TGFß1 signaling protects chondrocytes against oxidative stress via FOXO1-autophagy axis.

OBJECTIVE: The forkhead box O1 (FOXO1) transcription factor is a key regulator of autophagy. In chondrocytes, reduced FOXO1 expression with aging causes osteoarthritis due to dysfunction of autophagy, but the mechanisms underlying regulation of FOXO1 expression and the reduction in expression with aging remain unclear. We investigated the mechanism by which transforming growth factor ß1 (TGFß1) signaling regulates the FOXO1-autophagy axis. METHODS: Expression of FOXO1 was measured in chondrocytes after TGFß1 treatment. Immunohistochemistry was performed to estimate the levels of activin receptor-like kinase 5 (ALK5) and FOXO1 in the knee joints of young, middle-aged and old mice. The effects of the ALK5 inhibitor and SMAD3 or SMAD2 knockdown on FOXO1 expression were evaluated. The role of TGFß1 in autophagy after hydrogen peroxide (H2O2) treatment was analyzed. The protective effect of TGFß1 against H2O2 treatment was assessed by cell viability assay and TUNEL assay. RESULTS: TGFß1 promoted the expression of FOXO1 mRNA and protein. Both ALK5 and FOXO1 expression decreased with aging. ALK5 inhibition and SMAD3 knockdown suppressed induction of FOXO1 expression by TGFß1, whereas SMAD2 knockdown increased it. TGFß1 promoted the expression of microtubule-associated proteins 1A/1B light chain 3B (LC3)-I protein via the SMAD3-FOXO1 pathway. Furthermore, under H2O2 treatment, TGFß1 promoted expression of LC3-II. TGFß1 pretreatment suppressed cell death of chondrocytes following H2O2 treatment, but this protective effect was abolished by FOXO1 knockdown. CONCLUSIONS: TGFß1 protects chondrocytes against oxidative stress via the FOXO1-autophagy axis, and a reduction in ALK5 expression might cause reduced FOXO1 expression with aging.

Peroxiredoxins are involved in the pathogenesis of multiple sclerosis and neuromyelitis optica spectrum disorder.

Peroxiredoxins (PRXs) are intracellular anti-oxidative enzymes but work as inflammatory amplifiers under the extracellular condition. To date, the function of PRXs in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is not fully understood. The aim of this study was to investigate whether PRXs play a role in the pathogenesis of MS and NMOSD. We analyzed levels of PRXs (PRX1, PRX5 and PRX6) in the cerebrospinal fluid (CSF) and serum of 16 patients with MS, 16 patients with NMOSD and 15 patients with other neurological disorders (ONDs). We identified potential correlations between significantly elevated PRXs levels and the clinical variables in patients with MS and NMOSD. Additionally, pathological analyses of PRXs (PRX1-6) in the central nervous system (CNS) were performed using the experimental autoimmune encephalomyelitis (EAE), animal model of MS. We found that serum levels of PRX5 and PRX6 in patients with MS and NMOSD were higher compared with those in patients with ONDs (P < 0·05). Furthermore, high levels of PRX5 and PRX6 were partly associated with blood-brain barrier dysfunction and disease duration in NMOSD patients. No significant elevation was found in CSF PRXs levels of MS and NMOSD. Spinal cords from EAE mice showed remarkable PRX5 staining, especially in CD45+ infiltrating cells. In conclusion, PRX5 and PRX6 may play a role in the pathogeneses of MS and NMOSD.

Comparison of brain atrophy in patients with multiple sclerosis treated with first- versus second-generation disease modifying therapy without clinical relapse.

BACKGROUND AND PURPOSE: The silent progression of patients with multiple sclerosis (MS) has been reported. The aim of this study was to investigate the association between brain atrophy rates and disease-modifying drugs (DMDs) in patients with MS during their relapse-free period. METHODS: Patients with relapsing-remitting MS were classified into two groups on the basis of clinical records, i.e. a first-generation DMD group treated with interferon-beta-1a, interferon-beta-1b or glatiramer acetate and a second-generation DMD group treated with dimethyl fumarate, fingolimod or natalizumab. Brain volume was calculated with SPM12. RESULTS: A total of 45 patients with relapsing-remitting MS were enrolled in the first-generation (n = 22) or second-generation (n = 23) DMD group. The annualized relapse rate was lower in the first-generation than in the second-generation DMD group (median 0.26 vs. 0.59; P < 0.001). The annualized atrophy rate of the normalized brain volume was not different between the first- and second-generation DMD groups after analysis of covariance (median 0.13% vs. 0.59%; P = 0.17). CONCLUSIONS: The median annualized atrophy rate of normalized brain volume in the first-generation DMD group was similar to the previously reported annual brain atrophy rate of healthy controls, which may suggest that treatment with a first-generation DMD need not be changed when patients with MS are clinically inactive.

