High-mobility group box-1 and inter-alpha inhibitor proteins: In vitro binding and co-localization in cerebral cortex after hypoxic-ischemic injury.

The high-mobility group box-1 (HMGB1) protein is a transcription-regulating protein located in the nucleus. However, it serves as a damage-associated molecular pattern protein that activates immune cells and stimulates inflammatory cytokines to accentuate neuroinflammation after release from damaged cells. In contrast, Inter-alpha Inhibitor Proteins (IAIPs) are proteins with immunomodulatory effects including inhibition of pro-inflammatory cytokines. We have demonstrated that IAIPs exhibit neuroprotective properties in neonatal rats exposed to hypoxic-ischemic (HI) brain injury. In addition, previous studies have suggested that the light chain of IAIPs, bikunin, may exert its anti-inflammatory effects by inhibiting HMGB1 in a variety of different injury models in adult subjects. The objectives of the current study were to confirm whether HMGB1 is a target of IAIPs by investigating the potential binding characteristics of HMGB1 and IAIPs in vitro, and co-localization in vivo in cerebral cortices after exposure to HI injury. Solid-phase binding assays and surface plasmon resonance (SPR) were used to determine the physical binding characteristics between IAIPs and HMGB1. Cellular localizations of IAIPs-HMGB1 in neonatal rat cortex were visualized by double labeling with anti-IAIPs and anti-HMGB1 antibodies. Solid-phase binding and SPR demonstrated specific binding between IAIPs and HMGB1 in vitro. Cortical cytoplasmic and nuclear co-localization of IAIPs and HMGB1 were detected by immunofluorescent staining in control and rats immediately and 3 hours after HI. In conclusion, HMGB1 and IAIPs exhibit direct binding in vitro and co-localization in vivo in neonatal rats exposed to HI brain injury suggesting HMGB1 could be a target of IAIPs.

Primary malignant melanoma of the uterine cervix or vagina which were successfully treated with nivolumab.

Primary malignant melanomas (MM) originating from the gynecological tract are rare. They respond poorly to immunotherapy when compared with cutaneous MM. This study reports two cases. The first is of a 54-year-old woman with a cervical amelanotic polypoid mass who was diagnosed as having stage IB1 cervical melanoma according to the International Federation of Gynecology and Obstetrics system. At 17 months post-surgery, a computed tomography examination revealed recurrence of a 68 mm pelvic tumor. The second case is of a 37-year-old woman with a 7 cm hemorrhagic mass on the vaginal wall. The patient was diagnosed as having stage IV vaginal melanoma according to the American Joint Committee on Cancer definition. Both patients received nivolumab therapy, programmed cell death receptor 1 monoclonal antibodies, and the tumors almost disappeared. These cases may add the possibility of using colposcopy with narrow-band imaging and positron-emission tomography to diagnose and evaluate primary MM.

Twelve-year experience of office-setting removal of lost intrauterine devices in place for more than 10 years.

Objective: We investigated the effectiveness of removing lost intrauterine devices (IUDs) that had been in place for over 10 years, using Lin's biopsy grasper in an office setting. Methods:This single-centre, retrospective study conducted between March 2006 and June 2018 included 49 women who had had an IUD in place for contraception for more than 10 years and who underwent removal of the lost IUD using Lin's biopsy grasper under transabdominal sonography without use of a tenaculum, anaesthesia and analgesia, after dilation of the cervical os and hysteroscopy. Results: The women's median age was 52 years (range 34-80 years) and the median duration of insertion was 17 years (range 10-43 years). Forty-eight (98%) women had their lost IUD removed using Lin's biopsy grasper. Among the removed IUDs, there were eight FD-1 IUDs with a string, 13 FD-1 IUDs without a string, 13 Chinese IUDs, seven Ota ring IUDs, three KS ring IUDs, two Saf-T-Coil IUDs, two Lippe loop IUDs and one Wing IUD. All women tolerated the procedure and there were no major operative complications. Conclusions: Lin's biopsy grasper was effective in removing IUDs that had been in place for a long time.

Hysteroscopic Transcervical Resection for Atypical Polypoid Adenomyoma of the Uterus: A Valid, Fertility-Preserving Option.

