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The COVID-19 vaccine is effective in preventing severe cases of COVID-19. For women, gynecological adverse events, such as menstrual irregularities and irregular bleeding, could be a concern after COVID-19 vaccination. In this study, we investigated gynecological adverse events in the vaccinated Japanese female population.We conducted a survey-based study with health-care workers, including medical doctors and nurses, medical coworkers, and medical university faculty, staff, and students, at a single medical school and affiliated hospital in Japan. We used McNemar's test and network analysis.Overall, we obtained 819 responses, and 424 were from females. After the exclusion of contradictory answers, 309 surveys were finally considered appropriate for the analysis. The frequencies of abnormal bleeding were 0.6%, 1.0%, and 3.0% for the first, second, and third doses, respectively. An irregular menstrual cycle was more common than abnormal bleeding: 1.9%, 4.9%, and 6.6% for the first, second, and third doses, respectively. Network analysis revealed that abnormal bleeding and an irregular menstrual cycle were not associated with other adverse reactions.The present study showed that the effects of COVID-19 vaccination on menstruation seem limited.

The current COVID‐19 pandemic is a global concern. The recent introduction of vaccines has provided a reason for hope, but new problems, such as vaccine hesitancy, have arisen. One of the most important of these issues is the safety of vaccines for pregnant women. In this article, we collected worldwide indications for vaccination, including women who are pregnant or who wish to become pregnant, and reports of adverse reactions to COVID‐19 vaccination. The Japan Society of Obstetrics and Gynecology and the Japanese Society of Infectious Diseases in Obstetrics and Gynecology have published recommendations for the vaccination of pregnant women with a COVID‐19 vaccine. The guidelines are as follows: (1) pregnant women should not be excluded from vaccination; (2) informed consent should be obtained before vaccination; (3) healthcare workers and pregnant women with complications such as diabetes, hypertension, and obesity should be vaccinated preferentially; (4) vaccination should be avoided until 12 weeks of gestation during organogenesis; (5) spouse and family members should be vaccinated actively; and (6) nursing mothers are not particularly affected. This policy has been adopted in government guidelines. Additional efforts should be made to protect pregnant women from infection and severe illness with COVID‐19 by eliminating vaccine hesitancy.

Although SARS-CoV-2 can infect human placental tissue, vertical transmission is rare. Therefore, the placenta may function as a barrier to inhibit viral transmission to the foetus, though the mechanisms remain unclear. In this study, we confirmed the presence of the SARS-CoV-2 genome in human placental tissue by in situ hybridization with antisense probes targeting the spike protein; tissue staining was much lower when using sense probes for the spike protein. To the best of our knowledge, this is the first evidence directly indicating inefficient viral replication in the SARS-CoV-2-infected placenta. Additional studies are required to reveal the detailed mechanisms.

Patients with SARS-CoV-2 infection and with severe COVID-19 often have multiple coinfections, and their treatment is challenging. Here, we performed cytology analysis on sputum samples from two patients with severe COVID-19. The specimens were prepared using the rubbing method and stained with Papanicolaou stain. In both cases, several cells with frosted nuclei were observed, and the cytological findings per 100 cells were evaluated. The infected cells were mononuclear to multinuclear, showing chromatin aggregation at the nuclear margins, intranuclear inclusion bodies, eosinophilic cytoplasmic inclusion bodies, and mutual pressure exclusion of the nuclei. Immunocytochemical staining revealed that the cells were positive for AE1/AE3 and negative for CD68 expression, indicating their epithelial origin. Furthermore, infected cells with frosted nuclei were positive for surfactant protein A (SP-A) in Case 2, suggesting infection of type II alveolar pneumocytes or Clara cells. Moreover, in Case 2, the infected cells were positive for herpes simplex virus (HSV) I + II and SARS-CoV-2 spike protein, confirming double infection in these cells. In conclusion, sputum cytology is an important tool for determining the diversity of viral infection, and additional immunocytochemistry can be used for definitive diagnosis.

