Abstract: Morgagni hernia is an extremely rare form of congenital diaphragmatic hernia. Only 6 cases of this condition have been reported in the English literature, as diagnosed prenatally. The prognosis of the disease is determined by the severity of the pulmonary hypoplasia and associated anomalies. Here we report a case of Morgagni hernia with massive pericardial effusion diagnosed by ultrasonography and MRI during the second trimester, enabling planning of appropriate treatment in the pre- and perinatal periods.
Abstract: We report a case of a pregnant woman diagnosed as having vasa previa by magnetic resonance imaging (MRI). A parous woman was referred to our hospital at 31 weeks of gestation due to suspicion of placenta previa. Transvaginal ultrasound examination together with the Doppler techniques showed a fetal vessel on a lesion of low and high mixed echogenecities over the internal os, but could not confirm whether it was placental tissue or not. MRI demonstrated that it was not placenta but a hemorrhage between bilobed placentas and that the vessel was running over the internal os freely from the placenta. At 34 weeks of gestation, emergency cesarean section was performed due to increasing vaginal bleeding. MRI should be useful in the diagnosis of vasa previa when the relation between the position of the placenta and that of suspicious vessels cannot be adequately evaluated by ultrasound.
Abstract: BACKGROUND:
Pregnancy in patients with Parkinson disease is a rare occurrence. To the best of our knowledge, the effect of pregnancy as well as treatment in genetically confirmed autosomal recessive juvenile parkinsonism (ARJP) has never been reported. Here, we report the first case of pregnancy in a patient with ARJP associated with a parkin gene mutation, ARJP/PARK2.
CASE PRESENTATION:
A 27-year-old woman with ARJP/PARK2 was diagnosed as having a spontaneous dichorionic/diamniotic twin pregnancy. Exacerbation of motor disability was noted between ovulation and menstruation before pregnancy as well as during late pregnancy, suggesting that her parkinsonism might have been influenced by fluctuations in the levels of endogenous sex hormones. During the organogenesis period, she was only treated with levodopa/carbidopa, although she continued to receive inpatient hospital care for assistance in the activities of daily living. After the organogenesis period, she was administered sufficient amounts of antiparkinsonian drugs. She delivered healthy male twins, and psychomotor development of both the babies was normal at the age of 2 years.
CONCLUSION:
Pregnancy may worsen the symptoms of ARJP/PARK2, although appropriate treatments with antiparkinsonian drugs and adequate assistance in the activities of daily living might enable successful pregnancy and birth of healthy children.
Abstract: Objective: Our aim was to investigate the association between fetal growth and cerebrovascular resistance in fetuses with congenital heart disease (CHD). Methods: Fetal echocardiography was performed to measure the biparietal diameter, abdominal circumference, femur length, estimated fetal body weight, middle cerebral artery (MCA) resistance index (RI) and umbilical artery (UA) RI in 44 fetuses with CHD and 140 normal fetuses at a gestational age of 28–34 weeks. Results: Fetuses with CHD exhibited significantly lower values for femur length, estimated fetal body weight at the third trimester, body weight, length, and chest circumference at birth than normal controls. The percentages of fetuses showing MCA RI values <10th percentile and UA RI values >90th percentile were significantly higher in the CHD group than in the control group. However, there were no significant differences in any biometric parameters measured between cases with MCA RI values ≧10th percentile and values <10th percentile. Conclusions: Growth restriction and blood flow changes were observed significantly more frequently in fetuses with CHD than in those without CHD. Further studies are necessary to clarify the association between fetal growth and dynamic changes in fetal circulation.
Abstract: We present a case study of a patient with a congenital heart block associated with a left isomerism that was diagnosed during the 26th week of gestation. The mother had type 2 diabetes mellitus that was difficult to control during the early stages of the pregnancy. A fetal echocardiogram revealed an atrioventricular dissociation, with an atrial rate of 120 bpm and a ventricular rate of 55 bpm. Subsequent examinations also revealed a left isomerism in the fetus. To increase the fetal heart rate, a continuous intravenous infusion of ritodrine was administered. The fetal ventricular rate rapidly increased to 65 bpm. The pregnancy successfully continued until term and a female infant weighing 3,182 g was born via a cesarean section. A subsequent surgery was performed to provide the infant with a permanent cardiac pacemaker, and notably, the child is now 4 months of age and her growth has been within the normal range.
