Dementia is one of the priority public health problems in the older population, and the number of people with dementia is steadily increasing. The longitudinal association of muscle strength with risk of new-onset cognitive dysfunction in a general population including middle and older adults remains unknown. The purpose of this study was to investigate the effects of low muscle strength on risk for new-onset cognitive dysfunction over 6 years using a large nationwide sample of cognitively healthy adults. Study participants included 6,435 middle and older adults (33,554 person-years of follow-up), using data from the Korean Longitudinal Study of Ageing 2006-2012. Muscular strength was measured using the maximum handgrip strength of each participant as an index of muscle quality. Low muscle strength was defined as one standard deviation below the mean using the handgrip strength index based on the study population. Cognitive function was evaluated using the Mini-Mental Status Evaluation. The hazard ratio (HR) for cognitive dysfunction significantly and linearly increased according to muscle strength status independent of potential confounding factors (HR: 1.36, 95% confidence interval [CI]: 1.18-1.56 for low vs. normal-high group). Using stratified analyses, a significant association between muscle strength status and risk of cognitive impairment was observed in those with low physical activity, but not those with high physical activity. We show that handgrip strength is associated with increased risk of new-onset cognitive dysfunction over 6 years of follow-up in cognitively healthy middle aged and older adults at baseline.

Exercise induces the expression of peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) in skeletal muscle, which promotes the cleavage of fibronectin type III domain-containing protein 5 (FNDC5) to irisin. To explore the relationship between irisin and its regulators, we analyzed the plasma irisin levels and the muscle levels of FNDC5 and PGC-1α after exercise. Male C57BL/6J mice underwent a treadmill exercise (60% of VO_2max) for 30 min or one hour (h), and blood and gastrocnemius samples were collected before exercise (pre-exercise), immediately after exercise, and during 24-h recovery after 1-h exercise. We found that plasma irisin levels were significantly increased during exercise (P < 0.05), while FNDC5 protein levels were not significantly increased. Moreover, PGC-1α mRNA and protein levels were significantly increased during 30-min exercise, but were decreased during 1-h exercise. After 1-h exercise, the irisin levels peaked at 6 h (20.71 ± 0.25 ng/ml) and decreased to pre-exercise levels by 24 h (15.45 ± 0.27 ng/ml). Likewise, PGC-1α mRNA and protein levels were increased at 1 h and maintained at elevated levels for 6 h; thereafter, the expression levels of PGC1-α protein were decreased to pre-exercise levels at 12 h. Thus, the restoration of PGC-1α expression to the pre-exercise levels was followed by the decrease in plasma irisin levels. By contrast, during 24-h recovery, the expression levels of FNDC5 mRNA and protein were maintained at elevated levels. These results suggest that the coordinated expression of FNDC5 and PGC-1α may contribute to the increased levels of plasma irisin after exercise.

Congenital cataract is leading cause of visual impairment and blindness in children worldwide. Approximately one-third of congenital cataract cases are familial, whose genetic etiology can be distinguished by targeted exome sequencing. Here, a three-generation congenital cataract pedigree was recruited, and physical and ophthalmologic examinations were taken. Targeted exome sequencing of 139 cataract-related genes was performed on the proband III:1. Sanger sequencing was used to validate the presence of variation identified via exome sequencing in family members and 200 controls. Conservative and functional prediction was performed with bioinformatic tools. We, thus, found a heterozygous missense mutation c.10T>A (p.W4R) in gap junction protein alpha 8 (GJA8) in the patients. However, this mutation was not present in normal family members and 200 unrelated controls. The GJA8 gene encodes a gap junction protein, connexin 50 (Cx50), in lens fibers that provide channels for exchange of ions and small molecules between adjacent cells. Conservative and functional prediction suggests that the W-to-R substitution at codon 4 may impair the function of the human Cx50 protein. Accordingly, we analyzed the distribution of Flag-tagged mutant Cx50 protein in HeLa cervical cancer cells. Immunofluorescent staining showed that the W-to-R substitution impaired Cx50 trafficking to the plasma membrane to form the gap junction. In conclusion, c.10T>A (p.W4R) in GJA8 is the newly identified genetic cause of familial congenital cataract. The W-to-R substitution near the amino-terminus may alter the localization of mutant Cx50, thereby impairing gap junction formation, which is the molecular pathogenic mechanism of this mutation.

