Type 2 diabetes remission 2 years post Roux-en-Y gastric bypass and sleeve gastrectomy: the role of the weight loss and comparison of DiaRem and DiaBetter scores.

AIMS: The comparative efficacy of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy on Type 2 diabetes remission and the role of weight loss are unclear. The DiaRem diabetes remission prediction score uses HbA1c , age and diabetes medications but not diabetes duration. The aim of this study was to compare the DiaRem with the DiaBetter score that includes diabetes duration, upon combined (complete plus partial) 2-year post-surgery diabetes remission in people following RYGB and sleeve gastrectomy, and to investigate the relationship between weight loss and diabetes remission. METHODS: A retrospective single-centre cohort study of obese people with diabetes who underwent RYGB (107) or sleeve gastrectomy (103) and a validation cohort study (173) were undertaken. Diabetes remission, % weight loss, DiaRem, DiaBetter scores and areas under receiving operator characteristic (ROC) curves were calculated. The relationship between % weight loss and diabetes remission was investigated using logistic regression. RESULTS: The proportion of people achieving diabetes remission was highest for those with the lowest DiaBetter and DiaRem scores. Areas under the ROC curves were comparable [DiaBetter: 0.867 (95%CI: 0.817-0.916); DiaRem: 0.865 (95%CI: 0.814-0.915), P=0.856]. Two-year % weight loss was higher post RYGB [26.6 (95%CI: 24.8-28.4)] vs post-sleeve gastrectomy [20.6 (95%CI: 18.3-22.8), P<0.001]. RYGB had 151% higher odds of diabetes remission [OR 2.51 (95%CI: 1.12-5.60), P=0.025]. This association became non-significant when adjusted for % weight loss. CONCLUSION: DiaBetter and DiaRem scores predict diabetes remission following both procedures. Two-year % weight loss plays a key role in determining diabetes remission.

Cost-effectiveness of bariatric surgery in adolescents with severe obesity in the UK.

Evidence shows that surgery for severe obesity in adults improves health and psychological functioning, and is cost-effective. Data on bariatric surgery for adolescents with severe obesity are extremely limited, with no evidence on cost-effectiveness. We evaluated the lifetime cost-effectiveness of bariatric surgery compared with no surgery in adolescents with severe obesity from the UK's National Health Service perspective. Eighteen adolescents with body mass index ≥40 kg m-2 who underwent bariatric surgery (laparoscopic Roux en Y Gastric Bypass [RYGB] [N = 9], and laparoscopic Sleeve Gastrectomy [SG] [N = 9]) at University College London Hospitals between January 2008 and December 2013 were included. We used a Markov cohort model to compare the lifetime expected costs and quality-adjusted life years (QALYs) between bariatric surgery and no surgery. Mean cost of RYGB and SG procedures were £7100 and £7312, respectively. For RYGB vs. no surgery, the incremental cost/QALY was £2018 (95% CI £1942 - £2042) for males and £2005 (95% CI £1974 - £2031) for females. For SG vs. no surgery, the incremental cost/QALY was £1978 (95% CI £1954 - £2002) for males and £1941 (95% CI £1915 - £1969) for females. Bariatric surgery in adolescents with severe obesity is cost-effective; it is more costly than no surgery however it markedly improved quality of life.

Active Subjects With Autoimmune Type 1 Diabetes Have Better Metabolic Profiles Than Sedentary Controls.

Previous studies in humans with type 1 diabetes mellitus (T1D) and in nonobese diabetic mice have investigated the beneficial immunomodulatory potential of aerobic physical activity. Performing high volume of aerobic exercise may favorably regulate autoimmunity in diabetes. We tested whether increased physical activity is a self-sufficient positive factor in T1D subjects. During a 3-month observational period, active (six males; 40.5 ± 6.1 years; BMI: 24.5 ± 2.1) and sedentary (four males, three females; 35.9 ± 8.9 years; BMI: 25.7 ± 3.8) T1D individuals on insulin pump therapy were studied for metabolic, inflammatory, and autoimmune parameters. At baseline and at the end of a 3-month period, glycosylated hemoglobin (HbA1c), autoantibodies (anti-GAD, anti-ZnT8, anti-IA2, and ICA) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated. During the third month of the period, physically active T1D patients showed a significant reduction in the average glucose levels (-9%, p = 0.025, by CGM) compared to the first month values, and even their hyperglycemic episodes (>180 mg/dl) diminished significantly (-24.2%, p = 0.032 vs. first month). Moreover, active T1D subjects exhibited an improved body composition with respect to sedentary controls. No significant changes were detected as to the autoimmune and inflammatory profiles. This study confirms the beneficial role of physical exercise associated with insulin pump therapy in order to improve metabolic control in individuals with T1D. These preliminary positive observations need to be challenged in a prolonged interventional follow-up.

