How reciprocity impacts ordering and phase separation in active nematics?

Active nematics undergo spontaneous symmetry breaking and show phase separation instability. Within the prevailing notion that macroscopic properties depend only on symmetries and conservation laws, different microscopic models are used out of convenience. Here, we test this notion carefully by analyzing three different microscopic models of apolar active nematics. They share the same symmetry but differ in implementing reciprocal or non-reciprocal interactions, including a Vicsek-like implementation. We show how such subtle differences in microscopic realization determine if the ordering transition is continuous or first order. Despite the difference in the type of phase transition, all three models exhibit fluctuation-dominated phase separation and quasi-long-range order in the nematic phase.

Hereditary Thrombotic Thrombocytopenic Purpura.

Hereditary thrombotic thrombocytopenic purpura (hTTP), also known as Upshaw-Schulman syndrome, is a rare genetic disorder caused by mutations in the ADAMTS13 gene that leads to decreased or absent production of the plasma von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13. The result is circulating ultra-large multimers of VWF that can cause microthrombi, intravascular occlusion and organ damage, especially at times of turbulent circulation. Patients with hTTP may have many overt or clinically silent manifestations, and a high index of suspicion is required for diagnosis. For the treatment of hTTP, the goal is simply replacement of ADAMTS13. The primary treatment is prophylaxis with plasma infusions or plasma-derived factor VIII products, providing sufficient ADAMTS13 to prevent acute episodes. When acute episodes occur, prophylaxis is intensified. Recombinant ADAMTS13, which is near to approval, will immediately be the most effective and also the most convenient treatment. In this review, we discuss the possible clinical manifestations of this rare disease and the relevant differential diagnoses in different age groups. An extensive discussion on prophylaxis and treatment strategies is also presented. Unique real patient cases have been added to highlight critical aspects of hTTP manifestations, diagnosis and treatment.

Use of infusion ports in patients with sickle cell disease: Indications and complications.

BACKGROUND: Peripheral venous access in patients with sickle cell disease (SCD) can become difficult over time due to frequent access and scarring. Infusion ports provide reliable central venous access. Deep venous thrombosis (DVT) and infections are complications associated with SCD and infusion ports. METHODS: We performed a 17.5-year single-institution retrospective chart review (January 2000 to July 2018) with literature review regarding use of infusion ports in patients with SCD. RESULTS: We identified 32 patients with infusion ports placed for a total of 63 devices (48 for chronic transfusion [CT] and 15 for poor venous access [PVA], not on CT) for a total of 99,272 catheter days. The mean age at first insertion was 8 years (range 1-20 years). Complications included malfunction, infection, thrombosis, difficult access, and pain over infusion port site. The rate of infection was 0.2 per 1000 catheter days. Thrombosis was identified in three devices (5%) in three patients (9%), with a rate of 0.03 per 1000 catheter days. There was no difference in complications by site in either the left or right subclavian vein (p = 1). The rate of premature removal was 0.36 per 1000 catheter days, which was higher among patients with infusion ports solely for PVA (0.87 per 1000 catheter days) compared with those placed for CT (0.29 per 1000 catheter days). CONCLUSION: Infusion ports in patients with SCD was associated with low rates of thrombosis, infection, and malfunction, and may be considered as an alternative to frequent intravenous access, especially in patients requiring CT.

IDH1 mutated acute myeloid leukemia in a child with metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria.

D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare metabolic disorder characterized by developmental delay, hypotonia, and bi-allelic mutations in D-2-hydroxyglutarate dehydrogenase (D2HGDH) or a single gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2). Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) is a type of D-2-HGA that has been previously reported in ten patients (OMIM 614875), three of whom had somatic mosaicism for R132 variants in isocitrate dehydrogenase 1 (IDH1). We describe a 3-year-old boy with MC-HGA who subsequently developed acute myeloid leukemia (AML) and was found to have an IDH1 R132C mutation in a leukemic bone marrow sample. Further testing revealed presence of somatic mosaicism for IDH1 R132C variant, suggesting an association of IDH1 in inducing myeloid leukemogenesis.

Tackling Acute Lymphoblastic Leukemia-One Fish at a Time.

Despite advancements in the diagnosis and treatment of acute lymphoblastic leukemia (ALL), a need for improved strategies to decrease morbidity and improve cure rates in relapsed/refractory ALL still exists. Such approaches include the identification and implementation of novel targeted combination regimens, and more precise upfront patient risk stratification to guide therapy. New curative strategies rely on an understanding of the pathobiology that derives from systematically dissecting each cancer's genetic and molecular landscape. Zebrafish models provide a powerful system to simulate human diseases, including leukemias and ALL specifically. They are also an invaluable tool for genetic manipulation, in vivo studies, and drug discovery. Here, we highlight and summarize contributions made by several zebrafish T-ALL models and newer zebrafish B-ALL models in translating the underlying genetic and molecular mechanisms operative in ALL, and also highlight their potential utility for drug discovery. These models have laid the groundwork for increasing our understanding of the molecular basis of ALL to further translational and clinical research endeavors that seek to improve outcomes in this important cancer.

