Different changes in the biomarker C-terminal telopeptides of type II collagen (CTX-II) following intra-articular injection of high molecular weight hyaluronic acid and oral non-steroidal anti-inflammatory drugs in patients with knee osteoarthritis: a multi-center randomized controlled study.

OBJECTIVES: We previously reported, based on a multicenter randomized-control study, that the efficacy of intra-articular injections of hyaluronic acid (IA-HA) was not inferior to that of oral non-steroidal anti-inflammatory drugs (NSAIDs) in patients with knee osteoarthritis (OA). However, the molecular effects on the pathophysiology of knee OA remain unclear. C-terminal telopeptides of type II collagen (CTX-II) is reported to primarily originate from the interface between articular cartilage and subchondral bone, which is a site of potential remodeling in OA. We performed a predefined sub-analysis of the previous study to compare the changes of urinary CTX-II (uCTX-II) in response to IA-HA to those in response to NSAID for knee OA. DESIGN: A total of 200 knee OA patients were registered from 20 hospitals and randomized to receive IA-HA (2,700 kDa HA, 5 times at 1-week intervals) or NSAID (loxoprofen sodium, 180 mg/day) for 5 weeks. The uCTX-II levels were measured before and after treatment. RESULTS: The uCTX-II levels were significantly increased by IA-HA treatment (337.7 ± 193.8 to 370.7 ± 234.8 ng/µmol Cr) and were significantly reduced by NSAID treatment (423.2 ± 257.6 to 370.3 ± 250.9 ng/µmol Cr). The %changes of uCTX-II induced by IA-HA (11.6 ± 29.5%) and NSAID (-9.0 ± 26.7%) was significantly different (between-group difference: 20.6, 95% confidence intervals: 10.6 to 30.6). CONCLUSIONS: While both IA-HA and NSAID improved symptoms of knee OA, uCTX-II levels were increased by IA-HA and reduced by NSAIDs treatment, suggesting these treatments may improve symptoms of knee OA through different modes of action.

Unwillingness to cooperate with COVID-19 contact tracing in Japan.

OBJECTIVES: Contact tracing for COVID-19 relies heavily on the cooperation of individuals with authorities to provide information of contact persons. However, few studies have clarified willingness to cooperate and motivation to provide information for contact tracing. This study sought to describe willingness to cooperate and motivation to report contact persons for COVID-19 contact tracing among citizens in Japan, and to assess any associated sociodemographic factors. STUDY DESIGN: Cross-sectional study. METHODS: This was an online-based survey using quota sampling. Participants were asked about their willingness to cooperate in reporting contacts for COVID-19 contact tracing if they tested positive. Participants also responded to questions regarding their reasons for cooperating or not cooperating and provided sociodemographic data. Multiple logistic regression analysis was performed to clarify associations between sociodemographic factors and willingness to cooperate. RESULTS: This study included 2844 participants. The proportion of participants who were not willing to cooperate in reporting contacts was 27.6%, with their main reasons being concerns about causing trouble for the other person and being criticised for revealing their names. Willingness to cooperate was lower among men, young adults and those with an educational level less than a university degree. CONCLUSIONS: To improve the effectiveness of contact tracing, educational campaigns, such as reducing the fear and stigma associated with COVID-19, may be important. Furthermore, it is essential to understand that individuals may have contacts whom they do not wish to disclose to others and to be considerate when handling such situations.

Association of residual gastric acid secretion with persistent symptoms in gastroesophageal reflux disease patients receiving standard-dose proton pump inhibitor therapy.

