The Sottunga-Jurmo shear zone : structure and deformation history of a crustal-scale ductile shear zone in SW Finland

The aim of this study is to gain a better understanding of the structure and the deformation history of a NW-SE trending regional, crustal-scale shear structure in the Åland archipelago, SW Finland, called the Sottunga-Jurmo shear zone (SJSZ). Approaches involving e.g. structural geology, geochronology, geochemistry and metamorphic petrology were utilised in order to reconstruct the overall deformation history of the study area. The study therefore describes several features of the shear zone including structures, kinematics and lithologies within the study area, the ages of the different deformation phases (ductile to brittle) within the shear zone, as well as some geothermobarometric results. The results indicate that the SJSZ outlines a major crustal discontinuity between the extensively migmatized rocks NE of the shear zone and the unmigmatised, amphibolite facies rocks SW of the zone. The main SJSZ shows overall dextral lateral kinematics with a SW-side up vertical component and deformation partitioning into pure shear and simple shear dominated deformation styles that was intensified toward later stages of the deformation history. The deformation partitioning resulted in complex folding and refolding against the SW margin of the SJSZ, including conical and sheath folds, and in a formation of several minor strike-slip shear zones both parallel and conjugate to the main SJSZ in order to accommodate the regional transpressive stresses. Different deformation phases within the study area were dated by SIMS (zircon U-Pb), ID-TIMS (titanite U-Pb) and 40Ar/39Ar (pseudotachylyte wholerock) methods. The first deformation phase within the ca. 1.88 Ga rocks of the study area is dated at ca. 1.85 Ga, and the shear zone was reactivated twice within the ductile regime (at ca. 1.83 Ga and 1.79 Ga), during which the strain was successively increasingly partitioned into the main SJSZ and the minor shear zones. The age determinations suggest that the orogenic processes within the study area did not occur in a temporal continuum; instead, the metamorphic zircon rims and titanites show distinct, 10-20 Ma long breaks in deformation between phases of active deformation. The results of this study further imply slow cooling of the rocks through 600-700ºC so that at 1.79 Ga, 2 the temperature was still at least 600ºC. The highest recorded metamorphic pressures are 6.4-7.1 kbar. At the late stages or soon after the last ductile phase (ca. 1.79 Ga), relatively high-T mylonites and ultramylonites were formed, witnessing extreme deformation partitioning and high strain rates. After the rocks reached lower amphibolite facies to amphibolite-greenschist facies transitional conditions (ca. 500-550ºC), they cooled rapidly, probably due to crustal uplift and exhumation. The shear zone was reactivated at least once within the semi-brittle to brittle regime between ca. 1.79 Ga and 1.58 Ga, as evidenced by cataclasites and pseudotachylytes. In summary, the results of this study suggest that the Sottunga-Jurmo shear zone (and the South Finland shear zone) defines a major crustal discontinuity, and played a central role in accommodating the regional stresses during and after the Svecofennian orogeny.

Successful long-term ambulatory norepinephrine infusions in a patient with pure autonomic failure.

We present a case study of a patient with pure autonomic failure who was successfully treated with ambulatory norepinephrine (NE) infusions over a 9-year-period of time before death occurred unexpectedly. Given this patient's response to the NE infusion treatment, we discuss the option of ambulatory NE infusions as a treatment for severe orthostatic hypotension that is refractory to common treatments.

Involvement of long non-coding RNAs in beta cell failure at the onset of type 1 diabetes in NOD mice.

AIMS/HYPOTHESIS: Exposure of pancreatic beta cells to cytokines released by islet-infiltrating immune cells induces alterations in gene expression, leading to impaired insulin secretion and apoptosis in the initial phases of type 1 diabetes. Long non-coding RNAs (lncRNAs) are a new class of transcripts participating in the development of many diseases. As little is known about their role in insulin-secreting cells, this study aimed to evaluate their contribution to beta cell dysfunction. METHODS: The expression of lncRNAs was determined by microarray in the MIN6 beta cell line exposed to proinflammatory cytokines. The changes induced by cytokines were further assessed by real-time PCR in islets of control and NOD mice. The involvement of selected lncRNAs modified by cytokines was assessed after their overexpression in MIN6 cells and primary islet cells. RESULTS: MIN6 cells were found to express a large number of lncRNAs, many of which were modified by cytokine treatment. The changes in the level of selected lncRNAs were confirmed in mouse islets and an increase in these lncRNAs was also seen in prediabetic NOD mice. Overexpression of these lncRNAs in MIN6 and mouse islet cells, either alone or in combination with cytokines, favoured beta cell apoptosis without affecting insulin production or secretion. Furthermore, overexpression of lncRNA-1 promoted nuclear translocation of nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB). CONCLUSIONS/INTERPRETATION: Our study shows that lncRNAs are modulated during the development of type 1 diabetes in NOD mice, and that their overexpression sensitises beta cells to apoptosis, probably contributing to their failure during the initial phases of the disease.

