Impact of the motor function of individuals with spinal muscular atrophy on caregiver burden / Impacto de la función motora de los individuos con atrofia muscular espinal en la carga de sus cuidadores / Impacto da função motora de indivíduos com atrofia muscular espinhal na sobrecarga de seus cuidadores

ABSTRACT Spinal Muscular Atrophy (SMA) is a neurodegenerative disease that impairs motor function, justifying the help of a caregiver. This study aimed to analyze the impact of the motor function of individuals with SMA on caregiver burden. This is a cross-sectional study of 32 individuals with SMA and 27 caregivers, carried out in a rehabilitation center, using the identification questionnaire, anamnesis and sociodemographic profile, Motor Function Measurement Scale and Burden Interview. Motor function and caregiver burden were compared between SMA types using the analysis of covariance (ANCOVA) and correlated using Pearson's correlation test. Individuals with SMA type I had greater impairment of motor function when compared to types II and III, and individuals with type III had better scores in all domains of motor function. No correlation was observed between motor function and caregiver burden: however, most caregivers presented some level of burden, especially those from mild to moderate. Moderate to severe burden was found in caregivers with SMA in a considerable prevalence, which requires care and attention from health professionals.

RESUMEN La atrofia muscular espinal (AME) es una enfermedad neurodegenerativa que provoca un deterioro de la función motora, por lo que requiere la asistencia de cuidadores. El objetivo de este estudio fue analizar el impacto de la función motora de los individuos con AME en la carga de sus cuidadores. Se trata de un estudio transversal, realizado en un centro de rehabilitación con 32 individuos con AME y 27 cuidadores, utilizando como metodología el cuestionario de identificación, anamnesis y perfil sociodemográfico, la escala de medida de la función motora y la entrevista de carga. La función motora y la carga de los cuidadores se compararon entre los tipos de AME mediante el análisis de covarianza (Ancova) y se correlacionaron mediante la prueba de correlación de Pearson. Los individuos con AME tipo I tuvieron un mayor deterioro de la función motora en comparación con los tipos II y III, y los individuos de tipo III obtuvieron mejores puntuaciones en todos los dominios de la función motora. No se encontró correlación entre la función motora y la carga del cuidador, pero la mayoría de los cuidadores tenían algún nivel de carga, en particular de leve a moderada. Se encontró una carga de moderada a grave en los cuidadores con AME con una prevalencia considerable, lo que requiere cuidados y atención por parte de los profesionales de la salud.

RESUMO Atrofia muscular espinhal (AME) é uma doença neurodegenerativa que provoca comprometimento na função motora, justificando o auxílio de cuidador. O objetivo deste estudo foi analisar o impacto da função motora de indivíduos com AME na sobrecarga de seus cuidadores. Trata-se de um estudo transversal realizado em um centro de reabilitação com 32 indivíduos portadores de AME e 27 cuidadores, utilizando como metodologia o questionário de identificação, anamnese e perfil sociodemográfico, a escala da medida da função motora e Burden Interview. A função motora e a sobrecarga do cuidador foram comparadas entre os tipos de AME por meio da Análise da Covariância (Ancova) e correlacionadas pelo teste de correlação de Pearson. Os indivíduos com AME tipo I apresentaram maior comprometimento da função motora quando comparado entre os tipos II e III, e indivíduos tipo III apresentaram melhores escores em todos os domínios da função motora. Não foi percebida correlação entre função motora e sobrecarga de cuidador, entretanto encontramos a maior parte dos cuidadores apresentando algum nível de sobrecarga, com destaque ao de leve a moderado. A sobrecarga moderada a severa foi encontrada nos cuidadores com AME em uma prevalência considerável, o que requer cuidado e atenção dos profissionais de saúde.

Age-restricted functional and developmental differences of neonatal platelets.

