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Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months [95% confidence interval (CI) 1.6-2.9 months] with pimitespib versus 1.4 months (0.9-1.8 months) with placebo [hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006]. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo [HR 0.42 (0.21-0.85), one-sided P = 0.007]. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.

Introduction As Chimeric Antigen Receptor T-cell (CAR-T) therapy gains its clinical advantage in the management of diffuse large B cell lymphoma (DLBCL), accumulating evidence shows that it often accompanies cardiac dysfunction. Previous retrospective studies indicated the potential involvement of cytokine release syndrome (CRS) in cardiac dysfunction after CAR-T therapy, but no prospective study has reported the time course of cardiac dysfunction. Moreover, the relationship between the severity of CRS and cardiac dysfunction after CAR-T therapy remains unclear. Purpose The objectives of this study are to prospectively examine the sequential changes in cardiac markers overtime after CAR-T therapy and to clarify the association between the grade of CRS and cardiac markers. Methods In this prospective observational study, 30 DLBCL patients who underwent CAR-T therapy from July 2020 to March 2022 were enrolled. Before and after the treatment, the level of cardiac biomarkers and echocardiographic index were sequentially collected. We classified all patients into two groups according to the severity of CRS after CAR-T therapy, namely low-CRS group (CRS Results The average age of participants was 59.6 years, and 9 patients (30%) were female. The average duration of DLBCL was 2.7 years. The CRS showed its peak severity on day 3. The number of patients in low- and high-CRS group was 13 and 17, respectively and tocilizumab was administrated for 46% and 71% of the patients in low- and high-CRS group, respectively. At the baseline before CAR-T therapy, there were no significant differences in cardiac parameters between the two groups. During the follow-up, sequential measurements of cardiac biomarkers revealed that high-CRS group showed significantly higher NT-proBNP level compared to that of low-CRS group (NT-proBNP; 90pg/ml vs. 623pg/ml, p=0.0001, respectively) and both had their peak on day 3, whereas troponin T level did not show any differences. Likewise, sequential measurements of echocardiographic parameters revealed that high-CRS group showed significantly increased E/A compared to low-CRS group on day 7 (E/A; 0.77 vs. 0.90, p=0.021, respectively), but not in the later phase. The parameters for systolic function including GLS and EF and parameters for diastolic function such as E/e' and LAVI did not alter among the two groups throughout the follow-up. Conclusion In the patients who underwent CAR-T therapy for DLBCL, the elevation of NT-proBNP level and increase in E/A was transiently observed within a week and correlated with the severity of CRS. Funding Acknowledgement Type of funding sources: None.

Background An important therapeutic aim in ulcerative colitis (UC) is endoscopic remission. Although an endoscopic score with white light imaging (WLI) is mainly used to evaluate endoscopic findings, recently, the usefulness of linked color imaging (LCI) has been reported. We evaluated the relationship between LCI and histopathological findings and attempted to establish a new LCI endoscopic evaluation index for UC. Methods This study was conducted at Kyorin University, Kyoto Prefectural University, and Fukuoka University Chikushi Hospital. Ninety-two patients (median age, 46 years; male/female ratio, 48/34) with a Mayo endoscopic subscore (MES) ≤1 who underwent colonoscopy for UC in clinical remission between November 2016 and January 2019 were included. LCI index was defined as degree of redness (R) (grade 0–2), area of inflammation (A) (grade 0–3), and visibility of lymphoid follicles (L) (grade 0–3). Endoscopic scores were determined by three central endoscopic judgment committee members who are experts in colonoscopy for UC. Discussions were held among the three members, and when two or more of them had the same judgment this was adopted as the final evaluation. Each biopsy was performed from an identical site of colonoscopic image. Histological healing was defined as Geboes score Results In 92 patients, 85 biopsies from the sigmoid colon and 84 biopsies from the rectum (total 169 biopsies) were evaluated. Percentage of judgments that were consistent in two or more central endoscopic judgment committee members were 167/169 (98.8%) cases in MES, 164/169 (97.0%) cases in LCI index-R, 152/169 (89.9%) cases in LCI-index-A, and 150/169 (88.8%) cases in LCI-index-L. Regarding the κ-score in diagnosing by the two pathologists, "Chronic inflammatory infiltrate", "Crypt destruction", and "Crypt destruction" had a moderate agreement, and others had a stationary agreement. The overall histological healing rate was 84.0% (142/169). There were 22/117/30 cases of grade 0/1/2 in LCI index-R, 113/34/17/5 cases of grade 0/1/2/3 in LCI index-A, and 124/27/14/4 cases of grade 0/1/2/3 in LCI index-L. Histological healing was achieved in 84.1% (142/169) of the cases, and there were significant associations with histological healing/non-healing in LCI index-R (P=0.013) and A (P=0.0014). Conclusion A new LCI index is useful for predicting histological healing in UC patients with MES ≤1 and clinical remission.