Effects of Factor XIII Deficiency on Thromboelastography. Thromboelastography with Calcium and Streptokinase Addition is more Sensitive than Solubility Tests.

BACKGROUND: Homozygous or double heterozygous factor XIII (FXIII) deficiency is characterized by soft tissue hematomas, intracranial and delayed spontaneous bleeding. Alterations of thromboelastography (TEG) parameters in these patients have been reported. The aim of the study was to show results of TEG, TEG Lysis (Lys 60) induced by subthreshold concentrations of streptokinase (SK), and to compare them to the clot solubility studies results in samples of a 1-year-old girl with homozygous or double heterozygous FXIII deficiency. CASE: A year one girl with a history of bleeding from the umbilical cord. During her first year of life, several hematomas appeared in soft upper limb tissue after punctures for vaccination and a gluteal hematoma. One additional sample of a heterozygous patient and three samples of acquired FXIII deficiency were also evaluated. MATERIALS AND METHODS: Clotting tests, von Willebrand factor (vWF) antigen and activity, plasma FXIII-A subunit (pFXIII-A) were measured by an immunoturbidimetric assay in a photo-optical coagulometer. Solubility tests were performed with Ca(2+)-5 M urea and thrombin-2% acetic acid. Basal and post-FXIII concentrate infusion samples were studied. TEG was performed with CaCl2 or CaCl2 + SK (3.2 U/mL) in a Thromboelastograph. RESULTS: Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time, fibrinogen, factor VIIIc, vWF, and platelet aggregation were normal. Antigenic pFXIII-A subunit was < 2%. TEG, evaluated at diagnosis and post FXIII concentrate infusion (pFXIII-A= 37%), presented a normal reaction time (R), 8 min, prolonged k (14 and 11min respectively), a low Maximum-Amplitude (MA) ( 39 and 52 mm respectively), and Clot Lysis (Lys60) slightly increased (23 and 30% respectively). In the sample at diagnosis, clot solubility was abnormal, 50 and 45 min with Ca-Urea and thrombin-acetic acid, respectively, but normal (>16 hours) 1-day post-FXIII infusion. Analysis of FXIII deficient and normal plasma mixtures (< 2-102% of pFXIII-A), showed that Ca-urea solubility was abnormal at pFXIII-A < 9%, thrombin-acetic acid at pFXIII-A<18%, but TEG MA and elasticity at 23% and Lys60 with SK at pFXIII-A< 40%. CONCLUSIONS: TEG parameters MA and elasticity, and Lys 60 in TEG either with Ca(2+) or Ca(2+) and SK are more sensitive to low levels of pFXIII than solubility tests. The increased Lys60 induced by a subthreshold concentration of SK could probably reflect the clot characteristics "in vivo" in many patients with pFXIII levels between 5-40% and could be potentially considered as screening test.

Characterization of transient noise in Advanced LIGO relevant to gravitational wave signal GW150914.

On September 14, 2015, a gravitational wave signal from a coalescing black hole binary system was observed by the Advanced LIGO detectors. This paper describes the transient noise backgrounds used to determine the significance of the event (designated GW150914) and presents the results of investigations into potential correlated or uncorrelated sources of transient noise in the detectors around the time of the event. The detectors were operating nominally at the time of GW150914. We have ruled out environmental influences and non-Gaussian instrument noise at either LIGO detector as the cause of the observed gravitational wave signal.

Do PT and APTT sensitivities to factors' deficiencies calculated by the H47-A2 2008 CLSI guideline reflect the deficiencies found in plasmas from patients?

