bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk Factors For Cerebral Vasculopathy In a Sickle Cell Disease Newborn Cohort
Authors: Sommet Julie , Alberti Corinne , Holvoet Laurent , Haouari Zinedine , Missud Florence , Ithier Ghislaine , Verlhac Suzanne , Elmaleh Monique , Baruchel Andre , Benkerrou Malika 
Published: October 2019

Children with sickle cell disease (SCD) have a significant vascular morbidity responsible of pain and stroke. They are at high risk of cerebral vasculopathy (CV) that can be detected in these children by transcranial Doppler. The aim of this study was to identify risk factors for CV using longitudinal data in the 375 newborn cohort of Robert Debre Pediatric Sickle Cell Referral Center. Among the 59 children presented CV, seven had a stroke. There was a total of 2677 patient-years of follow up. Overall, the incidence rate of CV was 2.20/100 patient-years (95% CI 1.64-2.76) and the incidence rate of stroke was 0.26/100 patient-years (95% CI 0.07-0.46). The cumulative risk of CV by age 14 years was 26.0% (95% CI 20.0%-33.3%).To take into account longitudinal data, risk factors of CV were assessed by a survival Cox model built in two steps. The final Cox multivariable analyze for CV retained five variables. Upper airways obstruction (HR 1.41 95%CI 1.00-1.98), bronchial obstruction (HR 2.13 95%CI 1.77-2.57), acute anemic event (HR 1.15 95%CI 1.01-1.32) and reticulocyte count (HR 1.41 per 20000/mm3 increase 95%CI 1.16-1.71) were independent risk factors whereas hydroxycarbamide therapy (HR 0.03 95%CI 0.01-0.35) was protective. Evaluation and specific treatment for symptoms of asthma or sleep apnea or nocturnal respiratory abnormalities could potentially reduce the risk of CV and stroke after treatment. Our findings suggest that hydroxycarbamide could protect from CV.

Disclosures:
No relevant conflicts of interest to declare.
Exchange Transfusion In Adult Patients With Sickle Cell Disease With Refractory Vaso-Occlusive Crises
Authors: Moffett Padmini , Moffett Bryan K 
Published: October 2019

Sickle cell disease occurs in 1/500 African-American births. Pain is one of the most common complications of sickle cell disease and is associated with depression, anxiety, decreased quality of life and poor sleep patterns. Vaso-occlusive crises resulting in three or more hospitalizations per year occur in 48% of patients with sickle cell disease (Annals of Emergency Medicine - May 2009 (Vol. 53, Issue 5, Pages 587-593). Hydroxyurea has been shown to ameliorate the frequency of painful vaso-occlusive crises in sickle cell anemia (Charache et al, Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia NEJM. 1995), unfortunately many eligible patients are not treated due to psychosocial reasons and fear of teratogenicity or malignancy or have painful crisis refractory to hydroxyurea. A panel of experts has suggested that RBC exchange transfusion in these patients may decrease ED visits and subsequent hospitalizations based on anecdotal evidence [Best practices for transfusion for pateitns with sickle cell disease. T Wun, K Hagel. Hematology Review 2009, July 1; 1(22); e22]. We present the case of a 31 year old African-American male with Hgb S/beta thalassemia + with complications of sickle cell disease including Parvovirus B19 induced aplastic anemia, iron overload secondary to multiple simple transfusions, multiple vaso-occlusive crises as well as a left lower extremity ulcer precipitated by treatment with hydroxyurea. He was treated with folic acid as well as deferasirox for iron chelation. He began PRBC exchange transfusions every 6 weeks in March of 2011. In the one year prior to exchange transfusion initiation he had 13 ED visits and 4 hospitalizations for vaso-occlusive crises. After initiation of exchange transfusions he had 11 ED visits and 2 hospitalizations for vaso-occlusive crises the following year. An elevated WBC is associated with poor outcomes in sickle cell disease (Miller et al Predictors of adverse outcomes in children with sickle cell disease. N Engl J Med 2000). His average WBC level was 13 x 109/L, which decreased to 11 x 109/L after initiation of exchange transfusion. The patient underwent extended typing for E,C, and Kell RBC antigens to minimize development of antibodies. Though monthly exchange transfusions are costly and carry the attendant risk of antibody formation, this may be offset by reducing the financial and psychological burden of frequent hospitalizations for management of refractory vaso-occlusive crises. Exchange transfusion may also ameliorate the cost associated with long-term iron chelation. Further investigation is warranted to determine whether a program of monthly exchange transfusions can curtail ED visits and hospitalizations in adult patients with sickle cell disease and multiple, refractory vaso-occlusive crises.