Self-reported nonadherence to antiretroviral therapy as a predictor of viral failure and mortality

OBJECTIVE: To determine the effect of nonadherence to antiretroviral therapy (ART) on virologic failure and mortality in naive individuals starting ART. DESIGN: Prospective observational cohort study. METHODS: Eligible individuals enrolled in the Swiss HIV Cohort Study, started ART between 2003 and 2012, and provided adherence data on at least one biannual clinical visit. Adherence was defined as missed doses (none, one, two, or more than two) and percentage adherence (>95, 90-95, and <90) in the previous 4 weeks. Inverse probability weighting of marginal structural models was used to estimate the effect of nonadherence on viral failure (HIV-1 viral load >500 copies/ml) and mortality. RESULTS: Of 3150 individuals followed for a median 4.7 years, 480 (15.2%) experienced viral failure and 104 (3.3%) died, 1155 (36.6%) reported missing one dose, 414 (13.1%) two doses and, 333 (10.6%) more than two doses of ART. The risk of viral failure increased with each missed dose (one dose: hazard ratio [HR] 1.15, 95% confidence interval 0.79-1.67; two doses: 2.15, 1.31-3.53; more than two doses: 5.21, 2.96-9.18). The risk of death increased with more than two missed doses (HR 4.87, 2.21-10.73). Missing one to two doses of ART increased the risk of viral failure in those starting once-daily (HR 1.67, 1.11-2.50) compared with those starting twice-daily regimens (HR 0.99, 0.64-1.54, interaction P = 0.09). Consistent results were found for percentage adherence. CONCLUSION: Self-report of two or more missed doses of ART is associated with an increased risk of both viral failure and death. A simple adherence question helps identify patients at risk for negative clinical outcomes and offers opportunities for intervention.

FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature.

Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

A system to assess the stability of airborne nanoparticle agglomerates under aerodynamic shear

Stability of airborne nanoparticle agglomerates is important for occupational exposure and risk assessment in determining particle size distribution of nanomaterials. In this study, we developed an integrated method to test the stability of aerosols created using different types of nanomaterials. An aerosolization method, that resembles an industrial fluidized bed process, was used to aerosolize dry nanopowders. We produced aerosols with stable particle number concentrations and size distributions, which was important for the characterization of the aerosols' properties. Next, in order to test their potential for deagglomeration, a critical orifice was used to apply a range of shear forces to them. The mean particle size of tested aerosols became smaller, whereas the total number of particles generated grew. The fraction of particles in the lower size range increased, and the fraction in the upper size range decreased. The reproducibility and repeatability of the results were good. Transmission electron microscopy imaging showed that most of the nanoparticles were still agglomerated after passing through the orifice. However, primary particle geometry was very different. These results are encouraging for the use of our system for routine tests of the deagglomeration potential of nanomaterials. Furthermore, the particle concentrations and small quantities of raw materials used suggested that our system might also be able to serve as an alternative method to test dustiness in existing processes.

New Insights in the Diagnosis and Treatment of Heart Failure.

Cardiovascular disease is the leading cause of mortality in the US and in westernized countries with ischemic heart disease accounting for the majority of these deaths. Paradoxically, the improvements in the medical and surgical treatments of acute coronary syndrome are leading to an increasing number of "survivors" who are then developing heart failure. Despite considerable advances in its management, the gold standard for the treatment of end-stage heart failure patients remains heart transplantation. Nevertheless, this procedure can be offered only to a small percentage of patients who could benefit from a new heart due to the limited availability of donor organs. The aim of this review is to evaluate the safety and efficacy of innovative approaches in the diagnosis and treatment of patients refractory to standard medical therapy and excluded from cardiac transplantation lists.