STUDY OBJECTIVE: To evaluate hysteroscopic transcervical resection (TCR) for atypical polypoid adenomyoma of the uterus (APA). DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: Single tertiary hospital. PATIENTS: Women who underwent TCR for APA at Kawasaki Municipal Hospital between 2003 and 2015. INTERVENTIONS: Clinical records were obtained. MEASUREMENTS AND MAIN RESULTS: Thirty-five patients with APA were evaluated. The median patient age was 35 years (range, 23-43 years), and the median tumor diameter was 22 mm (range, 9-51 mm). The median duration of observation after the first TCR was 34.0 months (range, 4.2-133.7 months). In 19 patients, the tumor recurred after the first TCR. A second TCR was performed in 13 patients, 11 of whom experienced recurrence. A third TCR was performed in 7 patients, all 7 of whom experienced recurrence. A fourth TCR was performed in 4 patients, 3 of whom experienced recurrence. The recurrence rate after the second TCR was higher than that after the first TCR (71.4%-84.6% vs 54.3%; p < .01, t test). The median disease-free interval was 12.4 months after the first TCR, 15.3 months after the second TCR, 10.5 months after the third TCR, and 10.9 months after the fourth TCR. Seven patients progressed to endometrial cancer; however, there was no mortality. Six of the 35 patients conceived, and 4 had a normal spontaneous delivery. CONCLUSION: Owing to disease-free intervals that follow treatment, TCR is a promising treatment modality as a fertility-preserving option for patients with APA under careful observation. Twenty percent of patients with APA develop cancer; however, the present study showed no mortality.

Through the eyes into the brain, using artificial intelligence.

INTRODUCTION: Detection of neurological conditions is of high importance in the current context of increasingly ageing populations. Imaging of the retina and the optic nerve head represents a unique opportunity to detect brain diseases, but requires specific human expertise. We review the current outcomes of artificial intelligence (AI) methods applied to retinal imaging for the detection of neurological and neuro-ophthalmic conditions. METHOD: Current and emerging concepts related to the detection of neurological conditions, using AI-based investigations of the retina in patients with brain disease were examined and summarised. RESULTS: Papilloedema due to intracranial hypertension can be accurately identified with deep learning on standard retinal imaging at a human expert level. Emerging studies suggest that patients with Alzheimer's disease can be discriminated from cognitively normal individuals, using AI applied to retinal images. CONCLUSION: Recent AI-based systems dedicated to scalable retinal imaging have opened new perspectives for the detection of brain conditions directly or indirectly affecting retinal structures. However, further validation and implementation studies are required to better understand their potential value in clinical practice.

Adenocarcinoma in situ or early-stage cervical cancer is a risk factor for preterm delivery after cervical conization: a multicenter observational study.

OBJECTIVE: Pregnancy after conization is associated with a high risk of preterm delivery. However, because risk factors for preterm delivery after conization remain unknown, we conducted a multicenter observational study to investigate risk factors associated with preterm delivery. METHODS: We selected patients who had previously undergone conization and reviewed medical records from 18 hospitals in cooperation with Keio University School of Medicine between January 2013 and December 2019. Women were classified as nulliparous and primiparous, and a multiple logistic regression analysis was performed to evaluate the relative contributions of the various maternal risk factors for preterm delivery (i.e. delivery before 37 gestational weeks). RESULTS: Among 409 pregnant women after conization, 68 women delivered preterm (17%). The incidence of nulliparity (p = .014) was higher and a history of preterm delivery (p = .0010) was more common in the preterm delivery group than in the term delivery group. Furthermore, the proportion of women diagnosed with adenocarcinoma in situ (AIS) and cervical cancer in the preterm delivery group was higher than that in the term delivery group (p = .0099 and .0004, respectively). In multiple regression models in nulliparous women, cervical cancer or AIS (Odds ratio [OR]: 4.16, 95% CI: 1.26-13.68, p = .019) and a short cervix in the second trimester (OR: 13.41, 95% CI: 3.88-46.42, p < .0001) increased the risk of preterm delivery. Furthermore, a history of preterm delivery (OR: 7.35, 95% CI: 1.55-34.86, p = .012), cervical cancer or AIS (OR: 5.07, 95% CI: 1.24-20.73, p = .024), and a short cervix in the second trimester (OR: 4.29, 95% CI: 1.11-16.62, p = .035) increased the risk of preterm delivery in the multiple regression models in primiparous women. CONCLUSION: Pregnant women who previously underwent conization are at risk for preterm delivery. The histological type of AIS and cervical cancer was evaluated as a risk factor for preterm delivery. KEY MESSAGESPrior preterm delivery, presence of a short cervix, and cervical cancer or AIS were predictors of preterm delivery after conization.The depth of conization in cervical cancer or AIS group was significantly larger than that in the CIN group.

