SciCombinator

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Vascular complications after liver trans-plant can be lethal. High levels of suspicion and aggressive use of diagnostic tools may help with early diagnosis and treatment. Here, we share our experiences regarding this topic.

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Objective: Screen the pathogenic genes of a pedigree with clinical manifestation of familial dilated cardiomyopathy in Inner Mongolia. Methods: A total of 3 patients with dilated cardiomyopathy and 20 family members from the same family were examined in Ordos Central Hospital in Inner Mongolia from October, 2003 to August, 2017. Data on medical history, physical examinations, electrocardiograms, and echocardiography were obtained. 5 ml peripheral blood was sampled for per person. Chip Capture Sequencing technology was used to capture all the exons and splice sites of the genes that associated with hereditary cardiomyopathy and hereditary arrhythmia. The mutations in these genes were detected by high-throughput sequencing. All suspected pathogenic loci identified by high-throughput sequencing were verified by Sanger sequencing used for mutation detection. One hundred and fifty gender, age and race matched healthy people were included as the control group. Results: Pathogenic gene variations were detected in 3 symptomatic family members and 1 carrier from the pedigree. Five pathogenic gene variations were identified in the proband (Ⅱ1), a pSer236Gly and a pArg215Cys variation in the MYBPC3 gene, a pGln90Arg variation in the DSP gene, and pAsn2912Asp and pGlu2910Val variation in the DMD gene. One pathogenic variation was detected in Ⅲ3, which was a pArg215Cys variation in the MYBPC3 gene. Two pathogenic variations were detected in Ⅲ7, a pSer236Gly variation in the MYBPC3 gene and a pGln90Arg variation in the DSP gene. Two pathogenic variations were detected in the Ⅳ7, a pSer236Gly variation in the MYBPC3 gene and a pGln90Arg variation in the DSP gene. No gene variation loci were detected in the other family members and the control group. Conclusion: MYBPC3 gene, DSP gene and DMD gene variations are present in the familial dilated cardiomyopathy pedigree from Inner Mongolia, and these variations may be related with familial dilated cardiomyopathy.

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Objective: To observe the relationship between impaired myocardial untwisting and left ventricular diastolic dysfunction in patients with autoimmune diseases (AD). Methods: In this retrospective study, 95 AD patients (27 males, (38.6±14.2) years old) were enrolled as AD group and 71 gender and age matched healthy subjects (24 males, (37.6±12.2) years old) were enrolled as control group, all underwent transthoracic echocardiography and two-dimensional speckle-tracking echocardiography (STE) in our hospital between January 2014 and June 2018. Left ventricular untwisting and diastolic function parameters were measured. Multiple logistic regression analysis was used to identify related factors of left ventricular diastolic dysfunction in AD patients. Receiver operating characteristic (ROC) curve was used to identify the diagnosis value of untwisting parameters for left ventricular diastolic dysfunction in AD patients. Results: Compared with control group, left ventricular ejection fraction was lower (58(47, 66)% vs. 67 (62, 71) %, P<0.001), E/e' was higher (10.78 (7.28, 13.65) vs. 6.30 (5.55, 7.25) , P<0.001), isovolumic relaxation time was longer (73.5 (56.5, 88.0) ms vs. 62.0 (58.0, 68.5) ms, P<0.001),and untwist slope during isovolumic relaxation period (USIR) was lower (31.92 (14.09, 54.92) °/s vs. 59.90 (40.09, 87.18) °/s, P<0.001) in AD group than in control group. Multiple logistic regression analysis showed heart rate (OR=0.885, 95%CI 0.840-0.931, P<0.001), E/e' (OR=0.655, 95%CI 0.537-0.798, P<0.001) and USIR (OR=0.986, 95%CI 0.974-0.998, P=0.020) were independently related with left ventricular diastolic dysfunction in AD patients. ROC curve showed that area under the curve (AUC) was 0.919 (P<0.001), sensitivity was 87.6%, and specificity was 88.7%, when combining the heart rate, E/e', and USIR as assessment parameters for the diagnosis of left ventricular diastolic dysfunction in AD patients at a cutoff of 0.51. Conclusions: Impairment of myocardial untwisting indicates the presence of early stage left ventricular diastolic dysfunction in AD patients. USIR may be a sensitive parameter to evaluate early stage left ventricular diastolic dysfunction in AD patients.

