Subretinal Stimulation Chip Set with 3025 Electrodes, Spatial Peaking Filter, Illumination Adaptation and Implant Lifetime Optimization.

A subretinal stimulator chip has been designed and tested, which combines high pixel number with highest simulation voltages, lowest power consumption, spatial peaking and illumination adaptation. A supporting ASIC completes the implantable device electronics. Blind mouse retina has successfully been stimulated in vitro.

Change in Serum Biomarker CA 15-3 as an Early Predictor of Response to Treatment and Survival in Hypersensitivity Pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease with a heterogeneous course of disease and treatment response. Cancer antigen 15-3 (CA 15-3), part of mucin 1, is believed to reflect epithelial cell injury and lung permeability and could be a potential biomarker for treatment response in HP. OBJECTIVE: To assess the value of CA 15-3 as a predictive biomarker in non-fibrotic and fibrotic HP during immunosuppressive therapy. DESIGN: Serum levels of CA 15-3 and pulmonary function tests (PFTs) were retrospectively retrieved from 48 HP patients treated with prednisone or cyclophosphamide at initiation of therapy (baseline), after 3 and 6 months. Pearson's correlation coefficient was computed to assess correlations between change in serum levels and PFT. Survival was evaluated using Kaplan-Meier curves. RESULTS: After 6 months of immunosuppressive therapy CA 15-3 levels decreased significantly compared to baseline (p = 0.001). Change in CA 15-3 after 6 months correlated with FVC change (r = - 0.469; p = 0.001). Correlations with FVC change were observed in prednisone-treated HP (r = - 0.514; p = 0.005) and fibrotic HP (r = - 0.417; p = 0.007). Three-month CA 15-3 change correlated with 6-month FVC change (r = - 0.599; p < 0.001). CA 15-3 declines of at least 7.9% after 6 months were associated with increased survival compared to minor CA 15-3 changes (HR 0.34; p = 0.020). CONCLUSION: Serum CA 15-3 correlates with PFT during 6 months of immunosuppressive therapy in HP. Interestingly, early CA 15-3 changes could predict future PFT. Furthermore, a decrease in CA 15-3 is related to longer survival. Therefore, serum CA 15-3 is a promising biomarker for implementation in HP care.

Intra-Abdominal Cooling System Limits Ischemia-Reperfusion Injury During Robot-Assisted Renal Transplantation.

Robot-assisted kidney transplantation is feasible; however, concerns have been raised about possible increases in warm ischemia times. We describe a novel intra-abdominal cooling system to continuously cool the kidney during the procedure. Porcine kidneys were procured by standard open technique. Groups were as follows: Robotic renal transplantation with (n = 11) and without (n = 6) continuous intra-abdominal cooling and conventional open technique with intermittent 4°C saline cooling (n = 6). Renal cortex temperature, magnetic resonance imaging, and histology were analyzed. Robotic renal transplantation required a longer anastomosis time, either with or without the cooling system, compared to the open approach (70.4 ± 17.7 min and 74.0 ± 21.5 min vs. 48.7 ± 11.2 min, p-values < 0.05). The temperature was lower in the robotic group with cooling system compared to the open approach group (6.5 ± 3.1°C vs. 22.5 ± 6.5°C; p = 0.001) or compared to the robotic group without the cooling system (28.7 ± 3.3°C; p < 0.001). Magnetic resonance imaging parenchymal heterogeneities and histologic ischemia-reperfusion lesions were more severe in the robotic group without cooling than in the cooled (open and robotic) groups. Robot-assisted kidney transplantation prolongs the warm ischemia time of the donor kidney. We developed a novel intra-abdominal cooling system that suppresses the noncontrolled rewarming of donor kidneys during the transplant procedure and prevents ischemia-reperfusion injuries.

Athletes and blood clots: individualized, intermittent anticoagulation management.

Essentials Athletes on anticoagulants are typically prohibited from participation in contact sports. Short-acting anticoagulants allow for reconsideration of this precedent. An individualized pharmacokinetic/pharmacodynamics study can aid patient-specific management. Many challenges and unresolved issues exist regarding such tailored intermittent dosing. SUMMARY: Athletes with venous thromboembolism (VTE) are typically prohibited from participating in contact sports during anticoagulation therapy, but such mandatory removal from competition can cause psychological and financial detriments for athletes and overlooks patient autonomy. The precedent of compulsory removal developed when options for anticoagulation therapy were more limited, but medical advances now allow for rethinking of the management of athletes with VTE. We propose a novel therapeutic approach to the treatment of athletes who participate in contact sports and require anticoagulation. A personalized pharmacokinetic/pharmacodynamics study of a direct oral anticoagulant can be performed for an athlete, which can inform the timing of medication dosing. Managed carefully, this can allow athletic participation when plasma drug concentration is minimal (minimizing bleeding risk) and prompt resumption of treatment after the risk of bleeding sufficiently normalizes (maximizing therapeutic time).