BACKGROUND: Developmental ontogeny of neonatal thrombopoiesis retains characteristics that are distinct from adults although molecular mechanisms remain unestablished. METHODS: We applied multiparameter quantitative platelet responses with integrated ribosome profiling/transcriptomic studies to better define gene/pathway perturbations regulating the neonatal-to-adult transition. A bioinformatics pipeline was developed to identify stable, neonatal-restricted platelet biomarkers for clinical application. RESULTS: Cord blood (CB) platelets retained the capacity for linear agonist-receptor coupling linked to phosphatidylserine (PS) exposure and α-granule release, although a restricted block in cross-agonist activation pathways was evident. Functional immaturity of synergistic signaling pathways was due to younger ontogenetic age and singular underdevelopment of the protein secretory gene network, with reciprocal expansion of developmental pathways (E2F, G2M checkpoint, c-Myc) important for megakaryocytopoiesis. Genetic perturbations regulating vesicle transport and fusion (TOM1L1, VAMP3, SNAP23, and DNM1L) and PS exposure and procoagulant activity (CLCN3) were the most significant, providing a molecular explanation for globally attenuated responses. Integrated transcriptomic and ribosomal footprints identified highly abundant (ribosome-protected) DEFA3 (encoding human defensin neutrophil peptide 3) and HBG1 as stable biomarkers of neonatal thrombopoiesis. Studies comparing CB- or adult-derived megakaryocytopoiesis confirmed inducible and abundant DEFA3 antigenic expression in CB megakaryocytes, ~3.5-fold greater than in leukocytes (the most abundant source in humans). An initial feasibility cohort of at-risk pregnancies manifested by maternal/fetal hemorrhage (chimerism) were applied for detection and validation of platelet HBG1 and DEFA3 as neonatal thrombopoiesis markers, most consistent for HBG1, which displayed gestational age-dependent expression. CONCLUSIONS: These studies establish an ontogenetically divergent stage of neonatal thrombopoiesis, and provide initial feasibility studies to track disordered fetal-to-adult megakaryocytopoiesis in vivo.

Maternal Heart Failure.

Heart failure (HF) remains the most common major cardiovascular complication arising in pregnancy and the postpartum period. Mothers who develop HF have been shown to experience an increased risk of death as well as a variety of adverse cardiac and obstetric outcomes. Recent studies have demonstrated that the risk to neonates is significant, with increased risks in perinatal morbidity and mortality, low Apgar scores, and prolonged neonatal intensive care unit stays. Information on the causal factors of HF can be used to predict risk and understand timing of onset, mortality, and morbidity. A variety of modifiable, nonmodifiable, and obstetric risk factors as well as comorbidities are known to increase a patient's likelihood of developing HF, and there are additional elements that are known to portend a poorer prognosis beyond the HF diagnosis. Multidisciplinary cardio-obstetric teams are becoming more prominent, and their existence will both benefit patients through direct care and increased awareness and educate clinicians and trainees on this patient population. Detection, access to care, insurance barriers to extended postpartum follow-up, and timely patient counseling are all areas where care for these women can be improved. Further data on maternal and fetal outcomes are necessary, with the formation of State Maternal Perinatal Quality Collaboratives paving the way for such advances.

Shear-Induced Platelet Activation is Sensitive to Age and Calcium Availability: A Comparison of Adult and Cord Blood.

INTRODUCTION: Antiplatelet therapy for neonates and infants is often extrapolated from the adult experience, based on limited observation of agonist-induced neonatal platelet hypoactivity and poor understanding of flow shear-mediated platelet activation. Therefore, thrombotic events due to device-associated disturbed flow are inadequately mitigated in critically ill neonates with indwelling umbilical catheters and infants receiving cardiovascular implants. METHODS: Whole blood (WB), platelet-rich plasma (PRP), and gel-filtered platelets (GFP) were prepared from umbilical cord and adult blood, and exposed to biochemical agonists or pathological shear stress of 70 dyne/cm2. We evaluated α-granule release, phosphatidylserine (PS) scrambling, and procoagulant response using P-selectin expression, Annexin V binding, and thrombin generation (PAS), respectively. Activation modulation due to depletion of intracellular and extracellular calcium, requisite second messengers, was also examined. RESULTS: Similar P-selectin expression was observed for sheared adult and cord platelets, with concordant inhibition due to intracellular and extracellular calcium depletion. Sheared cord platelet Annexin V binding and PAS activity was similar to adult values in GFP, but lower in PRP and WB. Annexin V on sheared cord platelets was calcium-independent, with PAS slightly reduced by intracellular calcium depletion. CONCLUSIONS: Increased PS activity on purified sheared cord platelets suggest that their intrinsic function under pathological flow conditions is suppressed by cell-cell or plasmatic components. Although secretory functions of adult and cord platelets retain comparable calcium-dependence, PS exposure in sheared cord platelets is uniquely calcium-independent and distinct from adults. Identification of calcium-regulated developmental disparities in shear-mediated platelet function may provide novel targets for age-specific antiplatelet therapy.

