Long-Term Tocolysis With Magnesium Sulfate as a Risk Factor for Low Bone Mass: A Case Series.

Pregnancy and lactation-associated osteoporosis (PLO) is a disease caused by vertebral compression fracture, and it is characterized by low back pain during pregnancy or the postpartum period. However, it is difficult to predict and prevent PLO prepartum in high-risk groups. Recently, long-term tocolysis with magnesium sulfate (MgSO4) has been reported to be associated with PLO. The purpose of this case series was to assess postpartum bone mass after long-term tocolysis with MgSO4 and accumulated doses of MgSO4. We report the case of a pregnant woman with vertebral compression fractures during pregnancy following long-term tocolysis with MgSO4. We investigated whether long-term tocolysis with MgSO4 was a high risk factor for PLO. Therefore, we retrospectively evaluated bone mineral density after delivery in nine women who had long-term tocolysis with MgSO4 (more than 8 days) for treatment of threatened preterm birth at our hospital from January 2020 to December 2020. The age of the women was between 20 and 41 years (mean age, 30 years). The body mass index of the women was between 18.1 and 25.4 kg/m2 (mean 20.0 kg/m2). Three women had a positive smoking history, and none had a family history of osteoporosis. The average duration of tocolysis with MgSO4 was 11 - 97 days. The accumulated doses of MgSO4 were between 168 and 3,756 g. Four of nine cases were diagnosed with low bone mass of young adult mean (YAM) value ≤ 80%. Of them, one case (accumulated doses of MgSO4: 1,260 g) was diagnosed with PLO of YAM value ≤ 70%, and one case (accumulated doses of MgSO4: 3,756 g) was diagnosed with bone fracture with a YAM value of ≤ 70%. Long-term tocolysis with MgSO4 may be suggested as one of the risk factors of PLO. Nutritional guidance and rehabilitation are important interventions for target patients.

MIRAGE syndrome caused by a novel missense variant (p.Ala1479Ser) in the SAMD9 gene.

MIRAGE syndrome is a recently identified disorder characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. It is caused by a gain-of-function variant in the SAMD9 gene, but there is limited knowledge regarding the genotype-phenotype correlation. We herein report a Japanese patient with MIRAGE syndrome carrying a novel de novo heterozygous missense variant in the SAMD9 gene (c.4435 G > T; p.Ala1479Ser).

Efficient and accurate homologous recombination in hESCs and hiPSCs using helper-dependent adenoviral vectors.

Low efficiencies of gene targeting via homologous recombination (HR) have limited basic research and applications using human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Here, we show highly and equally efficient gene knockout and knock-in at both transcriptionally active (HPRT1, KU80, LIG1, LIG3) and inactive (HB9) loci in these cells using high-capacity helper-dependent adenoviral vectors (HDAdVs). Without the necessity of introducing artificial DNA double-strand breaks, 7-81% of drug-resistant colonies were gene-targeted by accurate HR, which were not accompanied with additional ectopic integrations. Even at the motor neuron-specific HB9 locus, the enhanced green fluorescent protein (EGFP) gene was accurately knocked in in 23-57% of drug-resistant colonies. In these clones, induced differentiation into the HB9-positive motor neuron correlated with EGFP expression. Furthermore, HDAdV infection had no detectable adverse effects on the undifferentiated state and pluripotency of hESCs and hiPSCs. These results suggest that HDAdV is one of the best methods for efficient and accurate gene targeting in hESCs and hiPSCs and might be especially useful for therapeutic applications.

Parvovirus B19-associated hemophagocytic lymphohistiocytosis in a child with precursor B-cell acute lymphoblastic leukemia under maintenance chemotherapy.

Development of hemophagocytic lymphohistiocytosis (HLH) is quite rare among acute lymphoblastic leukemia (ALL) patients. We present a 3-year-old boy with precursor B-cell ALL, who was complicated by HLH because of parvovirus B19 infection during maintenance chemotherapy. Remarkable erythroid hypoplasia, giant normoblasts, and hemophagocytosed macrophages in bone marrow were important clues for the diagnosis. The patient was successfully treated with high-dose steroids and intravenous immunoglobulins. To our knowledge, this is the first report describing parvovirus B19-associated HLH in ALL. Our case highlights that parvovirus B19 can cause HLH, a potentially fatal disorder, and prolonged unexpected cytopenia in childhood ALL.

Spinal cord compression by epidural involvement over 21 vertebral levels in acute lymphoblastic leukemia.

Spinal cord compression is a rare complication of acute lymphoblastic leukemia (ALL). We report a 13-year-old boy with B-precursor ALL, presenting with restriction of breathing and back pain. Cerebrospinal fluid examination showed extremely high protein levels. Radiologic examination indicated that leukemia extended from the thoracic to sacral epidural spaces over 21 vertebral lengths in a band-shaped form, threatening to induce compressive spinal cord neuropathy. Prompt initiation of systemic chemotherapy relieved the obstruction of cerebrospinal fluid flow without local irradiation or surgical intervention. To our knowledge, this patient has shown the most extensive epidural involvement among ALL patients previously reported.

Vascular endothelial growth factor directly inhibits primitive neural stem cell survival but promotes definitive neural stem cell survival.

There are two types of neural stem cells (NSCs). Primitive NSCs [leukemia inhibitory factor (LIF) dependent but exogenous fibroblast growth factor (FGF) 2 independent] can be derived from mouse embryonic stem (ES) cells in vitro and from embryonic day 5.5 (E5.5) to E7.5 epiblast and E7.5-E8.5 neuroectoderm in vivo. Definitive NSCs (LIF independent but FGF2 dependent) first appear in the E8.5 neural plate and persist throughout life. Primitive NSCs give rise to definitive NSCs. Loss and gain of functions were used to study the role of vascular endothelial growth factor (VEGF)-A and its receptor, Flk1, in NSCs. The numbers of Flk1 knock-out mice embryo-derived and ES cell-derived primitive NSCs were increased because of the enhanced survival of primitive NSCs. In contrast, neural precursor-specific, Flk1 conditional knock-out mice-derived, definitive NSCs numbers were decreased because of the enhanced cell death of definitive NSCs. These effects were not observed in cells lacking Flt1, another VEGF receptor. In addition, the cell death stimulated by VEGF-A of primitive NSC and the cell survival stimulated by VEGF-A of definitive NSC were blocked by Flk1/Fc-soluble receptors and VEGF-A function-blocking antibodies. These VEGF-A phenotypes also were blocked by inhibition of the downstream effector nuclear factor kappaB (NF-kappaB). Thus, both the cell death of primitive NSC and the cell survival of definitive NSC induced by VEGF-A stimulation are mediated by bifunctional NF-kappaB effects. In conclusion, VEGF-A function through Flk1 mediates survival (and not proliferative or fate change) effects on NSCs, specifically.