Methods for health workforce projection model: systematic review and recommended good practice reporting guideline.

BACKGROUND: Health workforce projection models are integral components of a robust healthcare system. This research aims to review recent advancements in methodology and approaches for health workforce projection models and proposes a set of good practice reporting guidelines. METHODS: We conducted a systematic review by searching medical and social science databases, including PubMed, EMBASE, Scopus, and EconLit, covering the period from 2010 to 2023. The inclusion criteria encompassed studies projecting the demand for and supply of the health workforce. PROSPERO registration: CRD 42023407858. RESULTS: Our review identified 40 relevant studies, including 39 single countries analysis (in Australia, Canada, Germany, Ghana, Guinea, Ireland, Jamaica, Japan, Kazakhstan, Korea, Lesotho, Malawi, New Zealand, Portugal, Saudi Arabia, Serbia, Singapore, Spain, Thailand, UK, United States), and one multiple country analysis (in 32 OECD countries). Recent studies have increasingly embraced a complex systems approach in health workforce modelling, incorporating demand, supply, and demand-supply gap analyses. The review identified at least eight distinct types of health workforce projection models commonly used in recent literature: population-to-provider ratio models (n = 7), utilization models (n = 10), needs-based models (n = 25), skill-mixed models (n = 5), stock-and-flow models (n = 40), agent-based simulation models (n = 3), system dynamic models (n = 7), and budgetary models (n = 5). Each model has unique assumptions, strengths, and limitations, with practitioners often combining these models. Furthermore, we found seven statistical approaches used in health workforce projection models: arithmetic calculation, optimization, time-series analysis, econometrics regression modelling, microsimulation, cohort-based simulation, and feedback causal loop analysis. Workforce projection often relies on imperfect data with limited granularity at the local level. Existing studies lack standardization in reporting their methods. In response, we propose a good practice reporting guideline for health workforce projection models designed to accommodate various model types, emerging methodologies, and increased utilization of advanced statistical techniques to address uncertainties and data requirements. CONCLUSIONS: This study underscores the significance of dynamic, multi-professional, team-based, refined demand, supply, and budget impact analyses supported by robust health workforce data intelligence. The suggested best-practice reporting guidelines aim to assist researchers who publish health workforce studies in peer-reviewed journals. Nevertheless, it is expected that these reporting standards will prove valuable for analysts when designing their own analysis, encouraging a more comprehensive and transparent approach to health workforce projection modelling.

Questionnaire survey on the prevention and development of cervical cancer in patients with systemic lupus erythematosus in Japan.

OBJECTIVES: The aim is to evaluate the prevention and development of cervical cancer in systemic lupus erythematosus (SLE) patients in Japan and its background based on a questionnaire survey. METHODS: The questionnaire was handed to 460 adult female SLE patients at 12 medical institutions. The participants were grouped by age, and data related to their human papillomavirus vaccination status, age at first coitus, cervical cancer screening, and diagnosis of cervical cancer were analysed. RESULTS: A total of 320 responses were received. Patients aged 35-54 years included a higher proportion of patients whose age at first coitus was <20 years. This group also showed a higher rate of cervical cancer/dysplasia. Only nine patients had a human papillomavirus vaccination history. Adequate frequency of cervical cancer screening was slightly higher (52.1%) among SLE patients than in the Japanese general population. However, 23% of the patients had never undergone examination, primarily because of a feeling of troublesome. The incidence of cervical cancer was significantly higher among SLE patients. One reason for this may be associated with the use of immunosuppressants, although the difference was not significant. CONCLUSIONS: SLE patients are at a higher risk of cervical cancer and dysplasia. Rheumatologists should proactively recommend vaccination and screening examinations for SLE female patients.

Effectiveness and safety of subcutaneous abatacept in biologic-naïve RA patients at Week 52: A Japanese multicentre investigational study (ORIGAMI study).

