Neural circuit repair after central nervous system injury.

Central nervous system injury often causes lifelong impairment of neural function, because the regenerative ability of axons is limited, making a sharp contrast to the successful regeneration that is seen in the peripheral nervous system. Nevertheless, partial functional recovery is observed, because axonal branches of damaged or undamaged neurons sprout and form novel relaying circuits. Using a lot of animal models such as the spinal cord injury model or the optic nerve injury model, previous studies have identified many factors that promote or inhibit axonal regeneration or sprouting. Molecules in the myelin such as myelin-associated glycoprotein, Nogo-A or oligodendrocyte-myelin glycoprotein, or molecules found in the glial scar such as chondroitin sulfate proteoglycans, activate Ras homolog A (RhoA) signaling, which leads to the collapse of the growth cone and inhibit axonal regeneration. By contrast, axonal regeneration programs can be activated by many molecules such as regeneration-associated transcription factors, cyclic AMP, neurotrophic factors, growth factors, mechanistic target of rapamycin or immune-related molecules. Axonal sprouting and axonal regeneration largely share these mechanisms. For functional recovery, appropriate pruning or suppressing of aberrant sprouting are also important. In contrast to adults, neonates show much higher sprouting ability. Specific cell types, various mouse strains and different species show higher regenerative ability. Studies focusing on these models also identified a lot of molecules that affect the regenerative ability. A deeper understanding of the mechanisms of neural circuit repair will lead to the development of better therapeutic approaches for central nervous system injury.

Comparison of gene expression profile of the spinal cord of sprouting-capable neonatal and sprouting-incapable adult mice.

BACKGROUND: The regenerative ability of severed axons in the central nervous system is limited in mammals. However, after central nervous system injury, neural function is partially recovered by the formation of a compensatory neural circuit. In a mouse pyramidotomy model, axonal sprouting of the intact side of the corticospinal tract is observed in the spinal cord, and the axons make new synapses with the denervated side of propriospinal neurons. Moreover, this sprouting ability is enhanced in neonatal mice compared to that in adult mice. Myelin-associated molecules in the spinal cord or intrinsic factors in corticospinal neurons have been investigated in previous studies, but the factors that determine elevated sprouting ability in neonatal mice are not fully understood. Further, in the early phase after pyramidotomy, glial responses are observed in the spinal cord. To elucidate the basal difference in the spinal cord, we compared gene expression profiles of entire C4-7 cervical cord tissues between neonatal (injured at postnatal day 7) and adult (injured at 8 weeks of age) mice by RNA-sequencing. We also tried to identify discordant gene expression changes that might inhibit axonal sprouting in adult mice at the early phase (3 days) after pyramidotomy. RESULTS: A comparison of neonatal and adult sham groups revealed remarkable basal differences in the spinal cord, such as active neural circuit formation, cell proliferation, the development of myelination, and an immature immune system in neonatal mice compared to that observed in adult mice. Some inflammation-related genes were selectively expressed in adult mice after pyramidotomy, implying the possibility that these genes might be related to the low sprouting ability in adult mice. CONCLUSIONS: This study provides useful information regarding the basal difference between neonatal and adult spinal cords and the possible differential response after pyramidotomy, both of which are necessary to understand why sprouting ability is increased in neonatal mice compared to that in adult mice.

Case of uterine rupture after multiple intrauterine operations and uterine artery embolization.

Uterine rupture is rare but may result in both maternal and fetal death. The factors involved in such deaths depend on each case, but uterine artery embolization (UAE), the common treatment for hemorrhage, is possibly one factor. UAE may be related to uterine rupture or placenta accreta, but few data exist regarding UAE and uterine rupture. Here, we present a case of uterine rupture associated with placenta accreta that occurred after UAE. The case is a 35-year-old woman who became pregnant after undergoing UAE because of treatment for placental polyps twice. She underwent emergency cesarean delivery for uterine rupture. At the same time, she underwent hysterectomy because of placenta accreta. The uterus ruptured at the location where the polyp had emerged previously. Therefore, we present a case where UAE, uterine rupture and placenta accreta are possibly associated, and highlight the need for caution when performing UAE multiple times.