INTRODUCTION: Prothrombin time (PT) and activated partial thromboplastin time (APTT) sensitivity for detecting isolated factor deficiencies varies with different reagents and coagulometers. The Clinical and Laboratory Standards Institute (CLSI) H47A2 guideline proposed a method to calculate these sensitivities, but some inconsistency has been reported. This study aimed to calculate factor sensitivities using CLSI guideline and to compare them with those obtained from single factor-deficient patients' data. METHODS: Different mixtures of normal pooled and deficient plasmas were prepared (<1IU/dL to 100 IU/dL) according to the CLSI H47A2 guideline. PT with rabbit brain (RB) and human recombinant (HR) thromboplastins, APTT and factors' activities were measured in an ACL TOP coagulometer. Sensitivities (maximum factor concentration that produces PT or APTT values out of the reference range) were calculated from mixtures and from patients with single-factor deficiencies: 17 factor FV, 36 FVII, 19 FX, 39 FVIII, 15 FIX 15 FXI and 24 FXII. RESULTS: PT sensitivity with RB was as follows: FV 38 and 59, FVII 35 and 58, FX 56 and 64 IU/dL; PT sensitivity with HR was as follows: FV 39 and 45, FVII 51 and 50, FX 33 and 61 IU/dL; and APTT sensitivity was as follows: FV 39 and 45, FX 32 and 38, FVIII 47 and 60, FIX 35 and 44, FXI 33 and 43, FXII 37 and 46 IU/dL, respectively. CONCLUSIONS: Reagent-coagulometer combination has adequate sensitivities to factor deficiencies according to guideline recommendations (>30 IU/dL). These should not be considered as actual sensitivities because those obtained by analysing patients' plasmas with single-factor deficiencies were higher for most factors and could induce misinterpretation of the basic coagulation test results.

Omental adipose tissue fibrosis and insulin resistance in severe obesity.

BACKGROUND/OBJECTIVES: The unresolved chronic inflammation of white adipose tissue (WAT) in obesity leads to interstitial deposition of fibrogenic proteins as reparative process. The contribution of omental adipose tissue (oWAT) fibrosis to obesity-related complications remains controversial. The aim of our study was to investigate whether oWAT fibrosis may be related to insulin resistance in severely obese population. SUBJECTS/METHODS: Forty obese subjects were studied by glucose clamp before undergoing bariatric surgery and thus stratified according to insulin resistance severity (M-value). From the first (Group B: n=13; M=1.9±0.7 mg kg(-1) min(-1)) and the highest (Group A: n=14; M=4.5±1.4 mg kg(-1) min(-1)) M-value tertiles, which were age-, waist- and body mass index-matched, oWAT samples were then obtained.Gene expression of collagen type I, III and VI, interleukin-6, profibrotic mediators (transforming growth factor (TGF)-ß1, activin A, connective tissue growth factor), hypoxia inducible factor-1α (HIF-1α) and macrophage (CD68, monocyte chemotactic protein (MCP)-1, CD86, CD206, CD150) markers were analyzed by quantitative reverse transcription PCR. Adipocyte size and total fibrosis were assessed by histomorphometry techniques. RESULTS: Fibrosis at morphological level resulted significantly greater in Group B compared with Group A, although collagens gene expression did not differ. Notably, collagen VI messenger RNA significantly correlated with collagen I, collagen III, HIF-1α, TGF-ß1, CD68, MCP-1 and CD86 transcription levels, supporting their relation with fibrosis development. CONCLUSIONS: In conclusion, we show for the first time that human oWAT fibrosis in severe obesity is consistent with a higher degree of insulin resistance measured by glucose clamp. Therefore, collagen deposition could represent a maladaptive mechanism contributing to obesity-related metabolic complications.

Iron status in obesity: An independent association with metabolic parameters and effect of weight loss.

BACKGROUND AND AIMS: Growing evidence has shown that ferritin concentrations are associated with obesity and insulin resistance, and with nonalcoholic fatty liver disease. However, it is unclear whether ferritin is simply an inflammatory marker, or it may directly contribute to the pathogenesis of obesity-related metabolic alterations. The aim of our study was to investigate the independent associations of ferritin levels with metabolic parameters in overweight/obese subjects before and after hypocaloric diet-induced weight changes. METHODS AND RESULTS: A sample study of 48 premenopausal, 39 postmenopausal women and 50 men was retrospectively analyzed. Clinical, bioimpedentiometry and biochemical data from baseline evaluations and after 3, 6 and 12 months of hypocaloric diet were collected. In the whole sample study, the baseline values of ferritin concentrations were positively correlated with body mass index (BMI) (r = 0.21, p < 0.05) and mass body fat (MBF) (r = 0.26, p < 0.05), whereas the serum iron level was negatively correlated with MBF (r = -0.29, p < 0.05). In premenopausal women, BMI-adjusted ferritin concentrations were negatively associated with high-density lipoprotein-cholesterol and positively related with triglycerides and aspartate aminotransferase. Moreover, the quantitative ferritin reduction at 12 months was positively associated with the relative reduction of BMI (r = 0.34, p < 0.05). Finally, the association between changes of alanine aminotransferase and ferritin levels at 12 months from baseline turned out to be independent of respective BMI changes (ß = 0.31, p < 0.05). CONCLUSION: In obesity, ferritin, putatively entailing increased iron storage, is independently associated with lipid derangements and transaminase levels, and the association with the latter persists after weight changes.

