Transfer of sulfur and chalcophile metals via sulfide-volatile compound drops in the Christiana-Santorini-Kolumbo volcanic field.

Efficient transfer of S and chalcophile metals through the Earth's crust in arc systems is paramount for the formation of large magmatic-hydrothermal ore deposits. The formation of sulfide-volatile compound drops has been recognized as a potential key mechanism for such transfer but their fate during dynamic arc magmatism remains cryptic. Combining elemental mapping and in-situ mineral analyzes we reconstruct the evolution of compound drops in the active Christiana-Santorini-Kolumbo volcanic field. The observed compound drops are micrometric sulfide blebs associated with vesicles trapped within silicate phenocrysts. The compound drops accumulate and coalesce at mafic-felsic melt interfaces where larger sulfide ovoids form. These ovoids are subsequently oxidized to magnetite during sulfide-volatile interaction. Comparison of metal concentrations between the sulfide phases and magnetite allows for determination of element mobility during oxidation. The formation and evolution of compound drops may be an efficient mechanism for transferring S and chalcophile metals into shallow magmatic-hydrothermal arc systems.

Ignition of the southern Atlantic seafloor spreading machine without hot-mantle booster.

The source of massive magma production at volcanic rifted margins remains strongly disputed since the first observations of thick lava piles in the 1980s. However, volumes of extruded and intruded melt products within rifted continental crust are still not accurately resolved using geophysical methods. Here we investigate the magma budget alongside the South Atlantic margins, at the onset of seafloor spreading, using high-quality seismic reflection profiles to accurately estimate the oceanic crustal thickness. We show that, along ~ 75% of the length of the Early-Cretaceous initial spreading centre, the crustal thickness is similar to regular oceanic thickness with an age > 100 Ma away from hot spots. Thus, most of the southernmost Atlantic Ocean opened without anomalously hot mantle, high magma supply being restricted to the Walvis Ridge area. We suggest that alternative explanations other than a hotter mantle should be favoured to explain the thick magmatic layer of seaward dipping reflectors landward of the initial mid-oceanic ridge.

Glomerulonephritis with non-Randall-type, non-cryoglobulinaemic monoclonal immunoglobulin G deposits (PGNMID and ITG).

Background: Glomerulonephritis (GN) with non-Randall-type, non-cryoglobulinaemic monoclonal immunoglobulin G deposits encompasses rare diseases [proliferative GN with non-organized deposits (PGNMID) and immunotactoid GN] that cannot be distinguished without ultrastructural analysis by electron microscopy (EM). Methods: Here, we report and analyse the prognosis of 41 EM-proven (PGNMID for 39/41) and 22 non-EM-proven/DNAJB9-negative cases, diagnosed between 2001 and 2019 in 12 French nephrology centres. Results: Median (interquartile range) serum creatinine (SCr) at presentation was 150 (92-256) µmol/L. The predominant histological pattern was membranoproliferative GN (79%), with IgG3 (74%) kappa (78%) deposits the most frequently observed. Disease presentation and patient management were similar between EM-proven and non-EM-proven cases. A serum monoclonal spike was detected for 21 patients and 10 had an underlying haematological malignancy. First-line therapy was mixed between clone-targeted therapy (n = 33), corticosteroids (n = 9) and RAAS inhibitors (n = 19). After 6 months, nine patients achieved complete and 23 partial renal recovery. In univariate analysis, renal recovery was associated with baseline SCr (odds ratio 0.70, P = 0.07). After a median follow-up of 52 (35-74) months, 38% of patients had progressed to end-stage kidney disease independently associated with baseline SCr [hazard ratio (HR) 1.41, P = 0.003] and glomerular crescentic proliferation (HR 4.38, P = 0.004). Conclusions: Our results confirm that non-cryoglobulinaemic and non-Randall GN with monoclonal IgG deposits are rarely associated with haematological malignancy. The prognosis is uncertain but may be improved by early introduction of a specific therapy.

