SWOT analysis of noninvasive tests for diagnosing NAFLD with severe fibrosis: an expert review by the JANIT Forum.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the prognosis of NAFLD/NASH has been reported to be dependent on liver fibrosis degree. Liver biopsy remains the gold standard, but it has several issues that must be addressed, including its invasiveness, cost, and inter-observer diagnosis variability. To solve these issues, a variety of noninvasive tests (NITs) have been in development for the assessment of NAFLD progression, including blood biomarkers and imaging methods, although the use of NITs varies around the world. The aim of the Japan NASH NIT (JANIT) Forum organized in 2020 is to advance the development of various NITs to assess disease severity and/or response to treatment in NAFLD patients from a scientific perspective through multi-stakeholder dialogue with open innovation, including clinicians with expertise in NAFLD/NASH, companies that develop medical devices and biomarkers, and professionals in the pharmaceutical industry. In addition to conventional NITs, artificial intelligence will soon be deployed in many areas of the NAFLD landscape. To discuss the characteristics of each NIT, we conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis in this study with the 36 JANIT Forum members (16 physicians and 20 company representatives). Based on this SWOT analysis, the JANIT Forum identified currently available NITs able to accurately select NAFLD patients at high risk of NASH for HCC surveillance/therapeutic intervention and evaluate the effectiveness of therapeutic interventions.

PDGFRα plays a crucial role in connective tissue remodeling.

Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling.

Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part I.

To develop effective drugs for hypogonadism, sarcopenia, and cachexia, we designed, synthesized, and evaluated selective androgen receptor modulators (SARMs) that exhibit not only anabolic effects on organs such as muscles and the central nervous system (CNS) but also neutral or antagonistic effects on the prostate. Based on the information obtained from a docking model with androgen receptor (AR), we modified a hit compound A identified through high-throughput screening. Among the prepared compounds, 1-(4-cyano-1-naphthyl)-2,3-disubstituted pyrrolidine derivatives 17h, 17m, and 17j had highly potent AR agonistic activities in vitro and good tissue selectivity in vivo. These derivatives increased the weight of the levator ani muscle without influencing the prostate and seminal vesicle. In addition, these compounds induced sexual behavior in castrated rats, indicating that the compounds could also act as agonists on the CNS.

Increased production of intestinal immunoglobulins in Syntenin-1-deficient mice.

Syntenin-1 is an intracellular PDZ protein that binds multiple proteins and regulates protein trafficking, cancer metastasis, exosome production, synaptic formation, and IL-5 signaling. However, the functions of Syntenin-1 have not yet been clearly characterized in detail, especially in vivo. In this study, we generated a Syntenin-1 knock out (KO) mouse strain and analyzed the role(s) of Syntenin-1 in IL-5 signaling, because the direct interaction of Syntenin-1 with the cytoplasmic domain of the IL-5 receptor α subunit and the regulation of IL-5 signaling by Syntenin-1 have been reported. Unexpectedly, the number of IL-5-responding cells was normal and the levels of fecal immunoglobulins were rather higher in the Syntenin-1 KO mice. We also found that IgA and IgM production of splenic B cells stimulated in vitro was increased in Syntenin-1 KO mice. In addition, we showed that a distribution of intestinal microbial flora was influenced in Syntenin-1 KO mice. Our data indicate that Syntenin-1 negatively regulates the intestinal immunoglobulin production and has a function to maintain the intestinal homeostasis in vivo. The analysis of Syntenin-1 KO mice may provide novel information on not only mucosal immunity but also other functions of Syntenin-1 such as cancer metastasis and neural development.

Cost-minimization analysis of IgPro20, a subcutaneous immunoglobulin, in Japanese patients with primary immunodeficiency.