Analysis of the Candida albicans Phosphoproteome.

Candida albicans is an important human fungal pathogen in both immunocompetent and immunocompromised individuals. C. albicans regulation has been studied in many contexts, including morphological transitions, mating competence, biofilm formation, stress resistance, and cell wall synthesis. Analysis of kinase- and phosphatase-deficient mutants has made it clear that protein phosphorylation plays an important role in the regulation of these pathways. In this study, to further our understanding of phosphorylation in C. albicans regulation, we performed a deep analysis of the phosphoproteome in C. albicans. We identified 19,590 unique peptides that corresponded to 15,906 unique phosphosites on 2,896 proteins. The ratios of serine, threonine, and tyrosine phosphosites were 80.01%, 18.11%, and 1.81%, respectively. The majority of proteins (2,111) contained at least two detected phosphorylation sites. Consistent with findings in other fungi, cytoskeletal proteins were among the most highly phosphorylated proteins, and there were differences in Gene Ontology (GO) terms for proteins with serine and threonine versus tyrosine phosphorylation sites. This large-scale analysis identified phosphosites in protein components of Mediator, an important transcriptional coregulatory protein complex. A targeted analysis of the phosphosites in Mediator complex proteins confirmed the large-scale studies, and further in vitro assays identified a subset of these phosphorylations that were catalyzed by Cdk8 (Ssn3), a kinase within the Mediator complex. These data represent the deepest single analysis of a fungal phosphoproteome and lay the groundwork for future analyses of the C. albicans phosphoproteome and specific phosphoproteins.

Probing transport mechanisms of BaFe2As2 superconducting films and grain boundary junctions by noise spectroscopy.

An important step forward for the understanding of high-temperature superconductivity has been the discovery of iron-based superconductors. Among these compounds, iron pnictides could be used for high-field magnet applications, resulting more advantageous over conventional superconductors, due to a high upper critical field as well as its low anisotropy at low temperatures. However, the principal obstacle in fabricating high quality superconducting wires and tapes is given by grain boundaries. In order to study these effects, the dc transport and voltage-noise properties of Co-doped BaFe2As2 superconducting films with artificial grain boundary junctions have been investigated. A specific procedure allows the separation of the film noise from that of the junction. While the former shows a standard 1/f behaviour, the latter is characterized by an unconventional temperature-dependent multi-Lorentzian voltage-spectral density. Moreover, below the film superconducting critical temperature, a peculiar noise spectrum is found for the grain boundary junction. Possible theoretical interpretation of these phenomena is proposed.

Frequent false-positive results of lupus anticoagulant tests in plasmas of patients receiving the new oral anticoagulants and enoxaparin.

INTRODUCTION: Oral direct thrombin and Xa inhibitors are worldwide distributed for prevention and treatment of thrombosis. It is important to recognize their effects on lupus anticoagulant (LA) testing. The aim of the study is to describe the rate of false-positive results of LA tests on plasmas of patients with previous negative LA tests results that receive dabigatran etexilate (DAB) 110 mg/twice a day, rivaroxaban (RIV) 10 mg/day or 15 mg/twice a day, or enoxaparin 40 mg/day. METHODS: Blood was taken between 1.5 and 4 h post administration. Tests evaluated are as follows: prothrombin time, APTT, dilute Russell viper venom time (DRVVT) screen, APTT, and DRVVT mixing studies, index of circulating anticoagulant (ICA) with normal plasma, screen/confirm normalized ratio (NR) for DRVVT and silica clotting time (SCT). RESULTS: Plasmas from patients taking DAB (n = 22) presented 100% prolonged APTT and DRVVT with ICA above the cutoff point and 81.8% positive screen/confirm NR, 100% prolonged SCT screen, but 4.5% positive confirmatory NR. All patients receiving RIV at 15 mg/twice a day (n = 4) presented positive DRVVT screen, mixing, and confirmatory tests, 75% and 100% prolonged APTT and SCT screen, with negative screen/confirm NR. Those taking RIV 10 mg/day (n = 22) showed 81.8% prolonged DRVVT screen, 82.3% and 76.5% of them with positive mixing and confirmatory studies. Patients receiving enoxaparin also presented high prevalence of APTT and DRVVT false-positive results. CONCLUSION: Dabigatran etexilate, RIV, and enoxaparin affect tests for LA not only in screening and mixing, but also in confirmatory studies. We considered that LA testing should not to be performed when patients are taken these drugs, particularly if blood is collected at peak, in order to avoid false-positive results.