New Magnetic Resonance Imaging Index for Renal Fibrosis Assessment: A Comparison between Diffusion-Weighted Imaging and T1 Mapping with Histological Validation.

A need exists to noninvasively assess renal interstitial fibrosis, a common process to all kidney diseases and predictive of renal prognosis. In this translational study, Magnetic Resonance Imaging (MRI) T1 mapping and a new segmented Diffusion-Weighted Imaging (DWI) technique, for Apparent Diffusion Coefficient (ADC), were first compared to renal fibrosis in two well-controlled animal models to assess detection limits. Validation against biopsy was then performed in 33 kidney allograft recipients (KARs). Predictive MRI indices, ΔT1 and ΔADC (defined as the cortico-medullary differences), were compared to histology. In rats, both T1 and ADC correlated well with fibrosis and inflammation showing a difference between normal and diseased kidneys. In KARs, MRI indices were not sensitive to interstitial inflammation. By contrast, ΔADC outperformed ΔT1 with a stronger negative correlation to fibrosis (R(2) = 0.64 against R(2) = 0.29 p < 0.001). ΔADC tends to negative values in KARs harboring cortical fibrosis of more than 40%. Using a discriminant analysis method, the ΔADC, as a marker to detect such level of fibrosis or higher, led to a specificity and sensitivity of 100% and 71%, respectively. This new index has potential for noninvasive assessment of fibrosis in the clinical setting.

D-dimer levels and recurrence in patients with unprovoked VTE and a negative qualitative D-dimer test after treatment.

BACKGROUND: The rate of recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who had a negative qualitative D-dimer test one month after stopping anticoagulant therapy was higher than expected in the D-dimer Optimal Duration Study (DODS). OBJECTIVES: To determine whether quantitative D-dimer levels using a low threshold, age- and sex-specific thresholds, or repeated measurements, would improve identification of patients at low risk of recurrent VTE. MATERIALS AND METHODS: D-dimer levels were quantified in banked samples from 307 patients in DODS who had a negative qualitative D-dimer test while on, and 1month after stopping, anticoagulant therapy and the rates of recurrent VTE were determined in patients with D-dimer levels below various predefined thresholds. RESULTS: The rate (per patient year) of recurrent VTE was: 5.9% with D-dimer levels<250µg/l at one month; 5.2% with D-dimer levels between 250 and 499µg/l at one month; 5.0% with D-dimer levels less than predefined age- and sex-specific thresholds at one month; and 6.3% when D-dimer levels were <500µg/l at both one and 7months after stopping anticoagulant therapy. These rates are similar to the overall event rate of 6.3% in patients who stopped treatment. CONCLUSIONS: Among unprovoked VTE patients who had a negative qualitative D-dimer test during and after anticoagulant therapy, low D-dimer thresholds, age and sex-adjusted thresholds or repeated measurements, did not identify subgroups with a very low rate of recurrence.

A single test to assay warfarin, dabigatran, rivaroxaban, apixaban, unfractionated heparin, and enoxaparin in plasma.