Disclosures:
No relevant conflicts of interest to declare.
The Function Of Transcription Elongation In Hematopoietic Stem Cell Development
Authors: Zhou Ting , Cook Jennifer , Liu Xiuli , Bai Xiaoying 
Published: October 2019

The specification of hematopoietic stem cells (HSCs) in vertebrate embryos is tightly regulated by RNA polymerase II (Pol II)-mediated transcription, which proceeds through multiple steps including initiation/activation, elongation and termination. Increasing evidences in recent years have demonstrated that transcriptionally engaged Pol II often pauses shortly after initiation by pausing factors DSIF and NELF, and its release requires positive elongation factors such as p-TEFb. Little is known about how pausing-to-elongation switch contribute to cell fate determination. In a zebrafish spt5 mutant, we detected a dramatic loss of runx1+ HSCs in the AGM region in 36-hour embryos. Spt5 is an essential subunit of DSIF, which pauses Pol II in early elongation stage but stimulates Pol II elongation upon phosphorylated by p-TEFb. The zebrafish mutant carries a single amino acid change in the Spt5 protein that disrupts the pausing function but leaves the stimulatory function intact, suggesting a requirement of Pol II pausing in HSC formation. Similarly, knocking down the other pausing factor NELF by morpholinos also greatly reduced the number of runx1+ HSCs in zebrafish embryos. This loss of HSCs is not caused by general developmental defects, as markers for vessels and aorta endothelium remain normal in mutants. We further demonstrated that reducing Pol II elongation by either p-TEFb inhibitors or morpholino knockdown of CDK9, the essential subunit of p-TEFb, could rescue the HSC defect in spt5 mutants. The rescue by cdk9 morpholino is dose-dependent. Low-dose morpholino that presumably caused partial knockdown of CDK9 was able to rescue spt5 mutants, whereas high-dose morpholino completely wiped out HSCs in both wild type and mutant embryos. In conclusion, our data suggested that HSC formation during embryonic development requires a balanced transcription that is regulated by both negative and positive elongation factors. Such mechanisms may also be employed in other tissues to regulate cell fate determination.

Disclosures:
No relevant conflicts of interest to declare.
Myocardial Iron overload In Thalassemia Major. how Early To Check?
Authors: Borgna-Pignatti Caterina , Meloni Antonella , Guerrini Giulia , Filosa Aldo , Ruffo Giovan Battista , Casini Tommaso , Romano Nicola , Maggio Aurelio , Chiodi Elisabetta , Positano Vincenzo , Lombardi Massimo , Pepe Alessia 
Published: October 2019

Introduction
It is still controversy in thalassemia major (TM) if Cardiovascular Magnetic Resonance (CMR) T2* screening should be initiated before the 10 years. To answer this question, we studied retrospectively the prevalence of cardiac iron and function and myocardial fibrosis by CMR in a consistent cohort of TM patients younger than 10 years.

Methods
From the 2171 patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, we retrospectively selected the 35 TM patients aged less than 10 years who had undergone at least one MRI scan. Myocardial iron overload (MIO) was measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated in a standard way by cine images. To detect myocardial fibrosis, late gadolinium enhancement images were acquired.

Results
Patients’ age ranged from 4.2 to 9.7 years. All MRI scans were performed without sedation. Nine patients (25.7%) showed no myocardial iron overload (MIO),22 patients (62.9%) showed an heterogeneous MIO with a T2* global value ≥ 20 ms; 2 patients (5.7%) showed an heterogeneous MIO and a T2* global value < 20 ms and 2 patients (5.7%) had a homogeneous MIO. No patients showed myocardial fibrosis.
Table 1 reports the data of the 4 patients (3 males and 1 female) with significant myocardial iron overload (global heart T2* < 20 ms). The youngest was 6 years old, all showed no heart dysfunction and in all the iron transfused was less than 35 g.

Conclusion
The first cardiac T2* assessment should be performed as early as possible without sedation and it is mandatory whenever poor compliance is suspected or if chelation has been started late. The use of the contrast medium to detect myocardial fibrosis can be postponed until after 10 years of age. A more sensitive segmental approach to detected heart iron should be considered. Therapy can be modified on the basis of the MRI results and serious organ damage can be prevented.