Effects of whole body vibration plus diet on insulin-resistance in middle-aged obese subjects.

We investigated the early effects of whole body vibration (WBV) added to hypocaloric diet on insulin-resistance and other parameters associated with glucose regulation in sedentary obese individuals. We randomly assigned 34 patients to WBV plus hypocaloric diet (WBV group) or diet alone (CON group) for 8 weeks. Fasting and post-load glucose, insulin, lipids, C-reactive protein, tumor necrosis factor-α, leptin, adiponectin were assessed. Insulin sensitivity index (ISI) was derived from oral-glucose-tolerance test. Body composition was evaluated with dual-energy X-ray absorptiometry. Both groups lost approximately 5% of weight, with greater reduction of body fat in WBV than in CON (-7.1±1.2 Kg vs. -5.3±1.0 Kg, p=0.003). Percent variation of ISI was more pronounced in WBV than in CON group (+35±4% vs. + 22±5%, p=0.002), accompanied by slight improvement in post-load glucose (-1.07±0.02 vs. - 0.12±0.01 mmol/l, p=0.031) but without changes in fasting levels. Adiponectin significantly increased in WBV group compared with CON (p=0.021 for comparison) whereas no differences in leptin and inflammatory markers were observed. In middle-aged sedentary obese subjects, WBV added to hypocaloric diet for 8 weeks improved body composition, insulin-resistance, glucose regulation and adiponectin levels to a greater extent compared with diet alone. Efficacy and feasibility of this approach in the long term need to be ascertained.

Atopic dermatitis (AD) management in an Italian pediatric clinic.

AIM: Atopic dermatitis (AD) is a common, chronic relapsing inflammatory skin disease characterized by dry skin and variable pruritus sometimes associated with allergic disease in other organs as asthma and rhinoconjunctivitis. AD affects deeply the Quality of Life, thus can be extremely disabling and may cause psychological problems for both affected children and their families. METHODS: In order to investigate the estimated prevalence of the disease and the beliefs of the Italian pediatricians, a group of 437 Italian family pediatricians covering a population of almost 380000 children participated in a study based on a questionnaire of 38 items. RESULTS: According to answers of the participants, the incidence of AD has been estimated around 10% of the population and food allergy is believed to be the trigger of the acute phase of the disease in infants. As a second opinion, dermatologists are consulted more frequently than allergologists. CONCLUSION: The use of emollients is advised in general whilst topical corticosteroids treatment is prescribed only in selected cases; more than 50% of pediatricians do not prescribe topical calcineurin inhibitors.

Infection and immunity for human parvovirus B19 in patients with febrile exanthema.

The contribution of parvovirus B19 (B19V) as a causative agent of febrile exanthema (FE) in Cordoba, Argentina, was analysed by detection of viral DNA, and specific IgM and IgG. Serum from 141 patients with FE who were negative for measles and rubella, collected during 2005-2009, plus serum from 31 healthy individuals, were assayed. B19V was the aetiological agent in 14·9% of all FE cases, and in 39·1% in an epidemic year (2007). B19V DNA was detected in 47·6% of IgM-positive FE patients, 30·2% of IgM-negative/IgG-positive FE patients, and 9·7% of healthy controls, indicating B19V long-term infection in ~10% of immunocompetent individuals. Persistent B19V DNA was significantly more frequent in children than adults and in males than females. All patients with acute B19V infection had rash and fever, 85·7% had adenopathy, and only 14·3% had arthropathy. This is the first follow-up study of markers of infection and immunity for B19V infection in Argentina.

