Development of new fabrication and measurement techniques of micro-electrodes with high aspect ratio for micro EDM using typical EDM machine

Micro-electrodes are used for micro holes EDM drilling in miniaturized products. This study represents novel fabricating and measuring processes of high aspect ratio micro-electrodes based on horizontal moving block electrical discharge grinding (horizontal moving BEDG [HM-BEDG]) and gage block with a typical EDM machine, as well as solving the problems that occur during micro-electrode fabrication. The EDM machine has been used as a coordinate measuring machine (CMM) for measuring micro-electrode diameter, where the gage block acts as a probe and the micro-electrode as a workpiece. As a result, a micro-electrode with the highest aspect ratio (over 60.25) was fabricated successfully with 78.19 μm diameter and 4.70 mm length after producing a through micro hole with 134.5 μm diameter on WC[sbnd]Co. As these processes are simple and do not require high investment for special equipment, micro-electrodes can be fabricated and measured for micro EDM drilling and milling in conventional workshops equipped with EDM machines

Polyunsaturated fatty acid deficiency reverses effects of alcohol on mitochondrial energy metabolism

BACKGROUND/AIMS: Polyunsaturated fatty acids (PUFA) deficiency is common in patients with alcoholic liver disease. The suitability of reversing such deficiency remains controversial. The aim was to investigate the role played by PUFA deficiency in the occurrence of alcohol-related mitochondrial dysfunction. METHODS: Wistar rats were fed either a control diet with or without alcohol (control and ethanol groups) or a PUFA deficient diet with or without alcohol (PUFA deficient and PUFA deficient+ethanol groups). After 6 weeks, liver mitochondria were isolated for energetic studies and fatty acid analysis. RESULTS: Mitochondria from ethanol fed rats showed a dramatic decrease in oxygen consumption rates and in cytochrome oxidase activity. PUFA deficiency showed an opposite picture. PUFA deficient+ethanol group roughly reach control values, regarding cytochrome oxidase activity and respiratory rates. The relationship between ATP synthesis and respiratory rate was shifted to the left in ethanol group and to the right in PUFA-deficient group. The plots of control and PUFA deficient+ethanol groups were overlapping. Phospholipid arachidonic over linoleic ratio closely correlated to cytochrome oxidase and oxygen uptake. CONCLUSIONS: PUFA deficiency reverses alcohol-related mitochondrial dysfunction via an increase in phospholipid arachidonic over linoleic ratio, which raises cytochrome oxidase activity. Such deficiency may be an adaptive mechanism

Irritable bowel syndrome is more frequent in patients hospitalized for ischaemic colitis: results of a case-control study.

International audienceIt has been suspected that there is an epidemiological link between irritable bowel syndrome (IBS) and ischaemic colitis (IC). We performed a retrospective case-control study to compare the frequency of IBS in patients hospitalized for IC compared with that of patients with peptic ulcer bleeding. Cases were patients with a first episode of IC and controls were patients with a first episode of peptic ulcer bleeding, matched to cases for sex and 10-year age-class. Diagnosis of IBS was based on medical information extracted from hospital medical files and a standard self-questionnaire. The association between IBS and IC was tested using Mc Nemar's paired odds ratio (OR); confidence interval at 95% (CI 95%) was calculated; Mantel-Haenzel's Chi(2) was applied. A total of 113 cases and 113 matched controls were studied. There were 37 males and 76 females and the mean age was 69 +/- 15 years in each group. The prevalence of IBS in cases was 16.9%vs 1.8% in controls. The risk of IBS was 11.05 times higher among cases than in controls (P < 0.001); CI 95%: (2.45-49.74). A total of 87 pairs with complete data were used for OR calculation. The risk of IBS was 7.5 times higher in cases than in controls (P = 0.002); CI 95%: (1.72-32.80). This case-control study shows that IBS is more frequent in IC patients than in controls

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial

Background There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. Methods In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (â\u89¥400 mg/day for â\u89¥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1â\u80\u933 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. Findings Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50â\u80\u930·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1â\u80\u9312·1) for regorafenib versus 7·8 months (6·3â\u80\u938·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), handâ\u80\u93foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. Interpretation Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib. Funding Bayer

A Phase 2 Study of Galunisertib (TGF-β1 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma.

IntroductionInhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment.MethodsThe combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-β1, safety, overall survival (OS), response rate, and pharmacokinetics (PK).ResultsPatients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-β1 responders (decrease of &gt;20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038).DiscussionThe combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome