PCSK9 inhibitor use during pregnancy in a case of familial hypercholesterolemia complicated with coronary artery disease.

Limited data have been reported on the use of proprotein convertase subtilisin/kexin type 9 (PCSK 9) inhibitors during pregnancy in women with familial hypercholesterolemia (FH). Here, we present the first case of initiating evolocumab (PCSK9 inhibitor) in a compound heterozygous FH mother. The patient was a 34-year-old primipara with severe dyslipidemia and a history of coronary artery bypass surgery. An elevated low-density lipoprotein cholesterol (LDL-C) level of 420 mg/dL was detected in the first trimester and persistently increased throughout pregnancy. Evolocumab was administered at 31 and 35 weeks of gestation, showing a positive effect on stabilizing LDL-C levels. Planned delivery with labor analgesia was performed at 38 + 4 weeks. Both the mother and infant were discharged without any notable complications. Hence, evolocumab, an IgG2 monochromatic antibody with little placental permeability, may be an alternative medication with limited influence on infants. Further studies are needed to assess the safety of evolocumab administration during pregnancy.

Pregnancy outcomes in female childhood cancer survivors: Nationwide survey in Japan.

BACKGROUND: The aim of this study was to investigate the outcomes of pregnancy in female childhood cancer survivors (CCS) in Japan, to encourage greater attention to the reproductive health of CCS. METHODS: This was a retrospective nationwide questionnaire survey of delivery at ≥22 weeks of gestation in CCS at perinatal centers registered with the Japanese Perinatologists Association between 2010 and 2014. We evaluated the maternal characteristics, pregnancy and neonatal outcomes and the relationship between cancer treatment and these outcomes. RESULTS: The total number of CCS was 61, and the total number of deliveries was 71, corresponding to 0.019% of total deliveries. Regarding cancer, 46% of the patients had had leukemia. Epilepsy was seen in seven (11%). Mean gestational age at delivery was 37.9 weeks. The rate of preterm delivery was 24%. Mean birthweight was 2,718 g. There were three congenital anomalies (4.2%). The rate of preterm delivery was higher and mean birthweight lower in the women treated with radiotherapy than in those without radiotherapy (42% vs 16%, P = 0.025; 2,436 ± 737 g vs 2,827 ± 483 g, P = 0.010). The adjusted OR of radiotherapy for preterm deliveries was 3.53 (P = 0.049). CONCLUSIONS: Although the number of deliveries by CCS was low in Japan, the pregnancy outcomes were favorable. The important points for managing pregnancy in CCS were preterm delivery as an obstetric complication, especially in CCS who had been treated with radiotherapy, and epilepsy as a maternal complication, which may be related to previously received treatment.

Clinical manifestation of a calyceal diverticular abscess in a pregnant woman.

Calyceal diverticula are congenital, nonsecretory abnormalities in which the transitional cell-lined cavity communicates with the renal collecting system. Here we present the case of a calyceal diverticular abscess during pregnancy. A 40-year-old primiparous woman developed the abscess at 23 weeks of gestation, with right flank pain and a 37.8°C fever. A transabdominal ultrasound revealed a 12 × 10 cm cystic mass in the right kidney. She was initially diagnosed with a simple renal cyst infection, and intravenous antibiotics were initiated. Percutaneous drainage was started at 26 weeks of gestation. When urine excretion from the cyst was confirmed by dye test using indigotindisulfonate sodium, the patient was diagnosed with a calyceal diverticular abscess. She gave birth to a 2,870 g healthy male at 38 weeks of gestation. Percutaneous drainage with low-dose antimicrobial therapy could thus allow for the continued pregnancy of women with a calyceal diverticular abscess until full term.

The anti-phospholipid antibody-dependent and independent effects of periodontopathic bacteria on threatened preterm labor and preterm birth.

PURPOSE: Periodontal disease is considered to be a risk factor for threatened preterm labor (TPL) and preterm birth (PB), but pathogenic mechanisms have not yet been elucidated. We hypothesized that infection with periodontopathic bacteria may enhance thrombosis through molecular mimicry with TLRVYK peptides on beta-2 glycoprotein I, a target molecule in anti-phospholipid syndrome. This study aimed to examine the effects of periodontitis on TPL and PB. METHODS: Ninety-five pregnant women (47 TPL and 48 healthy subjects) participated. Periodontal clinical parameters and periodontopathic bacteria were examined. Molecular mimicry between TLRVYK peptides and homologous peptides on the periodontopathic bacteria was examined by enzyme-linked immunosorbent assay (ELISA) using rabbit polyclonal antibodies specific for the respective peptides (SIRVYK on Aggregatibacter actinomycetemcomitans, TLRIYT on Porphyromonus gingivalis, and TLALYK on Treponema denticola). Serum high-sensitivity C-reactive protein, anti-TLRVYK and anti-SIRVYK IgG antibodies were measured using ELISA. RESULTS: Among the rabbit antibodies specific for the bacterial homologous peptides, only anti-SIRVYK IgG antibody reacted with TLRVYK peptides. Multivariable analysis showed that anti-SIRVYK IgG antibody was significantly associated with diagnosis of TPL. Of 95 births, 14 (14.7 %) delivered preterm. The preterm birth rate was higher in the anti-SIRVYK IgG antibody >median group than in the ≤median group. Of the 47 TPL subjects 13 had PB, and ordinal logistic regression analysis revealed that past smoking, presence of P. gingivalis and anti-SIRVYK IgG antibody were significantly correlated with PB. CONCLUSIONS: Infection with P. gingivalis and the antibody response to SIRVYK might be associated with TPL and PB.

