR in patients without preexisting diabetes, and adequate MMF doses are needed for sirolimus conversion.

Progesterone induces apoptosis of insulin-secreting cells: insights into the molecular mechanism.

Progesterone has been associated with the development of gestational diabetes (GD) due to the enhancement of insulin resistance. As ß-cell apoptosis participates in type 1 and type 2 diabetes pathophysiology, we proposed the hypothesis that progesterone might contribute to the development of GD through a mechanism that also involves ß-cell death. To address this question, RINm5F insulin-producing cells were incubated with progesterone (25-100 µM), in the presence or absence of α-tocopherol (40 µM). After 24 or 48 h, membrane integrity and DNA fragmentation were analyzed by flow cytometry. Caspase activity was used to identify the mode of cell death. The involvement of endoplasmic reticulum stress in the action of progesterone was investigated by western blotting. Oxidative stress was measured by 2',7'-dichlorofluorescein diacetate (DCFDA) oxidation. Isolated rat islets were used in similar experiments in order to confirm the effect of progesterone in primary ß-cells. Incubation of RINm5F cells with progesterone increased the number of cells with loss of membrane integrity and DNA fragmentation. Progesterone induced generation of reactive species. Pre-incubation with α-tocopherol attenuated progesterone-induced apoptosis. Western blot analyses revealed increased expression of CREB2 and CHOP in progesterone-treated cells. Progesterone caused apoptotic death of rat islet cells and enhanced generation of reactive species. Our results show that progesterone can be toxic to pancreatic ß-cells through an oxidative-stress-dependent mechanism that induces apoptosis. This effect may contribute to the development of GD during pregnancy, particularly under conditions that require administration of pharmacological doses of this hormone.