Cost-effectiveness analysis of cardiac resynchronization therapy in patients with NYHA I and NYHA II heart failure in Spain

Objectives: The aim of the study was to combine clinical results from the European Cohort of the REVERSE study and costs associated with the addition of cardiac resynchronization therapy (CRT) to optimal medical therapy (OMT) in patients with mild symptomatic (NYHA I-II) or asymptomatic left ventricular dysfunction and markers of cardiac dyssynchrony in Spain. Methods: A Markov model was developed with CRT + OMT (CRT-ON) versus OMT only (CRT-OFF) based on a retrospective cost-effectiveness analysis. Raw data was derived from literature and expert opinion, reflecting clinical and economic consequences of patient"s management in Spain. Time horizon was 10 years. Both costs (euro 2010) and effects were discounted at 3 percent per annum. Results: CRT-ON showed higher total costs than CRT-OFF; however, CRT reduced the length of hospitalization in ICU by 94 percent (0.006 versus 0.091 days) and general ward in by 34 percent (0.705 versus 1.076 days). Surviving CRT-ON patients (88.2 percent versus 77.5 percent) remained in better functional class longer, and they achieved an improvement of 0.9 life years (LYGs) and 0.77 years quality-adjusted life years (QALYs). CRT-ON proved to be cost-effective after 6 years, except for the 7th year due to battery depletion. At 10 years, the results were 18,431 per LYG and 21,500 per QALY gained. Probabilistic sensitivity analysis showed CRT-ON was cost-effective in 75.4 percent of the cases at 10 years. Conclusions: The use of CRT added to OMT represents an efficient use of resources in patients suffering from heart failure in NYHA functional classes I and II.

Prognostic Importance of the Cuse of Renal Failure in Patients With Cirrhosis

BACKGROUND & AIMS: The prognostic value of the different causes of renal failure in cirrhosis is not well established. This study investigated the predictive value of the cause of renal failure in cirrhosis. METHODS: Five hundred sixty-two consecutive patients with cirrhosis and renal failure (as defined by serum creatinine 1.5 mg/dL on 2 successive determinations within 48 hours) hospitalized over a 6-year period in a single institution were included in a prospective study. The cause of renal failure was classified into 4 groups: renal failure associated with bacterial infections, renal failure associated with volume depletion, hepatorenal syndrome (HRS), and parenchymal nephropathy. The primary end point was survival at 3 months. RESULTS: Four hundred sixty-three patients (82.4%) had renal failure that could be classified in 1 of 4 groups. The most frequent was renal failure associated with infections (213 cases; 46%), followed by hypovolemia-associated renal failure (149; 32%), HRS (60; 13%), and parenchymal nephropathy (41; 9%). The remaining patients had a combination of causes or miscellaneous conditions. Prognosis was markedly different according to cause of renal failure, 3-month probability of survival being 73% for parenchymal nephropathy, 46% for hypovolemia-associated renal failure, 31% for renal failure associated with infections, and 15% for HRS (P .0005). In a multivariate analysis adjusted for potentially confounding variables, cause of renal failure was independently associated with prognosis, together with MELD score, serum sodium, and hepatic encephalopathy at time of diagnosis of renal failure. CONCLUSIONS: A simple classification of patients with cirrhosis according to cause of renal failure is useful in assessment of prognosis and may help in decision making in liver transplantation.

Définition et prise en charge de l'échec d'une première injection de toxine botulique Botox(®) 200 U pour hyperactivité détrusorienne neurogène : résultats de l'enquête DETOX [Definition of botulinum toxin failure in neurogenic detrusor overactivity: Preliminary results of the DETOX survey].

OBJECTIVE: There is currently no guideline regarding the management of neurogenic detrusor overactivity (NDO) refractory to intra-detrusor botulinum toxin injections. The primary objective of the present study was to find a consensus definition of failure of botulinum toxin intra-detrusor injections for NDO. The secondary objective was to report current trends in the managment of NDO refractory to botulinum toxin. METHODS: A survey was created, based on data drawn from current literature, and sent via e-mail to all the experts form the Group for research in neurourology in french language (GENULF) and from the comittee of neurourology of the French urological association (AFU). The experts who did not answer to the first e-mail were contacted again twice. Main results from the survey are presented and expressed as numbers and proportions. RESULTS: Out of the 42 experts contacted, 21 responded to the survey. Nineteen participants considered that the definition of failure should be a combination of clinical and urodynamics criteria. Among the urodynamics criteria, the persistence of a maximum detrusor pressure>40cm H2O was the most supported by the experts (18/21, 85%). According to the vast majority of participants (19/21, 90.5%), the impact of injections on urinary incontinence should be included in the definition of failure. Regarding the management, most experts considered that the first line treatment in case of failure of a first intra-detrusor injection of Botox(®) 200 U should be a repeat injection of Botox(®) at a higher dosage (300 U) (15/20, 75%), regardless of the presence or not of urodynamics risk factors of upper tract damage (16/20, 80%). CONCLUSION: This work has provided a first overview of the definition of failure of intra-detrusor injections of botulinum toxin in the management of NDO. For 90.5% of the experts involved, the definition of failure should be clinical and urodynamic and most participants (75%) considered that, in case of failure of a first injection of Botox(®) 200 U, repeat injection of Botox(®) 300 U should be the first line treatment. Level of proof 4.