OBJECTIVES: To evaluate the effectiveness and safety of abatacept over 52 weeks in biologic-naïve rheumatoid arthritis (RA) patients with moderate disease activity in the prospective, 5-year, observational study (ORIGAMI study) in Japan. METHODS: Abatacept (125 mg) was administered subcutaneously once a week. Clinical outcomes included Simplified Disease Activity Index (SDAI) remission at Week 52 (primary endpoint), Japanese Health Assessment Questionnaire (J-HAQ), EuroQol 5-Dimension Questionnaire (EQ-5D), treatment retention, and safety. The results were compared with those of conventional synthetic disease-modifying antirheumatic drug (csDMARD) controls from the ongoing Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry. RESULTS: Overall, 325 patients were enrolled, with a mean age of 66.9 ± 12.7 years. The proportion of patients achieving SDAI remission (≤3.3) at Week 52 was 18.9% (95% CI: 14.3-23.6) and low disease activity (≤11) was 53.3% (95% CI: 47.4-59.1). A significant improvement was observed in J-HAQ and EQ-5D over 52 weeks in both the abatacept and csDMARD groups. The probability of abatacept treatment retention at Week 52 was 69.9% (95% CI: 64.7-75.5). Adverse events and serious adverse events were reported in 50.0% and 12.1% of patients, respectively. CONCLUSIONS: Abatacept significantly improved disease activity, physical disability, and quality of life for up to 52 weeks in RA patients in a real-world setting.

Kinetics of Anti-SARS-CoV-2 Antibody Response Following Two Doses of the BNT162b2 mRNA Vaccine: A Japanese Single-Center Primary Care Clinic Report Involving Volunteers and Patients with Autoimmune Disease.

Despite the promising effectiveness of the coronavirus disease 2019 vaccination using an mRNA vaccine, the short efficacy duration and some poor responses to the vaccination remain major concerns. We aimed to clarify the monthly kinetics of the anti-SARS-CoV-2 spike receptor-binding domain antibody response after two doses of the BNT162b2 vaccine in a Japanese population. A chemiluminescent enzyme immunoassay (CLIA) and an enzyme-linked immunosorbent assay were used to measure the antibody levels in 81 Japanese adults (age, <65 years). The antibody levels increased 10-fold at 2−3 weeks following the second dose of BNT162b2 and declined thereafter to approximately 50%, 20%, and 10% of the peak levels at 2, 3, and 6 months, respectively. To compare the antibody titers among different groups, older adults (age, >65 years; n = 38) and patients with systemic lupus erythematosus (SLE, n = 14) were also investigated. A decline in the mean relative antibody titers was observed in older men compared with younger men and in patients with SLE compared with individuals aged <65 years. Although the antibody levels increased drastically following two BNT162b2 doses, they then declined rapidly. Furthermore, poor responders to the vaccination were observed. Repeated vaccinations are required to maintain high antibody levels.

Carnitine/organic cation transporter 1 precipitates the progression of interstitial fibrosis through oxidative stress in diabetic nephropathy in mice.

Carnitine/organic cation transporter 1 (OCTN1) is the only known uptake transporter for ergothioneine which is a food-derived strong antioxidant amino acid that is absorbed by OCTN1. We previously reported the roles of OCTN1/ergothioneine in the progression of kidney fibrosis in ischemic kidney disease. In this study, we evaluated the roles of OCTN1 in the progression of diabetic kidney disease. A diabetic kidney disease model was induced in octn1 knockout and wild-type mice by streptozotocin (STZ). Oxidative stress, represented by urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), were higher in the octn1 knockout mice. Azan- and Sirius red-positive areas increased significantly in the octn1 knockout mice. Gene expression was evaluated by cluster analysis, and shown to be different in the octn1 knockout mice compared with the wild-type mice. In a pathway analysis, the pathway associated with the cytoskeleton and cell adhesion increased. In accordance with interstitial fibrosis in octn1 knockout mice, gene expression of moesin in the injured kidney, known as an associated protein of cytoskeleton and cell membranes, was doubled 28 weeks after STZ injection. In addition, the moesin protein was expressed in a part of α-SMA-positive renal tubular epithelial cells. These findings were confirmed by cultured murine proximal tubular epithelial cells: The expression of moesin was induced under oxidative stress with hydrogen peroxide. These data indicate that OCTN1 would play some roles in progression of interstitial fibrosis under oxidative stress via moesin expression in diabetic kidney disease.

Distinct decrease in peripheral lymphocytes in EBER-positive cases of MTX-LPD.