Risk Factors and Timing of Acute Myocardial Infarction Associated With Pregnancy: Insights From the National Inpatient Sample.

Background Pregnancy increases the risk of acute myocardial infarction (AMI). The purpose of this study was to examine timing and risk factors for AMI in pregnancy and poor outcome. Methods and Results National Inpatient Sample (2003-2015) was screened in pregnancy, labor and delivery, and postpartum. There were 11 297 849 records extracted with 913 instances of AMI (0.008%). One hundred eleven (12.2%) women experienced AMI during labor and delivery, 338 (37.0%) during pregnancy and most during the postpartum period (464; 50.8%). The prevalence of AMI in pregnancy has increased (P=0.0005). Most major adverse cardiovascular and cerebrovascular events occurred in the postpartum period (63.5%). Inpatient mortality was 4.5%. Predictors of AMI include known coronary artery disease (odds ratio [OR], 517.4; 95% CI, 420.8-636.2), heart failure (OR, 8.2; 95% CI, 1.9-35.2), prior valve replacement (OR, 6.4; 95% CI, 2.4-17.1), and atrial fibrillation (OR, 2.7; CI, 1.5-4.7; P<0.001). Risk factors of traditional atherosclerosis including hyperlipidemia, obesity, tobacco history, substance abuse, and thrombophilia were identified (P<0.001). Gestational hypertensive disorders (eclampsia OR, 6.0; 95% CI, 3.3-10.8; preeclampsia OR, 3.2; 95% CI, 2.5-4.2) were significant risk factors in predicting AMI. Risk factors associated with major adverse cardiovascular and cerebrovascular events included prior percutaneous coronary intervention (OR, 6.6; 95% CI, 1.4-31.2) and pre-eclampsia (OR, 2.3; 95% CI, 1.3-3.9). Conclusions AMI is associated with modifiable, nonmodifiable, and obstetric risk factors. These risk factors can lead to devastating adverse outcomes and highlight the need for risk factor modification and public health resource initiatives toward the goal of decreasing AMI in the pregnant population.

Influence of Diabetes complications and limitations on health-related quality of life: a study in a southeastern Brazilian city.

PURPOSE: The aim of this study was to measure how diabetes, its complications, and limitations are associated to the domains of health-related quality of life (HRQoL). METHODS: A population-based cross-sectional study was conducted with 2178 individuals from the 2014/2015 City of Campinas Health Survey. The SF-36 was used to measure HRQoL. Mean scores were calculated. Crude and adjusted beta coefficients were estimated using multiple linear regression. RESULTS: Diabetes was associated with a significant reduction in the scores of five SF-36 domains. However, no significant reduction of scores was found among diabetics without complications and with no reports of limitations. The reduction in HRQoL was more accentuated with the increase in the number of complications. Three domains were affected in diabetics with one complication and all were affected in those with two or more complications, especially the role physical, role emotional, and physical functioning. Five domains were affected among diabetics who reported some degree of limitation and all were affected in those who reported high degree of limitation. Patients who reported limitation even in the absence of complications had reductions of the scores especially in the role emotional and social functioning. CONCLUSIONS: The results reveal that the association between diabetes and HRQoL only prevail in the occurrence of complications and limitations imposed by the disease, indicating the necessity to avoid or delay the emergence of chronic complications with adequate control methods and paying attention to the perception of limitation reported by the patient.