Abstract: We experienced a case with fetal cardiac tumor, which was diagnosed by prenatal ultrasonographic examination, and the diagnosis was confirmed after birth. A pregnancy woman of the 26th week of gestation was referred to our hospital for close examinations of fetal cardiac tumor. Ultrasonographic examinations revealed single homogeneous tumor with the diameter of 14mm intracardiac space. The tumor was considered to emerge from the ventricular septum and to be occupied in left ventricle. Other cardiac abnormalities were not detected. The fetus was diagnosed to be complicated with the intracardiac tumor, and with the possible rhabdomyoma of heart. The serial ultrasonographic examinations revealed that the fetal cardiac function was normal. The size of the tumor gradually increased, although the fetal cardiac function revealed within normal range. The patient delivered a female infant weighing 2716g with the Apgar score of 9 and 10 at one and 5 minutes after delivery. The infant was confirmed to have cardiac tumors after examination by pediatric cardiologist, and the cardiac function of the infant was diagnosed as normal condition. The computed tomography of the head revealed the intracranial multiple calcification lesions, which indicated the symptoms of tuberous sclerosis.
Abstract: Anti-human platelet-specific antigen (HPA) antibody often causes neonatal alloimmune thrombocytopenia (NAIT). The antibody is produced due to the feto-maternal transfusion of incompatible platelets. In this case study, anti-HPA-5b was detected in the serum of a 30-year-old female patient. Using blood or amniotic fluid, the patient’s HPA-5 phenotype was determined to be a+b-, whereas those of the husband, son and fetus were a+b+. From these findings, we concluded that there was an incompatibility of maternal and fetal HPA. Cordocentesis was performed at 34 weeks of gestation and the fetal platelet count was sufficient for vaginal delivery. A transfusion of HPA-matched platelet was prepared. The baby was delivered by vaginal delivery and there were no physical signs of thrombocytopenia.
Abstract: Gastric cancer associated with pregnancy is quite rare, and is most often diagnosed at an advanced stage. Furthermore, physicians are confronted with two conflicting issues in this condition: the need for early treatment of the maternal gastric cancer and the continuation of the pregnancy. To clarify the characteristics of pregnancy-associated gastric cancer and to obtain useful information that would help us choose the best treatment strategy for pregnancy-associated gastric cancer, we reviewed the existing literature, using the key words "pregnancy" and "gastric cancer". We were able to accumulate 136 cases, including 100 cases reported previously in Japan, and 1 case that we report here. We analyzed a total of 137 cases in the present study. With respect to the stage of gastric cancer, 92.5% of the patients studied had advanced gastric cancer, and only 45.3% of the patients underwent gastrectomy, including incomplete resection. Accordingly, the prognosis was very poor; the 1- and 2-year survival rates were 18.0% and 15.1%, respectively. However, the number of patients found to have early gastric cancer by endoscopic examination has been increasing recently. An endoscopic examination should be conducted immediately in pregnant patients presenting with persistent gastrointestinal symptoms for the differential diagnosis of hyperemesis gravidarum. When an endoscopic examination reveals that pregnant patients have gastric cancer, a therapeutic plan should be promptly formulated, in accordance with the number of weeks of gestation, by a medical team consisting of specialists in perinatal obstetrics and gastric cancer specialists.