Disclosures:
No relevant conflicts of interest to declare.
Haemophagocytic Lymphohistiocytosis (HLH) Associated With a Heterozygous PRF1 Mutation Not Previously Described As Pathogenic
Authors: Arbelaez Alejandro , Catley Laurence 
Published: October 2019

Case Presentation
A 16 year old male presented with three weeks of fatigue, nausea, vomiting, anorexia, arthralgias, and pancytopaenia. He was febrile, with mouth ulcers, hepato splenomegaly, and palpable non tender supraclavicular and axillary lymphadenopathy. Neurological examination was normal. Remarkable abnormal tests: Hb 77 g/L, platelets 29 x109/L, WCC 0.7 x109/L (neutrophils 0.33), normal PT and APTT but hypofibrinogenaemia 0.8 g/L. Ferritin was elevated 56 061 ug/L (20– 150). Liver function tests showed a mixed pattern with elevated LDH (2137 U/L), mild hypertriglyceridaemia (4.6 mmol/L) and low haptoglobin (< 0.06 g/L), EBV IgM was equivocal with reactive IgG. Bone marrow showed evidence of haemophagocytosis (Fig 1). All HLH-2004 criteria were fulfilled except elevated sCD25 (unavailable). NK cell chromium release assay revealed severely suppressed NK cell function. In addition, perforin gene (PRF1) sequencing for mutation screening showed a missense mutation Ala437Val (1310 C>T) PRF1 heterozygous, a previously unclassified variant. There was no evidence of an underlying cause of HLH. Our patient received induction therapy with etoposide 150 mg/m2 and dexamethasone 10 mg/m2 with dosing and frequency as suggested by the HLH-94 protocol. Pancytopaenia recurred and an increase in ferritin concentration was interpreted as relapse of the condition. At that point, cyclosporine was added on in conjunction with maintenance etoposide and dexamethasone obtaining partial remission. He underwent allogeneic SCT successfully in another centre.Figure 1Bone marrow aspirate of this patient showing evidence of haemophagocytosis (H & E). A and B show large macrophages undergoing phagocytosis of different cellular elements of the bone marrow.Figure 1. Bone marrow aspirate of this patient showing evidence of haemophagocytosis (H & E). A and B show large macrophages undergoing phagocytosis of different cellular elements of the bone marrow.

Discussion
Several genes have been implicated in the genesis of primary HLH; all of them have in common impaired cytotoxic function by NK and T cells. It has been reported that mutations of the PRF1 gene comprise approximately 20 to 30% of the cases of primary HLH. This variant has been reported as a polymorphism and was not conclusive for the diagnosis of perforin deficiency as the cause of HLH in this case. In addition, the mutation was heterozygous. Although HLH is usually a recessive disorder, there are reports of potential disease associations in the heterozygous state. There is significant overlap between primary and secondary HLH and the role of some heterozygous mutations remain to be investigated.

Disclosures:
No relevant conflicts of interest to declare.
Proteasome Inhibitor Based Protocol For Antibody Mediated Rejection In Kidney Transplantation
Authors: Sanchorawala Vaishali , Quillen Karen , Gautam Amitabh , Francis Jean M 
Published: October 2019

Background
Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) of renal transplantation is rarely achieved with traditional antihumoral therapies. Current antihumoral therapies do not target the mature antibody producing plasma cells. Bortezomib is a first in class proteosome inhibitor for the treatment of plasma cell derived tumors like multiple myeloma. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR. Here, we report on our experience with plasma cell targeted therapy (bortezomib) as an antirejection strategy for refractory early and delayed AMR post renal transplantation.

Methods
Adult kidney transplant recipients with AMR, diagnosed by Banff criteria, received a bortezomib-based regimen after failing at least 2 traditional treatments for AMR. Bortezomib therapy was administered (1.3 mg/m2 IV D1,4,8,11) with plasmapheresis performed immediately before each dose of Bortezomib and a single dose of rituximab (375 mg/m2) given with the first bortezomib dose. Methylprednisolone was administered along with Bortezomib at 100 mg IV on D1,4 and 50 mg IV on D8,11. All patients received valganciclovir prophylaxis for prevention of herpes zoster and cytomegalovirus reactivation. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels, serum creatinine levels, urine protein excretion and repeated allograft biopsies.

Results
Ten episodes of AMR in eight renal transplant recipients were treated with bortezomib, rituximab, methylprednisone and plasmapheresis.
Post treatment reduction in immunodominant DSA was observed and this data will be available at the meeting. None of the patients experienced peripheral neuropathy from bortezomib and only one patient had GI toxicity with nausea and diarrhea, which was transient. None of the patients had reactivation of herpes zoster infection.
In conclusion, bortezomib, rituximab, methylprednisone and plasma exchange therapy provided reversal of AMR rejection post renal transplantation with improvement in renal function, proteinuria and histology, at a median follow-up of 15 months.