PURPOSE: IgPro20, Hizentra(®) an L-proline-stabilized 20% human subcutaneous immunoglobulin (SCIG), has been shown in a Phase III pivotal study to be well tolerated and efficacious in adult and pediatric Japanese patients with primary immunodeficiency. Economic aspects of SCIG treatment in comparison with previous intravenous immunoglobulin (IVIG) therapy were analyzed in this Phase III study in Japan. METHODS: Twenty-four Japanese patients with primary immunodeficiency on IVIG treatment were switched to IgPro20 at an equivalent dose (full analysis set). The study consisted of a screening period, an IVIG treatment period with 3 planned infusions every 3 or 4 weeks, a 12-week SCIG wash-in and wash-out period, and a 12-week SCIG efficacy period. The difference in medical cost and productivity loss resulting from changes in hospital frequency between the SCIG and IVIG treatment was evaluated. Information about treatment cost was collected as part of the Life Quality Index questionnaire. In addition, productivity loss and hospital-related absenteeism were evaluated. FINDINGS: Life Quality Index scores for all domains were higher with SCIG than with IVIG in this patient population. In the full analysis set, the mean (SD) Life Quality Index score of the Costs domain increased from 45.1 (26.34) at Week 1 (IVIG period) to 71.9 (18.52) at Week 24 (end of the SCIG efficacy period), representing a mean change of 26.74 and a large score improvement effect size (1.01). Median productivity loss was reduced by 60% from baseline to Weeks 12 and 24. This resulted in a reduction in costs of JPY 10,875 per patient per month at Weeks 12 and 24. Subcutaneous treatment with IgPro20 also reduced hospital-related absenteeism. The number of patients, parents, or guardians who were not absent from work or housework duties and had no reduction in working time increased from 4 (17.4%) at Week 1 to 9 (39.1%) at Week 24. Similar results were obtained in the per-protocol set (n = 21). IMPLICATIONS: Switching from IVIG to SCIG reduced markedly productivity loss and hospital-related absenteeism. The reduction in hospital visit frequency due to the use of home-based IgG therapy enabled by the change in administration route is expected to produce an important pharmacoeconomic benefit in Japan. Study Code: ZLB06_002CR, ClinicalTrials.gov identifier: NCT01199705.

Flavin-catalyzed aerobic oxidation of sulfides and thiols with formic acid/triethylamine.

An efficient and practical catalytic method for the aerobic oxidative transformation of sulfides into sulfoxides, and thiols into disulfides with formic acid/TEA in the presence of a new, readily available, and stable flavin catalyst 5d is described.

The long elusive IgM Fc receptor, FcµR.

IgM exists as both a monomer on the surface of B cells and a pentamer secreted by plasma cells. Both pre-immune "natural" and antigen-induced "immune" IgM antibodies are important for protective immunity and for immune regulation of autoimmune processes by recognizing pathogens and self-antigens. Effector proteins interacting with the Fc portion of IgM, such as complement and complement receptors, have thus far been proposed but fail to fully account for the IgM-mediated protection and regulation. A major reason for this deficit in our understanding of IgM function seems to be lack of data on a long elusive Fc receptor for IgM (FcµR). We have recently identified a bona fide FcµR in both humans and mice. In this article we briefly review what we have learned so far about FcµR.

Intrauterine growth restriction modifies gene expression profiling in cord blood.

BACKGROUND: Small-for-gestational-age (SGA) newborns are at an increased risk for perinatal morbidity and mortality and development of metabolic syndromes such as cardiovascular disease and type 2 diabetes mellitus (T2DM) in adulthood. The mechanism underlying this increased risk remains unclear. In this study, genetic modifications of cord blood were investigated to characterize fetal change in SGA newborns. METHODS: Gene expression in cord blood cells was compared between 10 SGA newborns and 10 appropriate-for-gestational-age (AGA) newborns using microarray analysis. Pathway analysis was conducted using the Ingenuity Pathways Knowledge Base. To confirm the microarray analysis results, quantitative real-time polymerase chain reaction (RT-PCR) was performed for upregulated genes in SGA newborns. RESULTS: In total, 775 upregulated and 936 downregulated probes were identified in SGA newborns and compared with those in AGA newborns. Of these probes, 1149 were annotated. Most of these genes have been implicated in the development of cardiovascular disease and T2DM. There was good agreement between the RT-PCR and microarray analyses results. CONCLUSIONS: Expression of certain genes was modified in SGA newborns in the fetal period. These genes have been associated with metabolic syndrome. To clarify the association between modified gene expression in cord blood and individual vulnerability to metabolic syndrome in adulthood, these SGA newborns will be have long-term follow up for examination of genetic and postnatal environmental factors. Gene expression of cord blood can be a useful and non-invasive method of investigation of genetic alterations in the fetal period.

Pneumothorax in patients with severe combined immunodeficiency.