BACKGROUND: Although a third of gastroesophageal reflux disease (GERD) patients are refractory to proton pump inhibitor (PPI) therapy, the underlying mechanism of the refractoriness remains unclear. We compared the level of gastric acid suppression during PPI treatment between responders and non-responders by directly measuring gastric acid secretion in GERD patients taking PPIs. METHODS: Seventy-five consecutive patients receiving standard-dose PPI therapy for GERD were prospectively recruited, irrespective of persistent GERD symptoms. They were asked about their GERD symptoms using a validated questionnaire, and simultaneously underwent both a routine endoscopic examination and a gastric acid secretory testing using an endoscopic gastrin test. Associations between residual gastric acid secretion during PPI treatment and persistent GERD symptoms were analyzed by a logistic regression analysis. RESULTS: Overall, 26 of 75 (34.7%) patients were judged to be positive for persistent GERD symptoms. The patients with and without persistent symptoms showed similar gastric acid secretion levels (1.3 [1.3] mEq/10 min vs. 1.4 [2.0] mEq/10 min). Sufficient gastric acid suppression, defined as < 0.6, was not significantly associated with persistent GERD symptoms (odds ratio 1.1, 95% confidence interval 0.40-3.5). CONCLUSIONS: This study provided solid evidence to support that the gastric acid suppression level during PPI treatment does not differ between patients with and without persistent GERD symptoms. The insignificant role of residual gastric acid in the persistent GERD symptoms suggests that the use of medications other than those that enhance gastric acid inhibitory effects would be an essential approach for the management of PPI-refractory GERD.

Outcome of maintenance systemic chemotherapy with drug-free interval for metastatic urothelial carcinoma.

OBJECTIVE: Aiming to achieve long-term disease control, maintenance systemic chemotherapy (MSC) with a 1-3-month drug-free interval is continued in selected patients. We report our experience of MSC for metastatic urothelial carcinoma (UC). METHODS: Of 228 metastatic UC patients treated with systemic chemotherapy, 40 (17.5%, 40/228) had continuously undergone MSC. Data on the regimen, cycle number, and reason for the discontinuation of MSC were also collected. We analyzed OS from the initiation of MSC until death or the last follow-up, using the log-rank test to assess the significance of differences. RESULTS: The median number of cycles of chemotherapy was 6, and the responses were CR in 6, PR in 20, SD in 13, and PD in 1 before MSC. Gemcitabine plus CDDP or carboplatin was mainly performed as MSC (70%, 28/40). MSC was repeated quarterly in 30 (75%, 30/40), every two months in 8 (20%, 8/40), and with other intervals in 2 (5%, 2/40). Overall, a median of 3.5 cycles (range: 1-29) of MSC was performed. The reason for the discontinuation of MSC was PD in 24 (60%, 24/40), favorable disease control in 9 (22.5%, 9/40), and myelosuppression in 3 (7.5%, 3/40), and for other reasons in 2 (5%, 2/40). MSC was ongoing in 2 (5%, 2/40). The median OS was 27 months from the initiation of MSC. PS0 (P = 0.0169), the absence of lung metastasis (P = 0.0387), and resection of the primary site (P = 0.0495) were associated with long-term survival after MSC. CONCLUSIONS: In selected patients, long-term systemic chemotherapy could be performed with a drug-free interval. Our maintenance strategy with cytotoxic drugs may become one of the treatment options for long-term disease control.

Kidney enlargement and multiple liver cyst formation implicate mutations in PKD1/2 in adult sporadic polycystic kidney disease.

Distinguishing autosomal-dominant polycystic kidney disease (ADPKD) from other inherited renal cystic diseases in patients with adult polycystic kidney disease and no family history is critical for correct treatment and appropriate genetic counseling. However, for patients with no family history, there are no definitive imaging findings that provide an unequivocal ADPKD diagnosis. We analyzed 53 adult polycystic kidney disease patients with no family history. Comprehensive genetic testing was performed using capture-based next-generation sequencing for 69 genes currently known to cause hereditary renal cystic diseases including ADPKD. Through our analysis, 32 patients had PKD1 or PKD2 mutations. Additionally, 3 patients with disease-causing mutations in NPHP4, PKHD1, and OFD1 were diagnosed with an inherited renal cystic disease other than ADPKD. In patients with PKD1 or PKD2 mutations, the prevalence of polycystic liver disease, defined as more than 20 liver cysts, was significantly higher (71.9% vs 33.3%, P = .006), total kidney volume was significantly increased (median, 1580.7 mL vs 791.0 mL, P = .027) and mean arterial pressure was significantly higher (median, 98 mm Hg vs 91 mm Hg, P = .012). The genetic screening approach and clinical features described here are potentially beneficial for optimal management of adult sporadic polycystic kidney disease patients.