Colectomías totalmente laparoscópicas con extracción de la pieza quirúrgica por orificios naturales / Totally laparoscopic colectomy with natural orifice specimen extraction

Objetivo: comunicación de la de la factibilidad de las colectomías totalmente laparoscópicas con extracción de la pieza quirúrgica por orificios naturales. Diseño: Trabajo descriptivo, retrospectivo, observacional. Pacientes y Método: Se incluyó una serie de 6 pacientes en quienes se realizó colectomía totalmente laparoscópica (con anastomosis intracorpórea) y extracción de la pieza quirúrgica por orificio natural. Resultados: Desde enero de 2007 a Agosto de 2011, en el Servicio de Cirugía General del Hospital San Roque, se llevaron a cabo 467 cirugías colorrectales, en 355 pacientes (76%), se realizó abordaje a cielo abierto y en 112 (24%), abordaje videolaparoscopico. En seis de ellos, una neoplasia de sigmoides (T2), y cinco enfermedades diverticulares recurrentes se realizó extracción de la pieza quirúrgica por orificios naturales con anastomosis colorrectal totalmente intracorporea. En 3 pacientes se extrajo la pieza por vía transrectoanal (masculinos) y en los 3 restantes por vía transvaginal. No se presentaron complicaciones intraoperatorias, tampoco postquirúrgicas inmediatas. La recuperación del tránsito intestinal, la ingesta de líquidos y el alta hospitalaria fueron similares a las observadas en las colectomías videoasistidas. Conclusiones: La resección de colon izquierdo por laparoscopía, realizando anastomosis intracorpórea, más extracción de la pieza por oríficios naturales (NOSE), puede ser considerada como una técnica alternativa para pacientes que requieren colectomías electivas, en patología benigna y neoplasias tempranas.

Objective: Communication of totally laparoscopic colectomy with natural orifice specimen extraction. Design: descriptive, retrospective, observational work. Patients and Methods: A series of 6 patients underwent totally laparoscopic colectomy (with intracorporeal anastomosis) and extraction of surgical specimen through natural orifice. Results: From January 2007 to August 2011, 467 colorectal surgeries were performed in the General Surgery Service of the Hospital San Roque. 355 (76%) underwent an open approach and 112 (24%) laparoscopic approach. In six of these cases, a sigmoid tumor (T2), and five recurrent diverticular diseases, we performed totally laparoscopic colectomy, with intracorporeal colorectal anastomosis. In 3 patients, the specimen was removed via transanal (male) and the remaining 3 by transvaginal route. There were no intraoperative or postoperative complications. The recovery of intestinal transit, fluid intake and hospital discharge were similar to those observed in video-assisted colectomy. Conclusions: The left colon resection by a totally laparoscopic technique, with intracorporeal anastomosis and the use of natural orifice specimell extraction (NOSE), can be considered as an alternative for patients requiring elective colectomy in benign disease and early neoplasia.

Single-incision laparoscopic right hemicolectomy (Br J Surg 2010; 97: 1881-1883).

The Editors welcome topical correspondence from readers relating to articles published in the Journal. Responses should be sent electronically via the BJS website (http://www.bjs.co.uk). All letters will be reviewed and, if approved, appear on the website. A selection of these will be edited and published in the Journal. Letters must be no more than 250 words in length.

Genetic inactivation of Kcnj16 identifies Kir5.1 as an important determinant of neuronal PCO2/pH sensitivity.

The molecular identity of ion channels which confer PCO(2)/pH sensitivity in the brain is unclear. Heteromeric Kir4.1/Kir5.1 channels are highly sensitive to inhibition by intracellular pH and are widely expressed in several brainstem nuclei involved in cardiorespiratory control, including the locus coeruleus. This has therefore led to a proposed role for these channels in neuronal CO(2) chemosensitivity. To examine this, we generated mutant mice lacking the Kir5.1 (Kcnj16) gene. We show that although locus coeruleus neurons from Kcnj16((+/+)) mice rapidly respond to cytoplasmic alkalinization and acidification, those from Kcnj16((-/-)) mice display a dramatically reduced and delayed response. These results identify Kir5.1 as an important determinant of PCO(2)/pH sensitivity in locus coeruleus neurons and suggest that Kir5.1 may be involved in the response to hypercapnic acidosis.