Prescription patterns of psychotropics in patients receiving synthetic glucocorticoids.

OBJECTIVE: Synthetic glucocorticoids cause various psychiatric symptoms. Prescription of psychotropic drugs could be considered to be a proxy for manifestation of psychiatric symptoms. The aim of this study was to investigate the prescriptions of psychotropics in outpatients receiving synthetic glucocorticoids. METHODS: We used the claims sampling data during January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan made by the Ministry of Health, Labor, and Welfare in Japan. We compared the prescription rates of psychotropics between outpatients receiving oral synthetic glucocorticoids and age- and sex-matched controls and the prescription rates of psychotropics among the eight dosage groups of synthetic glucocorticoids by chi-squared test, and chlorpromazine/imipramine/diazepam equivalent doses (or daily defined doses) of respective psychotropics among these groups using Welch's t-test. RESULTS: Synthetic glucocorticoids were prescribed to 3.1% (n = 18 122) of 581 990 patients. The prescription rates of psychotropics were significantly higher among the synthetic glucocorticoid recipients than among the non-recipients: antipsychotics, 1.8% (n = 321) vs. 1.1% (n = 201) (P = 1.4 × 10-7 ); antidepressants, 4.0% (n = 724) vs. 2.0% (n = 359) (P = 8.7 × 10-30 ); anxiolytics/hypnotics, 16.7% (n = 3029) vs. 10.2% (n = 1841) (P = 2.7 × 10-75 ); and mood stabilizers, 1.3% (n = 238) vs. 0.7% (n = 120) (P = 3.6 × 10-10 ) respectively. There was no significant difference in the prescription rates of any psychotropic drugs, other than anxiolytics/hypnotics, among the eight synthetic glucocorticoid dosage groups. CONCLUSION: Prescriptions of oral synthetic glucocorticoids were found to be associated with the use of any of the types of psychotropic drugs, other than anxiolytics/hypnotics, although a causal relationship could not be confirmed due to the retrospective and cross-sectional nature of this study.

Recombinant thrombomodulin ameliorates experimental autoimmune encephalomyelitis by suppressing high mobility group box 1 and inflammatory cytokines.

Recombinant thrombomodulin (rTM) has pleiotrophic properties, including anti-coagulation and anti-inflammation; however, its effectiveness as a treatment for multiple sclerosis (MS) has not been evaluated fully. High mobility group box 1 (HMGB1) and proinflammatory cytokines, working as inflammatory mediators, are reportedly involved in the inflammatory pathogenesis of MS. The aim of this study was to determine whether rTM can be a potential therapeutic agent for experimental autoimmune encephalomyelitis (EAE). EAE mice received rTM treatment (1 mg or 0·1 mg/kg/day) from days 11 to 15 after immunization. The clinical variables, plasma levels of inflammatory cytokines and HMGB1 and pathological findings in EAE were evaluated. rTM administration ameliorated the clinical and pathological severity of EAE. An immunohistochemical study of the spinal cord showed weaker cytoplasmic HMGB1 staining in the rTM-treated EAE mice than in the untreated EAE mice. Plasma levels of inflammatory cytokines and HMGB1 were suppressed by rTM treatment. In conclusion, rTM down-regulated inflammatory mediators in the peripheral circulation and prevented HMGB1 release from nuclei in the central nervous system, suppressing EAE-related inflammation. rTM could have a novel therapeutic potential for patients with MS.

Serum antinuclear antibody may be associated with less severe disease activity in neuromyelitis optica.