Chorioamnionitis caused by Staphylococcus aureus with intact membranes in a term pregnancy: A case of maternal and fetal septic shock.

Chorioamnionitis is usually caused by migration of cervicovaginal flora through the cervical canal in women with ruptured membranes. Common causative pathogens are genital mycoplasmas, anaerobes, enteric gram-negative bacilli, and group B streptococcus. There have been only seven previous reports of chorioamnionitis due to Staphylococcus aureus and their clinical courses are characterized by rapid disease progression and poor prognosis. This case report describes a case of acute chorioamnionitis due to S. aureus, which was successfully managed with immediate cesarean section and postoperative intensive care. A 22-year-old woman presented at 39 weeks' gestation with a fever and acute lower abdominal pain. Fetal heart monitoring showed fetal distress. Immediate cesarean delivery was performed under general anesthesia. A male infant weighing 2450 g was born. He had Apgar scores of 3 and 7 at 1 and 5 min, respectively. He was immediately intubated and admitted to the neonatal intensive care unit. Maternal blood culture, vaginal culture, neonatal nares, and blood and gastric fluid culture all showed methicillin-sensitive S. aureus. Histopathology of the placenta demonstrated focal acute funisitis and acute chorioamnionitis. Interestingly, most of the patients in the previous reports developed chorioamnionitis due to S. aureus despite the presence of intact membranes, as in our case. Bacterial spread in the absence of membrane rupture and the presence of bacteremia suggests hematogenous, rather than ascending, etiology of S. aureus chorioamnionitis.

Laparoscopic bilateral salpingo-oophorectomy for recurrent ovarian endometriotic cysts in a woman taking adjuvant tamoxifen for breast cancer: A case report.

The case report describes the management of endometriotic cysts in a woman taking adjuvant tamoxifen. A diagnosis of endometriosis was made at the age of 38, and the condition was initially managed with a low-dose estrogen-progestogen combination; the patient then switched to dienogest at the age of 45. Following a diagnosis of breast cancer at the age of 46, dienogest was stopped and adjuvant tamoxifen treatment started. After 4 months the patient was diagnosed with bilateral ovarian cysts and underwent laparoscopic bilateral salpingo-oophorectomy. Endometriosis was diagnosed in both ovaries on histopathological examination. This case report describes progression of endometriosis in a tamoxifen user.

Peritonitis caused by Mycoplasma hominis after laparoscopic total hysterectomy: A case report.

Infections after obstetric and gynecologic surgery are commonly caused by enterobacteria, commensal vaginal bacteria, or indigenous skin bacteria (primarily Staphylococcus aureus and Streptococcus). Mycoplasma hominis (M. hominis) rarely causes postoperative infection in the field of obstetrics and gynecology and its treatment is generally delayed. This report describes a case report of peritonitis caused by M. hominis after laparoscopic total hysterectomy. A 44-year-old patient (gravida 1, para 1) presented with heavy menstrual bleeding and severe anemia. She was diagnosed as having multiple uterine fibroids and bilateral endometriomas and underwent laparoscopic surgery. She subsequently developed postoperative peritonitis due to M. hominis. This microorganism was identified in the postoperative cultures of the vaginal discharge and the transvaginal drainage fluid by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The patient was treated successfully with the appropriate antimicrobial agents. It is important to consider M. hominis infection when gynecological postoperative infection persists despite treatment with beta-lactam antibiotics, and no causative organisms are identified by Gram staining.

Utilization of ethanolamine phosphate phospholyase as a unique astrocytic marker.