A NOTES approach for thoracic surgery: transgastric thoracoscopy via a diaphragmatic incision in a survival porcine model.

AIM: Recently the NOTES approach has been extended to mediastinum by a transesophageal access and to the thorax by a transvescical endoscopic approach. The aim of this study was to assess the feasibility and the safety of transgastric endoscopic approach to the thoracic cavity, with lung biopsy, in a survival porcine model. METHODS: The study was performed on four 20-30 kg female pigs (Sus scrofus domesticus). Following gastric wall incision, the muscular pars of the left diaphragmatic dome was incised along with the parietal pleura and the endoscope advanced into the thoracic cavity. In all animals, a thoracoscopy was performed as well as peripheral lung biopsy. At the end of the operation the endoscope was withdrawn from the thoracic cavity after pleural sac decompression and the diaphragmatic incision closed by endoscopic clips under maximal expansion of lungs. The gastric incision was finally closed by endoscopic clips. Chest-tube placement was not utilized. Animals were sacrificed by day 15 postoperatively. RESULTS: The gastroscope was easily introduced into the thoracic cavity that allowed to visualize the pleural cavity and to perform simple surgical procedures such as lung biopsies without complications. There were neither respiratory distress episodes nor surgical complications to report. No adverse event occurred during the survival period. The postmortem examination 15 days after surgery revealed a good closure of the diaphragmatic incision. At necropsy, the lung biopsies were completely healed. There were no signs of infection in both thoracic and peritoneal cavities. The length of follow-up and number of animals studied might have not been sufficient. CONCLUSION: This study demonstrates the feasibility of transgastric thoracoscopy in porcine model. Long-term follow-up of much larger series will be necessary for provision of more reliable answers if this approach should be adopted in the future and eventually translated for humans with advantages for patients.

PI3K p110 alpha and p110 beta have differential effects on Akt activation and protection against oxidative stress-induced apoptosis in myoblasts.

Catalytic subunits of phosphoinositide-3-kinase (PI3K) play a critical role in growth factor signaling and survival by phosphorylating inositol lipids. We found that PI3K Class-IA p110 alpha and p110 beta have distinct functions in myoblasts. Inhibition of p110 alpha reduced insulin-like growth factor-I (IGF-I)-stimulated Akt activity and prevented IGF-I-mediated survival in H(2)O(2)-treated cells; in contrast, siRNA knockdown of p110 beta increased IGF-I-stimulated Akt activity. However, inhibition of p110 beta catalytic activity did not increase IGF-I-stimulated Akt activity, suggesting a role for p110 beta protein interactions rather than decreased generation of phosphoinositides in this effect. Increased Akt activity in p110 beta-deficient myoblasts was associated with diminished extracellular signal-regulated kinase (ERK) activation as well as ERK-dependent IRS-1 636/639 phosphorylation, findings we show to be independent of p110 beta catalytic function, but associated with insulin-like growth factor-I receptor (IGF-IR) endocytosis. We also report that IGF-I protects myoblasts from H(2)O(2)-induced apoptosis through a mechanism that requires p110 alpha, but may be independent of Akt or ERK under conditions of Akt and ERK inhibition. These observations suggest that both p110 alpha and p110 beta are essential for growth and metabolism in myoblasts. Overall, our results provide new evidence for the roles of p110 isoforms in promoting cellular proliferation and homeostasis, IGF-IR internalization, and in opposing apoptosis.

A novel KCNA1 mutation identified in an Italian family affected by episodic ataxia type 1.

Episodic ataxia type 1 (EA1) is a rare human neurological syndrome characterized by continuous myokymia and attacks of generalized ataxia that can be triggered by abrupt movements, emotional stress and fatigue. An Italian family has been identified where related members displayed continuous myokymia, episodes of ataxia, attacks characterized by myokymia only, and neuromyotonia. A novel missense mutation (F414C), in the C-terminal region of the K(+) channel Kv1.1, was identified in the affected individuals. The mutant homotetrameric channels were non-functional in Xenopus laevis oocytes. In addition, heteromeric channels resulting from the co-expression of wild-type Kv1.1 and Kv1.1(F414C), or wild-type Kv1.2 and Kv1.1(F414C) subunits displayed reduced current amplitudes and altered gating properties. This indicates that the pathogenic effect of this KCNA1 mutation is likely to be related to the defective functional properties we have identified.