To control the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the promotion of vaccination is important. However, adverse reactions following vaccination remain a concern. To investigate adverse events in the vaccinated Japanese population, we conducted a survey-based study among health care workers, including medical doctors and nurses; other medical staff; and medical university faculty, staff, and students in a single medical school and affiliated hospital in Japan. In addition, we analyzed the association of different adverse events with individual factors (e.g., age, sex) by performing network analysis. While young age and female sex are often considered risk factors for more severe adverse events, the regression models showed neither age nor sex was associated with local injection-site reactions after the second dose in this study. In contrast to local reactions, systemic adverse events were associated with young age and female sex. However, myalgia was unique in that it was not associated with younger age even though the network analysis showed that myalgia was consistently related to arthralgia and belonged to the group of systemic events after both the first and second vaccine doses. Further study is needed to ensure safe and effective vaccination to aid in controlling the COVID-19 pandemic.

Transforming growth factor-beta 1 (TGF-β1) is a pleiotropic growth factor playing various roles in the human body including cell growth and development. More functions of TGF-β1 have been discovered, especially its roles in viral infection. TGF-β1 is abundant at the maternal–fetal interface during pregnancy and plays an important function in immune tolerance, an essential key factor for pregnancy success. It plays some critical roles in viral infection in pregnancy, such as its effects on the infection and replication of human cytomegalovirus in syncytiotrophoblasts. Interestingly, its role in the enhancement of Zika virus (ZIKV) infection and replication in first-trimester trophoblasts has recently been reported. The above up-to-date findings have opened one of the promising approaches to studying the mechanisms of viral infection during pregnancy with links to corresponding congenital syndromes. In this article, we review our current and recent advances in understanding the roles of TGF-β1 in viral infection. Our discussion focuses on viral infection during pregnancy, especially in the first trimester. We highlight the mutual roles of viral infection and TGF-β1 in specific contexts and possible functions of the Smad pathway in viral infection, with a special note on ZIKV infection. In addition, we discuss promising approaches to performing further studies on this topic.

We have previously demonstrated the ability of the human vaginal strain Lactobacillus crispatus 2029 (LC2029) for strong adhesion to cervicovaginal epithelial cells, expression of the surface layer protein 2 (Slp2), and antagonistic activity against urogenital pathogens. Slp2 forms regular two-dimensional structure around the LC2029 cells,which is secreted into the medium and inhibits intestinal pathogen-induced activation of caspase-9 and caspase-3 in the human intestinal Caco-2 cells. Here, we elucidated the effects of soluble Slp2 on adhesion of proteobacteria pathogens inducing necrotizing enterocolitis (NEC), such as Escherichia coli ATCC E 2348/69, E. coli ATCC 31705, Salmonella Enteritidis ATCC 13076, Campylobacter jejuni ATCC 29428, and Pseudomonas aeruginosa ATCC 27853 to Caco-2 cells, as well as on growth promotion, differentiation, vascular endothelial growth factor (VEGF) production, and intestinal barrier function of Caco-2 cell monolayers. Slp2 acts as anti-adhesion agent for NEC-inducing proteobacteria, promotes growth of immature Caco-2 cells and their differentiation, and enhances expression and functional activity of sucrase, lactase, and alkaline phosphatase. Slp2 stimulates VEGF production, decreases paracellular permeability, and increases transepithelial electrical resistance, strengthening barrier function of Caco-2 cell monolayers. These data support the important role of Slp2 in the early postnatal development of the human small intestine enterocytes.

The microbiome in the female reproductive tract (FRT) plays a critical role in modulating the immune system. The mucosal epithelial barrier reliably distinguishes commensal symbionts from pathogens. However, disruption of the barrier causes dysbiosis, excessive inflammation, and infections, potentially resulting in reproductive complications. In this chapter, we provide an overview of the interaction between the epithelial barrier function and the microbiota, focusing on the lower FRT and Lactobacillus, a major dominant genus in the vagina. Information about evolution and probiotics is also provided to promote an in-depth understanding of the topic.

