A survey of the views of program implementers on success factors of solar PV programs in Asia and the Pacific

Much effort has been invested in identifying the important barriers to the widespread take-up of renewable energy systems and in using information to develop best practice guidelines for the implementation of rural renewable energy electrification programs in developing countries. Many renewable electrification programs have been implemented in developing countries of Asia and the Pacific to improve the quality of life of the people living in remote rural areas. Those that have been successful demonstrate that a market for household renewable energy systems can be developed quickly and efficiently given the right combination of institutional, financial and policy instruments. The literature indicates, however, that a number of these programs have met with limited success. Much effort has been invested in attempting to identify the reasons behind this lack of success. Understanding the reasons behind the limited success of some programs, and for the relatively high success of others, is important as this information can inform program implementers and improve the success rates of future programs. Most of the research effort to date has focused on the identification of barriers to the widespread take-up of renewable energy systems and this information has been used in the development of best practice guidelines for the implementation of these programs. This narrow focus on barriers, however, does not consider other important factors behind the success of programs. An email survey of those implementing programs in SE Asian and Pacific countries was therefore undertaken with the aim of obtaining the views of program implementers on not only what barriers they see as hindering the uptake, but also on what essential factors they consider need to be included in designing and implementing programs in order ensure program success and the criteria to measure the program success

Molecular and clinical determinants of drug-induced long QT syndrome: an iatrogenic channelopathy.

More than 70 drugs present on the Swiss market can cause drug-induced long QT syndrome (LQTS), which is associated with torsades de pointes (TdP) arrhythmias, potentially leading to sudden cardiac death. Basic and clinical investigations performed during the last decade have helped a better understanding of the mechanisms and risk factors of this serious public health problem. In their vast majority, QT interval prolonging drugs block the human ERG (hERG) channel involved in the repolarisation phase of the cardiac action potential, and thus lengthen the QT interval. Beside the well-known QT interval prolonging action of class IA, IC and III anti-arrhythmic drugs, many antibiotics, neurotropic, antifungal, and antimalarial drugs are also able to cause drug-induced LQTS. Reviewing the literature indicates that the risk of QT interval prolongation and TdP is increased in females, in patients with organic heart diseases and hypokalaemia. Furthermore in a few cases, genetic factors have also been reported. However thus far, no genetic test is available to detect at-risk patients, and in consequence, drug prescribers are still relying only on the clinical history and findings to perform an evaluation of the risk. Treatment of drug-induced LQTS and TdP includes identifying and withdrawing the culprit drug(s), infusing magnesium and, in resistant cases acceleration of the heart rate. In this review article we provide a list of QT interval prolonging drugs adapted to the pharmaceuticals found on the Swiss market that can be used as a check-list for drug prescribers and at-risk patients

Clinically relevant concentrations of lidocaine and ropivacaine inhibit TNFα-induced invasion of lung adenocarcinoma cells in vitro by blocking the activation of Akt and focal adhesion kinase

BACKGROUND Matrix-metalloproteinases (MMP) and cancer cell invasion are crucial for solid tumour metastasis. Important signalling events triggered by inflammatory cytokines, such as tumour necrosis factor α (TNFα), include Src-kinase-dependent activation of Akt and focal adhesion kinase (FAK) and phosphorylation of caveolin-1. Based on previous studies where we demonstrated amide-type local anaesthetics block TNFα-induced Src activation in malignant cells, we hypothesized that local anaesthetics might also inhibit the activation and/or phosphorylation of Akt, FAK and caveolin-1, thus attenuating MMP release and invasion of malignant cells. METHODS NCI-H838 lung adenocarcinoma cells were incubated with ropivacaine or lidocaine (1 nM-100 µM) in absence/presence of TNFα (20 ng ml(-1)) for 20 min or 4 h, respectively. Activation/phosphorylation of Akt, FAK and caveolin-1 were evaluated by Western blot, and MMP-9 secretion was determined by enzyme-linked immunosorbent assay. Tumour cell migration (electrical wound-healing assay) and invasion were also assessed. RESULTS Ropivacaine (1 nM-100 μM) and lidocaine (1-100 µM) significantly reduced TNFα-induced activation/phosphorylation of Akt, FAK and caveolin-1 in NCI-H838 cells. MMP-9 secretion triggered by TNFα was significantly attenuated by both lidocaine and ropivacaine (half-maximal inhibitory concentration [IC50]=3.29×10(-6) M for lidocaine; IC50=1.52×10(-10) M for ropivacaine). The TNFα-induced increase in invasion was completely blocked by both lidocaine (10 µM) and ropivacaine (1 µM). CONCLUSIONS At clinically relevant concentrations both ropivacaine and lidocaine blocked tumour cell invasion and MMP-9 secretion by attenuating Src-dependent inflammatory signalling events. Although determined entirely in vitro, these findings provide significant insight into the potential mechanism by which local anaesthetics might diminish metastasi