BACKGROUND AND PURPOSE: Antinuclear antibody-positive multiple sclerosis (MS) patients have shorter disease duration and lower Expanded Disability Status Scale (EDSS) scores. The aim of this study was to compare clinical and laboratory features between MS and neuromyelitis optica (NMO) patients with and without autoantibodies and to investigate the prognosis of NMO in patients with and without autoantibodies. METHODS: The frequencies of antinuclear, anti-Sjögren's syndrome A (SSA)/Ro, anti-Sjögren's syndrome B (SSB)/La and anti-thyroid peroxidase (TPO) antibodies in the sera of 75 NMO patients and 131 MS patients were compared. Clinical and laboratory profiles were also compared between NMO patients with and without autoantibodies, including annual relapse rate and time from onset of NMO to EDSS scores of 4.0 (limited walking but without aid) and 6.0 (walking with unilateral aid). RESULTS: More NMO than MS patients had antinuclear and anti-SSA/Ro antibodies (31% vs. 10%, P < 0.001, and 21% vs. 3%, P < 0.001, respectively). Antinuclear antibody-positive NMO patients had a lower annual relapse rate from disease onset to serum sampling compared with antinuclear antibody-negative NMO patients, independent of treatment regimen. Antinuclear antibody-negative NMO patients reached an EDSS score of 6.0 earlier than antinuclear antibody-positive NMO patients (P = 0.026). Cerebrospinal fluid cell counts were higher in anti-SSA/Ro-positive than in anti-SSA/Ro-negative NMO patients. More anti-TPO antibody-positive than anti-TPO antibody-negative NMO patients had oligoclonal immunoglobulin G bands (60% vs. 11%, P = 0.048). CONCLUSIONS: Autoantibodies possibly modulate the pathophysiology of NMO. Antinuclear antibody may be associated with less severe disease activity or less disability in NMO.

RAD51 G135C genetic polymorphism and their potential role in gastric cancer induced by Helicobacter pylori infection in Bhutan.

In order to evaluate the role of the RAD51 G135C genetic polymorphism on the risk of gastric cancer induced by Helicobacter pylori infection, we determined allele frequency and genotype distribution of this polymorphism in Bhutan--a population documented with high prevalence of gastric cancer and extremely high prevalence of H. pylori infection. The status of RAD51 G135C was examined by restriction fragment length polymorphism analysis of PCR amplified fragments and sequencing. Histological scores were evaluated according to the updated Sydney system. G135C carriers showed significantly higher scores for intestinal metaplasia in the antrum than G135G carriers [mean (median) 0·33 (0) vs. 0·08 (0), P = 0·008]. Higher scores for intestinal metaplasia of G135C carriers compared to those of G135G carriers were also observed in H. pylori-positive patients [0·3 (0) vs. 0·1 (0), P = 0·002] and H. pylori-positive patients with gastritis [0·4 (0) vs. 0·1 (0), P = 0·002] but were not found in H. pylori-negative patients. Our findings revealed that a combination of H. pylori infection and RAD51 G135C genotype of the host showed an increasing score for intestinal metaplasia. Therefore, RAD51 G135C might be the important predictor for gastric cancer of H. pylori-infected patients.

Current symptomatology in multiple sclerosis and neuromyelitis optica.

BACKGROUND AND OBJECTIVES: Several symptoms and signs are characteristic of multiple sclerosis (MS) such as Lhermitte's sign, Uhthoff's phenomenon and painful tonic seizure. Neuromyelitis optica (NMO) is another inflammatory disease of the central nervous system, and most of the opticospinal form of MS is thought to be NMO. This study aimed to investigate the frequencies of symptoms and signs, previously regarded as characteristic of MS, in NMO and MS patients. METHODS: Consecutive Japanese NMO-plus patients [NMO (n = 30) or partial NMO (n = 18)] and MS patients (n = 128) seen at Chiba University Hospital between 2011 and 2012 were investigated for the frequencies of symptoms and signs characteristic of MS. Logistic regression analyses were used to identify factors that distinguished NMO-plus from MS. RESULTS: Univariate analyses revealed that tonic seizures, Lhermitte's sign, persistent pain, fatigue and girdle sensation were more frequent in NMO-plus patients than in MS patients. Multivariate logistic regression analysis showed that paroxysmal itching, Uhthoff's phenomenon, Lhermitte's sign and girdle sensation were more characteristic of NMO-plus than of MS. CONCLUSIONS: Several classical MS symptoms and signs are more frequent in NMO patients than MS patients, which may be caused by the differences in the severity of inflammation, and localization and extensiveness of demyelinated lesions.