Introduction Recent studies have shown that the endometrium possesses unique microbiomes, including Lactobacillus. However, the roles of these microbes are currently unknown, especially in placentation and the early stage of pregnancy. Methods The immortalized human first-trimester trophoblast cell line HTR-8/SVneo was cultured in the presence or absence of Lactobacillus crispatus. Invasive and migrative activities were directly evaluated using an optical microscope and a time-lapse imaging system. Protein levels of the invasion-related protein matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9 were evaluated using ELISA. Results Matrigel invasion of HTR-8/SVneo cells was significantly increased by L. crispatus, though migration was not affected. The culture supernatant of L. crispatus also promoted invasion. Additionally, levels of the active forms of MMP-1 and MMP-2 in the cell culture medium were upregulated by L. crispatus treatment, but that of MMP-9 was not changed. Discussion L. crispatus promotes trophoblast invasion with an increase in MMP-1 and MMP-2 activation. Our results might explain why Lactobacillus dominance in the endometrium seems beneficial for implantation. Nevertheless, further research is required to determine whether the promotion of trophoblast invasion by L. cripatus is favorable for successful placentation at the early stage of pregnancy.

Sumo is a traditional Japanese full-contact wrestling sport. Among sumo wrestlers, Ikezuki Geitazaemon (1827–1850) was one of the most famous wrestlers due to his large body size. Here, we hypothesize that the legendary Japanese sumo wrestler could have had gigantism or acromegaly, which are disorders caused by the hypersecretion of growth hormone (GH). GH-secreting pituitary adenoma leads to the hypersecretion of GH and insulin-like growth factor-1 (IGF-1). If GH-secreting pituitary adenoma develops during childhood/puberty, it can cause gigantism. Adenomas also occur in over 95% of patients with acromegaly. Based on his substantial height (227 cm), Geitazaemon may have had gigantism, or acromegaly considering his characteristics of mandibular prognathism, enlarged fingertips, and heel pad thickness, as shown in woodblock prints (ukiyo-e). He would thus be the first recorded patient with gigantism or acromegaly in premodern Japan.

Problem The functions of vaginal lactobacilli in susceptibility to infectious diseases as regards epithelial barrier integrity and wound healing remain incompletely understood. Method of study Lactobacillus crispatus, one of the most common Lactobacillus species in the vagina and among the most protective against sexually transmitted infections, was cocultured with an immortalized human vaginal epithelial cell line (MS74), and a scratch assay was performed to evaluate re-epithelialization. The concentration of vascular endothelial growth factor A (VEGF) was measured using enzyme-linked immunosorbent assay (ELISA). An immunofluorescence assay was performed to locate the expression of VEGF and VEGF receptor (VEGFR) 1 and 2. The effects of the bacterial supernatant of L. crispatus were also evaluated. Results Lactobacillus crispatus significantly accelerated re-epithelialization of MS74 cells, accompanied by an increase in VEGF concentration. In contrast, heat-killed L. crispatus did not show this effect. The bacterial supernatant of L. crispatus also induced re-epithelialization. The immunoreactivity of VEGF was higher at the scratched edge, whereas VEGFR1 and 2 stained site-independently. Recombinant VEGF induced cell migration in a dose-dependent manner. The bacterial supernatant of L. crispatus also significantly accelerated re-epithelialization in MS74 cells and increased the concentration of VEGF in the culture 24 hours after the scratch. Conclusion These results may enhance our knowledge of the importance of L. crispatus in the healing of damaged vaginal epithelium and protection against the consequent risk of pathogenic infections, such as human immunodeficiency virus (HIV), and improve our understanding of vaginal epithelial barrier integrity maintenance by this bacterium.