Host-derived factors alter gut microenvironment, and changes in gut microbiota also affect biological functions of host. Alterations of gut microbiota have been reported in a wide variety of diseases, but the whole picture of alterations in pancreatic diseases remains to be clarified. In particular, the gut microbiota may be affected by malnutrition or impaired exocrine pancreas function that is associated with pancreatic diseases. We here conducted comprehensive analysis of gut microbiota in patients with type 1 autoimmune pancreatitis (AIP), a pancreatic manifestation of the systemic IgG4-related disease, and chronic pancreatitis (CP). The two diseases were selected, because altered immune reactions in AIP and/or long-standing malnutrition in CP may influence the gut microbiota. Fecal samples were obtained from 12 patients with AIP before the steroid therapy and 8 patients with CP. Metagenome DNA was extracted, and microbiota was analyzed by next generation sequencing. Gut microbiota profiles were different between patients with AIP and those with CP; namely, the proportions of Bacteroides, Streptococcus and Clostridium species were higher in patients with CP. The reasons for the increased proportion of these bacterial species remain unknown, but may reflect malabsorption and/or decreased pancreatic enzymes, both of which are associated with CP. Incidentally, the identified Streptococcus species are oral cavity inhabitants and also known as pathogens for endocarditis. Despite the small sample size, this study has shown the differences in gut microbiota profiles between AIP and CP. Comprehensive analysis of the gut microbiota may be useful for the differential diagnosis of pancreatic diseases.

Premenstrual syndrome (PMS) is psychosomatic disorder that are limited to the late luteal phase in the menstrual cycle. PMS could impair athletic performance. To investigate associations between proportions of dietary plant and animal protein and PMS-related impairment of athletic performance, we surveyed 135 female athletes aged 18-23 years attending Kindai University. Participants belonged to authorized university clubs, all of which have high rankings in Japanese university sports. Participants completed self-administered questionnaires on diet history, demographics, and PMS-related impairment of athletic performance. Total protein, animal protein, and plant protein intake were examined, and the proportion of dietary plant protein was calculated for each participant. We divided athletes into two groups: those without PMS-related impairment of athletic performance (n = 117) and those with PMS-related performance impairment (n = 18). A t-test was used to compare mean values and multivariable adjusted mean values between groups; adjustment variables were energy intake, body mass index, and daily training duration. Total protein intake was not significantly different between the groups. However, athletes whose performance was affected by PMS reported higher intake of animal protein (mean 50.6 g) than athletes whose performance was unaffected by PMS (mean 34.9 g). Plant protein intake was lower among athletes with PMS-related impairment (mean 25.4 g) than among athletes without impairment (mean 26.9 g). The proportion of dietary plant protein was lower among athletes with PMS-related impairment (39.3%) than those without impairment (45.9%). A low proportion of dietary plant protein may cause PMS-related athletic impairment among athletes.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Its histological characteristics, such as progressive intrahepatic bile duct destruction, cholestasis, and liver cirrhosis, are caused by the body’s autoimmune disorders. Interleukin (IL)-35 has two subunits (p35 and Ebi3) and is a member of the IL-12 family of heterodimeric cytokines. IL-35 has immunosuppressive functions and plays an important role in many autoimmune diseases. In this study, we compared plasma levels of IL-35 and relative mRNA expression levels of p35 and Ebi3 in peripheral blood mononuclear cells (PBMCs) from 70 PBC patients and 70 healthy individuals. The results showed that the relative expression levels of Ebi3 mRNA were lower in PBMCs from PBC patients than in PBMCs from healthy individuals, whereas the levels of p35 mRNA were similar in both groups. Plasma IL-35 concentrations were lower in patients with PBC than in healthy individuals. Plasma levels were higher in PBC patients at an advanced stage compared to patients at an early stage. Variable plasma levels with different stages were also found in transforming growth factor beta (TGF-β), which is mainly produced by regulatory T cells (Tregs). IL-35 and TGF-β levels were positively correlated with each other, and IL-35 was capable of promoting the inhibitory functions of Tregs in PBC patients at both the early and late stages of disease. Lower plasma IL-35 levels were accompanied by higher levels of typical clinical parameters, such as alkaline phosphatase, or of proinflammatory cytokines, such as interferon-gamma (IFN-γ), in PBC patients (P < 0.05 for each). We propose that IL-35 may be involved in the pathogenesis of PBC and could be a potential biomarker for diagnosing this disease.