Ventricular arrhythmia and torsade de pointe: Dose limiting toxicities of the MDR-modulator S9788 in a phase I trial

Background: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. Patients and methods: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmaco-kinetics of S9788 were determined. Results: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. Conclusions: With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase I trials of S9788 infused over six hours precluded the further clinical development of S978

Volatile anaesthetics reduce neutrophil inflammatory response by interfering with CXC receptor-2 signalling

Background Growing evidence suggests a protective effect of volatile anaesthetics in ischaemia-reperfusion (I/R)-injury, and the accumulation of neutrophils is a crucial event. Pro-inflammatory cytokines carrying the C-X-C-motif including interleukin-8 (IL-8) and CXC-ligand 1 (CXCL1) activate CXC receptor-1 (CXCR1; stimulated by IL-8), CXC receptor-2 (CXCR2; stimulated by IL-8 and CXCL1), or both to induce CD11b-dependent neutrophil transmigration. Inhibition of CXCR1, CXCR2, or both reduces I/R-injury by preventing neutrophil accumulation. We hypothesized that interference with CXCR1/CXCR2 signalling contributes to the well-established beneficial effect of volatile anaesthetics in I/R-injury. Methods Isolated human neutrophils were stimulated with IL-8 or CXCL1 and exposed to volatile anaesthetics (sevoflurane/desflurane). Neutrophil migration was assessed using an adapted Boyden chamber. Expression of CD11b, CXCR1, and CXCR2 was measured by flow cytometry. Blocking antibodies against CXCR1/CXCR2/CD11b and phorbol myristate acetate were used to investigate specific pathways. Results Volatile anaesthetics reduced CD11b-dependent neutrophil transmigration induced by IL-8 by >30% and CD11b expression by 18 and 27% with sevoflurane/desflurane, respectively. This effect was independent of CXCR1/CXCR2 expression and CXCR1/CXCR2 endocytosis. Inhibition of CXCR1 signalling did not affect downregulation of CD11b with volatile anaesthetics. Blocking of CXCR2-signalling neutralized effects by volatile anaesthetics on CD11b expression. Specific stimulation of CXCR2 with CXCL1 was sufficient to induce upregulation of CD11b, which was impaired with volatile anaesthetics. No effect of volatile anaesthetics was observed with direct stimulation of protein kinase C located downstream of CXCR1/CXCR2. Conclusion Volatile anaesthetics attenuate neutrophil inflammatory responses elicited by CXC cytokines through interference with CXCR2 signalling. This might contribute to the beneficial effect of volatile anaesthetics in I/R-injur

Prospective Assessment of Sex-Related Differences in Symptom Status and Health Perception Among Patients With Atrial Fibrillation.

