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1.
Am J Clin Pathol ; 153(6): 821-832, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32112075

RESUMO

OBJECTIVES: Compare the morphologic, laboratory, and clinical features of asymptomatic and symptomatic Castleman disease in the pediatric population. METHODS: We reviewed clinical records and histopathology of patients with Castleman disease from 2 pediatric institutions. RESULTS: Of 39 patients with pediatric Castleman disease, 37 had unicentric disease, all classified with the hyaline vascular variant of Castleman disease, 8 of which were clinically symptomatic. These 8 patients demonstrated abnormal laboratory findings, including microcytic anemia, elevated erythrocyte sedimentation rate and C-reactive protein, and hypoalbuminemia. In addition, histopathologic evaluation showed that the 8 symptomatic cases had more hyperplastic germinal centers, fewer atrophic or regressed germinal centers, fewer mantle zones containing multiple germinal centers, reduced "onion skinning" of mantle zones, and fewer "lollipop" formations compared with the asymptomatic cases. CONCLUSIONS: This series of pediatric Castleman disease showed that lymph nodes from asymptomatic patients generally demonstrated the more classic hyaline vascular histology, whereas those with symptoms could lack or have only focal classic findings. As such, reactive lymph nodes with subtle Castleman-like features should prompt clinical correlation to ensure proper diagnosis.

2.
Am J Hematol ; 95(5): 492-496, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31990410

RESUMO

Reduced ferrochelatase activity in erythropoietic protoporphyria (EPP) causes the accumulation of protoporphyrin IX (PPIX) leading to acute cutaneous photosensitivity and liver injury. Many EPP patients also have a mild hypochromic, microcytic anemia and iron deficiency. Iron deficiency can lead to decreased PPIX accumulation in another erythropoietic porphyria, congenital erythropoietic porphyria (CEP). Expression of the iron regulatory peptide hepcidin is negatively regulated by the serine protease TMPRSS6. Hepcidin induction by siRNA-mediated inhibition of TMPRSS6 expression reduces iron availability and induces iron deficiency. To interrogate the therapeutic potential of iron deficiency to modify EPP, we treated an ethylnitrosourea-induced mouse model of EPP, Fech m1Pas , with a GalNAc-conjugated Tmprss6 siRNA and PPIX levels, anemia and iron parameters were monitored. The GalNAc-RNAi therapeutic reduces Tmprss6 expression and induces mild iron deficiency in Fech m1Pas animals. However, decreases in erythrocyte PPIX levels and liver PPIX accumulation were not seen. These results indicate short-term induction of iron deficiency, at least in a murine model of EPP, does not lead to decreased PPIX production.

3.
Ann Vasc Surg ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31953141

RESUMO

BACKGROUND: The role of inferior mesenteric artery (IMA) reimplantation during open aortic reconstruction is debated. We assessed outcomes after inferior mesenteric artery reimplantation (IMAR) for aortic aneurysmal disease to help shed light on this question. METHODS: A single-center retrospective review of all IMARs performed during open aortic surgery over a 10-year period between 2000 and 2009 was carried out. The primary outcome was patency, while secondary outcomes included colonic ischemia and overall survival. Analysis was performed using Cox models and Kaplan-Meier estimates. RESULTS: Of 840 patients who underwent elective abdominal aortic aneurysm (AAA) reconstructions during this period, 70 underwent IMAR. Indications for IMAR included intraoperative colonic ischemia (n = 24), poor back bleeding (n = 52), large IMA (n = 5), internal iliac disease (n = 5), and prior colon surgery (n = 1). Follow-up imaging studies were available in 35 of 70 patients (computed tomography in 30 [86%] and duplex in 5 [14%]). Patency was confirmed in 32 of 35 patients (91%) over a median follow-up of 98 months. Both losses in patency were at 4 months and did not require an operation. One patient underwent left colon resection on postoperative day 9 because of ischemia. (Patency could not be confirmed.) No statistically significant predictor of patency was noted. Incidence of colonic ischemia was 1.4% in patients undergoing IMAR. The overall mortality was 51% in patients undergoing IMAR over the median follow-up period. The overall 10-year survival was 30% in patients undergoing IMAR for aortic aneurysmal disease. The nature of aneurysm (juxtarenal or higher juxta renal abdominal aortic aneurysm [JRAAA]) was associated with mortality, with a hazard ratio of 1.8 (P = 0.08) approaching significance. Ten-year survival was worse if IMAR was performed for intraoperative colonic ischemia (26% vs 34%) or in JRAAA (19.0% vs 38%; P = 0.03). Age per year at the time of repair was the only statistically significant predictor of survival (P < 0.001). CONCLUSION: IMAR for AAA remains necessary for select patients. Reimplantation is associated with excellent long-term patency and low risk of colonic ischemia.