OBJECTIVES: To determine the clinical characteristics of methotrexate-associated lymphoproliferative disorder (MTX-LPD). METHODS: In this study, 12 RA patients who developed MTX-LPD were assessed. The peripheral blood lymphocyte (PBL) count at the onset of MTX-LPD was compared to that 6 months before the onset, in Epstein-Barr virus-encoded RNA (EBER)-positive and -negative subgroups. We examined the change in the PBL count after MTX withdrawal. In patients with relapsed LPD, changes in the PBL count before relapse were also examined. RESULTS: Regression of LPD after MTX withdrawal was noted in eight patients. In these patients, the PBL count was decreased at the onset of MTX-LPD compared to 6 months before the onset; the decrease was significantly more prominent in EBER-positive patients. In cases of spontaneous regression of LPD, the PBL count recovered quickly after MTX withdrawal. Four of eight patients showed a recurrence of LPD after they improved following MTX withdrawal. These patients also exhibited a decreased PBL count at recurrence compared to 6 months before recurrence. CONCLUSION: A decrease in the PBL count might be involved in the pathogenesis of MTX-LPD, especially in EBER-positive cases and in patients with LPD relapse after MTX withdrawal following initial improvement.

Screening of a Panel of Low Molecular Weight Compounds That Inhibit Synovial Fibroblast Invasion in Rheumatoid Arthritis.

Increased invasion of synovial fibroblasts and their involvement in cartilage damage are characteristic phenotypes of rheumatoid arthritis (RA). To identify low molecular weight compounds that suppress synovial fibroblast invasion, a panel of inhibitors (n = 330) was initially screened using a real-time cell analysis system for human synovial fibroblasts that were enzymatically isolated from surgical samples of RA patients. To evaluate the effects of the inhibitors identified in the screen, synovial fibroblast migration was measured using a wound-healing assay, and phosphorylation of intracellular signaling molecules was determined by immunoblots. Several candidate inhibitors were identified in the screen, including inhibitors against platelet-derived growth factor receptor (PDGFR), Akt, PI3K, and glycogen kinase synthetase 3 (GSK-3). These inhibitors strongly suppressed synovial fibroblast migration after 72 h and downregulated phosphorylation of Akt (Ser473) at 48 h. When the inhibitors were removed from the culture conditions, both migration and phosphorylated Akt (Ser473) levels were restored. Furthermore, all the categories of inhibitors except for PDGFR inhibitor IV decreased cell proliferation as well as IL-6 production in synovial fibroblasts. Interestingly, GSK-3 inhibitors increased anti-inflammatory cytokine IL-10 production but suppressed IL-23 production from LPS-primed macrophages obtained from healthy donors. In conclusion, blocking PDGFR, PI3K, or GSK-3 could have therapeutic value as an RA treatment that targets the invasion/migration of synovial fibroblasts.

Generation and characterization of antagonistic anti-human interleukin (IL)-18 monoclonal antibodies with high affinity: Two types of monoclonal antibodies against full-length IL-18 and the neoepitope of inflammatory caspase-cleaved active IL-18.

Interleukin-18 (IL-18) is a pro-inflammatory cytokine that evokes both innate and acquired immune responses. IL-18 is initially synthesized as an inactive precursor and the cleavage for processing into a mature, active molecule is mediated by pro-inflammatory caspases following the activation of inflammasomes. Two types of monoclonal antibodies were raised: anti-IL-1863-68 antibodies which recognize full-length1-193 and cleaved IL-18; and anti-IL-18 neoepitope antibodies which specifically recognize the new N-terminal 37YFGKLESK44 of IL-18 cleaved by pro-inflammatory caspase-1/4. These mAbs were suitable for Western blotting, capillary Western immunoassay (WES), immunofluorescence, immunoprecipitation, and function-blocking assays. WES analysis of these mAbs allowed visualization of the IL-18 bands and provided a molecular weight corresponding to the pro-inflammatory caspase-1/4 cleaved, active form IL-1837-193, and not to the inactive precursor IL-18, in the serum of patients with adult-onset Still's disease (6/14, 42%) and hemophagocytic activation syndrome (2/6, 33%). These monoclonal antibodies will be very useful in IL-18 and inflammasome biology and for diagnostic and therapeutic strategies for inflammatory diseases.

Effects of Osthol Isolated from Cnidium monnieri Fruit on Urate Transporter 1.