Is the risk of small for gestational age influenced by maternal body composition in young Japanese women?

Background: We aimed to investigate whether there was a high incidence of young Japanese mothers being underweight (pregravid body mass index [BMI] < 18.5 kg/m2) and if they delivered infants who were small for gestational age (SGA).Materials and methods: Our study was carried out from 2013 to 2017 and included adolescent women (maternal age at delivery: <20 years old; n = 94), women in their early twenties (maternal age at delivery: 20-24 years; n = 479), and controls (maternal age at delivery: 25-34 years; n = 2061).Results: In both the adolescent and early twenties groups, the incidence of being underweight, based on prepregnancy BMI, was significantly higher than controls (p < .0001 and p < .05, respectively). In both groups, gestational weight gain (GWG) was significantly higher than controls (p < .0001). There were no notable group differences in the incidences of SGA.Conclusion: The incidence of being underweight was higher in younger mothers than in controls. However, the risk of SGA did not increase in younger mothers, possibly because their GWG overcame the influence of their pre-pregnancy body composition.

The Association between Placenta Implantation at Prior Myomectomy Locations and Perinatal Outcomes in Pregnant Women Who Previously Underwent One-Step Hysteroscopic Myomectomy.

OBJECTIVES: There are no data describing the correlation between placenta implantation at prior myomectomy locations and perinatal outcomes in pregnant women after transcervical resection myomectomy (TCR-M). The aim of the study is to investigate the correlations between placenta implantation at prior myomectomy locations and perinatal outcomes in pregnant women who had previously undergone TCR-M. MATERIALS AND METHODS: This was a retrospective, single-center study. We reviewed the records of 34 pregnant women who had previously undergone TCR-M for submucosal myoma and perinatal care in our hospital between January 2012 and January 2019. We examined surgical and pregnancy outcomes and evaluated correlations between placenta implantation at prior myomectomy locations and perinatal outcomes in women who delivered after 22 gestational weeks (n = 24). RESULTS: Median maternal age at conception was 38 years (range, 28-44) and median duration between TCR-M and conception was 1.4 years (range, 0.3-5.8). There were 24 deliveries after 22 gestational weeks and 10 pregnancy losses. Among these 24 deliveries, the median gestational age at delivery was 39 weeks (range, 34-41); median birthweight, 3025 g (range, 2092-4012); and median blood loss at delivery, 573 g (range, 100-3000). There were no cases of placenta accreta and uterine rupture. Placenta implantation at a prior myomectomy location was detected in 14/24 women using transabdominal ultrasonography. Median blood loss was significantly higher in the implantation than in the nonimplantation group (P < 0.01). CONCLUSION: Our one-step TCR-M is useful for women with submucosal myoma. However, we suggest that clinicians should review and check the association between prior myomectomy locations and placenta implantation.

Effects of inter-alpha inhibitor proteins on brain injury after exposure of neonatal rats to severe hypoxia-ischemia.

Hypoxic-ischemic (HI) brain injury is one of the most common neurological problems occurring in premature and full-term infants after perinatal complications. Hypothermia is the only treatment approved for HI encephalopathy in newborns. However, this treatment is only partially protective, cannot be used to treat premature infants, and has limited efficacy to treat severe HI encephalopathy. Inflammation contributes to the evolution of HI brain injury in neonates. Inter-alpha Inhibitor Proteins (IAIPs) are immunomodulatory proteins that have neuroprotective properties after exposure to moderate HI in neonatal rats. The objective of the current study was to determine the neuroprotective efficacy of treatment with IAIPs starting immediately after or with a delay of one hour after exposure to severe HI of 120 min duration. One hundred and forty-six 7-day-old rat pups were randomized to sham control, HI and immediate treatment with IAIPs (60 mg/kg) or placebo (PL), and sham, HI and delayed treatment with IAIPs or PL. IAIPs or PL were given at zero, 24, and 48 h after HI or 1, 24 and 48 h after HI. Total brain infarct volume was determined 72 h after exposure to HI. Treatment with IAIPs immediately after HI decreased (P < 0.05) infarct volumes by 58.0% and 44.5% in male and female neonatal rats, respectively. Delayed treatment with IAIPs after HI decreased (P < 0.05) infarct volumes by 23.7% in male, but not in female rats. We conclude that IAIPs exert neuroprotective effects even after exposure to severe HI in neonatal rats and appear to exhibit some sex-related differential effects.