Identification of Helicobacter pylori infection in symptomatic patients in Surabaya, Indonesia, using five diagnostic tests.

SUMMARY The prevalence of Helicobacter pylori infection in Indonesia is controversial. We examined the H. pylori infection rate in 78 patients in a hospital in Surabaya using five different tests, including culture, histology, immunohistochemistry, rapid urease test, and urine antibody test. Furthermore, we analysed virulence factors in H. pylori strains from Indonesia. The H. pylori infection rate was only 11.5% in all patients studied, and 2.3% of Javanese patients and 18.0% of Chinese patients were infected (P = 0.01). Although severe gastritis was not observed, activity and inflammation were significantly higher in patients positive for H. pylori than in patients negative for H. pylori. Among genotypes identified from five isolated strains, cagA was found in four; two were vacA s1m1. All cagA-positive strains were oipA 'on' and iceA1 positive. We confirmed both a low H. pylori infection rate and a low prevalence of precancerous lesions in dyspeptic patients in a Surabaya hospital, which may contribute to the low incidence of gastric cancer in Indonesia.

Comparison of direct and indirect occlusal contact examinations with different clenching intensities.

The aims of this study were to examine the change of occlusal contact area following the increment of clenching intensity using silicone materials and electromyography (EMG) in normal subjects and to compare direct intra-oral examination with indirect examination using dental casts mounted by means of two impression methods. Participants were 7 men and 5 women with no more than one missing tooth per quadrant and no pain in the head and neck region. During the task, intercuspal position was maintained with minimal force, 20% maximum voluntary contraction (MVC) and 40% MVC using electromyography visual feedback. Three types of occlusal contact examinations were performed with the aid of blue silicone material in randomised order: (i) intra-oral direct occlusal contact examination (DE), (ii) indirect occlusal contact examination with dental casts using conventional impression method (IEC) and (iii) using occlusal impression method (IEO). Total occlusal contact area during DE and IEO significantly increased from baseline to 20% MVC and from baseline to 40% MVC, but not during IEC. Total occlusal contact area during DE in all tooth clenching conditions was significantly larger compared to IEO and IEC (P < 0·05). At 40% MVC, total occlusal contact area during IEO was significantly larger than during IEC (P < 0·05). These findings suggest that indirect occlusal contact examinations may not accurately reflect the intra-oral occlusal condition. If the intra-oral condition is reproduced using dental casts, these findings also suggest the occlusal impression method was more accurate compared to the conventional method (240 words).

Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease.

BACKGROUND: The number of long-term survivors after hematopoietic stem cell transplantation (HSCT) showed steady increase in the past two decades. Second malignancies after HSCT are a devastating late complication. We analyzed the incidence of, risk compared with that in the general population, and risk factors for secondary solid cancers. PATIENTS AND METHODS: Patients were 17 545 adult recipients of a first allogeneic stem cell transplantation between 1990 and 2007 in Japan. Risks of developing secondary solid tumors were compared with general population by using standard incidence ratios (SIRs). RESULTS: Two-hundred sixty-nine secondary solid cancers were identified. The cumulative incidence was 0.7% [95% confidence interval (CI), 0.6%-0.9%] at 5 years and 1.7% (95% CI, 1.4%-1.9%) at 10 years after transplant. The risk was significantly higher than that in the general population (SIR=1.8, 95% CI, 1.5-2.0). Risk was higher for oral cancer (SIR=15.7, 95% CI, 12.1-20.1), esophageal cancer (SIR=8.5, 95% CI, 6.1-11.5), colon cancer (SIR=1.9, 95% CI, 1.2-2.7), skin cancer (SIR=7.2, 95% CI, 3.9-12.4), and brain/nervous system cancer (SIR=4.1, 95% CI, 1.6-8.4). The risk of developing oral, esophageal, or skin cancer was higher at all times after 1-year post-transplant. Extensive-type chronic graft-versus-host disease (GVHD) was a significant risk factor for the development of all solid tumors (RR=1.8, P<0.001), as well as for oral (RR=2.9, P<0.001) and esophageal (RR=5.3, P<0.001) cancers. Limited-type chronic GVHD was an independent risk factor for skin cancers (RR=5.8, P=0.016). CONCLUSION: Recipients of allogeneic HSCT had a significantly higher ∼2-fold risk of developing secondary solid cancers than the general population. Lifelong screening for high-risk organ sites, especially oral or esophageal cancers, is important for recipients with active, or a history of, chronic GVHD.