Abstract: Several proangiogenic/proinflammatory factors involved in endometrial cancer are regulated by leptin, but the signaling mechanisms responsible for these leptin-induced actions are largely unknown. Here, we report that in benign (primary and HES) and cancerous-endometrial epithelial cells (EEC) (An3Ca, SK-UT2 and Ishikawa), leptin in a dose-dependent manner regulates vascular endothelial growth factor, (VEGF); interleukin-1 beta, (IL-1); leukemia inhibitory factor, (LIF) and their respective receptors, VEGFR2, IL-1R tI and LIFR. Remarkably, leptin induces a greater increase in VEGF/VEGFR2 and LIF levels in cancer than in benign cells. However, IL-1 was only increased by leptin in benign primary-EEC. Cancer-EEC expressed higher levels of leptin receptor (full-length OB-Rb and short isoforms) in contrast to benign primary-EEC. Leptin-mediated activation of JAK2 (janus kinase 2) was upstream to the activation of PI-3K (phosphatidylinositol-3 kinase) and/or MAPK (mitogen-activated protein kinase) signaling pathways. Leptin induction of cytokines/receptors generally involved JAK2 and MAPK activation, but PI-3K phosphorylation was required for leptin increase of LIF, IL-1/IL-1R tI. Leptin-mediated activation of mTOR (mammalian target of Rapamycin), mainly linked to MAPK, played a central role in leptin regulation of all cytokines and receptors. These results suggest that leptin's effects are cell-specific and could confer a proliferative or cell survival advantage or possibly promote endometrial thickness. Leptin's effects on proangiogenic molecules were more evident in malignant versus benign cells and may imply that there is an underlying shift in leptin-induced cell signaling pathways in endometrial cancer cells
Abstract: We performed transfection using cationic liposome. According to the gene expression level, lined cells were divided into two groups, high and low. Introduced gene was monitored with a confocal laser-scanning microscope. The percentages of the cells introduced gene reached more than 90% in all line. Then, introduced gene was stable in high group, while in low group, it significantly decreased. With lysosomotrophic agents, gene expression efficiency was significantly reduced. With colchicine, gene expression efficiency did not change in high group, but was significantly elevated in low group. A method of liposomal transfection could be effective, particularly in low group.
Abstract: The malignant transformation of mature cystic teratoma is rare, thus occurring in only 1–2% of all cases. The most common malignancy arising in mature cystic teratoma is squamous cell carcinoma. Adenocarcinoma occurs with less frequency. We herein present a patient with an ovarian mature cystic teratoma who demonstrated a malignant transformation to well-differentiated adenocarcinoma. Malignant transformation was diagnosed preoperatively by contrast enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Microscopically and immunohistochemically, the adenocarcinoma was considered to have arisen from the ciliated respiratory epithelium. After a 28-month of follow-up period, she remains free of the disease. This is the third reported case of adenocarcinoma arising in the respiratory epithelium of an ovarian mature cystic teratoma. Contrast enhanced CT and MRI are useful for making a preoperative diagnosis and an immunohistochemical study is helpful for defining its origin.
Abstract: Leptin, a 16-kDa cytokine, has been implicated in several reproductive processes and disorders. Notably, elevated leptin levels in the peritoneal fluid of women with mild endometriosis has been demonstrated, suggesting a role for this cytokine in the early stages of disease establishment. To gain insight into the functional significance of leptin during the initial requisite proliferative and neovascularization events involved in endometriosis, we investigated the effect of disruption of in vivo leptin signaling on the establishment and/or maintenance of an endometriosis-like lesion in a syngeneic immunocompetent mouse model of endometriosis. Findings of this study show that the disruption of leptin signaling by ip injection of the pegylated leptin peptide receptor antagonist (LPrA) impairs the establishment of endometriosis-like lesions (derived from uteri of C57BL/6 female siblings) and results in a reduction of viable organized glandular epithelium, vascular endothelial growth factor-A expression, and mitotic activity. LPrA treatment resulted in a significant reduction of microvascular density in endometriosis-like lesions after continuous and acute courses. Endometriosis-like lesions (derived from tissue with functional leptin receptor) of Lepr(db) hosts (nonfunctional leptin receptor) were phenotypically similar to those of LPrA-treated mice. Our results confirm that leptin signaling is a necessary component in lesion proliferation, early vascular recruitment, and maintenance of neoangiogenesis in a murine model of endometriosis.