Disclosures:
No relevant conflicts of interest to declare.
Increased Levels Of Tissue Factor, Adhesion Molecules, Nitric Oxide and Adiponectin In End Stage Renal Disease. A Complex Interplay
Authors: Fareed Jawed , Kaneva Kristiyana , Hoppensteadt Debra , Bansal Vinod 
Published: October 2019

Introduction
End stage renal disease (ESRD) represents the fifth (final) stage of chronic kidney disease characterized by an established kidney failure (GFR <15 mL/min/1.73 m2). To further understand the pathophysiology of ESRD, this study was designed to measure the circulating levels of tissue factor (TF), adhesion molecules, such as p-selectin (P-Sel), soluble ICAM (s-ICAM), nitric oxide and adiponectin (AD).

Methods
This study included 119 ESRD patients undergoing maintenance hemodialysis in conjunction with an ongoing IRB approved protocol on the profiling of inflammatory markers in this syndrome. Citrated blood plasma samples were collected from these patients prior to the routine dialysis session. Nitric oxide levels (NO) were measured using a commercial kit from R&D systems (Minneapolis, Minnesota) and ELISA based methods for TF, P-Sel, s-ICAM and adiponectin were also purchased from R&D systems. Chromogenic and thrombin substrate method were used to measure the anti-Xa activity thrombin generation.

Results
Tissue factor levels were found to be increased in the ESRD group (20.4±6.1pg/ml) vs the control (11.9±2.8pg/ml). The nitric oxide level was markedly higher in the ESRD group (32±17uM) vs the controls (7±3uM). The p-selectin levels were also elevated in the ESRD group (46±20ng/ml) vs the control (31±3ng/ml). The soluble ICAM levels were higher in the ESRD group (250±112ng/ml) vs the control (180±19ng/ml). Interestingly, the adiponectin levels were also increased in the ESRD group (19.2±9.3ug/ml) vs the control (11.2±4.1ug/ml). The pre-dialysis samples of the ESRD patients exhibited detectable levels of heparin.

Summary/Conclusions
These studies suggest that TF, NO, p-selectin and s-ICAM levels are increased in the ESRD patient. It is of interest to note that despite that a significant number of ESRD patients were diabetic; the AD levels were increased in this group. These results suggest that while ESRD represents a pro-inflammatory/hypercoagulable state, the repeated administration of heparin and other drugs may contribute to the regulation of the hemostatic process and inflammatory balance.

Disclosures:
No relevant conflicts of interest to declare.
Serotonin and Its Metabolism Enhances Megakaryopoiesis and Proplatelet Formation
Authors: Ye Jie yu , Meng Fan yi , Jiang Qianli , Li Su yi , Liang En yu , Chong Beng , Yang Mo 
Published: October 2019

Serotonin (5-HT) has been recently identified as a novel growth factor. We previously demonstrated that 5-HT enhances murine megakaryopoiesis via 5-HT2 receptors and has promotor effect on hematopoiesis(Yang M et al, Stem Cells, 2007). However, the molecular mechanism remains under explored. In the terminal stage of mammalian megakaryocyte development, platelets are released from proplatelet protruding from megakaryocytes via cytoskeleton reorganization. 5-HT is shown to modulate cell migration and remolding by activating cytoskeleton reorganization, but the effects of 5-HT on proplatelet formation have not been investigated. Our results showed that 5-HT significantly promoted human CFU-MK formation and reduced apoptosis on human megakaryocytes through phosphorylation of Akt. These effects were attenuated by addition of ketanserin, a 5HT2 receptor inhibitor. 5-HT also stimulated proplatelet formation through activating the p-Erk1/2 expression and F-actin reorganization. Melatonin, the metabolism of 5-HT, promoted the recovery of platelets and the formation of bone marrow colony forming units in irradiated mice. Our findings suggested that 5-HT and melatonin plays an important role in human megakaryopoiesis. Interaction of 5-HT and 5-HTR2B induced downstream activation of PI3-k/Akt signal pathway leading to human MK cell proliferation. In addition, activation of 5-HTR2B also induced Erk1/2 phosphorylation, which then promoted cytoskeleton reorganization and subsequent proplatelet formation. We also proved that melatonin exerts a protective effect on MK and platelets in the irradiation mice model.

Disclosures:
No relevant conflicts of interest to declare.
The Role Of Mycophenolate Mofetil In Patients With Refractory ITP
Authors: Atmakusuma Tubagus Djumhana , Hardi Fransiska 
Published: October 2019

Background
Referring to the ASH 2011 Guideline for ITP, several immune suppression agents are considered off-label use due to insufficient data for any specific agent to be recommended. In Indonesia mycophenolate mofetil (MMF) has been used as an alternative in ITP patients who failed to any recommended treatment in the ASH 2011 Guideline.