Postpartum Cardiovascular Outcomes Among Women With Heart Disease from A Nationwide Study.

There is limited data on postpartum maternal postpartum major adverse cardiovascular and cerebrovascular events (MACCE) among women with heart disease (HD) in the US. Therefore, we aimed to determine the prevalence and predictors of MACCE in the US. The Nationwide Readmissions Databases (2010 to 2014) were screened for patients with and without HD undergoing delivery. HD subtypes included cardiomyopathy (CDM), congenital heart disease, valvular heart disease, and pulmonary hypertension. Rates and reasons of 42-day readmission were determined using weighted national estimates. Independent predictors of postpartum MACCE were determined using multivariable logistic regression for complex survey data. We found among 15,273,247 patients hospitalized for delivery, 33,827 had HD (CDM 22.78%, congenital heart disease 45.98%, valvular heart disease 24.81%, and pulmonary hypertension 6.41%). Of these, 5.2% of HD patients and 1.4% of No HD were readmitted. MACCE was higher in HD vs No HD (2.68% vs 0.17%, p <0.0001). Median time to MACCE was 5.6 days (interquartile range 3 to 15 days). CDM had >10% readmission at 42 days. Among HD patients, cardiovascular, infectious, hypertensive syndromes, and complications of pregnancy were the most common reasons for 42-day readmission. MACCE predictors in women with HD included HD subtype, age, insurance status, obesity, eclampsia, postpartum hemorrhage, MACCE during delivery, preterm delivery, and thrombotic complications. In conclusion, among a nationwide analysis, postpartum MACCE was more common among patients with HD especially within 1 week of discharge from delivery. Predictors can be easily screened for by clinicians, including presence of any HD, hypertensive syndromes, age, obesity, and obstetrical events during index hospitalization.

Neonatal and Maternal Outcomes in Pregnant Women With Cardiac Disease.

Background Pregnant women with underlying heart disease ( HD ) are at increased risk for adverse maternal, obstetric, and neonatal outcomes. Methods and Results Inpatient maternal delivery admissions and linked neonatal stays for women with cardiomyopathy, adult congenital HD, pulmonary hypertension ( PH ), and valvular HD were explored utilizing the Statewide Planning and Research Cooperative System (New York), January 1, 2000, through December 31, 2014, with the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Maternal major adverse cardiac events, neonatal adverse clinical events ( NACE ), and obstetric complications were recorded. Outcomes were compared using multiple logistic regression modeling. Among 2 284 044 delivery admissions, 3871 women had HD ; 676 (17%) had cardiomyopathy, 1528 (40%) had valvular HD, 1367 (35%) had adult congenital HD, and 300 (8%) had PH . Major adverse cardiac events occurred in 16.1% of women with HD , with most in the cardiomyopathy (45.9%) and PH (25%) groups. NACE was more common in offspring of women with HD (18.4% versus 7.1%), with most in the cardiomyopathy (30.0%) and PH (25.0%) groups. Increased risk of NACE was noted for women with HD (odds ratio [ OR ]: 2.8; 95% confidence interval [ CI ], 2.5-3.0), with the highest risk for those with cardiomyopathy ( OR : 5.9; 95% CI , 5.0-7.0) and PH ( OR : 4.5; 95% CI , 3.4-5.9). Preeclampsia ( OR : 5.1; 95% CI , 3.0-8.6), major adverse cardiac events ( OR : 2.3; 95% CI , 1.8-2.9), preexisting diabetes mellitus ( OR : 4.3; 95% CI , 1.5-12.3), and obstetric complications ( OR : 2.9; 95% CI , 1.7-5.2) were independently associated with higher NACE risk. Conclusions Neonatal complications were higher in offspring of pregnant women with HD , particularly cardiomyopathy and PH . Preeclampsia, major adverse cardiac events, obstetric complications, and preexisting diabetes mellitus were independently associated with a higher risk of NACE .