We prospectively assessed sex-specific differences in health perception, overall symptom status, and specific symptoms in a large cohort of patients with atrial fibrillation. We performed a prospective multicenter observational cohort study of 1553 patients with atrial fibrillation. Patients completed questionnaires about personal characteristics, comorbidities, and symptoms on a yearly basis. Mean age was 70±11 years among women and 67±12 years among men. Health perception on a visual analogue scale ranging from 0 to 100 (with higher scores indicating better health perception) was significantly lower in women than in men (70 [interquartile range: 50-80] versus 75 [interquartile range: 60-85]; javax.xml.bind.JAXBElement@29592a5d <0.0001). More women than men had any symptoms (85.0% versus 68.3%; javax.xml.bind.JAXBElement@7ac0b4e4 <0.0001), palpitations (65.2% versus 44.4%; javax.xml.bind.JAXBElement@41229466 <0.0001), dizziness (25.6% versus 13.5%; javax.xml.bind.JAXBElement@61871784 <0.0001), dyspnea (35.7% versus 21.8%; javax.xml.bind.JAXBElement@16cc22b <0.0001), and fatigue (25.3% versus 19.1%; javax.xml.bind.JAXBElement@7ef43176 =0.006). At 1-year follow-up, symptoms decreased in both sexes but remained more frequent in women (49.1% versus 32.6%, javax.xml.bind.JAXBElement@2b200b6a <0.0001). In multivariable adjusted longitudinal regression models, female sex remained an independent predictor for lower health perception (ß=-4.8; 95% CI, -6.5 to -3.1; javax.xml.bind.JAXBElement@72c212bd <0.0001), any symptoms (odds ratio [OR]: 2.6; 95% CI, 2.1-3.4; javax.xml.bind.JAXBElement@15d8fb54 <0.0001), palpitations (OR: 2.6; 95% CI, 2.1-3.2; javax.xml.bind.JAXBElement@4af80718 <0.0001), dizziness (OR: 2.9; 95% CI, 2.1-3.9; javax.xml.bind.JAXBElement@61282e76 <0.0001), dyspnea (OR: 2.1; 95% CI, 1.6-2.8; javax.xml.bind.JAXBElement@31d9f14 <0.0001), fatigue (OR: 1.6; 95% CI, 1.2-2.2; javax.xml.bind.JAXBElement@51cdd678 =0.0008), and chest pain (OR: 1.8; 95% CI, 1.3-2.6; javax.xml.bind.JAXBElement@5b87db9e =0.001). Women with atrial fibrillation have a substantially higher symptom burden and lower health perception than men. These relationships persisted after multivariable adjustment and during prospective follow-up

Volatile anaesthetics reduce neutrophil inflammatory response by interfering with CXC receptor-2 signalling

BACKGROUND Growing evidence suggests a protective effect of volatile anaesthetics in ischaemia-reperfusion (I/R)-injury, and the accumulation of neutrophils is a crucial event. Pro-inflammatory cytokines carrying the C-X-C-motif including interleukin-8 (IL-8) and CXC-ligand 1 (CXCL1) activate CXC receptor-1 (CXCR1; stimulated by IL-8), CXC receptor-2 (CXCR2; stimulated by IL-8 and CXCL1), or both to induce CD11b-dependent neutrophil transmigration. Inhibition of CXCR1, CXCR2, or both reduces I/R-injury by preventing neutrophil accumulation. We hypothesized that interference with CXCR1/CXCR2 signalling contributes to the well-established beneficial effect of volatile anaesthetics in I/R-injury. METHODS Isolated human neutrophils were stimulated with IL-8 or CXCL1 and exposed to volatile anaesthetics (sevoflurane/desflurane). Neutrophil migration was assessed using an adapted Boyden chamber. Expression of CD11b, CXCR1, and CXCR2 was measured by flow cytometry. Blocking antibodies against CXCR1/CXCR2/CD11b and phorbol myristate acetate were used to investigate specific pathways. RESULTS Volatile anaesthetics reduced CD11b-dependent neutrophil transmigration induced by IL-8 by >30% and CD11b expression by 18 and 27% with sevoflurane/desflurane, respectively. This effect was independent of CXCR1/CXCR2 expression and CXCR1/CXCR2 endocytosis. Inhibition of CXCR1 signalling did not affect downregulation of CD11b with volatile anaesthetics. Blocking of CXCR2-signalling neutralized effects by volatile anaesthetics on CD11b expression. Specific stimulation of CXCR2 with CXCL1 was sufficient to induce upregulation of CD11b, which was impaired with volatile anaesthetics. No effect of volatile anaesthetics was observed with direct stimulation of protein kinase C located downstream of CXCR1/CXCR2. CONCLUSION Volatile anaesthetics attenuate neutrophil inflammatory responses elicited by CXC cytokines through interference with CXCR2 signalling. This might contribute to the beneficial effect of volatile anaesthetics in I/R-injury