Effect of brefelamide on proliferation of 1321N1 human astrocytoma cells induced by glial cell line-derived neurotrophic factor.

Malignant gliomas are highly resistant to chemotherapy and radiation and more effective options for treatment are urgently needed. We reported previously that the aromatic amide brefelamide, which is isolated from methanolic extracts of the cellular slime molds Dictyostelium giganteum and D. brefeldianum, hinders cellular proliferation in a glioma model utilizing 1321N1 human astrocytoma cells. Herein, we examined the mechanisms underlying the inhibition of 1321N1 cell proliferation by brefelamide. Glial cell line-derived neurotrophic factor (GDNF) was found to enhance the rate of proliferation of serum-free cultured 1321N1 cells, but did not affect proliferation in PC12 cells. Brefelamide pretreatment inhibited GDNF-induced cell proliferation and expression of rearranged during transfection (RET). GDNF enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and c-jun-N-terminal kinase (JNK); however, brefelamide pretreatment inhibited these effects. Brefelamide also reduced the expression of GDNF mRNA and GDNF secretion. Together, the findings from this study indicate that brefelamide inhibits the proliferation of 1321N1 cell via several mechanisms including reduced GDNF receptor expression and GDNF secretion, and reduced phosphorylation of ERK, AKT, and JNK.

A giant polymer lattice in a polymer-stabilized blue phase liquid crystal.

Ultrasmall-angle synchrotron X-ray scattering measurements showed that a three-dimensional polymer lattice of a few 100 nm order with body-centered cubic O(8-) symmetry was formed in a polymer-stabilized blue phase liquid crystal. We obtained clear experimental evidence that the polymer chains condensed selectively in the disclinations within the blue phase during photo-polymerization of monomers in the blue phase.

Phylogenetic study of the species within the family Streptomycetaceae.

Species of the genus Streptomyces, which constitute the vast majority of taxa within the family Streptomycetaceae, are a predominant component of the microbial population in soils throughout the world and have been the subject of extensive isolation and screening efforts over the years because they are a major source of commercially and medically important secondary metabolites. Taxonomic characterization of Streptomyces strains has been a challenge due to the large number of described species, greater than any other microbial genus, resulting from academic and industrial activities. The methods used for characterization have evolved through several phases over the years from those based largely on morphological observations, to subsequent classifications based on numerical taxonomic analyses of standardized sets of phenotypic characters and, most recently, to the use of molecular phylogenetic analyses of gene sequences. The present phylogenetic study examines almost all described species (615 taxa) within the family Streptomycetaceae based on 16S rRNA gene sequences and illustrates the species diversity within this family, which is observed to contain 130 statistically supported clades, as well as many unsupported and single member clusters. Many of the observed clades are consistent with earlier morphological and numerical taxonomic studies, but it is apparent that insufficient variation is present in the 16S rRNA gene sequence within the species of this family to permit bootstrap-supported resolution of relationships between many of the individual clusters.

Severity-based treatment for Japanese patients with MPO-ANCA-associated vasculitis: the JMAAV study.

We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients' disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.

Fine needle aspiration using forward-viewing endoscopic ultrasonography.