BACKGROUND: Most infants with pneumothorax have underlying conditions. Pneumocystis jirovecii pneumonia (PCP) frequently occurs in patients with severe combined immunodeficiency (SCID). The aim of this study was to determine clinical features of PCP-associated pneumothorax in SCID patients. METHODS: The medical records of four SCID patients with pneumothorax were retrospectively reviewed. RESULTS: All four patients were diagnosed as having SCID at the time of contracting PCP. All patients received mechanical ventilation because of severe respiratory failure. Only one patient was successfully extubated and was alive following hematopoietic stem cell transplantation (HSCT); of the remaining patients, however, two died of respiratory failure, and one patient died of early HSCT-related complications. CONCLUSIONS: Pneumothorax associated with PCP can occur in SCID patients, and they may have a poor prognosis. If pneumothorax occurs in infants, both respiratory management and prompt investigation of the underlying conditions are needed, considering the possibility of PCP associated with SCID.

Efficacy and safety of IgPro20, a subcutaneous immunoglobulin, in Japanese patients with primary immunodeficiency diseases.

PURPOSE: Intravenous (IVIG) and subcutaneous (SCIG) immunoglobulin infusions are widely used for the treatment of patients with primary immunodeficiency (PID) worldwide. This prospective, multicenter, open-label, single-arm Phase III study evaluated the efficacy, tolerability, and safety of IgPro20 (Hizentra®; L-proline-stabilized 20 % human SCIG) in adult and pediatric Japanese patients with PID. METHODS: Patients received three IVIG infusions at 3-4-week intervals followed by a dose-equivalent switch to weekly SCIG infusions. A 12-week wash-in/wash-out period was followed by a 12-week SCIG efficacy period. The primary efficacy endpoint was the comparison of total serum IgG trough levels during the IVIG and SCIG efficacy periods by calculating the geometric mean ratio (GMR). RESULTS: The GMR of IgG trough levels on SCIG versus IVIG was 1.09 (2-sided 90% confidence interval: 1.06-1.13). No serious bacterial infections were reported. Eleven patients (52.4%) had infectious episodes with an overall rate of 2.98 infections/patient/year; 7 patients (33.3%) missed school/work/daycare due to infection (3.48 days/patient/year). Sixteen patients (76.2%) were treated with antibiotics for an adverse event (AE; 47.6%) or prophylaxis (23.8%), resulting in 167.42 days/patient/year of antibiotic use. During SCIG treatment, 24 patients (96.0%) had 269 AEs (0.461 AEs per/infusion) including local reactions as the most common AE (20 patients, 80.0%). Local tolerability of IgPro20 was assessed as "very good" or "good" after 85.4% of SCIG infusions. One patient (4.0%) experienced a serious AE of moderate severity (bacterial infection) that was considered unrelated to study medication. CONCLUSION: IgPro20 was effective and well tolerated in Japanese patients with PID.

Clinical and radiologic features of encephalopathy during 2011 E coli O111 outbreak in Japan.

OBJECTIVE: To elucidate the clinical and radiologic features and analyze factors associated with neurologic outcomes of encephalopathy secondary to Shiga toxin-producing Escherichia coli (STEC) O111. METHODS: We reviewed medical records and neuroimaging in 22 patients with neurologic symptoms among 86 with STEC O111 infection. RESULTS: Twenty-one (6 males and 15 females, 10 children and 11 adults) of the 22 patients were diagnosed with encephalopathy. All patients with encephalopathy also presented with hemolytic-uremic syndrome. Five patients died, from day 1 to 6 months (days 1-5 in 4 patients), due to progressive encephalopathy with severe cerebral edema observed in neuroimaging (4 patients). Fifteen of the 16 surviving patients clinically recovered completely. Statistical analysis revealed differences between patients with poor (n = 6) and good (n = 15) outcomes in the interval from hemolytic-uremic syndrome presentation to encephalopathy, creatinine levels, and the methylprednisolone administration ratio. CONCLUSION: We note a high incidence of encephalopathy in the Toyama STEC O111 outbreak. All fatal cases resulted from progressive encephalopathy. Methylprednisolone pulse therapy represents a possible therapeutic choice. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that methylprednisolone pulse therapy increases the probability of a good outcome for patients with encephalopathy associated with STEC O111.

Allogeneic bone marrow transplantation appears to ameliorate IgA nephropathy in a patient with X-linked thrombocytopenia.