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The current therapeutic scenario for inflammatory bowel diseases (IBD) involves aminosalicylates, corticosteroids, and immunomodulators, but concerns regarding their safety profiles and high costs heavily impact their widespread use. In recent years, the beneficial effects thatbiophenols-from fruit and vegetables-have on human health have been investigated. The antioxidant and anti-inflammatory properties of phenolic fraction, from olive leaves and fruits, have been suggested, and a potential application in gut inflammation has been supported by in vitro and IBD-animal models studies. In the present review, we first introduced the potential therapeutic role of olive tree biophenolsin chronic inflammatory disease. Then, we aimed to describe their most interesting application for gut inflammation, as the results of basic science studies and animal experimental models. Finally, the potential role of olive tree biophenols in the setting of human IBD is discussed.

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The aim of the work is to evaluate the effectiveness of the risk communication strategies in cases of unsafe drinking water supply in Sardinia, the Italian context with the highest population distrust in drinking water safety. During the period 2010⁻2015, the ordinances published on the institutional websites were analyzed, and the population risk perception was evaluated by applying, for the first time in public health threats, the “OUTRAGE Prediction & Management” software released by Sandman. Overall, 417 ordinances issued by the Sardinian Municipalities were found. Only 1.5% of the ordinances reported information about parameters, concentrations, and risks to health, whereas 4.8% indicated only the parameters and non-standard levels. By contrast, 53.2% specified only the non-standard parameter, and 40.5% indicated a generic non-drinking motivation. The outrage assessment showed values exceeding the threshold of risk acceptance, attributable to the lack and low clarity of the information reported by the ordinances. The present study allowed us to highlight critical issues in risk communication of the quality of drinking water.

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Cardiovascular or arteriothrombotic adverse events (CV- or AT-AEs) are reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The incidence and characteristics across different TKI have not been systematically analyzed. We analyzed 531 patients treated with frontline TKIs in different prospective trials: imatinib 400 mg (n = 71) and 800 mg (n = 203), nilotinib (n = 108), dasatinib (n = 106), and ponatinib (n = 43). Characteristics and incidence of new-onset CV-AEs and AT-AEs were analyzed. Poisson regression models assessed factors associated with AE incidence. Median follow-up was 94 months (range, 2-195). Overall, 237 patients (45%) developed CV-AEs and 46 (9%) developed AT-AEs. Hypertension was the most common AE seen in 175 patients (33%; grade ¾ in 17%). CV-AE and AT-AE incidence ratios (IRs) with 95% confidence intervals (CIs) were 8.6 (7.6-9.8) and 1.7 (1.2-2.2) per 100 person-years. Among the TKIs, ponatinib showed the highest IR (95% CI) for CV-AEs and AT-AEs at 40.7 (27.9-59.4) and 9.0 (4.1-20.1). In multivariate analysis, ponatinib therapy was associated with increased incidence rate ratio (IRR) for CV-AEs (4.62; 95% CI, 2.7-7.7; P < .0001) and AT-AEs (6.38; 95% CI, 1.8-21.8; P < .0001) compared with imatinib 400. In summary, there is an increased risk of CV-AEs (except hypertension) and AT-AEs in CML patients treated with newer TKIs, particularly with ponatinib. Patients on TKIs must be informed and closely monitored for vascular AEs. These studies were registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, #NCT00050531, #NCT00254423, #NCT00129740, and #NCT01570868.

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Osteopetrosis (OP) is a rare disease caused by defective osteoclast differentiation or function. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available in the infantile “malignant” form of OP. Improved clinical and genetic diagnosis of OP has seen the emergence of a cohort of patients with less severe and heterogeneous clinical presentations. This intermediate form of OP does not call for urgent intervention, but patients accumulate debilitating skeletal complications over years and decades, which are severe enough to require curative treatment and may also require intermittent transfusion of blood products. Here we present data from 7 patients with intermediate OP caused by mutations in TCIRG1 (n = 2), CLCN7 (n = 2), RANK (n = 1), SNX10 (n = 1), and CA2 (n = 1), who were transplanted between the ages of 5 to 30 years (mean, 15; median, 12). Donors were matched siblings or family (n = 4), matched unrelated (n = 2), or HLA haploidentical family donors (n = 1). Conditioning was fludarabine and treosulfan based. All 6 patients transplanted from matched donors are currently alive with a follow-up period between 1 and 8 years at time of publication (median, 4 years) and have demonstrated a significant improvement in symptoms and quality of life. Patients with intermediate OP should be considered for HSCT.