BACKGROUND AND STUDY AIM: A prototype forward-viewing instrument has been developed for therapeutic endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA). We had the opportunity to use this forward-viewing echo endoscope and to study its clinical usefulness, mainly for diagnostic EUS-FNA. PATIENTS AND METHODS: The prototype forward-viewing echo endoscope was used for 15 months between November 2006 and March 2010, in a study group comprising 47 consecutive patients. Diagnostic EUS-FNA was done in 38 patients and the diagnostic accuracy of the forward-viewing device was compared with that from an oblique-viewing echo endoscope in reference patients who were matched by disease and puncture route. Therapeutic EUS was done in nine patients (pseudocyst drainage in six; celiac ganglia neurolysis, biliary drainage, and pancreatic duct drainage in one each). RESULTS: Diagnostic EUS-FNA provided a correct diagnosis in 97.4 % (37/38 patients), which was not significantly different from the 94.7 % (36/38) in the reference patients. Lesions considered difficult to access with an oblique-viewing scope, such as those located at the fornix, or the head of the pancreas, or associated with strictures, were easily punctured, as were those located at the body or tail of the pancreas or at the porta hepatis. Treatment was successful in all nine patients who underwent therapeutic EUS procedures. None of the 47 patients had any complications. CONCLUSIONS: A forward-viewing echo endoscope that allows target sites to be punctured more perpendicularly with minimal effort, can be used for diagnostic EUS-FNA and this may be advantageous, depending on the site of target lesions.

Endoscopic management of malignant biliary obstruction by means of covered metallic stents: primary stent placement vs. re-intervention.

BACKGROUND AND STUDY AIMS: Recent progress in chemotherapy has prolonged the survival of patients with malignant biliary strictures, leading to increased rates of stent occlusion. Occlusion of covered metallic stents now occurs in about half of all patients with malignant biliary strictures. The removal of metallic stents followed by placement of a second stent has been attempted, but outcomes remain controversial. The aim of the current study was to evaluate the effectiveness and safety of the primary placement and secondary placement (re-intervention) of covered metallic stents and to assess the feasibility and safety of stent removal. PATIENTS AND METHODS: The study included 186 patients with unresectable malignant biliary strictures who underwent primary stent placement between October 2001 and March 2010.  Covered biliary self-expandable metal stents (SEMSs) were removed in 39 of these patients, and 36 underwent re-intervention. The patency times, occlusion rates of the first stent and re-intervention, success rates of stent removal, and complications were investigated. RESULTS: Covered SEMSs were placed in 186 patients. The median patency time of the first stent was 352 days. Stent occlusion occurred in 48.9 % of the patients and was mainly caused by debris or food residue (37 %), dislocation (19 %), and migration with hyperplasia (19 %). Stent removal was attempted in 50 patients and was successful without complication in 39 (78 %). Most of the patients in whom stent removal was unsuccessful had migration with hyperplasia. The median patency time of the second stent was 263 days. The stent patency time did not significantly differ between the first and the second stent. CONCLUSIONS: Covered SEMSs could be safely removed at the time of stent occlusion. Patency rates were similar for initial stent placement and re-intervention.

Interleukin-6 and silent cerebral infarction in hemodialysis patients: a cross-sectional study.

BACKGROUND: In patients with chronic renal failure undergoing hemodialysis (HD), silent cerebral infarctions (SCI) are associated with high mortality. Levels of interleukin-6 (IL-6) increase with renal dysfunction and may be a novel predictor for cerebrovascular events. We tested the hypothesis that increased IL-6 levels correlate with the occurrence of SCI in HD patients. METHODS: Using cranial magnetic resonance imaging findings, we divided 50 Japanese patients undergoing HD into two groups: with SCI (60 ± 7 years, mean ± SD, n = 27) and without SCI (60 ± 6 years, n = 23). We compared the gender, body mass index, metabolic profiles, IL-6 levels, and smoking habits between the two groups. RESULTS: We made the following observations: (i) The prevalence of diabetes or hypertension did not differ between the two groups, (ii) the level of IL-6 was higher in the with-SCI group than in the without-SCI group (P < 0.0001), (iii) the proportion of smokers was higher in the with-SCI group (P < 0.05), (iv) plasma level of high-density lipoprotein cholesterol was lower, whilst uric acid level was higher, in the with-SCI group (P < 0.05 and P < 0.05, respectively), and (v) multiple logistic regression analysis identified IL-6 levels as being significantly associated with the presence of SCI (odds ratio 3.13, 95% CI = 1.42-7.89, P < 0.0001). CONCLUSIONS: This study indicates that patients with chronic renal failure who are maintained on HD exhibit an increased prevalence of SCI and that IL-6 is significantly associated with the presence of SCI in HD patients.