Immune-mediated thrombotic thrombocytopenic purpura prognosis is affected by blood pressure.

Background: The prevalence, prognostic role, and diagnostic value of blood pressure in immune-mediated thrombotic thrombocytopenic purpura (iTTP) and other thrombotic microangiopathies (TMAs) remain unclear. Methods: Using a national cohort of iTTP (n = 368), Shigatoxin-induced hemolytic uremic syndrome (n = 86), atypical hemolytic uremic syndrome (n = 84), and hypertension-related thrombotic microangiopathy (n = 25), we sought to compare the cohort's blood pressure profile to assess its impact on prognosis and diagnostic performances. Results: Patients with iTTP had lower blood pressure than patients with other TMAs, systolic (130 [interquartile range (IQR) 118-143] vs 161 [IQR 142-180] mmHg) and diastolic (76 [IQR 69-83] vs 92 [IQR 79-105] mmHg, both p < 0.001). The best threshold for iTTP diagnosis corresponded to a systolic blood pressure <150 mmHg. iTTP patients presenting with hypertension had a significantly poorer survival (hazard ratio 1.80, 95% confidence interval 1.07-3.04), and this effect remained significant after multivariable adjustment (hazard ratio = 1.14, 95% confidence interval 1.00-1.30). Addition of a blood pressure criterion modestly improved the French clinical score to predict a severe A disintegrin and metalloprotease with thrombospondin type 1 deficiency in patients with an intermediate score (i.e., either platelet count <30 × 109/L or serum creatinine <200 µM). Conclusions: Elevated blood pressure at admission affects the prognosis of iTTP patients and may help discriminate them from other TMA patients. Particular attention should be paid to blood pressure and its management in these patients.

Percutaneous trans-axilla transcatheter aortic valve replacement.

The left axillary artery is an attractive alternative access route for transcatheter aortic valve replacement (TAVR) and may provide better outcomes compared to other alternatives. Nevertheless, there remain concerns about vascular complications, lack of compressibility, and thorax-related complications. Between March 2019 and March 2021, 13 patients underwent transaxillary TAVR for severe aortic stenosis at the University Hospital Bonn. The puncture was performed with a puncture at the distal segment of the axillary artery through the axilla, with additional femoral access for applying a safety wire inside the axillary artery. Device success was defined according to the VARC 2 criteria. The study participants were advanced in age (77 ± 9 years old), and 54% were female, with an intermediate risk for surgery (STS risk score 4.7 ± 2.0%). The average diameter of the distal segment of the axillary artery was 5.8 ± 1.0 mm (i.e., the puncture site) and 7.6 ± 0.9 mm for the proximal axillary artery. Device success was achieved in all patients. 30-day major adverse cardiac and cerebrovascular events were 0%. With complete percutaneous management, stent-graft implantation was performed at the puncture site in 38.5% of patients. Minor bleeding was successfully managed with manual compression. Moreover, no thorax-related complications, hematomas, or nerve injuries were observed. Percutaneous trans-axilla TAVR was found to be feasible and safe. This modified approach may mitigate the risk of bleeding and serious complications in the thorax and be less invasive than surgical alternatives.

Immune-mediated thrombotic thrombocytopenic purpura in childhood treated by caplacizumab, about 3 cases.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease in adults and exceptional in childhood. Caplacizumab has proven its effectiveness in the treatment of iTTP in adulthood in association with standard of care. Unfortunately, this treatment is restricted to adults. We report our experience in three children who were treated successfully with caplacizumab.

A novel scoring system to estimate chemotherapy-induced myocardial toxicity: Risk assessment prior to non-anthracycline chemotherapy regimens.