Wiskott-Aldrich syndrome (WAS) is caused by a mutation in the WAS gene, and it is clinically characterized by the triad of thrombocytopenia, eczema and immunodeficiency. X-linked thrombocytopenia (XLT), which is a clinically mild form of WAS, is also caused by a WAS gene mutation. Patients with WAS/XLT sometimes also have autoimmune diseases such as IgA nephropathy. Progression of IgA nephropathy may lead to chronic renal failure with a poor prognosis. Here, we describe an XLT patient who also had IgA nephropathy. The patient underwent bone marrow transplantation (BMT) because of an associated-lymphoproliferative disorder, and clinical and histological improvement in his IgA nephropathy was observed after BMT. The amount of galactose-deficient IgA in the patient's serum markedly decreased after BMT. Therefore, immunological reconstitution might improve autoimmune diseases in patients with WAS/XLT.

Giardiasis in a patient undergoing chemotherapy for retinoblastoma and acute myelogenous leukemia.

Giardiasis is a common cause of diarrhea in undeveloped countries, but is very rare in developed countries. A patient with acute myelogenous leukemia and retinoblastoma presented with a high fever and severe watery diarrhea during induction chemotherapy. On microscopy, cysts were seen in her stool, suggesting Giardia intestinalis, which was confirmed on polymerase chain reaction (PCR). G. intestinalis was also detected in the patient's asymptomatic parents, who may have transmitted it to the patient. Giardiasis should be tested for in patients with severe and persistent diarrhea during chemotherapy, when other etiologies have been excluded. PCR used to amplify the DNA of G. intestinalis is rapid and sensitive.

Lymphoproliferative disorders in immunocompromised individuals and therapeutic antibodies for treatment.

The incidence of lymphoproliferative disease (LPD) is significantly higher in individuals who have congenital, acquired or iatrogenically induced immunodeficiency. Although there are a wide range of LPDs including lymphoma and leukemia, this article only covers LPDs in patients with impaired immune function, which are called immunodeficiency-associated LPDs (ID-LPDs). Three of the four ID-LPD categories recognized by WHO have been selected for discussion: LPD in primary immune disorders, post-transplant LPD and LPD in HIV infection. Because of the high incidence and mortality of ID-LPDs, careful evaluation of the morphology, immunophenotype, genotype, viral status and clinical history is required for accurate diagnosis and treatment. Recently, treatment with monoclonal antibodies (mAbs) has been widely used and developed because of its potential benefits. The aim of this review is to describe new information concerning mAb treatment in LPDs and to draw physicians' attention to mAb therapy, which should be effective for some types of LPD.

Rhinitis has an association with asthma in school children.

BACKGROUND: A relevant relationship exists between the upper and lower airway, indicating the concept of a unified airway. This study aimed to evaluate whether rhinitis has an association with asthma in children. METHODS: A cross-sectional nationwide survey was performed among children 6-7, 13-14, and 16-17 years old, using the International Study of Asthma and Allergies in Children (ISAAC) questionnaire in Japan. According to the responses to the ISAAC core questions, a child who had experienced nasal symptoms in the past 12 months in the absence of a cold was defined as having current rhinitis. RESULTS: After excluding 11,475 children because of incomplete data, 136,506 children were analyzed. Even after adjusting for demographics, sex, and obesity, children with current rhinitis were more likely to have asthma (adjusted odds ratio [OR], 3.10 [95% CI, 2.92-3.30] in children aged 6-7 years; OR, 3.76 [95% CI, 3.45-4.10] in children aged 13-14 years; and OR, 3.59 [95% CI, 3.33-3.88] in children aged 16-17 years). Children whose daily activities were more impaired by rhinitis symptoms had a significantly higher prevalence of severe asthma. The adjusted ORs for severe asthma among asthmatic children whose daily activities were severely impaired by rhinitis symptoms were 3.66 (95% CI, 2.29-5.85) in children aged 6-7 years, 2.55 (95% CI, 1.64-3.96) in children aged 13-14 years, and 1.87 (95% CI, 1.24-2.82) in children aged 16-17 years compared with asthmatic children whose daily activities were not impaired at all. CONCLUSION: There was a close association between rhinitis and asthma in young children to adolescents. Asthma should be examined in children with rhinitis symptoms.