(1) Background: Crude drugs used in traditional Japanese Kampo medicine or folk medicine are major sources of new chemical entities for drug discovery. We screened the inhibitory potential of these crude drugs against urate transporter 1 (URAT1) to discover new drugs for hyperuricemia. (2) Methods: We prepared the MeOH extracts of 107 different crude drugs, and screened their inhibitory effects on URAT1 by measuring the uptake of uric acid by HEK293/PDZK1 cells transiently transfected with URAT1. (3) Results: We found that the extract of the dried mature fruit of Cnidium monnieri inhibited urate uptake via URAT1. We isolated and identified osthol as the active ingredient from this extract. Osthol noncompetitively inhibited URAT1 with an IC50 of 78.8 µM. We evaluated the effects of other coumarins and found that the prenyl group, which binds at the 8-position of coumarins, plays an important role in the inhibition of URAT1. (4) Conclusions: Cnidium monnieri fruit may be useful for the treatment of hyperuricemia or gout in traditional medicine, and its active ingredient, osthol, is expected to be a leading compound for the development of new drugs for hyperuricemia.

Mindfulness as a Moderator in the Relation Between Income and Psychological Well-Being.

The relation between income and life satisfaction has been found to be weak, albeit positive (r = 0.10-0.20). This study introduced psychological well-being (PWB) as a dependent variable predicted by income in addition to life satisfaction. Furthermore, individual differences might determine the strength of this relation, that is, act as moderators. Thus, this study introduced mindfulness as one such possible moderator. Participants (N = 800, 50% women, aged 20-59 years) completed an Internet questionnaire. Of them, 734 reported income and were included in the analyses. Income had weak, yet positive, zero-order correlations with life satisfaction and PWB (r = 0.13 and 0.11). Hierarchical regression controlling for demographics indicated that the relation between income and PWB was moderated by mindfulness facets. Specifically, among those low in not judging or describing of experiences, PWB was positively related to income. On the other hand, those high in these mindfulness dimensions indicated higher PWB irrespective of income.

Impairment of the carnitine/organic cation transporter 1-ergothioneine axis is mediated by intestinal transporter dysfunction in chronic kidney disease.

Carnitine/organic cation transporter 1 (OCTN1) is a specific transporter of the food-derived antioxidant ergothioneine. Ergothioneine is absorbed by intestinal OCTN1, distributed through the bloodstream, and incorporated into each organ by OCTN1. OCTN1 expression is upregulated in injured tissues, and promotes ergothioneine uptake to reduce further damage caused by oxidative stress. However, the role of the OCTN1-ergothioneine axis in kidney-intestine cross-talk and chronic kidney disease (CKD) progression remains unclear. Here we assessed ergothioneine uptake via intestinal OCTN1 and confirmed the expression of OCTN1. The ability of OCTN1 to absorb ergothioneine was diminished in mice with CKD. In combination with OCTN1 dysfunction, OCTN1 localization on the intestinal apical cellular membrane was disturbed in mice with CKD. Proteomic analysis, RT-PCR, Western blotting, and immunohistochemistry revealed that PDZ (PSD95, Dlg, and ZO1), a PDZK1 domain-containing protein that regulates the localization of transporters, was decreased in mice with CKD. Decreased intestinal ergothioneine uptake from food decreased ergothioneine levels in the blood of mice with CKD. Despite increased OCTN1 expression and ergothioneine uptake into the kidneys of mice with CKD, ergothioneine levels did not increase. To identify the role of the OCTN1-ergothioneine axis in CKD, we evaluated kidney damage and oxidative stress in OCTN1-knockout mice with CKD and found that kidney fibrosis worsened. Oxidative stress indicators were increased in OCTN1-knockout mice. Moreover, ergothioneine levels in the blood of patients with CKD decreased, which were restored after kidney transplantation. Thus, a novel inter-organ interaction mediated by transporters is associated with CKD progression.

Attention Moderates the Relationship Between Primary Psychopathy and Affective Empathy in Undergraduate Students.

Psychopathy is personality traits, which is consisted of primary psychopathy characterized by affective and interpersonal problems and secondary psychopathy characterized by behavioral problems. Prior researchers have suggested that people with psychopathy have peculiar attention, which prevents them from detecting information peripheral to their concern, and we hypothesized that this explains their low empathy. Based on these reasoning, the present study assessed whether attention moderates the relationship between psychopathy and affective empathy. Eighty-five undergraduates (40 men and 45 women; mean age = 19.8 years; SD = 1.6) completed the Levenson Self-Report Psychopathy Scale, the Interpersonal Reactivity Index, and a perceptual load task. Hierarchical regression showed that a significant moderation effect was found: primary psychopathy was negatively associated with affective empathy, among those with reduced interference from task-irrelevant stimuli under a medium level of perceptual load. Future study should need to replicate this finding with clinical population.