Abstract: Cables 1, a cyclin-dependent kinase binding protein, is primarily involved in cell cycle regulation. Loss of nuclear Cables 1 expression is observed in human colon, lung and endometrial cancers. We previously reported that loss of nuclear Cables 1 expression was also observed with high frequency in a limited sample set of human ovarian carcinomas, although the mechanisms underlying loss of nuclear Cables 1 expression remained unknown. Our present objective was to examine Cables 1 expression in ovarian cancer in greater detail, and determine the predominant mechanisms of Cables 1 loss. We assessed potential genetic and epigenetic modifications of the Cables 1 locus through analyses of mutation, polymorphisms, loss of heterozygosity and DNA methylation. We observed a marked loss of nuclear Cables 1 expression in serous and endometrioid ovarian carcinomas that correlated with decreased Cables 1 mRNA levels. Although we detected no Cables 1 mutations, there was evidence of LOH at the Cables 1 locus and epigenetic modification of the Cables 1 promoter region in a subset of ovarian carcinomas and established cancer cell lines. From a functional perspective, over-expression of Cables 1 induced apoptosis, whereas, knockdown of Cables 1 negated this effect. Together these findings suggest that multiple mechanisms underlie the loss of Cables 1 expression in ovarian cancer cells, supporting the hypothesis that Cables 1 is a tumor suppressor in human ovarian cancer.
Abstract: To gain insight into the mechanism(s) by which leptin contributes to mammary tumor (MT) development we investigated the effects of leptin, kinase inhibitors, and/or leptin receptor antagonists (LPrA2) on 4T1 mouse mammary cancer cells in vitro and LPrA2 on 4T1-MT development in vivo. Leptin increases the expression of vascular endothelial growth factor (VEGF), its receptor (VEGF-R2), and cyclin D1 through phosphoinositide 3-kinase, Janus kinase 2/signal transducer and activator of transcription 3, and/or extracellular signal-activated kinase 1/2 signaling pathways. In contrast to leptin-induced levels of cyclin D1 the changes in VEGF or VEGF-R2 were more dependent on specific signaling pathways. Incubation of 4T1 cells with anti-VEGF-R2 antibody increased leptin-mediated VEGF expression suggesting an autocrine/paracrine loop. Pretreatment of syngeneic mice with LPrA2 prior to inoculation with 4T1 cells delayed the development and slowed the growth of MT (up to 90%) compared with controls. Serum VEGF levels and VEGF/VEGF-R2 expression in MT were significantly lower in mice treated with LPrA2. Interestingly, LPrA2-induced effects were more pronounced in vivo than in vitro suggesting paracrine actions in stromal, endothelial, and/or inflammatory cells that may impact the growth of MT. Although all the mechanism(s) by which leptin contributes to tumor development are unknown, it appears leptin stimulates an increase in cell numbers, and the expression of VEGF/VEGF-R2. Together, these results provide further evidence suggesting leptin is a MT growth-promoting factor. The inhibition of leptin signaling could serve as a potential adjuvant therapy for treatment of breast cancer and/or provide a new target for the designing strategies to prevent MT development.
Abstract: Advanced peritoneal carcinomatoses is very difficult to treat. We have explored the potential therapeutic application of gene therapy using cationic liposomes in this disease. The lacZ gene was introduced in vitro into ovarian and endometrial cancer cells using cationic liposomes. The transfection efficiency was similar to that of commercially available liposomes in serum-free medium (11.0-20.9% vs. 5.4-26.0%). In serum-containing medium, the efficiency was 1.9-18.1%, which is comparable with the efficiency in serum-free medium. However, the efficiency of commercial liposomes decreased drastically to between 0.1% and 4.7% in the serum-containing medium. When cultured cells were transfected with the herpes simplex virus thymidine kinase (HSV-tk) gene and ganciclovir (GCV) was added, the anti-tumor effect of GCV was 47-640 times greater than when the same experiment was performed with lacZ gene. Evaluation of anti-tumor effect was performed with the MTT assay. In vivo, the HRA and mEIIL ascitic mice were treated with HSV-tk gene and GCV using the peritoneal route, a significant prolongation of the mean survival time was observed by Kaplan-Meier analysis (16-18 days and 15-30 days, respectively, p < 0.05). These results indicate a potential role for gene therapy in the treatment of advanced intraperitoneal carcinomatoses using the novel cationic liposomes.