4.
Lancet Haematol ; 7(3): e238-e246, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31879230

RESUMO

BACKGROUND: Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies. METHODS: We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients. FINDINGS: We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts. INTERPRETATION: Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome. FUNDING: National Institute of Health.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/mortalidade , Síndromes Mielodisplásicas/mortalidade , Síndrome de Shwachman-Diamond/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Estudos Retrospectivos , Síndrome de Shwachman-Diamond/patologia , Síndrome de Shwachman-Diamond/terapia , Taxa de Sobrevida , Adulto Jovem
6.
Am J Hum Genet ; 105(5): 947-958, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31668704

RESUMO

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e-7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.

7.
Blood ; 134(18): 1547-1557, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31439541

RESUMO

The mechanisms underlying thrombocytosis in patients with iron deficiency anemia remain unknown. Here, we present findings that support the hypothesis that low iron biases the commitment of megakaryocytic (Mk)-erythroid progenitors (MEPs) toward the Mk lineage in both human and mouse. In MEPs of transmembrane serine protease 6 knockout (Tmprss6-/-) mice, which exhibit iron deficiency anemia and thrombocytosis, we observed a Mk bias, decreased labile iron, and decreased proliferation relative to wild-type (WT) MEPs. Bone marrow transplantation assays suggest that systemic iron deficiency, rather than a local role for Tmprss6-/- in hematopoietic cells, contributes to the MEP lineage commitment bias observed in Tmprss6-/- mice. Nontransgenic mice with acquired iron deficiency anemia also show thrombocytosis and Mk-biased MEPs. Gene expression analysis reveals that messenger RNAs encoding genes involved in metabolic, vascular endothelial growth factor, and extracellular signal-regulated kinase (ERK) pathways are enriched in Tmprss6-/- vs WT MEPs. Corroborating our findings from the murine models of iron deficiency anemia, primary human MEPs exhibit decreased proliferation and Mk-biased commitment after knockdown of transferrin receptor 2, a putative iron sensor. Signal transduction analyses reveal that both human and murine MEP have lower levels of phospho-ERK1/2 in iron-deficient conditions compared with controls. These data are consistent with a model in which low iron in the marrow environment affects MEP metabolism, attenuates ERK signaling, slows proliferation, and biases MEPs toward Mk lineage commitment.


Assuntos
Anemia Ferropriva/metabolismo , Diferenciação Celular/fisiologia , Células Progenitoras de Megacariócitos/metabolismo , Megacariócitos/metabolismo , Anemia Ferropriva/complicações , Animais , Proliferação de Células , Humanos , Ferro , Células Progenitoras de Megacariócitos/citologia , Megacariócitos/citologia , Camundongos , Camundongos Knockout , Trombocitose/etiologia , Trombocitose/metabolismo
8.
Cancer Cell ; 35(2): 283-296.e5, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30712845

RESUMO

SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor signaling, which we also identified in human CLL cases. Notably, human CLLs harboring SF3B1 mutations exhibit altered response to BTK inhibition. Our murine model of CLL thus provides insights into human CLL disease mechanisms and treatment.