Astrocytes play diverse roles in the central nervous system (CNS) in both physiological and pathological conditions. Previous studies have identified many markers of astrocytes to analyze their complicated roles. Recently, closure of the critical period by mature astrocytes has been revealed, and the need for finding mature astrocyte-specific markers has been growing. We previously found that Ethanolamine phosphate phospholyase (Etnppl) was almost not expressed in the developing neonatal spinal cord, and its expression level slightly decreased after pyramidotomy in adult mice, which showed weak axonal sprouting, suggesting that its expression level negatively correlates with axonal elongation. Although the expression of Etnppl in astrocytes in adult is known, its utility as an astrocytic marker has not yet been investigated in detail. Here, we showed that Etnppl was selectively expressed in astrocytes in adult. Re-analyses using published RNA-sequencing datasets revealed changes in Etnppl expression in spinal cord injury, stroke, or systemic inflammation models. We produced high-quality monoclonal antibodies against ETNPPL and characterized ETNPPL localization in neonatal and adult mice. Expression of ETNPPL was very weak in neonatal mice, except in the ventricular and subventricular zones, and it was heterogeneously expressed in adult mice, with the highest expression in the cerebellum, olfactory bulb, and hypothalamus and the lowest in white matter. Subcellular localization of ETNPPL was dominant in the nuclei with weak expression in the cytosol in the minor population. Using the antibody, astrocytes in adult were selectively labeled in the cerebral cortex or spinal cord, and changes in astrocytes were detected in the spinal cord after pyramidotomy. ETNPPL is expressed in a subset of Gjb6 + astrocytes in the spinal cord. The monoclonal antibodies we created, as well as fundamental knowledge characterized in this study, will be valuable resources in the scientific community and will expand our understanding of astrocytes and their complicated responses in many pathological conditions in future analyses.

Single-nucleus RNA sequencing identified cells with ependymal cell-like features enriched in neonatal mice after spinal cord injury.

The adult mammalian central nervous system has limited regenerative ability, and spinal cord injury (SCI) often causes lifelong motor disability. While regeneration is limited in adults, injured spinal cord tissue can be regenerated and neural function can be almost completely restored in neonates. However, difference of cellular composition in lesion has not been well characterized. To gain insight into the age-dependent cellular reaction after SCI, we performed single-nucleus RNA sequencing, analyzing 4076 nuclei from sham and injured spinal cords from adult and neonatal mice. Clustering analysis identified 18 cell populations. We identified previously undescribed cells with ependymal cell-like gene expression profile, the number of which was increased in neonates after SCI. Histological analysis revealed that these cells line the central canal under physiological conditions in both adults and neonates. We confirmed that they were enriched in the lesion only in neonates. We further showed that these cells were positive for the cellular markers of ependymal cells, astrocytes and radial glial cells. This study provides a deeper understanding of neonate-specific cellular responses after SCI, which may determine regenerative capacity.

Bilateral ovarian endometriomas after laparoscopic hysterectomy following adjuvant tamoxifen therapy for breast cancer: A case report.

Tamoxifen, a selective estrogen receptor modulator, is widely used as adjunctive therapy for women with breast cancer. However, tamoxifen has an agonistic effect on the endometrium and may be associated with endometrial proliferation, hyperplasia, polyp formation and carcinoma. The case report describes a 50-year-old woman who developed bilateral ovarian endometriomas while taking tamoxifen for breast cancer after total laparoscopic hysterectomy. She had undergone total laparoscopic hysterectomy for multiple uterine fibroids with no ovarian pathology at age 48 years, had been diagnosed with breast cancer and had commenced tamoxifen as post-mastectomy adjuvant therapy. One year after starting tamoxifen, she developed bilateral ovarian swelling accompanied by acute abdominal pain. At laparoscopic bilateral salpingo-oophorectomy, endometriomas were visible on both ovaries. Pathological examination confirmed endometriotic cysts with no evidence of malignancy. Postoperatively, anastrozole (an aromatase inhibiter) was substituted for tamoxifen as adjuvant therapy for her breast cancer.

Targeting the heparin-binding epidermal growth factor-like growth factor in ovarian cancer therapy.

PURPOSE OF REVIEW: Therapeutics targeting the ErbB protein family receptors have not always yielded favorable or successful results in present cancer therapy. This review discusses the possibility of the clinical adaptation of targeting against heparin-binding epidermal growth factor-like growth factor (HB-EGF), one of the ligands of the ErbB system, in ovarian cancer therapy. RECENT FINDINGS: We have previously described the results of studies concerning roles of HB-EGF in tumor formation in ovarian cancer. In brief, lisophosphatidic acid (LPA) and HB-EGF are predominantly expressed in advanced ovarian cancer, and LPA-induced, a disintegrin and metalloprotease-mediated ectodomain shedding of HB-EGF was found to be critical to tumor formation. We also noted that exogenous expression of HB-EGF enhanced tumor formation but inhibition blocked both extracellular signal-related kinase and serine/threonine protein kinase activation. Finally we investigated the antitumor effects of CRM197 - a specific HB-EGF inhibitor - on ovarian cancer cells by evaluating human ovarian cancer cell proliferation. SUMMARY: We discuss alternative strategies to develop the chemotherapeutic agent based on targeting ErbB family ligands rather than their receptors. A phase I study of CRM197 for advanced ovarian cancer has already begun, which is the first approved trial of ErbB-ligand-targeted therapy. We also discuss clinical adaptations based on combination of CRM197 with other conventional chemotherapeutic agents.