Anti-CD19 chimeric antigen receptor targeting of CD19 + acute myeloid leukemia.

Aberrant expression of CD19 in acute myeloid leukemia (AML) is commonly associated with t(8;21)(q22;q22), although AML cases lacking this translocation occasionally express CD19. Mixed-phenotype acute leukemia also frequently expresses CD19. Chimeric antigen receptor (CAR) technology is a major breakthrough for cancer treatment, with the recent approval of CD19-directed CAR (CD19CAR) for treating B-cell malignancies. However, little information exists on using CD19CAR for other CD19 positive neoplasms such as AML. Our findings indicate that CD19CAR therapy can potentially be used for those with mixed phenotype leukemia and a subset of AML cases.

Identification of a potent small molecule capable of regulating polyploidization, megakaryocyte maturation, and platelet production.

BACKGROUND: Megakaryocytic cell maturation involves polyploidization, and megakaryocyte (MK) ploidy correlates with their maturation and platelet production. Retardation of MK maturation is closely associated with poor MK engraftment after cord blood transplantation and neonatal thrombocytopenia. Despite the high prevalence of thrombocytopenia in a range of setting that affect infants to adults, there are still very limited modalities of treatment. METHODS: Human CD34+ cells were isolated from cord blood or bone marrow samples acquired from consenting patients. Cells were cultured and induced using 616452 and compared to current drugs on the market such as rominplostim or TPO. Ploidy analysis was completed using propidium iodide staining and flow cytometry analysis. Animal studies consisted of transplanting human CD34+ cells into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice followed by daily injections of 15 mg/kg of 616452. RESULTS: Within one week of culture, the chemical was able to induce polyploidization, the process required for megakaryocyte maturation with the accumulation of DNA content, to 64 N or greater to achieve a relative adult size. We observed fold increases as high as 200-fold in cells of 16 N or greater compared to un-induced cells with a dose-dependent manner. In addition, MK differentiated in the presence of 616452 demonstrated a more robust capacity of MK differentiation than that of MKs cultured with rominplostim used for adult idiopathic thrombocytopenic purpura (ITP) patients. In mice transplanted with human cord blood, 616452 strikingly enhanced MK reconstitution in the marrow and human peripheral platelet production. The molecular therapeutic actions for this chemical may be through TPO-independent pathways. CONCLUSION: Our studies may have an important impact on our fundamental understanding of fetal MK biology, the clinical management of thrombocytopenic neonates and leukemic differentiation therapy.

Pregnant women with heart disease: Placental characteristics and their association with fetal adverse events.

BACKGROUND: Pregnant women with heart disease (HD) have higher rates of adverse fetal outcomes. We describe placental pathologic characteristics and their association with fetal events. METHODS: In pregnant women, known HD were categorized into: (1) cardiomyopathy (CM) or (2) other HD (congenital, coronary, arrhythmia, or valvular). Outcomes were maternal major adverse cardiac events (MACE), fetal adverse clinical events (FACE), a composite of infant death, prematurity, underweight status, intracranial hemorrhage, and respiratory distress. Only pathologically reported placental analyses were included. RESULTS: We studied 86 pregnancies in women with CM and HD, with pathologic analyses on 35 CM and 52 HD placentas. CM placentas, compared with those with HD, were more likely to have ischemic changes (65.7% vs. 37%, p 0.008), demonstrate immaturity (62.90% vs. 10%, p < 0.001), and have a lower weight (p < 0.001), despite similar gestational age. CM was independently associated with increased risk for MACE (OR 7.38, 95%CI 2.20-24.76). Ischemic placental changes were associated with increased odds of FACE (OR 24.78, 95%CI 2.37-259.03). CONCLUSIONS: Women with CM were more likely to have ischemic placentas, with lower placental and fetal weights, and evidence of immaturity compared with those with other forms of HD, and an increased odds of MACE.

Direct Conversion of Cord Blood CD34+ Cells Into Neural Stem Cells by OCT4.