Assuntos
Linfócitos B/imunologia , Senescência Celular , Deleção de Genes , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Neoplasias Experimentais/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Receptores de Antígenos de Linfócitos B/imunologia , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Processamento Alternativo , Animais , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Senescência Celular/efeitos dos fármacos , Dano ao DNA , Predisposição Genética para Doença , Instabilidade Genômica , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Fenótipo , Fosfoproteínas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Fatores de Processamento de RNA/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
9.
J Exp Med ; 216(3): 527-538, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30728174

RESUMO

Leukemia phenotypes vary with age of onset. Delineating mechanisms of age specificity in leukemia could improve disease models and uncover new therapeutic approaches. Here, we used heterochronic transplantation of leukemia driven by MLL/KMT2A translocations to investigate the contribution of the age of the hematopoietic microenvironment to age-specific leukemia phenotypes. When driven by MLL-AF9, leukemia cells in the adult microenvironment sustained a myeloid phenotype, whereas the neonatal microenvironment supported genesis of mixed early B cell/myeloid leukemia. In MLL-ENL leukemia, the neonatal microenvironment potentiated B-lymphoid differentiation compared with the adult. Ccl5 elaborated from adult marrow stroma inhibited B-lymphoid differentiation of leukemia cells, illuminating a mechanism of age-specific lineage commitment. Our study illustrates the contribution of the developmental stage of the hematopoietic microenvironment in defining the age specificity of leukemia.

10.
Haematologica ; 104(7): 1342-1354, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30630985

RESUMO

Ncoa4 mediates autophagic degradation of ferritin, the cytosolic iron storage complex, to maintain intracellular iron homeostasis. Recent evidence also supports a role for Ncoa4 in systemic iron homeostasis and erythropoiesis. However, the specific contribution and temporal importance of Ncoa4-mediated ferritinophagy in regulating systemic iron homeostasis and erythropoiesis is unclear. Here, we show that Ncoa4 has a critical role in basal systemic iron homeostasis and both cell autonomous and non-autonomous roles in murine erythropoiesis. Using an inducible murine model of Ncoa4 knockout, acute systemic disruption of Ncoa4 impaired systemic iron homeostasis leading to tissue ferritin and iron accumulation, a decrease in serum iron, and anemia. Mice acutely depleted of Ncoa4 engaged the Hif2a-erythropoietin system to compensate for anemia. Mice with targeted deletion of Ncoa4 specifically in the erythroid compartment developed a pronounced anemia in the immediate postnatal stage, a mild hypochromic microcytic anemia at adult stages, and were more sensitive to hemolysis with higher requirements for the Hif2a-erythropoietin axis and extramedullary erythropoiesis during recovery. These studies demonstrate the importance of Ncoa4-mediated ferritinophagy as a regulator of systemic iron homeostasis and define the relative cell autonomous and non-autonomous contributions of Ncoa4 in supporting erythropoiesis in vivo.

11.
Pediatr Dev Pathol ; 22(4): 315-328, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30600763

RESUMO

Germline mutations in RUNX1 result in autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM). To characterize the hematopathologic features associated with a germline RUNX1 mutation, we reviewed a total of 42 bone marrow aspirates from 14 FPDMM patients, including 24 cases with no cytogenetic clonal abnormalities, and 18 with clonal karyotypes or leukemia. We found that all aspirate smears had ≥10% atypical megakaryocytes, predominantly characterized by small forms with hypolobated and eccentric nuclei, and forms with high nuclear-to-cytoplasmic ratios. Core biopsies showed variable cellularity and variable numbers of megakaryocytes with similar features to those in the aspirates. Granulocytic and/or erythroid dysplasia (≥10% cells per lineage) were present infrequently. Megakaryocytes with separate nuclear lobes were increased in patients with myelodysplastic syndrome (MDS) and acute leukemia. Comparison to an immune thrombocytopenic purpura cohort confirms increased megakaryocytes with hypolobated eccentric nuclei in FPDMM patients. As such, patients with FPDMM often have atypical megakaryocytes with small hypolobated and eccentric nuclei even in the absence of clonal cytogenetic abnormalities; these findings are related to the underlying RUNX1 germline mutation and not diagnostic of MDS. Isolated megakaryocytic dysplasia in patients with unexplained thrombocytopenia should raise the possibility of an underlying germline RUNX1 mutation.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/patologia , Transtornos Plaquetários/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/patologia , Adolescente , Adulto , Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Plaquetários/genética , Plaquetas/patologia , Medula Óssea/patologia , Criança , Pré-Escolar , Aberrações Cromossômicas , Estudos de Coortes , Progressão da Doença , Feminino , Mutação em Linhagem Germinativa , Humanos , Cariótipo , Leucemia Mieloide Aguda/genética , Masculino , Megacariócitos/patologia , Isoformas de Proteínas , Adulto Jovem
12.
Blood ; 133(1): 59-69, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30401706