Rubella virus (RuV), which belongs to the family Togaviridae and genus Rubivirus, causes systemic infection in children and young adults and congenital rubella syndrome in developing fetuses if the infection occurs during pregnancy. The mechanisms of fetal infection by RuV are not completely understood. Myelin oligodendrocyte glycoprotein (MOG) is reported to be a cellular receptor for RuV; however, it is mainly expressed in the central nervous system. Therefore, it is thought that other receptors are also responsible for virus entry into susceptible cells. In this study, we found that first-trimester trophoblast cells were resistant to RuV. In addition, we showed that HaCaT cells (an immortalized keratinocyte cell line) that did not express MOG on their surface were infected with RuV. This finding is one of the first demonstrations of MOG-independent RuV infection of susceptible host cells and suggests that it is important to continue searching for alternative RuV receptors. In addition, this study reports the resistance of first-trimester trophoblast cells to RuV and suggests that utilizing an epithelial–mesenchymal transition approach to study the mechanisms of transplacental vertical RuV infection.

Background High-mobility group box 1 (HMGB1), a DNA-binding protein, has recently been shown to have effects on HIV replication, but the effects are dependent on the cell type and the timing of infection. Using human primary T cells, this study aimed to investigate the role of HMGB1 in HIV-1 replication in newly infected cells. Methods Human primary T cells were infected with the HIV-1 LAI (X4) strain and then cultured in the presence of recombinant HMGB1 protein or an anti-HMGB1 antibody at various concentrations. At the indicated time points, HIV-1 p24 concentrations in the culture media were measured by ELISA. Cell proliferation, basal HMGB1 concentration, and CD3, CD4, CXCR4, and receptor for advanced glycation end products (RAGE) expression were also examined. Results Recombinant HMGB1 could enhance HIV replication in newly infected primary T cells. In the presence of an anti-HMGB1 antibody (5 µg/mL or higher), significantly lower concentrations of HIV-1 p24 were observed in the cultures of primary T cells during the post-infection period. Conclusions The data presented suggest that HMGB1 plays a role in the enhancement of HIV-1 replication in newly infected T cells. This finding provides useful information toward understanding HIV pathogenesis and for the development of new therapeutic strategies.

Thalidomide, an inhibitor of tumor necrosis factor-α (TNF-α) production, has been indicated to be useful for many inflammatory and oncogenic diseases. In the present study, we examined whether thalidomide (50 mg/kg/day, p.o.) has a protective effect against N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity in rats. A morphometric analysis showed that systemic administration of thalidomide protects neural cells in the ganglion cell layer (GCL) in a dose-dependent manner and significantly decreases the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in GCL and in the inner nuclear layer (INL). ELISA showed that thalidomide significantly suppressed the elevation of TNF-α 6 and 24 hr after an NMDA injection. Western blot analysis revealed a significant increase in nuclear factor-κB (NF-κB) p65 level in the retinas treated with NMDA at 24 hr after the injection, but not at 6 or 72 hr. Furthermore, an increase in p-JNK and p-p38 levels was also observed in the retina after NMDA injection. Thalidomide suppressed the increased expressions of NF-κB p65, p-JNK, and p-p38 after NMDA injection. Immunohistochemical analysis showed that thalidomide attenuated NF-κB p65 immunoreactivity in the GCL induced by NMDA treatment. In the NMDA-treated group, translocation of NF-κB p65 from the cytoplasm to the nucleus was detected in TUNEL-positive cells exposed to NMDA treatment. These results suggest new indications for thalidomide against neurodegenerative diseases.

This study is for chemoradiotherapy of unresectable and recurrent cholangiocarcinoma (CCC).Between April 2005 and March 2007, 5 patients were evaluated for unresectable and recurrent CCC. All patients were performed percutaneous transhepatic biliary drainage (PTBD) and treated with chemoradiotherapy. The radiation method was an external beam radiotherapy (EBRT) and remote after loading system (RALS). The chemotherapy was 5-FU and gemcitabine by intravenous injection.Three patients had unresectable and 2 had recurrent CCC. As for the side effects, 4 patients had a slight neutropenia and 1 had an uncontrollable gastric bleeding. No patient had cholangitis. The mean survival time for unresectable and recurrent CCC was 13.7 months and 17 months, respectively.Our results indicated that chemoradiotherapy had been consistent with efficacy in patients with unresectable and recurrent CCC.