UNLABELLED: Essentials Simple and fast assaying of different anticoagulants (ACs) is useful in emergent situations. We used highly diluted prothrombin time (dPT) or highly diluted Fiix-PT (dFiix-PT) to assay ACs. Both tests could quantify target specific anticoagulants and warfarin anticoagulation. Improved results were consistently observed with the dFiix-PT compared with the dPT. SUMMARY: Background Assaying anticoagulants is useful in emergency situations or before surgery. Different specific assays are currently needed depending on the anticoagulant. Objectives We hypothesized that levels of warfarin, dabigatran, rivaroxaban, apixaban, and heparins could be measured with use of the diluted prothrombin time (dPT) and diluted Fiix-PT (dFiix-PT), using highly diluted thromboplastin (TP). The latter test is affected only by reduced levels of active factors II and X but corrects test plasma for other deficiencies Methods Increasing TP dilutions were used to identify suitable dilutions to measure dabigatran, rivaroxaban, apixaban, unfractionated heparin (UFH), and enoxaparin. Calibrators containing known amounts of direct oral anticoagulants (DOACs) were used to make standard curves. Citrated plasma samples were obtained from patients taking warfarin or DOACs with known drug concentrations as determined by specific assays. Results The dFiix-PT at a TP dilution of 1:1156 could be used to measure all of the drugs tested at therapeutic concentrations except for fondaparinux. The dPT achieved the same but required two TP dilutions (1:750 and 1:300). The warfarin effect could be assessed by using dFiix-PT at 1:1156 with a PT ratio identical to the international normalized ratio. Six different TPs yielded similar results, but two were less sensitive. Dabigatran, rivaroxaban, and apixaban could be accurately measured in patient samples using both dilute PT assays, but a better correlation was consistently observed between the dFiix-PT and specific assays than with the dPT. Conclusion The dFiix-PT using a single dilution of TP may be suitable to assess the anticoagulant effects of warfarin, dabigatran, rivaroxaban, apixaban, heparin, and enoxaparin.

[Oxalate nephropathy: a new entity of acute kidney injury in diabetic patients?]. / La néphropathie aiguë à oxalates: une cause d'insuffisance rénale aiguë à rechercher.

Acute oxalate nephropathy is a severe cause of acute kidney injury characterized by tubule-interstitial oxalate deposits with an inflammatory infiltrate. Three cases of AKI occuring in diabetic patients, and whose renal biopsy gave a diagnosis of acute oxalate nephropathy are reported. This cristal deposit AKI is due to either primary hyperoxaluria or secondary to enteric hyperabsorption. Its prognosis is dismal and rapid recognition by renal biopsy and determination of the cause of hyperoxaluria is mandatory in order to avoid end-stage kidney disease. This diagnosis should be suspected in cases of non resolving AKI, especially in diabetic patients who may have undetected pancreatic exocrine insufficiency.

Evaluating the use of commercial drug-specific calibrators for determining PT and APTT reagent sensitivity to dabigatran and rivaroxaban.

Suitable laboratory methodologies for quantifying the non-vitamin K oral anticoagulants (NOAC) include liquid chromatography-tandem mass spectrometry (LC-MS/MS) or drug-calibrated assays such as the dilute thrombin time for dabigatran or anti-Xa measurements for rivaroxaban. In situations when these tests are unavailable, it has been suggested that using commercial drug calibrators on APTT and PT assays would theoretically provide reagent sensitivity to these drugs. The purpose of this study was to determine whether commercial drug calibrators deliver similar reagent sensitivity information as samples from patients receiving dabigatran or rivaroxaban as part of their routine care. Two laboratory sites tested commercial calibrator material for dabigatran and rivaroxaban (Hyphen Biomedical) using PT and APTT reagents and data was compared to samples collected from patients taking NOACs that were quantified by LC-MS/MS. Correlation statistics and calculating the amount of drug required to double the clotting time of normal plasma were performed. All drug calibrator material correlated more strongly (R²> 0.95) for any reagent/drug combination than patient samples (R² ranged from 0.29-0.86). Dabigatran calibrator results and patient data were equivalent for SynthASil and PTT-A APTT reagents. The dabigatran and rivaroxaban calibrator material over-estimated drug sensitivity for all PT reagents when compared to sensitivity data calculated based on drug levels obtained by LC-MS/MS from patient samples. In conclusion, drug-specific calibrators overestimated reagent sensitivity which may underestimate in vivo drug concentration in a given patient. Further studies are required to assess whether this method of determining relative sensitivity of NOAC on routine coagulation assays should be recommended.

Direct observation of interstitial dislocation loop coarsening in α-iron.

Interstitial loop coarsening by Ostwald ripening can provide insight into single point defects but is very difficult to observe in α-iron and many other metals where nanoscale vacancy clusters dissociate and annihilate loops. We show that by implanting helium in the samples at a carefully chosen energy, it is possible to observe Ostwald ripening of loops by transmission electron microscopy during in situ isochronal annealings. This coarsening of loops results in a sharp increase of the mean loop radius at around 850 K. Using cluster dynamics simulations, we demonstrate that loops evolve due to vacancy emission and that such experiments give a robust estimation of the sum of the formation and migration free energies of vacancies. In particular, our results are in good agreement with self-diffusion experiments and confirm that entropic contributions are large for the vacancy in α-iron.

Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels.

BACKGROUND: Knowledge of anticoagulation status during dabigatran therapy may be desirable in certain clinical situations. OBJECTIVE: To determine the coagulation tests that are most useful for assessing dabigatran's anticoagulant effect. METHODS: Peak and trough blood samples from 35 patients taking dabigatran 150 mg twice daily, and one sample each from 30 non-anticoagulated individuals, were collected. Mass spectrometry and various coagulation assays were performed. 'Therapeutic range' was defined as the range of plasma dabigatran concentrations determined by mass spectrometry between the 2.5th and 97.5th percentiles of all values. RESULTS: The therapeutic range was 27-411 ng mL(-1) . The prothrombin time (PT) and activated partial thromboplastin time (APTT), determined with multiple reagents, and activated clotting time (ACT) were insensitive to therapeutic dabigatran: 29%, 18% and 40% of samples had a normal PT, APTT, and ACT, respectively. However, normal PT, ACT and APTT ruled out dabigatran levels above the 75th percentile. The thrombin clotting time (TCT) correlated well and linearly with dabigatran levels below the 50th percentile, but was unmeasurable above it. The dilute thrombin time, ecarin clotting time and ecarin chromogenic assay showed linear correlations with dabigatran levels over a broad range, and identified therapeutic and supratherapeutic levels. CONCLUSIONS: The prothrombin time, APTT and ACT are often normal in spite of therapeutic dabigatran plasma levels. The TCT is useful for detecting minimal dabigatran levels. The dilute thrombin time and chromogenic and clotting ecarin assays accurately identify therapeutic and supratherapeutic dabigatran levels. This trial is registered at www.clinicaltrials.gov (#NCT01588327).

Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity.

OBJECTIVE: NADPH oxidase 4 (NOX4) is a reactive oxygen species (ROS) producing NADPH oxidase that regulates redox homeostasis in diverse insulin-sensitive cell types. In particular, NOX4-derived ROS is a key modulator of adipocyte differentiation and mediates insulin receptor signaling in mature adipocytes in vitro. Our study was aimed at investigating the role of NOX4 in adipose tissue differentiation, whole body metabolic homeostasis and insulin sensitivity in vivo. DESIGN: Mice with genetic ablation of NOX4 (NOX4-deficient mice) were subjected to chow or high-fat-containing diet for 12 weeks. Body weight gain, adiposity, insulin sensitivity, and adipose tissue and liver gene and protein expression were analyzed and compared with similarly treated wild-type mice. RESULTS: Here, we report that NOX4-deficient mice display latent adipose tissue accumulation and are susceptible to diet-induced obesity and early onset insulin resistance. Obesity results from accelerated adipocyte differentiation and hypertrophy, and an increase in whole body energy efficiency. Insulin resistance is associated with increased adipose tissue hypoxia, inflammation and adipocyte apoptosis. In the liver, more severe diet-induced steatosis was observed due to the lack of proper upregulation of mitochondrial fatty acid ß-oxidation. CONCLUSION: These findings identify NOX4 as a regulator of metabolic homeostasis. Moreover, they indicate an anti-adipogenic role for NOX4 in vivo and reveal its function as a protector against the development of diet-induced obesity, insulin resistance and hepatosteatosis.

Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation.

Renal thrombotic microangiopathy (TMA) is a severe complication of systemic lupus erythematosus (SLE), which is associated with the presence of antiphospholipid (aPL) antibodies. In its most fulminant form, TMA leads to a rapid and irreversible end-stage renal failure. Eculizumab, an anti-C5 monoclonal antibody, is a novel therapy of choice for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. Here, we report the case of a 27-year-old woman, known for SLE and end-stage renal disease due to fulminant TMA. Both aPL antibodies and antinucleosome antibodies were positive. The patient underwent a living-related kidney transplantation with immediate production of urine. Although serum creatinine was remaining high, a graft biopsy, performed on day 6, demonstrated a TMA recurrence. Despite a treatment with plasma exchange, the situation got worse and dialysis was started. Eculizumab treatment was subsequently administered and renal function improved rapidly. Three months after transplantation, serum creatinine was at 100 µmol/L, without proteinuria. This case illustrates the benefit of eculizumab therapy in a fulminant recurrence of TMA after kidney transplantation, resistant to classical therapy.