[Background] A multidisciplinary approach based on guidelines and pathological diagnosis by specialized pathologists are important for improving the prognosis and QoL of GIST patients. This study examined the adherence to the guidelines and the concordance of the pathological diagnosis of high-risk GISTs. [Patients and methods] Among 541 patients with high-risk GISTs recruited to the prospective registry between Dec. 2012 and Dec. 2015, 534 patients were analyzed after central pathology with KIT and DOG1 IHC and genotyping of KIT and PDGFRA. [Results] Of the 534 patients, 432 (81%) received imatinib adjuvant therapy at a starting dose of 400 or 300 mg/day. Multivariate analysis indicated that age (HR 0.71; 95% CI 0.58–0.88), tumor size (HR for > 10 cm vs 10 vs

Using a fiber optic temperature sensing system based on the cross-correlation of picosecond optical pulses from a gain-switched semiconductor laser, the thermal time constants of several types of optical fiber in water were measured.

Background Cancer chemotherapy is associated with a variety of side effects/adverse events. It is very important that patients adhere to the planned chemotherapy regimen, which necessitates a minimum of side effects and that these side effects be kept under control. We have investigated patients’ concerns and symptoms during chemotherapy with the aim to seek solutions that will improve patients’ quality of life during chemotherapy. Methods Forty-nine patients with malignant diseases on parenteral antineoplastic agents were sequentially enrolled in this study. These patients completed a questionnaire consisting of 42 items related to non-physical concerns and 52 items of physical symptoms related to chemotherapy. Each patient was also asked to select the three items among these 94 items which affected him/her the most. Results The median age of the cancer patients was 62 years and the male-to-female ratio was 18:31. Among the non-physical concerns, the most frequently chosen concern was ‘affects my family or partner,’ followed by anxiety related to treatment. Regarding the physical symptoms, the most frequent complaints were fatigue, alopecia and constipation, while the most troublesome symptoms were nausea, poor taste and paresthesia. Overall, the most frequently expressed concerns were ‘affects my family or partner’ and anxiety related to treatment. Male patients suffered most from fever, fatigue and nausea, and female patients complained more of poor taste and gastrointestinal problems. Conclusion Patient perceptions of adverse events associated with cancer chemotherapy apparently have changed from physical symptoms to non-physical concerns. In our patient cohort ‘affects my family or partner’ was the most important concern. One important point to note is that female patients often complained of poor taste because this meant they were unable to cook well. Electronic supplementary material The online version of this article (doi:10.1007/s10147-017-1117-y) contains supplementary material, which is available to authorized users.

We have measured anisotropic electrical resistivity of quasi-one-dimensional Ta2NiSe5 single crystals under pressure. While the in-plane anisotropy is almost pressure independent, the inter-plane one greatly decreases at P c ∼ 3 GPa accompanied by a pressure-induced semiconductor-semimetal transition. Nevertheless, a similar anomaly in the temperature dependence of in-plane anisotropy has been observed in each phase. This anomaly in the low-pressure phase below P c is regarded as an excitonic transition, and thus both of these anomalies are suppressed with increasing pressure. These results suggest that the suppression of the excitonic binding energy with pressure is caused by the increase of free carrier densities and the inter-plane conductivity.