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Plerixafor, a direct antagonist of CXCR4/stromal-derived factor 1, can safely and rapidly mobilize allografts without the use of granulocyte colony-stimulating factor (G-CSF). We conducted a phase 2, multicenter, prospective study of plerixafor-mobilized HLA-identical sibling allografts for allogeneic hematopoietic cell transplantation in recipients with hematological malignancies. Donors (n = 64) were treated with subcutaneous plerixafor (240 µg/kg) and started leukapheresis (LP) 4 hours later. The primary objective was to determine the proportion of donors who were successfully mobilized: defined as collection of ≥2.0 × 106 CD34+ cells per kilogram recipient weight in ≤2 LP sessions. Recipients subsequently received reduced intensity (RIC; n = 33) or myeloablative (MAC; n = 30) conditioning. Sixty-three of 64 (98%) donors achieved the primary objective. The median CD34+ cell dose per kilogram recipient weight collected within 2 days was 4.7 (0.9-9.6). Plerixafor was well tolerated with only grade 1 or 2 drug-related adverse events noted. Bone pain was not observed. Plerixafor-mobilized grafts engrafted promptly. One-year progression-free and overall survivals were 53% (95% confidence interval [CI], 36% to 71%) and 63% (95% CI, 46% to 79%) for MAC and 64% (95% CI, 47% to 79%) and 70% (95% CI, 53% to 84%) for RIC recipients, respectively. Donor toxicity was reduced relative to G-CSF mobilized related donors. This is the first multicenter trial to demonstrate that, as an alternative to G-CSF, plerixafor rapidly and safely mobilizes sufficient numbers of CD34+ cells from matched sibling donors for HCT. Engraftment was prompt, and outcomes in recipients were encouraging. This trial was registered at clinicaltrials.gov as #NCT01696461.

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Cold storage of blood for 5 to 6 weeks has been shown to impair endothelial function after transfusion and has been associated with measures of end-organ dysfunction. Although the products of hemolysis, such as cell-free plasma hemoglobin, arginase, heme, and iron, in part mediate these effects, a complete analysis of transfused metabolites that may affect organ function has not been evaluated to date. Blood stored for either 5 or 42 days was collected from 18 healthy autologous volunteers, prior to and after autologous transfusion into the forearm circulation, followed by metabolomics analyses. Significant metabolic changes were observed in the plasma levels of hemolytic markers, oxidized purines, plasticizers, and oxidized lipids in recipients of blood stored for 42 days, compared with 5 days. Notably, transfusion of day 42 red blood cells (RBCs) increased circulating levels of plasticizers (diethylhexyl phthalate and derivatives) by up to 18-fold. Similarly, transfusion of day 42 blood significantly increased circulating levels of proinflammatory oxylipins, including prostaglandins, hydroxyeicosatrienoic acids (HETEs), and dihydroxyoctadecenoic acids. Oxylipins were the most significantly increasing metabolites (for 9-HETE: up to ∼41-fold, P = 3.7e-06) in day 42 supernatants. Measurements of arginine metabolism confirmed an increase in arginase activity at the expense of nitric oxide synthesis capacity in the bloodstream of recipients of day 42 blood, which correlated with measurements of hemodynamics. Metabolic changes in stored RBC supernatants impact the plasma metabolome of healthy transfusion recipients, with observed increases in plasticizers, as well as vasoactive, pro-oxidative, proinflammatory, and immunomodulatory metabolites after 42 days of storage.

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Chronic lymphocytic leukemia (CLL) is characterized by chronic clonal expansion of mature CD19-expressing B lymphocytes and global dysfunction of immune effectors, including natural killer (NK) cells. CLL remains incurable, and novel approaches to refractory CLL are needed. Our group has previously described trispecific killer engager (TriKE) molecules that redirect NK cell function against tumor cells. TriKE reagents simultaneously bind an activating receptor on NK cells, CD16, and a tumor antigen while also providing an NK cell expansion signal via an interleukin-15 moiety. Here we developed the novel CD19-targeting 161519 TriKE. We demonstrate that 161519 TriKE induced killing of a CD19-expressing Burkitt’s lymphoma cell line and examined the impact on primary CLL targets using healthy donor and patient NK cells. 161519 TriKE induced potent healthy donor NK cell activation, proliferation, and directed killing. Furthermore, 161519 TriKE rescued the inflammatory function of NK cells obtained from CLL patient peripheral blood samples. Finally, we show that 161519 TriKE induced better directed killing of CLL in vitro when compared with rituximab. In conclusion, 161519 TriKE drives a potent activating and proliferative signal on NK cells, resulting in enhanced NK cell expansion and CLL target killing. Our findings indicate the potential immunotherapeutic value of 161519 TriKE in CLL.