Methods
A retrospective study has been conducted to review data of ITP patients in three hospitals in Jakarta Indonesia. All ITP patients have been excluded from any potential causes of thrombocytopenia, including anamnesis, physical examination and laboratory tests for SLE, hepatitis C, hepatitis B and HIV.

Results
52 ITP patients have been assessed which comprised 38 female (73,1 %) and 14 male (26.9%) with mean age 36.31 years old (ranged between 18 to 67 years old).13 of 52 patients have received MMF. 8 of 13 patients received MMF after failure to prednisone, 3 of 13 patients received MMF after failure to prednisone and azathioprine, 1 of 13 patients received MMF after failure to prednisone, then received thrombopoietin receptor agonist. Mean platelet count at diagnosed was 28.211/µL (ranged between 1,000 to 86,000/µL).
6 of 13 patients achieved good response (increased platelet count > 100,000/µ) and 3 of 13 patients achieved intermediate response (increased platelet count > 30,000 to < 100,000/µL). 4 other patients had no response to MMF (platelet count remained < 30,000/µL) in whom 1 patient has previously received prednisone, followed by MMF, 1 patient has previously received prednisone, then azathioprine, followed by MMF, 1 patient has previously received prednisone, then azathioprine , subsequently MMF followed by vincristine, and 1 patient has previously received prednisone, then azathiprone, subsequently MMF followed by eltrombopage.

Conclusion
9 of 13 patients (almost 70 %) have responded to MMF. The remaining 30 % had no response to MMF.

Disclosures:
Off Label Use: Mycophenolate mofetil.
Long-Term Outcomes Of Splenectomy-Sparing Therapies For Immune Thrombocytopenia
Authors: Varma Mala , Grossbard Michael L. 
Published: October 2019

Background
Anti-Rh(D) (Cooper Blood 2002), rituximab (Godeau Blood 2008), and dapsone (Sharma ASH 2006) have been shown to be splenectomy-sparing agents for the treatment of immune thrombocytopenia (ITP). In these studies, patients treated with anti-Rh(D) and rituximab were followed for 2 years; patients were treated with dapsone for 6 to 48 months.

Specific Aims
To determine long-term outcomes in unsplenectomized patients with ITP treated with anti-Rh(D), rituximab, or dapsone.

Methods
Institutional Review Board approval was obtained. The charts of 52 consecutive patients with ITP followed in a hematology practice between 07/01/03 and 06/30/13 were reviewed. Response was defined as a platelet count (PLT) > 100,000/µL. Relapse was defined as PLT < 30,000/µL.

Results
Twenty-one patients have been treated with anti-Rh(D), rituximab, or dapsone. Some patients treated with anti-Rh(D) or rituximab received brief concurrent steroids. For the entire cohort the mean duration of ITP was 3.50 years (y), range 0.008 to 19 y and the mean duration of follow-up was 3.84 y, range 0.10 to 8.81 y. Among 16 patients who received anti-Rh(D), 85% responded to the initial infusion. Among the 10 responders who have had follow-up exceeding 1 year, 4 have had a sustained response following the first infusion (mean follow-up duration 3.35 y, range 2.66 y to 5.98 y; six have relapsed, all have responded to retreatment. Among 7 patients who received rituximab, 71% responded to the initial treatment. All 5 responders have had follow-up exceeding 1 year, among whom 2 have had a sustained response following the first infusion (mean follow-up duration 2.24 y, range 2.19 y to 6.67 y); three have relapsed, all have responded to retreatment. Among 3 patients who received dapsone, 66.7% responded; the response is partial in 1 patient with PLT 50,000/µL (mean follow-up duration 3.94 y, range 0.11 y to 8 y). Toxicities have included: with anti-Rh(D) 1 case each of grade II uterine pain, grade II chills, and grade II non-cardiac chest pain; with rituximab 1 case of grade II back pain. Therapeutic switches have included 2 cases of anti-Rh(D) to rituximab and 1 case each of anti-Rh(D) to rituximab to dapsone, anti-Rh(D) to rituximab to dexamethasone, anti-Rh(D) to romiplostim, and dapsone to rituximab. No patients have undergone splenectomy.

Conclusion
Anti-Rh(D), rituximab, and dapsone are splenectomy-sparing therapies for ITP over an extended period. For patients treated with anti-Rh(D) or rituximab who relapse, retreatment is effective.

Disclosures:
Off Label Use: Rituximab and dapsone therapies of ITP.