Do NK cells contribute to the pathophysiology of transplant-associated thrombotic microangiopathy?

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication caused by the aggregation of platelets exposed to the thrombogenic subendothelial matrix of injured endothelial cells. Here, we present a case of a patient transplanted for idiopathic aplastic anemia with a T-cell depleted hematopoietic stem cell graft from an HLA-C mismatched unrelated donor. At day 7 posttransplant, she suffered from acute renal failure with hematuria. The presence of numerous schistocytes, an increased level of lactate dehydrogenase and a renal biopsy with multiple vascular injuries confirmed the diagnosis of severe TA-TMA. At day 14, she developed graft versus host disease and died 7 months posttransplantation of multiorgan failure. At day 15, we observed a sizable population of natural killer (NK) cells in the peripheral blood, the number of which reached 0.8 G/L at 4 months posttransplant. Most NK cells lacked inhibitory killer immunoglobulin-like receptors (KIR) specific for the KIR-ligands expressed in the patient. NK cells were also abundantly present in pericardial and pleural fluids and had invaded the kidney, where they colocalized with the renal vasculopathy. Because there are several mechanisms through which NK cells and platelets can activate each other reciprocally, it is conceivable that NK cells contribute to TA-TMA and its progression.

Side plate fixation vs. intramedullary nailing in an unstable medial femoral neck fracture model: A comparative biomechanical study.

BACKGROUND: The objective of this study was to investigate primary stability of the proximal femoral nailing antirotation for the indication of unstable medial femoral neck fractures. The device was compared to the dynamic hip screw blade, which is a "gold standard" in the treatment of proximal femoral fractures. METHODS: Six pairs of human cadaver femurs were tested in a cyclic loading model with loads up to 200 N, 400 N, 600 N, 800 N, and 1000 N, respectively. Iliotibial tract was simulated by a chain that applied forces on the greater trochanter during loading. In vitro combined axial and bending loads were applied. Angular displacements during loading were recorded in all directions, and loads to failure were recorded. FINDINGS: For the cyclic loading test no statistically significant differences between the two groups could be detected. Specimens fixed with the dynamic hip screw blade showed higher displacements in the varus direction at 400 N and 600 N, in the external rotation at 200 N, 400 N and 600 N, and in the anterior direction at 400 N. Load to failure revealed no statistical difference between the two implants. INTERPRETATION: The proximal femoral nailing antirotation achieves primary stability comparable to the dynamic hip screw blade. The proximal femoral nailing antirotation combines the biomechanical favorable concept of intramedullary fixation with a minimally invasive surgical technique, which theoretically may be advantageous in clinical use. Further biomechanical studies are required to clarify to what extent the results of the present study can be transferred to the clinical situation.

Visceral leishmaniasis in a kidney transplant recipient: parasitic interstitial nephritis, a cause of renal dysfunction.

Visceral leishmaniasis (VL) due to Leishmania infantum is an endemic parasitic infection in the Mediterranean area. It most commonly affects immunosuppressed individuals, especially HIV patients and less frequently organ transplant recipients. Renal involvement seems to be frequent and is mostly associated with tubulointerstitial nephritis, as described in autopsy reports. In the 61 cases of renal transplant recipients with VL reported in the literature, renal dysfunction was noted at clinical presentation and was more frequently observed as a complication of antiparasitic therapy. However, no pathological analysis of the allograft lesions was reported. We present the case of a Swiss renal transplant recipient who developed VL after vacations in Spain and Tunisia, complicated by acute parasitic nephritis in the renal allograft 3 months after a well-conducted treatment of liposomal amphotericin B.

[Hemolytic uremic syndrome following gemcitabine treatment]. / Syndrome hémolytique et urémique suite a un traitement de gemcitabine.

Hemolytic uremic syndrome (HUS) in children is classically associated with diarrheas related to the production of a shiga-toxin. HUS occurs among oncologic patients, in relation with the cancer itself, or as a complication of the cytostatic treatment. The physician should be familiar with the triad of HUS (microangiopathic hemolytic anemia, thrombocytopenia and renal failure) and search actively for this pathology in oncologic patient. The treatment is essentially empirical. It includes plasma exchanges, control of blood pressure, hydro-electrolytic balance control with dialysis, if necessary. Blood transfusion should be avoided. Potential mortal complications associated with HUS can be prevented by a rapid diagnosis and a prompt initiation of adequate therapy.