RESUMO

The sideroblastic anemias (SAs) are a group of inherited and acquired bone marrow disorders defined by pathological iron accumulation in the mitochondria of erythroid precursors. Like most hematological diseases, the molecular genetic basis of the SAs has ridden the wave of technology advancement. Within the last 30 years, with the advent of positional cloning, the human genome project, solid-state genotyping technologies, and next-generation sequencing have evolved to the point where more than two-thirds of congenital SA cases, and an even greater proportion of cases of acquired clonal disease, can be attributed to mutations in a specific gene or genes. This review focuses on an analysis of the genetics of these diseases and how understanding these defects may contribute to the design and implementation of rational therapies.


Assuntos
Anemia Sideroblástica/genética , Células Precursoras Eritroides/patologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Ferro/metabolismo , Anemia Sideroblástica/metabolismo , Anemia Sideroblástica/patologia , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos
13.
Soc Sci Med ; 220: 49-55, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30391641

RESUMO

Our paper explores how legal status stratification shapes the health and health care of low-income patients with chronic illnesses in the U.S. healthcare safety net. Drawing on data from over two years of ethnographic fieldwork at urban safety-net clinics, we examine efforts by Complex Care Management (CCM) teams to stabilize patients with uncontrolled chronic illnesses through primary care-integrated support. We show that stratified citizenship and geographic variability correspond to different possibilities for health care. We suggest an approach to immigration as a structural determinant of health that accounts for the complex, stratified, and changing nature of citizenship status. We also highlight how geographical differences and interactions among local, state, and federal policies support the notion that citizenship is stratified across multiple tiers with distinctive possibilities and constraints for health. While county-based health plans at each of the study sites include residents with varying legal status, lack of formal legal status remains a substantial obstacle to care. Many immigrants are unable to take full advantage of primary and specialty care, resulting in unnecessary morbidity and mortality. In some cases, patients have returned to their country of origin to die. While CCM teams provide an impressive level of support to assist immigrant patients in navigating healthcare and immigration bureaucracies, legal and geographic stratification limit their ability to address broader aspects of these patients' social context.

14.
Med Anthropol Q ; 33(2): 173-190, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30291726

RESUMO

Hospitals throughout the United States are implementing new forms of care delivery meant to address social needs for structurally vulnerable patients as a strategy to prevent emergency department visits and hospitalizations and to thereby reduce costs. This article examines how the deployment of social assistance within a neoliberal institutional logic involves the negotiation and alignment of economistic values with ethics of care. We focus on care practices meant to stabilize the socioeconomic conditions of the most expensive patients in the health care system-the "super-utilizers"-through the provisioning of basic resources such as housing, food, transportation, and social support. These patients typically suffer from multiple chronic illnesses accompanied by conditions of poverty, housing and food insecurity, exposure to violence and trauma, and associated substance use and mental health problems. We offer an account of how practices of social assistance are being forged within contexts defined by neoliberal governance.