Abstract: PURPOSE: To maintain in vitro granulosa cell function by adenoviral-mediated FSHR gene transduction. METHODS: Rat granulosa cells were cultured and transduced with adenovirus carrying FSHR gene. The number of receptors and the rate of steroidogenesis were assessed. RESULTS: The number of FSHR on the granulosa cells was 4,874 per cell immediately after extraction, it was 2,176 by the third day, and had further reduced to 693 by the seventh day. On the third day of culture, the amount of production of estradiol by FSH stimulation also decreased to about one-quarter of the first day's quantity. Compared to the untransduced granulose cells, when the cells contained FSHR gene, the FSHR expression and steroidogenesis were both enhanced (2,176 vs. 7,206 per cell (p<0.001) and 192 vs. 5940 pg/mL (p<0.01), respectively). CONCLUSION: Granulosa cell functions can be maintained or increased by novel gene therapy. This can be a useful component of assisted reproductive therapy.
Abstract: AIM: Because of its effectiveness against many gynecologic malignancies, chemotherapy including cisplatin is mainly used as the first-line chemotherapy for epithelium ovarian cancer. However, one of the major problems that is well recognized is that tumor cells can easily acquire resistance to cisplatin. Various trials were carried out in order to establish treatment against cisplatin-resistant tumor cells. METHOD: Using both in vivo and in vitro studies, we examined whether or not the newly developed liposome could be used to demonstrate sufficient transfection activity as the anticancer reagent for cisplatin-resistant tumor cells. RESULT: With our newly developed liposome, GTE 319 and GTE 321, the lac-Z gene was more efficiently transfected in cisplatin-resistant variant cells, mEIIL-R, KF-ra and KF-rb, than in parental cells, mEIIL and KF, using X-gal staining. In cytotoxic assay, transfection of herpes simplex thymidine kinase (HSV-tk) gene conjugated with GTE319 or GTE 321, and cultivation with aciclovir for 5 days revealed accelerated tumor-inhibition activity in all of the cisplatin-resistant tumor cells compared with that in the naive parental cells. In addition, the high anti-tumor effect was obtained from intratumoral local injection of the tk gene conjugated with GTE-321 liposome following aciclovir administration against KF-rb-transplanted tumor formed in nude mouse hypodermic. CONCLUSION: These results suggest that gene therapy using a newly developed liposome-conjugated suicide gene can be an attractive approach for treatment against cisplatin-resistant ovarian cancer cells.
Abstract: Cationic liposomes are useful to transfer genes into eukaryotic cells in vitro and in vivo. However, liposomes with good transfection efficiency are often cytotoxic, and also require serum-free conditions for optimal activity. In this report, we describe a new formulation of cationic liposome containing DC-6-14, O,O'-ditetradecanoyl-N-(alpha-trimethylammonioacetyl)diethan olamine chloride, dioleoylphosphatidylethanolamine and cholesterol for gene delivery into cultured human cells. This liposome, dispersed in 5% serum-containing growth medium, efficiently delivered a plasmid DNA for GFP (green fluorescent protein) into more than 80% of the cultured human cell hybrids derived from HeLa cells and normal fibroblasts. Flow cytometric analysis revealed that the efficiency of the GFP gene expression was 40-50% in a tumor-suppressed cell hybrid, while it was greatly reduced in the tumorigenic counterpart. The enhanced GFP expression in tumor-suppressed cell hybrids was quantitatively well correlated with a prolonged presence of the plasmid DNA, which had been labeled with another fluorescent probe, ethidium monoazide, within the cells. These results suggest that a newly developed cationic liposome is useful for gene delivery in serum-containing medium into human cells and the stability of the plasmid DNA inside the cell is a crucial step in this liposome-mediated gene expression. The mechanisms by which cationic liposome mediates gene transfer into eukaryotic cells are also discussed.