Presence of Leishmania RNA Virus 1 in Leishmania guyanensis Increases the Risk of First-Line Treatment Failure and Symptomatic Relapse.

Treatment failure and symptomatic relapse are major concerns in American tegumentary leishmaniasis (TL). Such complications are seen frequently in Leishmania guyanensis infections, in which patients respond variously to first-line antileishmanials and are more prone to develop chronic cutaneous leishmaniasis. The factors underlying this pathology, however, are unknown. Recently, we reported that a double-stranded RNA virus, Leishmania RNA virus 1 (LRV1), nested within L. guyanensis parasites is able to exacerbate experimental murine leishmaniasis by inducing a hyperinflammatory response. This report investigates the prevalence of LRV1 in human L. guyanensis infection and its effect on treatment efficacy, as well as its correlation to symptomatic relapses after the completion of first-line treatment. In our cohort of 75 patients with a diagnosis of primary localized American TL, the prevalence of LRV1-positive L. guyanensis infection was elevated to 58%. All patients infected with LRV1-negative L. guyanensis were cured after 1 dose (22 of 31 [71%]) or 2 doses (31 of 31 [100%]) of pentamidine. In contrast, 12 of 44 LRV1-positive patients (27%) presented with persistent infection and symptomatic relapse that required extended therapy and the use of second-line drugs. Finally, LRV1 presence was associated with a significant increase in levels of intra-lesional inflammatory markers. In conclusion, LRV1 status in L. guyanensis infection is significantly predictive (P = .0009) of first-line treatment failure and symptomatic relapse and has the potential to guide therapeutic choices in American TL.

Impact of Aldosterone Antagonists on Sudden Cardiac Death Prevention in Heart Failure and Post-Myocardial Infarction Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND OBJECTIVES: Sudden cardiac death (SCD) is a severe burden of modern medicine. Aldosterone antagonist is publicized as effective in reducing mortality in patients with heart failure (HF) or post myocardial infarction (MI). Our study aimed to assess the efficacy of AAs on mortality including SCD, hospitalization admission and several common adverse effects. METHODS: We searched Embase, PubMed, Web of Science, Cochrane library and clinicaltrial.gov for randomized controlled trials (RCTs) assigning AAs in patients with HF or post MI through May 2015. The comparator included standard medication or placebo, or both. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Event rates were compared using a random effects model. Prospective RCTs of AAs with durations of at least 8 weeks were selected if they included at least one of the following outcomes: SCD, all-cause/cardiovascular mortality, all-cause/cardiovascular hospitalization and common side effects (hyperkalemia, renal function degradation and gynecomastia). RESULTS: Data from 19,333 patients enrolled in 25 trials were included. In patients with HF, this treatment significantly reduced the risk of SCD by 19% (RR 0.81; 95% CI, 0.67-0.98; p = 0.03); all-cause mortality by 19% (RR 0.81; 95% CI, 0.74-0.88, p<0.00001) and cardiovascular death by 21% (RR 0.79; 95% CI, 0.70-0.89, p<0.00001). In patients with post-MI, the matching reduced risks were 20% (RR 0.80; 95% CI, 0.66-0.98; p = 0.03), 15% (RR 0.85; 95% CI, 0.76-0.95, p = 0.003) and 17% (RR 0.83; 95% CI, 0.74-0.94, p = 0.003), respectively. Concerning both subgroups, the relative risks respectively decreased by 19% (RR 0.81; 95% CI, 0.71-0.92; p = 0.002) for SCD, 18% (RR 0.82; 95% CI, 0.77-0.88, p < 0.0001) for all-cause mortality and 20% (RR 0.80; 95% CI, 0.74-0.87, p < 0.0001) for cardiovascular mortality in patients treated with AAs. As well, hospitalizations were significantly reduced, while common adverse effects were significantly increased. CONCLUSION: Aldosterone antagonists appear to be effective in reducing SCD and other mortality events, compared with placebo or standard medication in patients with HF and/or after a MI.