Respiratory failure in a mouse model of myotonic dystrophy does not correlate with the CTG repeat length.

Myotonic dystrophy (DM1) is a multisystemic disease caused by an expansion of CTG repeats in the region of DMPK, the gene encoding DM protein kinase. The severity of muscle disability in DM1 correlates with the size of CTG expansion. As respiratory failure is one of the main causes of death in DM1, we investigated the correlation between respiratory impairment and size of the (CTG)n repeat in DM1 animal models. Using pressure plethysmography the respiratory function was assessed in control and transgenic mice carrying either 600 (DM600) or >1300 CTG repeats (DMSXL). The statistical analysis of respiratory parameters revealed that both DM1 transgenic mice sub-lines show respiratory impairment compared to control mice. In addition, there is no significant difference in breathing functions between the DM600 and DMSXL mice. In conclusion, these results indicate that respiratory impairment is present in both transgenic mice sub-lines, but the severity of respiratory failure is not related to the size of the (CTG)n expansion.

Development of fluid conduits in the auriferous shear zones of the Hutti Gold Mine, India: evidence for spatially and temporally heterogeneous fluid flow

The gold mineralization of the Hutti Mine is hosted by nine parallel, N - S trending, steeply dipping, 2 - 10 m wide shear zones, that transect Archaean amphibolites. The shear zones were formed after peak metamorphism during retrograde ductile D, shearing in the lower amphibolite facies. They were reactivated in the lower to mid greenschist facies by brittle-ductile D-3 shearing and intense quartz veining. The development of a S-2-S-3 crenulation cleavage facilitates the discrimination between the two deformation events and contemporaneous alteration and gold mineralization. Ductile D, shearing is associated with a pervasively developed distal chlorite - sed cite alteration assemblage in the outer parts of the shear zones and the proximal biotite-plagioclase alteration in the center of the shear zones. D3 is characterized by development of the inner chlorite-K-feldspar alteration, which forms a centimeter-scale alteration halo surrounding the laminated quartz veins and replaces earlier biotite along S-3. The average size of the laminated vein systems is 30-50 m along strike as well as down-dip and 2-6 m in width. Mass balance calculations suggest strong metasomatic changes for the proximal biotite-plagioclase alteration yielding mass and volume increase of ca. 16% and 12%, respectively. The calculated mass and volume changes of the distal chlorite-sericite alteration (ca. 11%, ca. 8%) are lower. The decrease in 6180 values of the whole rock from around 7.5 parts per thousand for the host rocks to 6-7 parts per thousand for the distal chlorite-sericite and the proximal biotite-plagioclase alteration and around 5 parts per thousand for the inner chlorite-K-feldspar alteration suggests hydrothermal alteration during two-stage deformation and fluid flow. The ductile D-2 deformation in the lower amphibolite facies has provided grain scale porosities by microfracturing. The pervasive, steady-state fluid flow resulted in a disseminated style of gold-sulfide mineralization and a penetrative alteration of the host rocks. Alternating ductile and brittle D3 deformation during lower to mid greenschist facies conditions followed the fault-valve process. Ductile creep in the shear zones resulted in a low permeability environment leading to fluid pressure build-up. Strongly episodic fluid advection and mass transfer was controlled by repeated seismic fracturing during the formation of laminated quartz(-gold) veins. The limitation of quartz veins to the extent of earlier shear zones indicate the importance of preexisting anisotropies for fault-valve action and economic gold mineralization. (C) 2003 Elsevier B.V. All rights reserved.

Sofosbuvir and ribavirin before liver re-transplantation for graft failure due to recurrent hepatitis C: a case report.

BACKGROUND: Recurrent hepatitis C virus infection after liver transplantation is associated with reduced graft and patient survival. Re-transplantation for graft failure due to recurrent hepatitis C is controversial and not performed in all centers. CASE PRESENTATION: We describe a 54-year-old patient with hepatitis C virus genotype 1b infection and a null response to pegylated interferon-α and ribavirin who developed decompensated graft cirrhosis 6 years after a first liver transplantation. Treatment with sofosbuvir and ribavirin allowed for rapid negativation of serum HCV RNA and was well tolerated despite advanced liver and moderate renal dysfunction. Therapeutic drug monitoring did not reveal any clinically significant drug-drug interactions. Despite virological response, the patient remained severely decompensated and re-transplantation was performed after 46 days of undetectable serum HCV RNA. The patient is doing well 12 months after his second liver transplantation and remains free of hepatitis C virus. CONCLUSIONS: The use of directly acting antivirals may allow for successful liver re-transplantation for recipients who remain decompensated despite virological response and is likely to improve the outcome of liver re-transplantation for end-stage recurrent hepatitis C.

Analysis of flow dynamics in right ventricular outflow tract.

BACKGROUND: The mechanism behind early graft failure after right ventricular outflow tract (RVOT) reconstruction is not fully understood. Our aim was to establish a three-dimensional computational fluid dynamics (CFD) model of RVOT to investigate the hemodynamic conditions that may trigger the development of intimal hyperplasia and arteriosclerosis. METHODS: Pressure, flow, and diameter at the RVOT, pulmonary artery (PA), bifurcation of the PA, and left and right PAs were measured in 10 normal pigs with a mean weight of 24.8 ± 0.78 kg. Data obtained from the experimental scenario were used for CFD simulation of pressure, flow, and shear stress profile from the RVOT to the left and right PAs. RESULTS: Using experimental data, a CFD model was obtained for 2.0 and 2.5-L/min pulsatile inflow profiles. In both velocity profiles, time and space averaged in the low-shear stress profile range from 0-6.0 Pa at the pulmonary trunk, its bifurcation, and at the openings of both PAs. These low-shear stress areas were accompanied to high-pressure regions 14.0-20.0 mm Hg (1866.2-2666 Pa). Flow analysis revealed a turbulent flow at the PA bifurcation and ostia of both PAs. CONCLUSIONS: Identified local low-shear stress, high pressure, and turbulent flow correspond to a well-defined trigger pattern for the development of intimal hyperplasia and arteriosclerosis. As such, this real-time three-dimensional CFD model may in the future serve as a tool for the planning of RVOT reconstruction, its analysis, and prediction of outcome.

Effects of Sucroferric Oxyhydroxide Compared to Lanthanum Carbonate and Sevelamer Carbonate on Phosphate Homeostasis and Vascular Calcifications in a Rat Model of Chronic Kidney Failure.

Elevated serum phosphorus, calcium, and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease in chronic renal disease. This study evaluated the effects of sucroferric oxyhydroxide (PA21), a new iron-based phosphate binder, versus lanthanum carbonate (La) and sevelamer carbonate (Se), on serum FGF23, phosphorus, calcium, and intact parathyroid hormone (iPTH) concentrations, and the development of vascular calcification in adenine-induced chronic renal failure (CRF) rats. After induction of CRF, renal function was significantly impaired in all groups: uremic rats developed severe hyperphosphatemia, and serum iPTH increased significantly. All uremic rats (except controls) then received phosphate binders for 4 weeks. Hyperphosphatemia and increased serum iPTH were controlled to a similar extent in all phosphate binder-treatment groups. Only sucroferric oxyhydroxide was associated with significantly decreased FGF23. Vascular calcifications of the thoracic aorta were decreased by all three phosphate binders. Calcifications were better prevented at the superior part of the thoracic and abdominal aorta in the PA21 treated rats. In adenine-induced CRF rats, sucroferric oxyhydroxide was as effective as La and Se in controlling hyperphosphatemia, secondary hyperparathyroidism, and vascular calcifications. The role of FGF23 in calcification remains to be confirmed.

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.