Pharmacokinetics of Inter-Alpha Inhibitor Proteins and Effects on Hemostasis After Hypoxic-Ischemic Brain Injury in Neonatal Rats.

BACKGROUND: Hypoxic-ischemic (HI) brain injury is a leading cause of long-term neurodevelopmental morbidities in neonates. Human plasma-derived Inter-Alpha Inhibitor Proteins (hIAIPs) are neuroprotective after HI brain injury in neonatal rats. The light chain (bikunin) of hIAIPs inhibits proteases involved in the coagulation of blood. Newborns exposed to HI can be at risk for significant bleeding in the brain and other organs. OBJECTIVE: The objectives of the present study were to assess the pharmacokinetics (PK) and the duration of bleeding after intraperitoneal (IP) administration of hIAIPs in HI-exposed male and female neonatal rats. METHODS: HI was induced with the Rice-Vannucci method in postnatal (P) day-7 rats. After the right common carotid artery ligation, rats were exposed to 90 min of 8% oxygen. hIAIPs (30 mg/kg, IP) were given immediately after Sham or HI exposure in the PK study and serum was collected 1, 6, 12, 24, or 36 h after the injections. Serum hIAIP concentrations were measured with a competitive ELISA. ADAPT5 software was used to fit the pooled PK data considering first-order absorption and disposition. hIAIPs (60 mg/kg, IP) were given in the bleeding time studies at 0, 24 and 48 h after HI with tail bleeding times measured 72 h after HI. RESULTS: IP administration yielded significant systemic exposure to hIAIPs with PK being affected markedly including primarily faster absorption and reduced elimination as a result of HI and modestly of sex-related differences. hIAIP administration did not affect bleeding times after HI. CONCLUSION: These results will help to inform hIAIP dosing regimen schedules in studies of neuroprotection in neonates exposed to HI.

Inter-alpha Inhibitor Proteins Modulate Neuroinflammatory Biomarkers After Hypoxia-Ischemia in Neonatal Rats.

Neuroinflammation contributes to hypoxic-ischemic (HI) brain injury. Inter-alpha inhibitor proteins (IAIPs) have important immunomodulatory properties. Human (h) plasma-derived IAIPs reduce brain injury and improve neurobehavioral outcomes after HI. However, the effects of hIAIPs on neuroinflammatory biomarkers after HI have not been examined. We determined whether hIAIPs attenuated HI-related neuroinflammation. Postnatal day-7 rats exposed to sham-placebo, or right carotid ligation and 8% oxygen for 90 minutes with placebo, and hIAIP treatment were studied. hIAIPs (30 mg/kg) or PL was injected intraperitoneally immediately, 24, and 48 hours after HI. Rat complete blood counts and sex were determined. Brain tissue and peripheral blood were prepared for analysis 72 hours after HI. The effects of hIAIPs on HI-induced neuroinflammation were quantified by image analysis of positively stained astrocytic (glial fibrillary acid protein [GFAP]), microglial (ionized calcium binding adaptor molecule-1 [Iba-1]), neutrophilic (myeloperoxidase [MPO]), matrix metalloproteinase-9 (MMP9), and MMP9-MPO cellular markers in brain regions. hIAIPs reduced quantities of cortical GFAP, hippocampal Iba-1-positive microglia, corpus callosum MPO, and cortical MMP9-MPO cells and the percent of neutrophils in peripheral blood after HI in male, but not female rats. hIAIPs modulate neuroinflammatory biomarkers in the neonatal brain after HI and may exhibit sex-related differential effects.

Neuroprotective effects of inter-alpha inhibitor proteins after hypoxic-ischemic brain injury in neonatal rats.