Double deficiency in IL-17 and IFN-γ signalling significantly suppresses the development of diabetes in the NOD mouse.

AIMS/HYPOTHESIS: T helper type (Th) 17 cells have been shown to play important roles in mouse models of several autoimmune diseases that have been classified as Th1 diseases. In the NOD mouse, the relevance of Th1 and Th17 is controversial, because single-cytokine-deficient NOD mice develop diabetes similarly to wild-type NOD mice. METHODS: We studied the impact of IL-17/IFN-γ receptor double deficiency in NOD mice on the development of insulitis/diabetes compared with IL-17 single-deficient mice and wild-type mice by monitoring diabetes-related phenotypes. The lymphocyte phenotypes were determined by flow cytometric analysis. RESULTS: IL-17 single-deficient NOD mice showed delayed onset of diabetes and reduced severity of insulitis, but the cumulative incidence of longstanding diabetes in the IL-17-deficient mice was similar to that in wild-type mice. The IL-17/IFN-γ receptor double-deficient NOD mice showed an apparent decline in longstanding diabetes onset, but not in insulitis compared with that in the IL-17 single-deficient mice. We also found that double-deficient NOD mice had a severe lymphopenic phenotype and preferential increase in regulatory T cells among CD4(+) T cells compared with the IL-17 single-deficient mice and wild-type NOD mice. An adoptive transfer study with CD4(+)CD25(-) T cells from young non-diabetic IL-17 single-deficient NOD mice, but not those from older mice, showed significantly delayed disease onset in immune-deficient hosts compared with the corresponding wild-type mice. CONCLUSIONS/INTERPRETATION: These results indicate that IL-17/Th17 participates in the development of insulitis and that both IL-17 and IFN-γ signalling may synergistically contribute to the development of diabetes in NOD mice.

Genetic deletion of granzyme B does not confer resistance to the development of spontaneous diabetes in non-obese diabetic mice.

Granzyme B (GzmB) and perforin are proteins, secreted mainly by natural killer cells and cytotoxic T lymphocytes that are largely responsible for the induction of apoptosis in target cells. Because type 1 diabetes results from the selective destruction of ß cells and perforin deficiency effectively reduces diabetes in non-obese diabetic (NOD) mice, it can be deduced that ß cell apoptosis involves the GzmB/perforin pathway. However, the relevance of GzmB remains totally unknown in non-obese diabetic (NOD) mice. In this study we have focused on GzmB and examined the consequence of GzmB deficiency in NOD mice. We found that NOD.GzmB(-/-) mice developed diabetes spontaneously with kinetics similar to those of wild-type NOD (wt-NOD) mice. Adoptive transfer study with regulatory T cell (Treg )-depleted splenocytes (SPCs) into NOD-SCID mice or in-vivo Treg depletion by anti-CD25 antibody at 4 weeks of age comparably induced the rapid progression of diabetes in the NOD.GzmB(-/-) mice and wt-NOD mice. Expression of GzmA and Fas was enhanced in the islets from pre-diabetic NOD.GzmB(-/-) mice. In contrast to spontaneous diabetes, GzmB deficiency suppressed the development of cyclophosphamide-promoted diabetes in male NOD mice. Cyclophosphamide treatment led to a significantly lower percentage of apoptotic CD4(+) , CD8(+) and CD4(+) CD25(+) T cells in SPCs from NOD.GzmB(-/-) mice than those from wt-NOD mice. In conclusion, GzmB, in contrast to perforin, is not essentially involved in the effector mechanisms for ß cell destruction in NOD mice.

Fine structural and immunohistochemical detection of collar enamel in the teeth of Polypterus senegalus, an actinopterygian fish.