UNLABELLED: : Cellular reprogramming or conversion is a promising strategy to generate desired stem cell types from somatic cells. Neural stem cells (NSCs) have the potential to regenerate central nervous system tissue and repair damage in response to injury. However, NSCs are difficult to isolate from human tissues and expand in sufficient quantities for therapy. Here, we report a method to generate neural stem cells from cord blood CD34-positive cells by ectopic expression of OCT4 in a feeder-free system. The induced cells (iNSCs) show a characteristic NSC-like morphology and can be expanded in vitro for more than 20 passages. In addition, the iNSCs are positive for neural stem cell-specific markers such as Nestin and Musashi-1 and are similar in gene expression patterns to a human neural stem cell line. The iNSCs express distinct transcriptional factors for forebrain, hindbrain, and spinal cord regions. Upon differentiation, the iNSCs are able to commit into multilineage mature neural cells. Following in vivo introduction into NOD/SCID mice, iNSCs can survive and differentiate in the mouse brain 3 months post-transplantation. Alternatively, we were also able to derive iNSCs with an episomal vector expressing OCT4. Our results suggest a novel, efficient approach to generate neural precursor cells that can be potentially used in drug discovery or regenerative medicine for neurological disease and injury. SIGNIFICANCE: This study describes a novel method to generate expandable induced neural stem cells from human cord blood cells in a feeder-free system by a single factor, OCT4. The data are promising for future applications that require the generation of large amounts of autologous neural stem cells in disease modeling and regenerative medicine.

Usefulness of two clinical chorioamnionitis definitions in predicting neonatal infectious outcomes: a systematic review.

OBJECTIVE: To assess the usefulness of two definitions of acute clinical chorioamnionitis (ACCA) in predicting risk of neonatal infectious outcomes (NIO) and mortality, the first definition requiring maternal fever alone (Fever), and the second requiring ≥ 1 Gibbs criterion besides fever (Fever + 1). STUDY DESIGN: PubMed, Web of Science, and the Cochrane Database of Systematic Reviews were searched from January 1, 1979 to April 9, 2013. Twelve studies were reviewed (of 316 articles identified): three studies with term patients, four with preterm premature rupture of membranes (PPROM) patients, and five mixed studies with mixed gestational ages and/or membrane status (intact and/or ruptured). RESULTS: Both definitions demonstrated an increased NIO risk for ACCA versus non-ACCA patients, with an odds ratio increase for the Fever + 1 definition that was about twofold larger than the Fever definition. CONCLUSION: As the Fever definition demonstrated increased NIO risk for ACCA versus non-ACCA patients, the Fever alone ACCA definition should be used to trigger future clinical treatment in many clinical situations.

Enhancing bone marrow regeneration by SALL4 protein.

Hematopoietic stem cells (HSCs) are widely used in transplantation therapy to treat a variety of blood diseases. The success of hematopoietic recovery is of high importance and closely related to the patient's morbidity and mortality after Hematopoietic stem cell transplantation (HSCT). We have previously shown that SALL4 is a potent stimulator for the expansion of human hematopoietic stem/progenitor cells in vitro. In these studies, we demonstrated that systemic administration with TAT-SALL4B resulted in expediting auto-reconstitution and inducing a 30-fold expansion of endogenous HSCs/HPCs in mice exposed to a high dose of irradiation. Most importantly, TAT-SALL4B treatment markedly prevented death in mice receiving lethal irradiation. Our studies also showed that TAT-SALL4B treatment was able to enhance both the short-term and long-term engraftment of human cord blood (CB) cells in NOD/SCID mice and the mechanism was likely related to the in vivo expansion of donor cells in a recipient. This robust expansion was required for the association of SALL4B with DNA methyltransferase complex, an epigenetic regulator critical in maintaining HSC pools and in normal lineage progression. Our results may provide a useful strategy to enhance hematopoietic recovery and reconstitution in cord blood transplantation with a recombinant TAT-SALL4B fusion protein.

Association of smoking with wound complications after cesarean delivery.