Relationships Between Refraining From Catastrophic Thinking, Repetitive Negative Thinking, and Psychological Distress.

Skills to refrain from catastrophic thinking were negatively related to worry and a wide range of psychological distress. Repetitive negative thinking (including worry) is proposed as a common etiological factor for a wide range of psychological distress. Therefore, reduced repetitive negative thinking would mediate the negative relation between refraining from catastrophic thinking and psychological distress (depression, social anxiety, phobia, generalized anxiety, and obsessions and compulsions). As an overlap between five indices of psychological distress was expected, we first computed latent factors underlying them, which were then predicted by refraining from catastrophic thinking and repetitive negative thinking. Cross-sectional questionnaire data from 125 nonclinical voluntarily participating students (M age = 19.0 years, SD = 3.6; 54% women) supported the predictions: refraining from catastrophic thinking was negatively correlated with depression, social anxiety, phobia, generalized anxiety, and obsession and compulsion. Repetitive negative thinking mediated the negative relationship between refraining from catastrophic thinking and latent factors underlying psychological distress (Fear and Distress). Refraining from catastrophic thinking may be negatively correlated with psychological distress due to its negative relation to repetitive negative thinking.

Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis.

Xenobiotic transporters play key roles in disposition of certain therapeutic agents, although limited information is available on their roles other than pharmacokinetic issues. Here, suppressive effect of multispecific organic cation transporter OCTN1/SLC22A4 on liver fibrosis was proposed in liver injury models. After injection of hepatotoxins such as dimethylnitrosamine (DMN) or concanavalin A, hepatic fibrosis, and oxidative stress, evaluated in terms of Sirius red and 4-hydroxy-2-nonenal staining, respectively, were more severe in liver of octn1/slc22a4 gene knockout (octn1(-/-)) mice than that in wild-type mice. DMN treatment markedly increased α-smooth muscle actin and F4/80, markers of activated stellate and Kupffer cells, respectively, in liver of octn1(-/-), but had less effect in wild-type mice. Thus, octn1/slc22a4 gene deletion results in more severe hepatic fibrosis, oxidative stress, and inflammation. DMN-treated wild-type mice showed increased Octn1 staining and hepatic concentration of its food-derived antioxidant ergothioneine (ERGO). The upregulated Octn1 was co-localized with α-smooth muscle actin. Functional expression of Octn1 was demonstrated in activated human hepatic stellate cell lines, LI90 and LX-2. Provision of ERGO-rich feed ameliorated DMN-induced liver fibrosis and oxidative stress. Overall, Octn1 is upregulated in activated stellate cells, resulting in increased delivery of its substrate antioxidant ERGO and a protective effect against liver fibrosis.

Emotional intensity reduces later generalized anxiety disorder symptoms when fear of anxiety and negative problem-solving appraisal are low.

While research based on the emotion dysregulation model indicates a positive relationship between intense emotions and generalized anxiety disorder (GAD) symptoms, emotion-focused intervention involves the use of techniques to enhance emotional experiences, based on the notion that GAD patients are engaging in avoidance strategies. To reveal the conditions under which intense emotions lead to reduced GAD symptoms, we designed a longitudinal study to monitor changes in GAD symptoms among students (N = 129) over 3 months. Our focus was on possible moderators of the effect of emotional intensity. Results indicated that when fear of emotions and negative appraisals about problem solving were low, negative emotional intensity reduced later GAD symptoms. Moreover, under the condition of high responsibility to continue thinking, emotional intensity tended to reduce later GAD symptoms. Results suggest that reduced fear of emotions and reduced negative appraisals about problem solving may enhance the use of emotional processing techniques (e.g., emotional exposure). The interaction between responsibility to continue thinking and emotional intensity requires further examination.

Gene ablation of carnitine/organic cation transporter 1 reduces gastrointestinal absorption of 5-aminosalicylate in mice.