Abstract: Development of more reliable liposomal formulations and preparation methods which can be used for gene therapy instead of commonly used viral vectors is expected. We have already developed the freeze-dried empty (non-drug-containing) liposomes (FDEL) method for mass-production of liposomal products. After these freeze-dried empty liposomes are rehydrated with aqueous drug solutions, many kinds of drugs can be encapsulated highly efficiently, and particle size can be controlled well. This study evaluated the usefulness of this FDEL method for preparation of liposomes containing DNA with a particular attention to the stability of DNA. When the liposomes were prepared by the conventional lipid-film method on a relatively large scale with use of a Potter-homogenizer (a teflon homogenizer), significant degradation and conformational change of DNA was observed during homogenization. Loss of DNA was also significant after extrusion for sizing and sterilization; residual DNA in the final preparation was hardly detected. When the FDEL method was used, on the other hand, no degradation, conformational change or loss of DNA was observed, and particle size was easily controlled. Moreover, there was no significant difference in luciferase activity between the lipid-film method used on a small scale with use of a vortex mixer and the FDEL method after transfection of tumor cells (HRA, HEC-1A and Colo320DM) by the liposomes containing DNA (PGV-C). These findings suggest that the FDEL method is very useful for preparation of liposomes containing DNA.
Abstract: A novel series of cationic lipids has been found, by in vivo screening, to be effective for gene transfer into peritoneal disseminated tumor. O,O'-Ditetradecanoyl-N-(alpha-trimethylammonioacetyl)diethan olamine chloride (DC-6-14), having dimyristyl acid, has shown the highest transfection activity in vitro, provided that 10% fetal bovine serum is present. To enhance the transfection efficiency of DC-6-14, we added dioleoylphosphatidylethanolamine (DOPE) and/or cholesterol (Chol) as helper lipids in various ratios. Cationic liposomes containing DC-6-14, DOPE, and Chol in molar ratios of 1:0.75:0.75 and 1:1:0.8 maintained efficient transfection activity under serum-containing conditions in HRA, mEIIL, and ES-2 cell lines in vitro, as determined by luciferase assay. With our novel liposomes, transfection efficiencies were higher in cells proliferating faster than in cells proliferating slower, depending on mitotic activity as represented by labeling index. In the mEIIL peritoneal disseminated tumor model, cancer cells were specifically transfected with the lacZ gene. Gene transfer was observed by X-Gal staining not only in floating cancer cells in the ascites, but also in the peritoneal disseminated cancer tissue. The percentage of LacZ-positive cells was about 1%, which was significantly higher than with commercially available Lipofectin (0.38%), LipofectACE (0.62%), or LipofectAMINE (0.23%). In the mEIIL peritoneal disseminated tumor-nude mouse model, herpes simplex thymidine kinase gene (HSV tk) transfer with our novel liposomes, followed by ganciclovir (GCV) treatment, resulted in significantly longer survival compared with control mice (p < 0.05, Cox-Mantel). These results suggest that these liposomes show promise as tools in gene therapy for patients with intraperitoneal disseminated cancer.
Abstract: Granisetron (G) is an effective antiemetic drug that is used to prevent cisplatin-induced emesis, although it is less effective for delayed emesis. To enhance the antiemetic effects of granisetron, corticosteroid analogues such as methylprednisolone (M) and dexamethasone (D) were employed in a study of patients treated with cisplatin (CDDP). We investigated the clinical response and urinary excretion of 5-hydroxyindole acetic acid (5-HIAA), the main metabolite of serotonin, in 31 patients with ovarian cancer or uterine endometrial cancer who received CAP therapy (CDDP 75 mg/m2) in a 3-day cross-over trial comparing G + M and G + D treated patients. Both regimens were and delayed emesis than G + D. We conclude that G + D is a more efficacious combination than G + D in protecting patients from CDDP-induced acute and delayed emesis.