OBJECTIVE: To determine whether smoking is an independent risk factor for wound dehiscence after cesarean delivery. METHODS: In this case-control study, medical records were reviewed for all patients with wound dehiscence after cesarean delivery during a 7-month period. Wound dehiscence was defined as separation of wound edges requiring treatment. Three control patients without such complications were randomly selected for each case patient. Univariate associations were assessed using t test or Fisher's exact test; univariate odds ratios (OR) and 95% confidence intervals (CI) were calculated with logistic regression. Multivariate associations were assessed with logistic regression on variables with a univariate association significant at p ≤ 0.10. RESULTS: Of 597 cesarean deliveries, 30 cases (5 %) with wound dehiscence were identified. As individual variables, smoking (46.7 vs. 21.1%, p < 0.01, cases vs. controls), histological chorioamnionitis (27.6 vs. 6.7%, p < 0.01) and preoperative hematocrit (34.0 ± 3.2 vs. 35.4 ± 3.4, p < 0.05) were significantly associated with wound complications. In a multivariate logistic regression model, only smoking (OR 5.32; 95% CI 1.77-15.97, p < 0.01) and histological chorioamnionitis (OR 5.62; 95% CI 1.43-22.11, p < 0.01) were independently associated with wound dehiscence. CONCLUSIONS: Smoking and histological chorioamnionitis are independently associated with wound dehiscence after cesarean delivery.

High-resolution imaging diagnosis of human fetal membrane by three-dimensional optical coherence tomography.

Microscopic chorionic pseudocyst (MCP) arising in the chorion leave of the human fetal membrane (FM) is a clinical precursor for preeclampsia which may progress to fatal medical conditions (e.g., abortion) if left untreated. To examine the utility of three-dimensional (3D) optical coherence tomography (OCT) for noninvasive delineation of the morphology of human fetal membranes and early clinical detection of MCP, 60 human FM specimens were acquired from 10 different subjects undergoing term cesarean delivery for an ex vivo feasibility study. Our results showed that OCT was able to identify the four-layer architectures of human FMs consisting of high-scattering decidua vera (DV, average thickness d(DV) ≈ 92±38 µm), low-scattering chorion and trophoblast (CT, d(CT) ≈ 150±67 µm), high-scattering subepithelial amnion (A, d(A) ≈ 95±36 µm), and low-scattering epithelium (E, d(E) ≈ 29±8 µm). Importantly, 3D OCT was able to instantaneously detect MCPs (low scattering due to edema, fluid buildup, vasodilatation) and track (staging) their thicknesses d(MCP) ranging from 24 to 615 µm. It was also shown that high-frequency ultrasound was able to compliment OCT for detecting more advanced thicker MCPs (e.g., d(MCP)>615 µm) because of its increased imaging depth.

SALL4 is a robust stimulator for the expansion of hematopoietic stem cells.

HSCs are rare cells that have the unique ability to self-renew and differentiate into cells of all hematopoietic lineages. The lack of donors and current inability to rapidly and efficiently expand HSCs are roadblocks in the development of successful cell therapies. Thus, the challenge of ex vivo human HSC expansion remains a fertile and critically important area of investigation. Here, we show that either SALL4A- or SALL4B-transduced human HSCs obtained from the mobilized peripheral blood are capable of rapid and efficient expansion ex vivo by >10 000-fold for both CD34(+)/CD38(-) and CD34(+)/CD38(+) cells in the presence of appropriate cytokines. We found that these cells retained hematopoietic precursor cell immunophenotypes and morphology as well as normal in vitro or vivo potential for differentiation. The SALL4-mediated expansion was associated with enhanced stem cell engraftment and long-term repopulation capacity in vivo. Also, we demonstrated that constitutive expression of SALL4 inhibited granulocytic differentiation and permitted expansion of undifferentiated cells in 32D myeloid progenitors. Furthermore, a TAT-SALL4B fusion rapidly expanded CD34(+) cells, and it is thus feasible to translate this study into the clinical setting. Our findings provide a new avenue for investigating mechanisms of stem cell self-renewal and achieving clinically significant expansion of human HSCs.