Aerotaxis and aerokinesis of Dictyostelium discoideum under hypoxic microenvironments.

Although spatiotemporal changes of oxygen in a microenvironment are known to affect the cellular dynamics of various eukaryotes, the details are not fully understood. Here, we describe the aerotaxis and aerokinesis of Dictyostelium discoideum (Dd), which has long been employed as a model organism for eukaryotic cells. We developed a microfluidic device capable of time-lapse observation of cultured cells while controlling oxygen concentrations in microchannels. Migratory behaviors of Dd were observed and quantitatively evaluated under an oxygen concentration gradient from 0% to 21% O2, as well as in various uniform oxygen conditions. In a hypoxic region within the oxygen concentration gradient, Dd migrated toward regions of higher oxygen concentration at increased velocity, which was independent of cell density. Observed under uniform oxygen concentrations of 1%, 2%, 3%, and 21%, the migration velocity of Dd increased significantly in hypoxic environments of 2% O2 or less. Thus, Dd shows aerotaxis, directed by the oxygen concentration gradient, and simultaneously shows aerokinesis, changing the migration velocity according to the oxygen concentration itself.

Interleukin 5 enhances interleukin 2-mediated lymphokine-activated killer activity.

IL-5 expresses various biologic effects on several types of lymphocytes, including B cells, eosinophils, and T cells. We demonstrated that the incubation of resting splenocytes from C57BL/6 mice in murine rIL-5 enhances IL-2-mediated lymphokine-activated killer (LAK) activity against various tumor cells. IL-5 alone, however, does not induce killer activity. IL-2-mediated LAK activity increases in proportion to the dose of IL-5. During the late phase of the culture period, IL-5 seems to have some effect on the induction of IL-2-mediated LAK activity. We expect that IL-5 will prove useful for adoptive immunotherapy.

Sample collection from asteroid (162173) Ryugu by Hayabusa2: Implications for surface evolution.

The near-Earth asteroid (162173) Ryugu is thought to be a primitive carbonaceous object that contains hydrated minerals and organic molecules. We report sample collection from Ryugu's surface by the Hayabusa2 spacecraft on 21 February 2019. Touchdown images and global observations of surface colors are used to investigate the stratigraphy of the surface around the sample location and across Ryugu. Latitudinal color variations suggest the reddening of exposed surface material by solar heating and/or space weathering. Immediately after touchdown, Hayabusa2's thrusters disturbed dark, fine grains that originate from the redder materials. The stratigraphic relationship between identified craters and the redder material indicates that surface reddening occurred over a short period of time. We suggest that Ryugu previously experienced an orbital excursion near the Sun.

Histopathology of the ruptured pulmonary artery aneurysm in a patient with Behçet's disease.

OBJECTIVE: Vascular involvement (vasculo-Behçet's disease) is relatively common in Behçet's disease. Although pulmonary artery aneurysm (PAA) is rare, it is the most serious and sometimes fatal complication. However, the mechanism of the development of PAA is unclear. In the present study, we carried out immunohistological examination of the ruptured pulmonary aneurysm in a patient with vasculo-Behçets disease. METHODS: Light microscopic examination was carried out on paraffin-embedded sections of autopsied pulmonary arteries of a Behçet's disease patient who died of the rupture of the left pulmonary artery aneurysm. RESULTS: Histopathology of the ruptured aneurysm revealed the formation of thrombus and recanalization. In addition, there was proliferation of small vessels in the vascular wall, as if the recanalization was extended to the vascular wall. Of note, marked perivascular cuffing of mononuclear cells, consisting of CD45RO+ T cells and CD68+ monocytes, were observed around the recanalizing capillaries as well as around the proliferating small vessels in the wall of the pulmonary artery. Of note, pericapillary infiltration of CD20+ B cells was noted exclusively in the vascular wall. The ruptured portion of the aneurysm lacks the lamina elastica, indicating that the aneurysm was so called pseudo-aneurysm. CONCLUSION: It is likely that the first event might be the formation of inflammatory thrombus in the pulmonary artery. During the process of recanalization of the thrombus, the basic inflammatory process of Behçet's disease caused marked angiogenesis as well as perivascular cuffing of inflammatory cells in the thrombus and the wall, leading to fragility of the wall.