5-Aminosalicylic acid (5-ASA) is an orally administered therapeutic agent for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. We hypothesized that the absorption of 5-ASA is mediated by the polyspecific carnitine/organic cation transporter (OCTN1/SLC22A4), based on the similarity of chemical structure between 5-ASA and other OCTN1 substrates. Therefore, we examined the involvement of this transporter in the disposition of 5-ASA in vivo by using octn1 gene knockout (octn1(-/-)) mice. After oral administration of 5-ASA, the plasma concentrations of 5-ASA and its primary metabolite, N-acetyl-5-aminosalicylate (Ac-5-ASA), in octn1(-/-) mice were much lower than those in wild-type mice. The time required to reach maximum plasma concentration was also delayed in octn1(-/-) mice. On the other hand, the plasma concentration profiles of both 5-ASA and Ac-5-ASA after intravenous administration of 5-ASA (bolus or infusion) were similar in the two strains. Uptake of 5-ASA from the apical to the basal side of isolated small-intestinal tissues of octn1(-/-) mice, determined in an Ussing-type chamber, was lower than that in wild-type mice. Further, uptake of 5-ASA in HEK293 cells stably transfected with the OCTN1 gene, assessed as the sum of cell-associated 5-ASA and Ac-5-ASA, was higher than that in HEK293 cells transfected with the vector alone. Overall, these results indicate that OCTN1 is involved, at least in part, in the gastrointestinal absorption of 5-ASA.

Common Factors of Meditation, Focusing, and Cognitive Behavioral Therapy: Longitudinal Relation of Self-Report Measures to Worry, Depressive, and Obsessive-Compulsive Symptoms Among Nonclinical Students.

Meditation has a long tradition with substantial implications for many psychotherapies. It has been postulated that meditation may cultivate therapeutic processes similar to various psychotherapies. A previous study used joint factor analysis to identify five common factors of items of scales purported to capture psychological states cultivated by meditation, focusing, and cognitive behavioral therapy, namely, refraining from catastrophic thinking, logical objectivity, self-observation, acceptance, and detached coping. The present study aimed to extend previous research on these five factors by examining their longitudinal relationship to symptoms of depression, obsession and compulsion, and worrying, with two correlational surveys without intervention. Potential mediators of their effect on worrying were also explored. Longitudinal questionnaire studies from two student samples (n = 157 and 232, respectively) found that (a) detached coping was inversely related to obsessive-compulsive symptoms about 5 weeks later; (b) detached coping was inversely related to depressive symptoms about 5 weeks later; (c) refraining from catastrophic thinking was inversely related to worrying, while self-observation was positively related to worrying about 2 months later; and (d) the relation of refraining from catastrophic thinking to worrying was mediated by negative beliefs about worrying, while the relation of self-observation to worrying was mediated by negative beliefs about worrying and monitoring of one's cognitive processes. As refraining from catastrophic thinking involves being detached from one's negative thinking and detached coping involves distancing oneself from external circumstances and problems, the results suggest that distancing attitudes are useful for long-term reduction of various psychological symptoms.

Pharmacokinetics and pharmacodynamics following intravenous administration of recombinant human hepatocyte growth factor in rats with renal injury.

BACKGROUND/AIM: Hepatocyte growth factor (HGF) plays a role in the regeneration and protection of the kidney, but little information is available concerning the pharmacokinetics of therapeutic treatment with HGF. In this study, HGF was administered after the onset of renal injury, and pharmacokinetic analysis was performed simultaneously with an efficacious dose. METHODS: For the study of pharmacodynamics, recombinant human HGF was intravenously administered to rats with glycerol-induced acute kidney injury (AKI). In the pharmacokinetic study, rats subjected to glycerol injection or renal ischemia-reperfusion were used as models of AKI, and rats subjected to 5/6 nephrectomy were used as models of chronic kidney disease (CKD). RESULTS: After intravenous administration of HGF at doses of 0.5-2.0 mg/kg, the elevation of blood urea nitrogen was suppressed, indicating that HGF had a pharmacodynamic effect. However, no significant difference was seen in the pharmacokinetic parameters such as clearance, distribution volume and half-life between the normal, AKI and CKD groups. CONCLUSION: The intravenous administration of HGF after the onset of renal dysfunction exerted a pharmacological effect on AKI, and renal injury did not affect the clearance of plasma HGF. This unaffected profile may serve as a base for the safety of HGF during therapeutic administration.