Splenectomy is not associated with a higher tricuspid regurgitant jet velocity in people with sickle cell anemia.

BACKGROUND: Vascular complications such as pulmonary hypertension (PH) occur at an increased rate following splenectomy in patients with various hemolytic blood disorders including thalassemia. The goal of this retrospective cross-sectional analysis was to assess the independent association of splenectomy with an elevated tricuspid regurgitation velocity (TRV) in people with homozygous sickle cell disease (HbSS). TRV is a noninvasive screening test for PH and a surrogate marker of prognosis in sickle cell disease (SCD). PROCEDURE: Data were obtained from the multicenter Walk-PHaSST (treatment of pulmonary hypertension and sickle cell disease with sildenafil therapy) study of PH (NCT00492531). We compared TRV in the cohort of patients with HbSS who were surgically splenectomized with patients who were not surgically splenectomized. RESULTS: We found no significant differences in TRV between the two groups. CONCLUSIONS: The lack of difference in TRV between the two groups is most likely because members of the comparator nonsurgical group in many cases experienced autoinfarction of the spleen in childhood. Splenectomy does not seem to confer additional risk for the development of a higher TRV in HbSS, unlike in patients with thalassemia or other hemolytic anemias. This could be an important consideration when weighing the risks and benefits of splenectomy in patients with HbSS.

Concise Review: Hematopoietic Stem Cell Origins: Lessons from Embryogenesis for Improving Regenerative Medicine.

Hematopoietic stem cells (HSCs) have extensive regenerative capacity to replace all blood cell types, an ability that is harnessed in the clinic for bone marrow transplantation. Finding appropriate donors remains a major limitation to more extensive usage of HSC-based therapies. Derivation of patient-specific HSCs from pluripotent stem cells offers great promise to remedy this problem if scientists could crack the code on how to make robust, transplantable HSCs in a dish. Studies delving into the native origins of HSC production during embryonic development should supply the necessary playbook. This review presents recent discoveries from animal models, with a focus on zebrafish, and discusses the implications of these new advances in the context of prior knowledge. The focus is on the latest research exploring the role of epigenetic regulation, signaling pathways, and niche components needed for proper HSC formation. These studies provide new directions that should be explored for de novo generation and expansion of HSCs for regenerative therapies. Stem Cells Translational Medicine 2017;6:60-67.

Decreased fetal hemoglobin over time among youth with sickle cell disease on hydroxyurea is associated with higher urgent hospital use.

BACKGROUND: Hydroxyurea (HU) induces dose-dependent increased fetal hemoglobin (HbF) for sickle cell disease (SCD). Large deviation from historical personal best (PBest) HbF, a clinic-based version of maximum dose, may identify a subset with suboptimal HU adherence over time. PROCEDURE: Retrospective clinical data from youth ages 10-18 years prescribed HU at two centers were extracted from medical records at three time points: pre-HU initiation, PBest and a recent assessment. Decrease from PBest HbF of 20% or more at recent assessment despite stable dosing was designated as high deviation from PBest. Acute hospital use was compared between 1-year periods, pre-HU and ±6 months for PBest and recent assessment. Groups were compared using descriptive and bivariate nonparametric statistics. RESULTS: Seventy-five youth, mean HU duration 5.9 years, met eligibility criteria. Mean ages of HU initiation, PBest and recent assessment were 8.0, 10.9 and 13.9 years, respectively. Despite stable dosing, average HbF of 19.5% at PBest overall declined by 31.8% at recent assessment. PBest HbF declined by 11.7 and 40.1% in two groups, the latter comprised 70.7% of the sample, had lower pre-HU and recent HbF and higher dosing. They experienced more urgent hospital use during the year framing recent assessment than during PBest; these findings were supported by sensitivity analysis. CONCLUSIONS: Decline from PBest HbF is a novel approach to assess HU effectiveness, is common among youth and may represent suboptimal adherence. Larger prospective studies using additional adherence measures are needed to confirm our approach of tracking HbF deviation over time and to define an appropriate cutoff.

Successful bone marrow transplantation of an adolescent young adult female with pregnancy-associated aplastic anemia.

Cases of pregnancy-associated severe aplastic anemia (SAA) have been reported in the literature with historically high rates of mortality. We report the case of a 17-year-old female diagnosed with SAA at 26 weeks of gestation. She experienced intrauterine fetal demise and did not achieve hematologic remission after delivery. She received a histocompatible sibling donor bone marrow transplant 7 weeks after her diagnosis and remains in remission, at 1-year posttransplant. We review available literature and suggest that when a histocompatible sibling donor is available, bone marrow transplantation should be considered as a first-line therapy for patients with pregnancy-associated SAA.