Successful steroid withdrawal after long-term administration in renal transplant patients.

OBJECTIVE: This study evaluated the effect of steroid withdrawal after long-term administration on stably functioning renal transplant recipients. METHODS: Between April 2000 and October 2006, steroid administration was safely withdrawn in 47 patients with stable graft function for >1 year after renal transplantation. The period between renal transplantation and steroid withdrawal varied from 12 to 234 months. We also investigated the current steroid doses of all 274 outpatients who had undergone renal transplantation at our hospital between July 1977 and October 2006. RESULTS: Twelve patients out of 47 had to resume steroid administration, 10 (21%) owing to acute rejection with/without recurrent glomerulonephritis, 1 owing to treatment of subacute thyroiditis, and the other owing to accompanying cessation of azathioprine for ovarian cancer. Thirty-five patients have maintained stable graft function for 12 to 90 months (median, 49) after steroid withdrawal as confirmed by follow-up. At present, only 1 of the 47 patients had to resume hemodialysis owing to chronic deterioration of renal graft function. The current steroid doses (prednisolone equivalent) of the 274 outpatients at our hospital are as follows: The number of patients for withdrawn, <5 mg, 5 mg, >5 to 10 mg, and >10 mg/d is 38, 20, 155, 57, and 4, respectively. Of 294 patients, 213 (77.7%) are maintaining stable renal graft functions on

The geomorphology, color, and thermal properties of Ryugu: Implications for parent-body processes.

The near-Earth carbonaceous asteroid 162173 Ryugu is thought to have been produced from a parent body that contained water ice and organic molecules. The Hayabusa2 spacecraft has obtained global multicolor images of Ryugu. Geomorphological features present include a circum-equatorial ridge, east-west dichotomy, high boulder abundances across the entire surface, and impact craters. Age estimates from the craters indicate a resurfacing age of [Formula: see text] years for the top 1-meter layer. Ryugu is among the darkest known bodies in the Solar System. The high abundance and spectral properties of boulders are consistent with moderately dehydrated materials, analogous to thermally metamorphosed meteorites found on Earth. The general uniformity in color across Ryugu's surface supports partial dehydration due to internal heating of the asteroid's parent body.

Effects of colloidal iron overload on renal and hepatic siderosis and the femur in male rats.

Genetic hemochromatosis is an iron overload disorder, and osteopenic and osteoporotic. Femoral neck bone mineral density (BMD) appears to fall with rising hepatic iron concentrations. A critical role for iron in mediating tissue injury is played via hydroxyl radical formation in nephrotoxicity. We investigated the effects of a colloidal iron overload on renal function, organ siderosis, and femoral bone in male rats. Iron overload reduced body growth, and increased the weights of the liver and spleen. Marked deposition of iron was noted in liver and kidney. Activities of lactate dehydrogenase and alkaline phosphatase were decreased, and the concentrations of blood urea nitrogen and creatinine were increased with the reduction in plasma calcium and inorganic phosphorus levels, i.e. functions of the liver and kidney might be affected by reactive oxygen species such as the superoxide radical, H2O2, and the hydroxyl radical produced by overloaded iron. Damage to the proximal tubular epithelial cells of the kidney and a loss of connectivity of cancellous bone in the epiphysis and of trabecular bone in the metaphysis of the distal femur were observed in iron-overloaded rats with a reduction of femoral bone mineral density, i.e. reabsorption of calcium from the proximal tubular epithelial cells of the kidney might be affected and urinary discharge of calcium might be elevated. It was suggested that iron overload gave rise to osteoporosis combined with renal dysfunction and liver iron overload syndrome.