Uterine inversion due to a leiomyoma on postpartum day 41: a case report.

Uterine leiomyomas are common tumors in women of reproductive age and are frequently detected during pregnancy. The major complications during pregnancy include abortion, preterm delivery, abruptio placentae, intrauterine growth retardation, dystocia, and postpartum hemorrhage. Little attention is given to uterine leiomyomas postpartum compared to leiomyomas prior to childbirth. In the present case, a 27-year-old woman, gravida 1 para 1, presented with massive vaginal bleeding, urinary retention and lower abdominal pain on postpartum day 41. She was diagnosed with uterine inversion due to leiomyoma. After a vaginal myomectomy, the uterus was re-placed with a combined vaginal and abdominal approach. Because of timely medical intervention, the patient managed to overcome the crisis and her reproductive organs were successfully preserved.

Primary leiomyosarcoma of the fallopian tube.

Primary sarcoma of the fallopian tube is a very rare neoplasm. We report the case of a 69-year-old woman affected with leiomyosarcoma of the left fallopian tube. Her chief complaint was lower abdominal pain. The preoperative diagnosis was a left adnexal malignant tumor based on pelvic examination, abdominal computed tomography, and magnetic resonance imaging. Following a laparotomy, she was ultimately diagnosed with a FIGO IIc fallopian tube leiomyosarcoma. She was treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, partial omentectomy, and low anterior resection for rectal invasion. The patient subsequently received adjuvant chemotherapy with pirarubicin and ifosfamide. Thirty months after the first therapy, a computed tomography scan revealed metastasis of the liver, lung, and supraclavicular lymph node. The patient died of the disease 39 months after the initial treatment.

Change in cervical length in cases resulting in threatened preterm labor.

PURPOSE: To determine the predisposing changes in cervical length (CL) and the critical range of CL in which significant uterine contractions emerge resulting in threatened preterm labor (TPL). METHODS: Sixty-eight uncomplicated singleton pregnancies where the CL was <25 mm before 31 weeks were divided into cases with TPL (n = 23) or without (n = 45). CL and uterine contractions were monitored sequentially starting between 16 and 20 weeks. The gestational ages when a CL of <25 or <15 mm was first observed, the interval between these two measurements, and the CL value at TPL diagnosis were analyzed retrospectively. RESULTS: (1) The gestational ages when a CL of <25 and <15 mm was first detected were lower in the TPL group (25 (median); 18-30 (range) and 28; 25-33 weeks, respectively) than in the non-TPL group (27; 20-30 and 33; 26-35 weeks; P = 0.030 and P < 0.001). (2) The interval between the two measurements was shorter in the TPL group (2.5; 0-15 weeks) than in the non-TPL group (5.5; 0-13 weeks, P = 0.034). (3) The CL value at TPL diagnosis was 13 mm (median), ranging from 7 to 18 mm. CONCLUSION: Cases with early onset and subsequent rapid CL shortening before 31 weeks resulted in TPL when CL decreased below the range 7-18 mm.

Monitoring of endometrial K-ras mutation in tamoxifen-treated patients with breast cancer.