This is the first detailed report about the collar enamel of the teeth of Polypterus senegalus. We have examined the fine structure of the collar enamel and enamel organ of Polypterus during amelogenesis by light and transmission electron microscopy. An immunohistochemical analysis with an antibody against bovine amelogenin, an antiserum against porcine amelogenin and region-specific antibodies or antiserum against the C-terminus, middle region and N-terminus of porcine amelogenin has also been performed to examine the collar enamel matrix present in these teeth. Their ameloblasts contain fully developed Golgi apparatus, rough endoplasmic reticulum and secretory granules. During collar enamel formation, an amorphous fine enamel matrix containing no collagen fibrils is found between the dentin and ameloblast layers. In non-demineralized sections, the collar enamel (500 nm to 1 µm thick) is distinguishable from dentin, because of its higher density and differences in the arrangement of its crystals. The fine structural features of collar enamel in Polypterus are similar to those of tooth enamel in Lepisosteus (gars), coelacanths, lungfish and amphibians. The enamel matrix shows intense immunoreactivity to the antibody and antiserum against mammalian amelogenins and to the middleregion- and C-terminal-specific anti-amelogenin antibodies. These findings suggest that the proteins in the enamel of Polypterus contain domains that closely resemble those of bovine and porcine amelogenins. The enamel matrix, which exhibits positive immunoreactivity to mammalian amelogenins, extends to the cap enameloid surface, implying that amelogenin-like proteins are secreted by ameloblasts as a thin matrix layer that covers the cap enameloid after enameloid maturation.

Double-balloon endoscopy versus magnet-imaging enhanced colonoscopy for difficult colonoscopies, a randomized study.

BACKGROUND AND STUDY AIMS: Studies have estimated that failure of cecal intubation occurs with conventional colonoscopy in up to 10 % of cases. Double-balloon endoscopy (DBE) systems, magnetic endoscope imaging (MEI), and transparent cap have been shown to improve success rates for colonoscopy. This study evaluated the utility of DBE for complete examination of the colon compared with MEI plus cap (MEI-Cap) after incomplete or technically difficult colonoscopy in a randomized comparative manner. PATIENTS AND METHODS: A total of 94 patients with incomplete or technically difficult colonoscopy were randomly assigned to receive either DBE (n = 47) or colonoscopy with MEI-Cap (n = 47). The primary end point was cecal intubation rate within 30 minutes. Secondary end points included intubation time, pain score using a visual analog scale, abdominal pressure attempts, doses of sedative medication, and changes in patient position during colonoscopy. RESULTS: Patient characteristics were comparable in both groups. Cecal intubation rate within 30 minutes was significantly higher for DBE (45 /47, 95.7 %) than for MEI-Cap (34 /47, 72.3 %) (P = 0.0049). Mean time to reach the cecum was significantly lower in the DBE group (13.0 ±â€Š5.3 minutes) than in the MEI-Cap group (16.4 ±â€Š4.8 minutes; P = 0.0003). No complications were encountered in either group.   CONCLUSION: DBE is more useful for complete examination of the colon than MEI-Cap in patients with incomplete or technically difficult colonoscopy.

Retrieving microcatheters from Onyx casts in a series of brain arteriovenous malformations: a technical report.

INTRODUCTION: To date, the "monorail snare technique" for the retrieval of entombed microcatheter tips during Onyx(TM) (ev3, Irvine, CA) embolisation of brain arteriovenous malformations (BAVM) has not been described. We report our experiences and some technical aspects in using this technique for the retrieval of entombed Marathon(TM) microcatheter (ev3, Plymouth, MN) tips during Onyx embolisation of BAVM treatment. METHODS: Onyx was used in the embolisation of 11 patients using 25 feeders over 14 sessions. The 'monorail snare technique' was employed for 14 feeders. Each time, an Amplatz 4 mm Gooseneck Microsnare(TM) (ev3, Plymouth, MN) was loaded into an Excelsior 1018(TM) microcatheter (Boston Scientific, Natick, MA). The Marathon microcatheter was cut just distal to the hub, and the Amplatz/Excelsior combination was introduced along the length of the Marathon microcatheter towards its distal end, as far as possible. The embedded catheter was ensnared and both catheters were pulled free. RESULTS: Microcatheter tip removal was successful in all cases, except for one microcatheter tip becoming detached and needing no further intervention. There were no complications as a direct result of the snare technique. CONCLUSIONS: The monorail snare technique is a safe and easy technique for retrieving Onyx-encased microcatheter tips in the treatment of BAVM.