Primary lung cancer is the most frequent cause of cancer-related deaths worldwide. Cisplatin has been used as a key drug in the treatment for patients with lung cancer; however, most of the patients failed to respond to cisplatin within several months, and the mechanisms underlying the cisplatin resistance have not been fully elucidated. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein in the formation of inflammasomes. ASC is also involved in apoptotic signaling. Importantly, ASC expression is decreased in lung cancer and various cancers, but its precise function in tumor progression remains unknown. To explore the hitherto unknown role of ASC in lung cancer, we initially searched for lung cancer cell lines with higher expression levels of ASC using Cancer Cell Line Encyclopedia (CCLE) database, thereby identifying the A549 human non-small cell lung cancer cell line. Accordingly, with retroviral shRNA, the expression of ASC was forced to decrease in A549 cells. Stable ASC-knockdown cells, thus established, showed the increased activities of proliferation, motility, and invasion, compared with control cells. Importantly, ASC-knockdown cells also became resistant to cisplatin, but not to other anti-cancer agents, 5-fluorouracil and paclitaxel. Bcl-2 and phospho-Src levels were increased in ASC-knockdown cells. A Bcl-2 inhibitor, ABT-199, induced an apoptotic response in ASC-knockdown cells, and dasatinib, a Src inhibitor, blocked cell invasiveness. Thus, ASC may be involved in tumor suppression and cell death via Bcl-2 and pSrc. Targeting Bcl-2 and Src in ASC-downregulated populations of lung cancer may improve treatment outcome.

Leukemoid reaction (LR) is a reactive disease that exhibits abnormal blood values similar to leukemia, but not due to leukemia. One report showed that neonatal LR (NLR) was associated with elevated serum granulocyte colony stimulating factor (G-CSF) in only 30% of the study neonates. NLR is not always associated with the elevation of serum G-CSF. NLR was defined as a white blood cell count of ≥ 40 × 10³/μL and/or blast cell concentration of > 2%. We have focused on NLR with fetal inflammatory response syndrome (FIRS), defined as a fetal systemic inflammatory reaction triggered by intrauterine infection. FIRS was diagnosed based on a cord serum interleukin-6 (IL-6) concentration ≥ 17.5 pg/mL and histopathological chorioamnionitis. Because NLR is highly associated with FIRS, we have hypothesized that NLR is associated with the elevation of both G-CSF and IL-6. This is the first report to measure multiple cytokines in NLR at the same time. The study comprised 19 preterm infants with FIRS: 8 with NLR (study group) and 11 without NLR (control group). Serum G-CSF and IL-6 concentrations were significantly higher in the study group than the control group. There was a positive correlation between G-CSF and IL-6 levels in the study group but not in the control group. These results suggest that elevated serum G-CSF and IL-6 may underlie NLR. Thus, G-CSF and IL-6 concentrations may be predictive of the onset of NLR. Measuring these cytokines is useful for judging the prognosis of preterm infants and for their post-natal clinical management.

Saltatory conduction is an essential phenomenon to facilitate the fast conduction in myelinated nerves. The conventional conductive models assumed electric circuits with local current along the axonal membrane to explain the nerve conduction in unmyelinated nerves. However, whether such models with local current can be also applied to the saltatory conduction in myelinated nerves is unknown. In this report, I propose a new model of saltatory conduction by focusing on the behavior of electric charges in the axoplasm, not limited to the membrane. In myelinated nerves, because of the large internodal length and the low ion channel density in the internodal segment, the whole cross-section of the internodal axoplasm would contribute to the signal conduction. Because the conducted signals originate from the sodium ion influx through the voltage-gated sodium (NaV) channel at the Ranvier’s nodes, an individual conducted signal can be described as a single electrostatic compressional wave of positive charges in the internodal axoplasm. Based on this model, the total number of NaV channels in one Ranvier’s node would regulate the strength of the wave. Also, the internodal length would be important for the faster conduction in larger myelinated axons. Based on the linear relationships between axonal diameter, internodal length, and conduction velocity, the internodal length would be inversely proportional to the ratio of the transmitted overall wave strength at a Ranvier’s node to the original strength at the proximal adjacent node. This new mathematical model may have wide applicability and usability for the conduction in myelinated nerves.