Effect of salt intake on bioavailability of mizoribine in healthy Japanese males.

Bioavailability of mizoribine in subjects with the concentrative nucleoside transporter 1 (CNT1, SLC28A1) 565-A/A allele is significantly lower than that in subjects with the SLC28A1 565-G/G allele. The aims of the present study were to investigate the cellular uptake of mizoribine in CNT1- and CNT2-expressing Madin-Darby canine kidney type II (MDCKII) cells, and to evaluate the effect of salt intake on bioavailability of mizoribine in healthy Japanese volunteers with SLC28A1 565-A/A and -G/A alleles. Eight healthy males participated in the present study, and took 150 mg mizoribine concomitantly with/without 300 mg salt. Bioavailability of mizoribine was estimated by total cumulative urinary excretion of the drug. Mizoribine was taken up Na(+)-dependently into not only CNT1-expressing but also CNT2-expressing MDCKII cells, indicating that mizoribine is a substrate for both CNT1 and CNT2. Mean bioavailability of mizoribine taken with salt (83.8%) was significantly higher than that taken without salt (73.0%). These findings suggest that the salt intake is expected to improve the bioavailability of mizoribine in patients with insufficient intestinal absorption.

Successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed-onset adenosine deaminase deficiency.

In this case report, we describe successful BMT with RIC in a patient with delayed-onset ADA deficiency. A three-yr-old Japanese boy was diagnosed with delayed-onset ADA deficiency because of recurrent bronchitis, bronchiectasia, and lymphopenia. In addition, autoimmune thyroiditis and neutropenia were present. At four yr of age, he underwent BMT with a RIC regimen, including busulfan and fludarabine, from an HLA-identical healthy sister. Engraftment after BMT was uneventful without GVHD. Decreased ADA levels in blood immediately increased following BMT, and the patient was disease-free 13 months after BMT. These results suggest that BMT with RIC may sufficiently restore immune regulation in delayed-onset ADA deficiency. A longer follow-up period is needed to confirm these observations.

Developmental trajectories of the fronto-temporal lobes from infancy to early adulthood in healthy individuals.

Brain development during early life in healthy individuals is rapid and dynamic, indicating that this period plays a very important role in neural and functional development. The frontal and temporal lobes are known to play a particularly important role in cognition. The study of healthy frontal and temporal lobe development in children is therefore of considerable importance. A better understanding of how these brain regions develop could also aid in the diagnosis and treatment of neurodevelopmental disorders. Some developmental studies have used magnetic resonance imaging (MRI) to examine infant brains, but it remains the case that relatively little is known about cortical brain development in the first few years of life. In the present study we examined whole brain, temporal lobe and frontal lobe developmental trajectories from infancy to early adulthood in healthy individuals, considering gender and brain hemisphere differences. We performed a cross-sectional, longitudinal morphometric MRI study of 114 healthy individuals (54 females and 60 males) aged 1 month to 25 years old (mean age ± SD 8.8 ± 6.9). We measured whole brain, temporal and frontal lobe gray matter (GM)/white matter (WM) volumes, following previously used protocols. There were significant non-linear age-related volume changes in all regions. Peak ages of whole brain, temporal lobe and frontal lobe development occurred around pre-adolescence (9-12 years old). GM volumes for all regions increased significantly as a function of age. Peak age was nevertheless lobe specific, with a pattern of earlier peak ages for females in both temporal and frontal lobes. Growth change in whole brain GM volume was larger in males than in females. However, GM volume growth changes for the temporal and frontal lobes showed a somewhat different pattern. GM volume for both temporal and frontal lobes showed a greater increase in females until around 5-6 years old, at which point this tendency reversed (GM volume changes in males became greater), with male GM volume increasing for a longer time than that of females. WM volume growth changes were similar across regions, all increasing rapidly until early childhood but slowing down thereafter. All regions displayed significant rightward volumetric asymmetry regardless of sex. Furthermore, the right temporal and frontal lobes showed a greater volumetric increase than the left for the first several years, with this tendency reversing at around 6 years of age. In addition, the left frontal and temporal lobes increased in volume for a longer period of time. Taken together, these findings indicated that brain developmental trajectories differ depending on brain region, sex and brain hemisphere. Gender-related factors such as sex hormones and functional laterality may affect brain development.