INTRODUCTION: A high incidence of endometrial K-ras mutations has been reported in tamoxifen (TAM)-treated patients with breast cancer. We examined the changes in the frequency of the endometrial K-ras mutations after the cessation of TAM treatment. METHODS: DNA was extracted from fresh cytological or polypectomy samples of the endometrium in 28 patients who had undergone TAM treatment of breast cancer. Mutations were detected by an enriched polymerase chain reaction-enzyme-linked minisequence assay (Sumitomo Metal Industry, Inc, Tokyo, Japan). K-ras codon 12 mutations were monitored in these 28 patients. RESULTS: An initial examination detected endometrial K-ras mutations in 13 of the 28 patients. However, repeated examinations performed after cessation of TAM treatment did not detect endometrial K-ras mutations in any of these 13 patients. No endometrial K-ras mutation has been detected in the repeated examinations performed for these patients for more than 2 years since the cessation of TAM treatment. In addition, the 15 patients who did not have endometrial K-ras mutations in the initial examination did not demonstrate them in repeat examinations. CONCLUSIONS: The cessation of TAM treatment may reduce the risk of developing endometrial cancers through K-ras mutations.

Incidence and risk factors for postpartum hemorrhage among transvaginal deliveries at a tertiary perinatal medical facility in Japan.

Postpartum hemorrhage (PPH) remains a leading cause of maternal death worldwide, and it is important to understand the relative contributions of different risk factors. We assessed the incidence of these among cases of transvaginal delivery. Between June 2013 and July 2016, a prospective cohort study was conducted at a tertiary perinatal medical facility in Japan. Women were administered a questionnaire to ascertain risk factors for PPH, defined as a blood loss of 1,000 ml or more assessed using a calibrated under-buttocks drape and collection vessel at childbirth. We analyzed 1,068 transvaginal deliveries of singleton pregnancies. The incidence of PPH was 8.7%, and of severe PPH (1,500 ml blood loss or more) was 2.1%. Risk factors for postpartum hemorrhage among the deliveries were: fetal macrosomia (over 4000 g); pregnancy-induced hypertension; pregnancy generated by assisted reproductive technology; severe vaginal or perineal lacerations; and weight gain over 15 kg during pregnancy. Such high weight gain significantly increased the incidence of PPH compared with women showing less than 10 kg weight gain during pregnancy. Monitoring these identified risk factors could enable extra vigilance during labor, and preparedness for managing PPH in all women giving birth.

Validation of HB-EGF and amphiregulin as targets for human cancer therapy.

Aberrant expression levels of epidermal growth factor receptor (EGFR) and its cognate ligands have been recognized as one of the causes of cancer progression. To investigate the validity of EGFR ligands as targets for cancer therapy, we examined the expression of EGFR ligands and in vitro anti-tumor effects of small interference RNA (siRNA) for EGFR ligands in various cancer cells. HB-EGF expression was dominantly elevated in ovarian, gastric, and breast cancer, melanoma and glioblastoma cells, whereas amphiregulin was primarily expressed in pancreatic, colon, and prostate cancer, renal cell carcinoma and cholangiocarcinoma cells. Transfection of siRNAs for HB-EGF or amphiregulin into these cells significantly increased the numbers of apoptotic cells with attenuation of EGFR and ERK activation. In lung cancer cells, any EGFR ligand was not recognized as a validated target for cancer therapy. These results suggest that HB-EGF and amphiregulin are promising targets for cancer therapy.

Primary peritoneal carcinosarcoma arising from the Douglas pouch: A case report.

Primary peritoneal carcinosarcoma is extremely rare and only few cases have been reported in the literature to date. We herein present a case of carcinosarcoma of the Douglas pouch in a 73-year-old Japanese woman. The patient complained of fever and lower abdominal pain, and a large pelvic mass (>10 cm in diameter) was detected, with rectal invasion. Laparotomy was performed and revealed a left ovarian abscess and a Douglas pouch mass; however, there was no obvious tumor involvement of the bilateral ovaries or uterus. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and tumor debulking, with a reduction rate of ~30%. Sigmoid colostomy was also performed due to the deep and wide rectal invasion. Histologically, the tumor was composed of a mixture of ovarian high-grade serous carcinoma and spindle-cell sarcoma mimicking leiomyosarcoma. Immunohistochemically, the serous carcinoma component was positive for cytokeratin (CK)7, Wilms' tumor-1 and p53 (null type), while CDX-2 and CK20 were negative. The spindle-cell sarcoma component was positive for vimentin and α-smooth muscle actin. The present case was diagnosed as carcinosarcoma of the homologous type derived from the peritoneum in the Douglas pouch. The patient received several courses of combination chemotherapy with paclitaxel, carboplatin and bevacizumab, and achieved complete remission. The principal treatment for such cases is surgery, and several chemotherapeutic regimens, including paclitaxel and carboplatin, or cisplatin and ifosfamide, have been reported. The accumulation of more clinical cases is crucial for understanding the clinicopathological characteristics of these rare tumors and establishing effective therapeutic strategies.