Thrombopoietin receptor agonists in refractory immune thrombocytopenia: differential responses to eltrombopag and romiplostim: a case report and possible explanations.

WHAT IS KNOWN AND OBJECTIVE: Although new thrombopoietin (TPO) receptor agonist drugs, such as romiplostim and eltrombopag, are highly effective and well tolerated for patients with immune thrombocytopenia (ITP) refractory to first-line treatments such as prednisolone, the cross-resistance of these two TPO receptor agonists is still unknown. CASE SUMMARY: An 84-year-old Japanese female patient with steroid-refractory ITP received eltrombopag with a gradually increasing dose schedule from 12.5 to 25 mg/day, 37.5 mg/day and finally 50 mg/day. As no increase in platelet count was observed even at the maximum dose of 50 mg/day, and eltrombopag-related grade 3 elevation of aspartate aminotransferase was observed, another TPO receptor agonist, romiplostim, was administered at 1 µg/kg/week subcutaneously. A rapid increase in platelet count was observed 1 week after the first injection. The dose of romiplostim was escalated to 4 µg/kg according to the platelet count and a complete response was achieved 7 weeks after the first injection without any adverse events. WHAT IS NEW AND CONCLUSION: The successful treatment of ITP refractory to eltrombopag with romiplostim strongly suggests that the absence of cross-resistance between these two approved TPO receptor agonists and possible differences in mechanism of action. Further study of the mechanisms of action of TPO receptor agonists is called for along with further exploration of the potential of romiplostim in refractory ITP.

Transient ligation of umbilical vessels elevates placental tissue oxygen index (TOI) values measured by near-infrared spectroscopy (NIRS) in clawn miniature pig animal model.

We recently found a significant elevation in placental tissue oxygen index (TOI) values in cases of fetal growth restriction using near-infrared spectroscopy (NIRS), indicating high oxygenation in the placental tissue. We hypothesized that insufficient fetoumbilical blood flow is causatively associated with high oxygenation levels in placental tissue. We transiently (for 15 sec) ligated the whole umbilicus, umbilical arteries, or veins of pregnant Clawn miniature pigs (102-113 days of gestation) and assessed the changes in TOI values of the placenta and fetus. The ligation significantly increased placental TOI values (p<0.01, respectively), but concomitantly decreased fetal TOI values (p<0.01, respectively), suggesting a decline in oxygen inflow from the maternal to fetal circulation in the placental tissue to be causative of the elevated placental TOI values. These observations suggest the promising clinical use of placental TOI values measured noninvasively by the transabdominal application of NIRS to assess the fetoplacental circulation.

Behavior of Stimulus Response Signals in a Rat Cortical Neuronal Network Under Xe Pressure.

Neurons cultured on a multi-electrode array show not only spontaneous firing, but also network-specific burst firing, the latter of which develops into synchronous bursting. Such synchronous bursting can be suppressed by exposure to xenon (Xe) gas. To better understand such suppression of bursting by Xe, we investigate here whether signal transmission between neurons is also suppressed under these conditions. In these experiments, we apply a pulse electrical-stimulus to one electrode and observe the response signals within 10 ms at other active electrodes. When put under a sufficient Xe pressure, some response signals become delayed or vanish after disappearance of synchronous-bursts, particularly signals passing through multiple synaptic bonds. Such bonds have a high probability of having delayed or vanishing signals when the Xe pressure is above 0.3 MPa. The pressure dependence of the response ratio to the stimulus suggests that Xe suppresses multiple points of action simultaneously when suppressing synaptic signal transduction, as observed in the suppression of the synchronized bursting. In addition, we find that the signal that transmits not via synaptic bonding (axon conduction) is also suppressed under Xe gas pressures over 0.3 MPa. Therefore, we conclude that Xe-induced suppression of synchronized bursting is caused mainly by a decrease in the apparent number of active neurons that contribute to the neuronal network, a decrease due to inhibition of signal transmission via synaptic connections.