The formation and conduction of electrocardiosignals and the synchronous contraction of atria and ventricles with rhythmicity are both triggered and regulated by the cardiac conduction system (CCS). Defect of this system will lead to various types of cardiac arrhythmias. In recent years, the research progress of molecular genetics and developmental biology revealed a clearer understanding of differentiation and development of the cardiac conduction system and their regulatory mechanisms. Short stature homeobox 2 (Shox2) transcription factor, encoded by Shox2 gene in the mouse, is crucial in the formation and differentiation of the sinoatrial node (SAN). Shox2 drives embryonic development processes and is widely expressed in the appendicular skeleton, palate, temporomandibular joints, and heart. Mutations of Shox2 can lead to dysembryoplasia and abnormal phenotypes, including bradycardiac arrhythmia. In this review, we provide a summary of the latest research progress on the regulatory effects of the Shox2 gene in differentiation and development processes of the cardiac conduction system, hoping to deepen the knowledge and understanding of this systematic process based on the cardiac conduction system. Overall, the Shox2 gene is intimately involved in the differentiation and development of cardiac conduction system, especially sinoatrial node. We also summarize the current information about human SHOX2. This review article provides a new direction in biological pacemaker therapies.

The cytokine interleukin-21 (IL-21) is mainly produced from activated CD4⁺ T cells and natural killer T (NKT) cells. IL-21 enhances the proliferation and differentiation of T cells and B cells and also increases cytotoxicity of CD8⁺ T cells and NK cells through the IL-21 receptor and its downstream signaling molecules such as signal transducers and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2). SH2 domain-containing tyrosine phosphatase (SHP-2) is ubiquitously expressed, including hematopoietic cells. SHP-2 has been implicated in the regulation of IL-6 and IL-3 signaling, but its function in IL-21 signaling has not been investigated. Therefore, we studied the role of SHP-2 in IL-21 signaling by SHP-2 overexpression and knockdown experiments. For the SHP-2 overexpression, we used 293T human embryonic kidney cells, in which the IL-21 receptor system were easily reconstituted and high amounts of exogenous SHP-2 were expressed by vector transfection. In 293T cells, overexpressed SHP-2 caused the increase in the degree of the IL-21-induced ERK1/2 activation. Subsequently, SHP-2 knockdown experiments were performed in the mouse pro-B cell line, BAF21RWT-1, which constitutively expresses human IL-21 receptor and proliferates in an IL-21-dependent manner. SHP-2 knockdown reduced the degree of the IL-21-induced ERK1/2 activation and suppressed cell proliferation. These results suggest that SHP-2 may augment the ERK1/2 activity and cell proliferation activity in IL-21 signaling. We propose that SHP-2 is involved in the IL-21-mediated ERK1/2 activation and cell proliferation.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile duct, representing the second most common primary liver cancer. Wntless (Wls) is a highly conserved transmembrane protein that shuttles palmitoylated Wnt proteins from the endoplasmic reticulum to the plasma membrane. Wls is highly expressed in various types of cancers and is essential for cell proliferation, anti-apoptotic activity, and survival. The profile of Wls expression and its clinical significance has not been well clarified in ICC. In the present study, we analyzed Wls expression in a set of ICC tissues (n = 44) by immunohistochemistry and the relationship between Wls expression and clinicopathological parameters. Immunoreactive Wls was detected in normal cholangiocytes, but was undetectable in normal hepatocytes. The intensity for immunoreactive Wls was varied, depending on ICC specimens. The degree of Wls expression was scored as 0 or 1+ in 8 specimens (18.2%), 2+ in 24 (54.5%), and 3+ in 12 (27.3%) out of the 44 ICC specimens, based on the staining intensity and percentage of Wls-positive cells. In normal cholangiocytes, the scores were varied from 0 to 2+. The intensity of Wls expression was positively associated with tumor stage (T stage, P = 0.005, r = 0.413), tumor-node-metastasis stage (TNM stage, P = 0.000, r = 0.548), and lymphatic invasion (P = 0.000, r = 0.548). Our results show that Wls is differentially expressed in ICC tissues and positively related to tumor stage and lymphatic invasion. Wls is a potential marker for advanced tumor stage and metastasis in ICC.

Ankle and foot injuries are common among athletes and physically active individuals. The most common residual disability, ankle sprain, is characterized by instability along with postural sway. If the supporting structures around a joint become lax, posture stability and balance are also affected. Previous studies have examined muscle stiffness and elasticity and postural sway separately; however, the relationship between these factors is yet unknown. It is well known that the levels of sex hormones, especially estrogen, change in women over the phase of the menstrual cycle. Therefore, this study examined the relationship between the mechanical properties of tissue and balance activity using a non-invasive digital palpation device to determine if they undergo any changes over the menstrual cycle in young women. Sixteen young women with regular menstrual cycles completed the study. Tone, stiffness, and elasticity of the ankle muscles (lateral gastrocnemius, peroneus longus, and tibialis anterior) were measured using a non-invasive digital palpation device. Postural sway was recorded while the participants performed balance tasks during ovulation and menstruation. Significantly greater posture sway characteristics and ankle muscle elasticity were found during ovulation than during menstruation; lower tone and stiffness of the ankle muscles were observed at ovulation (p < 0.05). Additionally, weak-to-strong relationships between ankle muscle mechanical properties and postural sway characteristics were found (p < 0.05). These results suggest the effect of estrogen on human connective tissues. We therefore postulate that estrogen increases joint and muscle laxity and affects posture stability according to the phase of the menstrual cycle.