Healthcare utilization after natural disasters remains understudied. In general, people in Japan pay 10%-30% of total amount of costs, according to their health insurance plan. A policy exempting survivors from copayments was introduced after the Great East Japan Earthquake in March 2011, which had a magnitude of 9.0 on the Richter scale and followed by devastating tsunamis. Among the disaster-affected areas, Miyagi prefecture experienced the largest number of deaths and the greatest extent of damage. However, the exemption was suspended in Miyagi prefecture from April, 2013, because of the huge governmental financial burden due to the immensity of damage from the disaster. Subsequently, in April 2014, the exemption was re-introduced, with smaller coverage. We, therefore, evaluated the influence of this policy change on monthly healthcare utilization in Miyagi prefecture between April 2008 and June 2015. We also evaluated the association between the proportion of people exempted from copayment in each municipality and the difference in healthcare utilization before and after the suspension using multivariable linear regression. Healthcare utilization in Miyagi increased immediately after the institution of the exemption policy and it peaked after one year. In March 2013, just before the suspension, a rapid increment in healthcare utilization was observed, suggesting that the copayment may be a barrier for people in the disaster-affected area to access to healthcare. The exemption policy did help the survivors to use healthcare utilization in Miyagi. After devastating natural disasters, policymakers should guarantee that all survivors can utilize healthcare services on demand.

Retracted Review article: Nucleophagy in Human Disease: Beyond the Physiological Role. [Tohoku J. Exp. Med., 2018, 244 (1), 75-81. doi: 10.1620/tjem.244.75.]

The above Review article was published online on January 27, 2018. Soon after its publication (on February 1, 2018), Dr. Nian Fu and Prof. Linxi Chen informed the Editor-in-Chief, The Tohoku Journal of Experimental Medicine (TJEM), about serious violation of publication ethics. Indeed, Dr. Nian Fu and Prof. Linxi Chen were astonished to find their names as coauthors of this Review article, because they were not involved in the submission process of this Review article and they do not know any of other coauthors. In addition, the Review article is similar to their unpublished manuscript.

After a thorough investigation in accordance with the recommendations of the Committee on Publication Ethics (COPE), the Editor-in-Chief of TJEM decided to retract this Review article. The reasons for Retraction are summarized below: forged authors and an unexpected case of plagiarism.

Forged authors: Dr. Nian Fu and Prof. Linxi Chen were added as co-authors of the Review article without their knowledge. In fact, the signature provided by Prof. Linxi Chen is apparently different from the signature of a coauthor, named Linxi Chen, on the AUTHORS’ RESPONSIBILITY FORM, provided by the corresponding author of the Review article. More critically, the signature provided by Dr. Nian Fu is completely different from the signature of Nian Fu, because the Chinese characters are different between the two signatures. In addition, the replies from three authors (Ming Zhou, Hongwen Ji and Yong Xia) clearly indicate that they misunderstand the identity of Dr. Nina Fu. We also attempted to contact two authors, named Nian Fu and Linxi Chen, via e-mail. As expected, the forged authors did not respond to our inquiries, despite that their e-mail addresses appear to be active.

An unexpected case of plagiarism: This Review article is similar to the unpublished manuscript prepared by Dr. Nian Fu and Prof. Linxi Chen. Moreover, two figures used in the Review article are identical to the preliminary figures of their unpublished manuscript. According to Dr. Nian Fu, a local agency for language editing had transferred their unpublished manuscript to a third party. Unfortunately, the check system of TJEM is not effective for plagiarism of unpublished materials. We believe that the corresponding author of the Review article included the names of the original two authors to avoid the criticism of plagiarism. Eventually, the corresponding author agreed to retract the Review article.

We apologize for any inconvenience caused by this retraction to readers. We also hope that the publication of the plagiarized Review article will not trouble Dr. Nian Fu and Prof. Linxi Chen too much.