Organic cation transporter-mediated ergothioneine uptake in mouse neural progenitor cells suppresses proliferation and promotes differentiation into neurons.

The aim of the present study is to clarify the functional expression and physiological role in neural progenitor cells (NPCs) of carnitine/organic cation transporter OCTN1/SLC22A4, which accepts the naturally occurring food-derived antioxidant ergothioneine (ERGO) as a substrate in vivo. Real-time PCR analysis revealed that mRNA expression of OCTN1 was much higher than that of other organic cation transporters in mouse cultured cortical NPCs. Immunocytochemical analysis showed colocalization of OCTN1 with the NPC marker nestin in cultured NPCs and mouse embryonic carcinoma P19 cells differentiated into neural progenitor-like cells (P19-NPCs). These cells exhibited time-dependent [(3)H]ERGO uptake. These results demonstrate that OCTN1 is functionally expressed in murine NPCs. Cultured NPCs and P19-NPCs formed neurospheres from clusters of proliferating cells in a culture time-dependent manner. Exposure of cultured NPCs to ERGO or other antioxidants (edaravone and ascorbic acid) led to a significant decrease in the area of neurospheres with concomitant elimination of intracellular reactive oxygen species. Transfection of P19-NPCs with small interfering RNA for OCTN1 markedly promoted formation of neurospheres with a concomitant decrease of [(3)H]ERGO uptake. On the other hand, exposure of cultured NPCs to ERGO markedly increased the number of cells immunoreactive for the neuronal marker ßIII-tubulin, but decreased the number immunoreactive for the astroglial marker glial fibrillary acidic protein (GFAP), with concomitant up-regulation of neuronal differentiation activator gene Math1. Interestingly, edaravone and ascorbic acid did not affect such differentiation of NPCs, in contrast to the case of proliferation. Knockdown of OCTN1 increased the number of cells immunoreactive for GFAP, but decreased the number immunoreactive for ßIII-tubulin, with concomitant down-regulation of Math1 in P19-NPCs. Thus, OCTN1-mediated uptake of ERGO in NPCs inhibits cellular proliferation via regulation of oxidative stress, and also promotes cellular differentiation by modulating the expression of basic helix-loop-helix transcription factors via an unidentified mechanism different from antioxidant action.

Association between a C8orf13-BLK polymorphism and polymyositis/dermatomyositis in the Japanese population: an additive effect with STAT4 on disease susceptibility.

BACKGROUND: Accumulating evidence has shown that several non-HLA genes are involved in the susceptibility to polymyositis/dermatomyositis. This study aimed to investigate the involvement of C8orf13-BLK, one of the strongest candidate genes for autoimmune diseases, in susceptibility to polymyositis/dermatomyositis in the Japanese population. A possible gene-gene interaction between C8orf13-BLK and STAT4, which we recently showed to be associated with Japanese polymyositis/dermatomyositis, was also analyzed. METHODS: A single-nucleotide polymorphism in C8orf13-BLK (dbSNP ID: rs13277113) was investigated in the Japanese population using a TaqMan assay in 283 polymyositis patients, 194 dermatomyositis patients, and 656 control subjects. RESULTS: The C8orf13-BLK rs13277113A allele was associated with overall polymyositis/dermatomyositis (P<0.001, odds ratio [OR] 1.44, 95% confidence interval [CI] 1.19-1.73), as well as polymyositis (P = 0.011, OR 1.32, 95% CI 1.06-1.64) and dermatomyositis (P<0.001, OR 1.64, 95% CI 1.26-2.12). No association was observed between the C8orf13-BLK rs13277113A allele and either interstitial lung disease or anti-Jo-1 antibody positivity. The C8orf13-BLK rs13277113 A and STAT4 rs7574865 T alleles had an additive effect on polymyositis/dermatomyositis susceptibility. The strongest association was observed in dermatomyositis, with an OR of 3.07 (95% CI; 1.57-6.02) for the carriers of four risk alleles at the two SNP sites, namely, rs1327713 and rs7574865. CONCLUSIONS: This study established C8orf13-BLK as a new genetic susceptibility factor for polymyositis/dermatomyositis. Both C8orf13-BLK and STAT4 exert additive effects on disease susceptibility. These observations suggested that C8orf13-BLK, in combination with STAT4, plays a pivotal role in creating genetic susceptibility to polymyositis/dermatomyositis in Japanese individuals.