Acute loss of DP1, but not DP2, induces p53 mRNA and augments p21Waf1/Cip1 and senescence.

The transcription factors DP1 and DP2 have been implicated in crucial gene regulation as heterodimer partners of E2F; however, the functional differences between DP1 and DP2 remain poorly understood. To gain insight into DPs in human somatic cells, we first suppressed endogenous DP1 and DP2 using RNA interference and examined the effect of their loss on gene expression changes in HeLa cervical cancer cells. A DNA microarray and gene pathway analysis revealed that the suppression of well-known E2F/DP-regulated pathways, including the G1 to S phase transition of the cell cycle and DNA replication, was manifested in accordance with the acute loss of DP1 and DP2. On the other hand, the acute loss of DP1 and DP2 increased the p21Waf1/Cip1 mRNA level compared with the control RNA treatment. We further showed that the inactivation of DP1, but not DP2, resulted in mRNA induction for p53, an upstream regulator of p21Waf1/Cip1. Furthermore, in A549 lung cancer cells as well as HeLa cells, the mRNA and protein levels of p53 and p21Waf1/Cip1 were stabilized specifically upon DP1 depletion, whereas p53-regulated apoptotic factor BAX mRNA was unchanged. Finally, the impairment of DP1, but not DP2, increased senescence in HeLa, A549 and WI-38 diploid fibroblasts but not in p53 null Saos-2 osteosarcoma cells. Taken together, these results suggest that DP1, but not DP2, is uniquely involved in the regulation of the p53 and p21Waf1/Cip1 pathway, thereby augmenting senescence in human somatic cells.

Enforced expression of the transcription factor HOXD3 under the control of the Wnt1 regulatory element modulates cell adhesion properties in the developing mouse neural tube.

HOX genes expressed in a specific spatial and temporal manner play a crucial role in determining the body plan during the early development of vertebrates. In adult tissues, many HOX genes participate in normal hematopoiesis and carcinogenesis. We previously found that overexpression of the homeobox gene HOXD3 alters expression levels of cell adhesion molecules in human cancer cell lines. Here, we have investigated whether HOXD3 expression is related to the cell adhesion processes during mouse development focusing on dorsal midline cells or roof-plate cells of the neural tube and neural crest cells. We created transgenic mouse embryos, in which HOXD3 is expressed in the dorsal midline under the control of the Wnt1 regulatory element, and analyzed these embryos at embryonic day 10.5-13.5. In HOXD3-expressing transgenic embryos, although neural crest-derived structures in the trunk region appeared to be normal, striking abnormalities were found in the neural tube. In transgenic embryos expressing the lacZ gene under the control of the Wnt1 regulatory element, expression of lacZ was restricted to roof-plate cells within the neural tube. By contrast, in HOXD3-expressing transgenic embryos, expression of HOXD3 was not only located in the dorsal neural tube, but also had spread inside the ventricular zone in more ventral regions of the neural tube. These findings show that the HOXD3 transgene is expressed more broadly than the Wnt1 gene is normally expressed. Expression of both Wnt1 and Msx1, marker genes in the roof plate, was further extended ventrally in HOXD3-expressing embryos than in normal embryos, suggesting that expression of the HOXD3 transgene expands the roof plate ventrally within the neural tube. In the ventricular zone of HOXD3-expressing embryos at embryonic day 10.5, we observed an increase in the number of mitotic cells and failure of interkinetic nuclear migration of progenitor cells. Furthermore, in HOXD3-expressing embryos at embryonic day 12.5, the ventricular zone, in which progenitor cells became more loosely connected to each other, was composed of a large number of cells that did not express N-cadherin. Our results indicate that expression of HOXD3 is closely associated with modulation of cell-adhesive properties during embryonic development.

Multiple organ dysfunction in congenital murine toxoplasmosis.

Infection of gravid Nya: NYLAR (NYLAR), C57BL/6J (C57), and BALB/c mice with Toxoplasma gondii, on gestation day 7, resulted in fetal resorptions, abortions, and stillbirths. Fetal wastage (estimated) was 35 and 40% in the NYLAR and C57 strains and 55% in the BALB/c strain. Postnatally, pups were cachectic and growth-retarded, with some developing hind limb weakness, petechial lesions on ears and tail, and a blood-tinged nasal exudate. Only 13 of 97 BALB/c pups, 14 of 41 C57 pups, and 46 of 153 NYLAR pups survived the first month of life. At necropsy, swollen, blotched livers, enlarged spleens, pallid kidneys and pulmonary hemorrhages were observed. Cysts of T. gondii were detected in every pup, via press-smears of brain. Histologic examination revealed mineralizing cavitations, ventricular deformations, and periventricular edema in the central nervous system; extensive liver pathology marked by hepatocellular necrosis and calcification, sinusoidal dilatation, and giant cell granulomas; congestion of the spleen with blurring of red and white compartments and cavitations in the white pulp; and tubule and glomerular necrosis and calcification in the kidney. The pulmonary hemorrhages and dermal petechial lesions may reflect a bleeding diathesis due to hepatic insufficiency. The pathogenesis of congenital toxoplasmosis, in the 3 strains of mice, appears due to microvascular dysfunction characterized by dysregulation of hemostasis, perfusion failure, and multiple organ dysfunction, rather than to parasite-mediated cytopathology. We suggest that hematogenous dissemination and endothelial invasion by the parasite induced a systemic inflammatory response syndrome (i.e; toxoplasmic sepsis) leading to the microvascular dysfunction.