15.
J Vasc Surg ; 68(5): 1505-1516, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30369411

RESUMO

OBJECTIVE: Patients receiving dialysis are at increased risk for lower extremity amputations (LEAs) and postoperative morbidity. Limited studies have examined differences in 30-day outcomes of mortality and health care use after amputation or the preoperative factors that relate to worsened outcomes in dialysis patients. Our objective was to examine dialysis dependency and other preoperative factors associated with readmission or death after LEA. METHODS: A retrospective cohort study was conducted of dialysis-dependent and nondialysis patients undergoing major LEA in the 2012 to 2013 American College of Surgeons National Surgical Quality Improvement Program. Primary outcomes included death and hospital readmission within 30 days of amputation. RESULTS: Of 6468 patients, 1166 (18%) were dialysis dependent. The dialysis cohort had more blacks (39% vs 23%), diabetes (76% vs 58%), below-knee amputations (62% vs 55%), and in-hospital deaths (8% vs 3%; all P < .001). The 30-day postoperative death rates (15% vs 7%) and readmission rates (35% vs 20% per 30 person-days; both P < .001) were higher in dialysis patients. Among the live discharges, the rate of any readmission or death within 30 days from amputation was highest in those aged ≥50 years (40% per 30 person-days). Multivariable analyses in the dialysis cohort revealed increased age, above-knee amputation, decreased physical status, heart failure, high preoperative white blood cell count, and low platelet count to be associated with death (P < .05; C statistic, 0.75). The only preoperative factor associated with readmission in dialysis patients was race (P = .04; C statistic, 0.58). CONCLUSIONS: Readmission or death after amputation is increased among dialysis patients. Predicting which dialysis patients are at highest risk for death is feasible, whereas predicting which will require readmission is less so. Risk factor identification may improve risk stratification, inform reimbursement policies, and allow targeted interventions to improve outcomes.


Assuntos
Amputação/efeitos adversos , Amputação/mortalidade , Extremidade Inferior/irrigação sanguínea , Readmissão do Paciente , Doença Arterial Periférica/cirurgia , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Bases de Dados Factuais , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/etnologia , Doença Arterial Periférica/mortalidade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia
16.
Haematologica ; 103(12): 2008-2015, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30026338

RESUMO

YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype.


Assuntos
Acidose Láctica/genética , Anemia Sideroblástica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação em Linhagem Germinativa , Síndrome MELAS/genética , Proteínas Mitocondriais/genética , Tirosina-tRNA Ligase/genética , Acidose Láctica/enzimologia , Adolescente , Anemia Sideroblástica/enzimologia , Feminino , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Humanos , Lactente , Síndrome MELAS/enzimologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Adulto Jovem
20.
Blood ; 132(13): 1399-1412, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-29898956

RESUMO

Unlike primary myelofibrosis (PMF) in adults, myelofibrosis in children is rare. Congenital (inherited) forms of myelofibrosis (cMF) have been described, but the underlying genetic mechanisms remain elusive. Here we describe 4 families with autosomal recessive inherited macrothrombocytopenia with focal myelofibrosis due to germ line loss-of-function mutations in the megakaryocyte-specific immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B (G6b, C6orf25, or MPIG6B). Patients presented with a mild-to-moderate bleeding diathesis, macrothrombocytopenia, anemia, leukocytosis and atypical megakaryocytes associated with a distinctive, focal, perimegakaryocytic pattern of bone marrow fibrosis. In addition to identifying the responsible gene, the description of G6b-B as the mutated protein potentially implicates aberrant G6b-B megakaryocytic signaling and activation in the pathogenesis of myelofibrosis. Targeted insertion of human G6b in mice rescued the knockout phenotype and a copy number effect of human G6b-B expression was observed. Homozygous knockin mice expressed 25% of human G6b-B and exhibited a marginal reduction in platelet count and mild alterations in platelet function; these phenotypes were more severe in heterozygous mice that expressed only 12% of human G6b-B. This study establishes G6b-B as a critical regulator of platelet homeostasis in humans and mice. In addition, the humanized G6b mouse will provide an invaluable tool for further investigating the physiological functions of human G6b-B as well as testing the efficacy of drugs targeting this receptor.


Assuntos
Mutação com Perda de Função , Mielofibrose Primária/congênito , Receptores Imunológicos/genética , Trombocitopenia/congênito , Adolescente , Adulto , Animais , Plaquetas/metabolismo , Plaquetas/patologia , Criança , Pré-Escolar , Feminino , Técnicas de Introdução de Genes , Humanos , Lactente , Masculino , Megacariócitos/metabolismo , Megacariócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linhagem , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Trombocitopenia/genética , Trombocitopenia/patologia , Adulto Jovem
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