Hypoxic-ischemic (HI) brain injury is one of the most common neurological problems occurring in the perinatal period. Hypothermia is the only approved intervention for neonatal HI encephalopathy. However, this treatment is only partially protective, has a narrow therapeutic time window after birth and only can be used to treat full-term infants. Consequently, additional therapies are critically needed. Inflammation is an important contributing factor to the evolution of HI brain injury in neonates. Inter-alpha Inhibitor Proteins (IAIPs) are immunomodulatory proteins with anti-inflammatory properties. We have previously shown that IAIPs reduce neuronal cell death and improve behavioral outcomes when given after carotid artery ligation, but before hypoxia in male neonatal rats. The objective of the current study was to investigate the neuroprotective effects of treatment with IAIPs given immediately or 6 h after HI in both male and female neonatal rats. HI was induced with the Rice-Vannucci method in postnatal (P) day 7 rats. After ligation of the right common carotid artery, P7 rats were exposed to 90 min of hypoxia (8% oxygen). Human plasma-derived IAIPs or placebo (phosphate buffered saline) was given at zero, 24, and 48 h after HI. Brains were perfused, weighed and fixed 72 h after HI at P10. In a second, delayed treatment group, the same procedure was followed except that IAIPs or placebo were given at 6, 24 and 48 h after HI. Separate sham-operated, placebo-treated groups were exposed to identical protocols but were not exposed to carotid artery ligation and remained in room air. Rat sex was recorded. The effects of IAIPs on HI brain injury were examined using histopathological scoring and immunohistochemical analyses of the brain and by using infarct volume measurements on frozen tissue of the entire brain hemispheres ipsilateral and contralateral to HI injury. IAIPs given immediately after HI improved (P < 0.050) histopathological brain injury across and within the cingulate, caudate/putamen, thalamus, hippocampus and parietal cortex in males, but not in females. In contrast, IAIPs given immediately after HI reduced (P < 0.050) infarct volumes of the hemispheres ipsilateral to HI injury in similarly both the males and females. Treatment with IAIPs also resulted in higher (P < 0.050) brain weights compared with the placebo-treated HI group, reduced (P < 0.050) neuronal and non-neuronal cell death in the cortex and total hemisphere, and also increased the total area of oligodendrocytes determined by CNPase in the ipsilateral hemisphere and corpus callosum (P < 0.050) of male, but not female subjects exposed to HI. Delayed treatment with IAIPs 6 h after HI did not improve histopathological brain injury in males or females, but resulted in higher (P < 0.050) brain weights compared with the placebo-treated HI males. Therefore, treatment with IAIPs immediately after HI improved brain weights and reduced neuropathological brain injury and cell death in male rats, and reduced infarct volume in both male and female neonatal rats. We conclude that IAIPs exert neuroprotective effects after exposure to HI in neonatal rats and may exhibit some sex-related differential effects.

Development of pseudoaneurysm in cesarean section scar pregnancy: a case report and literature review.

Cesarean scar pregnancy (CSP) is a rare type of ectopic pregnancy. It is becoming more common, but it can lead to uterine rupture and severe hemorrhage. Here, we report a case of a 37-year-old woman with CSP complicated with pseudoaneurysm. The pseudoaneurysm emerged following focal injection of methotrexate (MTX) and potassium chloride with systemic MTX treatment. Due to a risk of sudden bleeding, uterine artery embolization (UAE) was recommended, but the patient hoped to avoid this if possible. Because the serum human chorionic gonadotropin level and the gestational sac were still persistent, dilation and curettage were performed with interventional radiologists on standby. Severe hemorrhage occurred and continued during the procedure, which necessitated emergent UAE. We reviewed six CSP case reports with vascular abnormalities, and all of them necessitated UAE, surgical excision, or hysterectomy. In the case of CSP combined with pseudoaneurysm, treatment should be planned carefully considering the risk of massive hemorrhage.

Clinical application of Lin's biopsy grasper for intrauterine targeted biopsy and polypectomy during office hysteroscopy.

OBJECTIVE: Hysteroscopy has widely been used for diagnosis of the uterine cavity; however, target biopsy has often been difficult in part to the inherent limitations of ancillary instruments. Lin's biopsy grasper was specifically designed to work in conjunction with a flexible hysteroscope to obtain intrauterine biopsy under transabdominal sonography. Herein, we share our clinical experience in the management of endometrial abnormalities with the use of Lin's biopsy grasper during office-based hysteroscopy. MATERIALS AND METHODS: From February 2006 to November 2016, the use of Lin's biopsy grasper for tissue biopsy was attempted on 126 cases. We retrospectively recorded and analyzed the patients' preoperative characteristics and biopsy outcomes to demonstrate the feasibility and efficacy of Lin's biopsy grasper. RESULTS: Out of the one hundred and twenty-six enrolled patients, satisfactory targeted biopsies were achieved; including high diagnostic rate (92.1%, with 116 cases confirmed histologically) and adequate tissue retrieval (77.8%, with 98 cases obtaining optimal specimen volume). All patients tolerated the procedure without analgesics or anesthesia. CONCLUSION: Diagnostic flexible hysteroscopy combined with the use of Lin's biopsy grasper has proven to be an effective tool for intrauterine evaluation and obtaining tissue sample.