Malignant lymphoma of the uterine cervix presumptively diagnosed by Pap smear: A case report.

Malignant lymphoma of the uterine cervix is exceedingly rare and is difficult to diagnose by cervical cytology. The current study presents a case of malignant lymphoma of the uterine cervix that was presumptively diagnosed by cervical cancer screening in which the patient had no clinical symptoms. The anterior lip of the uterine cervix was occupied by a macroscopic hemorrhagic tumor. The obtained tumor cells exhibited typical cytological features of malignant lymphoma and were positive for CD20. The final diagnosis was diffuse large B cell lymphoma of the uterine cervix, stage IIEA (Ann Arbor classification). The patient received 6 courses of R-CHOP chemotherapy and achieved complete remission. Despite its rarity, the possibility of malignant lymphoma should be considered while screening for cervical cancers using Pap smears. The Pap test screening may be useful for the early diagnosis of malignant lymphoma of the uterine cervix in certain cases. By reaching a rapid and accurate diagnosis, immediate treatment may be initiated and surgery may be avoided.

interleukin-11 induces and maintains progenitors of different cell lineages during Xenopus tadpole tail regeneration.

Unlike mammals, Xenopus laevis tadpoles possess high ability to regenerate their lost organs. In amphibians, the main source of regenerated tissues is lineage-restricted tissue stem cells, but the mechanisms underlying induction, maintenance and differentiation of these stem/progenitor cells in the regenerating organs are poorly understood. We previously reported that interleukin-11 (il-11) is highly expressed in the proliferating cells of regenerating Xenopus tadpole tails. Here, we show that il-11 knockdown (KD) shortens the regenerated tail length, and the phenotype is rescued by forced-il-11-expression in the KD tadpoles. Moreover, marker genes for undifferentiated notochord, muscle, and sensory neurons are downregulated in the KD tadpoles, and the forced-il-11-expression in intact tadpole tails induces expression of these marker genes. Our findings demonstrate that il-11 is necessary for organ regeneration, and suggest that IL-11 plays a key role in the induction and maintenance of undifferentiated progenitors across cell lineages during Xenopus tail regeneration. Xenopus laevis tadpoles have maintained their ability to regenerate various organs. Here, the authors show that interleukin-11 is necessary for organ regeneration, by inducing and maintaining undifferentiated progenitors across cell lineages during Xenopus tail regeneration.

Choosing the uterine preservation surgery for placental polyp determined by blood flow evaluation: A retrospective cohort study.

BACKGROUND: A placental polyp is an intrauterine polypoid mass or pedunculated mass occurring from residual trophoblastic tissue following abortion, cesarean section or vaginal delivery. Recently uterine preservation surgery represented by transcervical resection (TCR) has been performed for placental polyps. However TCR without intravascular intervention, including uterine artery embolization (UAE) may cause profound bleeding which necessitate emergency laparotomy. METHODS: Seventeen cases of placental polyp were retrospectively examined. We divided cases into two groups: strong vascularity group (n = 13) and weak vascularity group (n = 4). Mass extraction of polyp by TCR was conducted in 16 cases, 6 case without UAE and 10 cases with UAE. RESULTS: As for the weak vascularity group, one case was naturally resolved while planning surgery and 3 cases were treated with TCR without UAE without major intra- and/or postoperative bleeding. On the other hand in the strong vascularity group, 2 out of 3 cases of TCR without UAE resulted in major bleeding during and after the surgery, both needed transfusion and one needing postoperative UAE. Ten cases of strong vascularity group, TCR with UAE were performed and all of them were accomplished without major bleeding. TCR without UAE was safely performed in cases where there was absent or mild to moderate blood flow. CONCLUSIONS: Our report suggests that adding UAE might be safer to treat placental polyps that have strong vascularity.