BACKGROUND: Myocardial toxicity is a common side effect of chemotherapy and is associated with adverse outcomes in cancer patients. Sufficient prediction of chemotherapy-induced myocardiotoxicity (CIMC) is desirable. Therefore, we sought to develop a feasible scoring system to predict CIMC in cancer patients undergoing non-anthracycline chemotherapy. METHODS: We determined a scoring system, the "Cardiotoxicitiy Score" (the CardTox-Score), by multivariable regression of the parameters considered relevant to the development of CIMC, based on previously published data and current guidelines. Variables of the risk model consist of clinical (age, presence of cardiovascular risk conditionsconditions), blood tests (NT-proBNP), and echocardiographic parameters (left ventricular (LV) ejection fraction, LV strain analysis). The CardTox-Score was examined in an internal validation cohort by use of ROC and regression analysis. RESULTS: We prospectively investigated 225 patients (58.21 ± 6.3 years, 52.8% female) who received non-anthracycline myocardiotoxic anticancer agent as a derivation cohort. All patients underwent echocardiography before, during and after anticancer therapy. The mean follow-up duration was 25 ± 4 months. We found the CardTox-Score (>6 points) to be a strong independent predictor (AUC: 0.983, OR: 6.38, 95% CI: 1.6 2.8, p < 0.001) for the development of CIMC with high sensitivity (100%) and specificity (84.2%) in the validation cohort (n = 30, 59.2 ± 6.5 years, 57% female). Moreover, the CardTox-Score appropriately predicted all-cause mortality with high specificity (93.7%) and sensitivity (92.9%) as well (OR: 4.85, AUC: 0.978, p = 0.01). CONCLUSION: The CardTox-Score offers a promising, feasible, and easy-to-handle scoring system for predicting CIMC in cancer patients undergoing non-anthracycline regimes, independent from the type of cancer.

A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP.

The anti-von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.

[Intravascular large B cell lymphoma pathological findings led by positron emission tomography findings: About one case]. / Diagnostic histologique de lymphome intravasculaire guidé par une hyperfixation corticale rénale à la tomographie par émission de positons : à propos d'un cas.

Intravascular large B cell lymphoma is a rare non-Hodgkin large B cell lymphoma disease, with heterogeneous clinical manifestation and difficult pathological diagnosis. Positron emission tomography may be helpfull in this context and has already been reported. A 45-year-old woman was admitted for persistent high fever, inflammatory syndrome and unexplained haemophagocytic syndrome. Bilateral cortical renal hypermetabolism at positron emission tomography initially misled to pyelonephritis diagnosis and secondarily led to kidney biopsy, which showed intravascular large B cell lymphoma. Renal involvement in intravascular large B cell lymphoma is rare and is usually characterized by acute renal failure and proteinuria. Global hypermetabolism at positron emission tomography has already been described in this context, but cortical hypermetabolism has never been associated with pathological findings. In front of persistent high fever without etiology, this positron emission tomography feature must lead to intravascular large B cell lymphoma suspicion and to kidney biopsy to obtain pathological proof.

Organ Transplantation in Hereditary Fibrinogen A α-Chain Amyloidosis: A Case Series of French Patients.

RATIONALE & OBJECTIVE: Fibrinogen A α-chain amyloidosis (AFib amyloidosis) is a form of amyloidosis resulting from mutations in the fibrinogen A α-chain gene (FGA), causing progressive kidney disease leading to kidney failure. Treatment may include kidney transplantation (KT) or liver-kidney transplantation (LKT), but it is not clear what factors should guide this decision. The aim of this study was to characterize the natural history and long-term outcomes of this disease, with and without organ transplantation, among patients with AFib amyloidosis and various FGA variants. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 32 patients with AFib amyloidosis diagnosed by genetic testing in France between 1983 and 2014, with a median follow-up of 93 (range, 4-192) months, were included. RESULTS: Median age at diagnosis was 51.5 (range, 12-77) years. Clinical presentation consisted of proteinuria (93%), hypertension (83%), and kidney failure (68%). Manifestations of kidney disease appeared on average at age 57 (range, 36-77) years in patients with the E526V variant, at age 45 (range, 12-59) years in those with the R554L variant (P<0.001), and at age 24.5 (range, 12-31) years in those with frameshift variants (P<0.001). KT was performed in 15 patients and LKT was performed in 4. In KT patients with the E526V variant, recurrence of AFib amyloidosis in the kidney graft was less common than with a non-E526V (R554L or frameshift) variant (22% vs 83%; P=0.03) and led to graft loss less frequently (33% vs 100%). Amyloid recurrence was not observed in patients after LKT. LIMITATIONS: Analyses were based on clinically available historical data. Small number of patients with non-E526V and frameshift variants. CONCLUSIONS: Our study suggests phenotypic variability in the natural history of AFib amyloidosis, depending on the FGA mutation type. KT appears to be a viable option for patients with the most common E526V variant, whereas LKT may be a preferred option for patients with frameshift variants.