Health care disparities among people with schizophrenia is a global concern. Our previous study revealed cancer screening rates in Japanese people with schizophrenia lower than rates of approximately 40% of the general population. However, that study was based on self-reports, which can be inaccurate, and rates did not differentiate the types of cancer screening provider (i.e., municipal screening, collective opportunistic screening, and individual opportunistic screening). This study aimed to investigate records-based cancer screening rates, focusing on participation rates of people with schizophrenia who are subject to municipal cancer screening programs. We conducted a cross-sectional study at a psychiatric hospital outpatient clinic from September to November 2016. We randomly extracted 420 potential participants from among 680 eligible patients and asked them to participate. We then selected subgroups of participants living in Okayama city who were enrolled in the National Health Insurance or Public Assistance systems and were subject to colorectal, gastric, lung, breast, or cervical cancer screening provided by Okayama city (n = 97, 96, 97, 42, and 64, respectively). Participation in cancer screenings was assessed based on local government records. Municipal cancer screening rates were as follows: 13.4% (95% confidence interval: 6.6%-20.2%) for colorectal, 7.3% (2.1%-12.5%) for gastric, 16.5% (9.1%-23.9%) for lung, 21.4% (9.0%-33.8%) for breast, and 14.1% (5.6%-22.6%) for cervical cancers. The findings demonstrated extremely low cancer screening rates among people with schizophrenia subject to municipal cancer screenings in Japan. A strategy to promote municipal cancer screening for people with schizophrenia is needed.

Curcuma longa is rich in curcumin and used to treat disease and in food as a spice, especially in curry dishes. The objective of the present study was to determine whether curry intake reduces blood levels of heavy metals and hypertension (HTN) using Korean National Health and Nutrition Examination Survey 2013 data (n = 1,350). Study subjects (n = 1,350) were divided into two groups: 1) a curry intake group (n = 603), members of which had consumed a curry dish more than once a month over the previous year, and 2) a non-curry intake group (n = 747). Analysis showed the curry intake group had significantly lower heavy metal blood concentrations (Pb, Hg, and Cd) and blood concentrations of heavy metals were significantly associated with prevalence of HTN (P < 0.001 for Pb, Hg, and Cd). Curry intake also reduced the risk of HTN prevalence (odd ratios for curry intake vs. non-curry intake; Pb, 1.503 vs. 1.862; Hg, 1.112 vs. 1.149; Cd, 1.676 vs. 1.988). Logistic regression analysis was used to confirm the association between blood heavy metal levels and HTN. After adjusting for age, sex, lifetime smoking, and body mass index, the odd ratio of HTN was significant in the non-curry intake group, but not in the curry intake group, implying other factors influenced relations in the curry intake group. In view of the importance of curry consumption with reduced concentrations of heavy metals in blood and the prevalence of HTN, we suggest further well-designed clinical trials be conducted.

Opportunistic infections (OIs) are the most significant complication of human immunodeficiency virus (HIV) infection. The prevalence of OIs differs among various countries in part due to different climates and socio-economic conditions. We, therefore, carried out the retrospective study at the Public Health Clinical Center of Chengdu, Sichuan to comprehensively investigate the prevalence of OIs, predictors of OIs, and risk factors for in-hospital death among HIV-infected patients. Sichuan in West China is characterized by the largest population living with HIV/Acquired immunodeficiency syndrome (AIDS) across China. In total, we reviewed 954 cases of HIV infection, admitted to the hospital during January 2014 to December 2015, and found that bacterial pneumonia (25.8%) was the most common OIs, followed by candida infection (18.3%), Pneumocystis jiroveci pneumonia (11.9%), tuberculosis (11.5%), infectious diarrhoea (9.3%), cryptococcus infection (7.3%), cytomegalovirus infection (4.9%), toxoplasmosis (4.6%), hepatitis C (4.0%), nontuberculous mycobacteria desease (2.2%) and Penicillium marneffei infection (0.3%). We also found two strongest risk factors for in-hospital mortality: CD4+T cell counts of less than 100 cells/μL and not receiving antiretroviral therapy. Moreover, the study revealed the specific pathogens causing bacterial pneumonia and/or candida infection, the effect of tuberculosis on CD4+T cell counts, and the drug resistance of Mycobacterium tuberculosis among HIV-infected and non-HIV-infected patients. The present findings may aid in the clinical diagnosis and treatment of HIV-infected patients, and could help developing efficient public health strategies in China.

Up to 8% of pregnant women suffer from preeclampsia (PE), a deadly disease characterized by high blood pressure (BP), blood vessel damage, called endotheliosis (vascular endothelial swelling with narrowing of capillary lumen), and high levels of protein in the urine. PE is often associated with premature delivery, which is a risk factor of cardiovascular and metabolic diseases among the offspring. Accordingly, establishing drug treatments of PE is in immediate needs. Currently, many of anti-hypertensive drugs cause malformation of the fetuses and are contraindicated for pregnant women. Anti-hypertensive drugs that are allowed to be used for treating pregnant women could lower BP of the mothers and reduce the risk of maternal death due to cardiovascular diseases such as cerebral hemorrhage. However, these anti-hypertensives do not improve endotheliosis and proteinuria. In fact, they reduce blood supply to the placentae and fetuses, which could lead to fetal growth restriction (FGR) and fetal and neonatal death. Until now, the only treatment for preeclamptic women has been delivery of the baby and placenta. Using three mechanistically different mouse models of PE, we have found that vitamin B₃ nicotinamide (Nam) is the first safe drug that alleviates PE, and that Nam also alleviates or prevents miscarriage, prolongs pregnancy period, and improves the growth of the fetuses in mice with PE. Importantly, Nam has been used for pregnant and nursing women who have difficulty in taking sufficient meal. Nam could help treat or prevent PE and FGR associated with PE, if the treatment works in humans.