Personalized cardiac regeneration by stem cells-Hype or hope?

Cardiac diseases are the leading cause of death and reach epidemic proportions with aging. Advanced heart disease results from an abrupt or progressive loss of contractile cardiomyocytes. Following percutaneous coronary intervention and revascularization regenerative medicine aims at effectively repair damaged tissue and replacement of lost cardiomyocytes. However, mixed results were obtained from trials using bone marrow-derived stem cells. Benefits were rather attributed to paracrine effects leading to inhibition or reverse of negative remodeling processes than to regeneration of viable cardiomyocytes. Thus the aim of regenerative medicine, in particular stem cell research, to generate viable cardiac muscle has so far not been achieved in humans, reflecting our incomplete understanding of underlying biological mechanisms. Moreover, there is growing evidence that substantial person-to-person differences in the outcome of stem cell therapy exists. We here review our present knowledge in evolving stem cell based cardiovascular medicine and highlight personalized aspects of stem cell interventions.

Role of the multidrug resistance protein-1 (MRP1) for endothelial progenitor cell function and survival.

The multidrug resistance related protein-1 (MRP1) is a member of the ATP binding cassette (ABC) of cell surface transport proteins expressed in multiple cell lines and tissues including endothelial cells and haematopoietic stem cells. MRP1 blockade has been shown to prevent endothelial cell apoptosis and improve endothelial function. Besides mature endothelial cells vascular homing of endothelial progenitor cells (EPC) contributes to endothelial regeneration after vascular damage. Thus, we hypothesized that MRP1 influences number and function of EPCs and mechanisms of vascular repair. To test this, we investigated the effects of MRP1 inhibition in vitro and in vivo. MRP1 is abundantly expressed in cultured human early outgrowth EPCs. Pharmacological inhibition of MRP1 by MK571 increased intracellular glutathione levels and reduced intracellular reactive oxygen species levels. This stabilization of the intracellular redox homeostasis via inhibition of MRP1 prevented angiotensin II-induced apoptosis and increased the number of early outgrowth EPCs and colony forming units in vitro. To extend the observed cytoprotective effect of MRP1 blockade in EPCs to an in vivo situation, MRP1(-/-) knockout mice were investigated. MRP1(-/-) knockout mice showed significantly increased numbers of EPCs circulating in the peripheral blood and residing in the bone marrow. Consistently, colony forming unit formation was enhanced and rate of apoptosis reduced in early outgrowth EPCs derived from MRP1(-/-) knockout mice. In addition, MRP1(-/-) knockout mice showed improved reendothelialization after carotid artery injury, and transfusion of MNCs derived from MRP1(-/-) knockout mice into wild-type mice accelerated reendothelialization compared to transfusion of wild-type cells. These findings indicate that the enhanced function and survival of EPCs in MRP1(-/-) knockout mice resulted in improved reendothelialization. In conclusion, MRP1 negatively influences EPC function and survival via perturbation of the intracellular redox homeostasis which finally leads to increased cellular apoptosis. These results reveal novel mechanistic insights and may identify MRP1 as therapeutic target to improve reendothelialization after vascular damage.