The current study aimed to compare cytology using SurePathBetween January 2014 and December 2016, 57 patients underwent endoscopic retrograde cholangiopancreatography for the diagnosis of biliary disease. Biliary cytological samples were processed using SP-LBC and subsequently BTH was performed. A final diagnosis was confirmed by surgery (23 malignant cases) and clinical follow-up (34 benign and malignant cases): 18 extrahepatic cholangiocarcinoma; 17 intrahepatic/hilar cholangiocarcinoma (intra/H-CC); eight other malignant disease; and 14 benign biliary disease. The diagnoses made using SP-LBC and BTH were classified into four categories: (1) benign; (2) indeterminate; (3) suspicious for malignancy/malignant; and (4) inadequate. In addition, diagnostic accuracy was compared between SP-LBC and BTH.Although 23% (13/57) of BTH samples were classified as inadequate, all SP-LBC cases were classified as adequate. Among 43 malignant cases, 11 normal, four indeterminate and 28 suspicious for malignancy/malignant were found using SP-LBC (26%, 9% and 65%, respectively), in contrast to 10 inadequate, nine normal, 10 indeterminate and 14 suspicious for malignancy/malignant observed using BTH (23%, 21%, 23%, and 33%, respectively). The identification of malignant cells was strikingly different between SP-LBC and BTH. Furthermore, limited to intra/H-CC, accuracy was significantly higher using SP-LBC than using BTH (P .001).SP-LBC of the biliary tract is a useful and reliable method for diagnosing biliary malignant disease and has an advantage over BTH for detecting malignant cells and accurately diagnosing intra/H-CC.

Background Rikkunshito, a standardized Japanese herbal medicine, is thought to accelerate gastric emptying and relieve dyspepsia, although no large-scale, randomized, placebo-controlled trials of rikkunshito have been conducted. This study aimed to determine the efficacy and safety of rikkunshito for treating functional dyspepsia (FD). Methods FD patients received 2.5 g rikkunshito or placebo three times a day for 8 weeks in this multicenter, randomized, placebo-controlled, parallel-group trial. The primary end point was the proportion of responders at 8 weeks after starting test drug, determined by global patient assessment (GPA). The improvement in four major dyspepsia symptoms severity scale was also evaluated. In addition, plasma ghrelin levels were investigated before and after treatment. Key Results Two hundred forty-seven patients were randomly assigned. In the eighth week, the rikkunshito group had more GPA responders (33.6%) than the placebo (23.8%), although this did not reach statistical significance (p = 0.09). Epigastric pain was significantly improved (p = 0.04) and postprandial fullness tended to improve (p = 0.06) in the rikkunshito group at week 8. Rikkunshito was relatively more effective among Helicobacter pylori-infected participants (rikkunshito: 40.0% vs placebo: 20.5%, p = 0.07), and seemed less effective among H. pylori-uninfected participants (rikkunshito: 29.3% vs placebo: 25.6%, p = 0.72). Among H. pylori-positive individuals, acyl ghrelin levels were improved just in rikkunshito group. There were no severe adverse events in both groups. Conclusions & Inferences Administration of rikkunshito for 8 weeks reduced dyspepsia, particularly symptoms of epigastric pain and postprandial fullness. (UMIN Clinical Trials Registry, Number UMIN000003954).

Full-aperture ion optics simulations have been conducted for the inhomogeneous plasma source of a miniature ion propulsion system (MIPS) to design a high-efficiency accelerator grid that provides high degree of the neutral confinement and absence of direct ion impingement. The designed accelerator grid has flat upstream and smoothly curved downstream surfaces with straight holes for easy low-cost manufacture. The diameter of the accelerator aperture was changed from the nominal value of 0.40 mm to 0.25 mm, which decreased neutral leakage and increased the propellant utilization efficiency from 31 to 50%. The direct impingement of ions caused by decreasing the accelerator aperture diameter was compensated by reducing the thickness of the accelerator grid while taking into account the inhomogeneous ion beam current density profile of the MIPS. An off-design performance simulation was conducted to validate the proposed grid design; the obtained results showed that the ion beam could be accelerated smoothly even during throttling the beam current between 75 and 150%. A grid wear simulation was also performed to compare the changes in the propellant utilization efficiency between the nominal and high-efficiency grids caused by erosion. It was found that the propellant utilization efficiency of the high-efficiency grid was greater than that of the nominal grid within the first 5,000 h of operation and that its lifetime exceeded 10,000 h of the accumulated operation time. By using the proposed high-efficiency accelerator grid and MIPS plasma source, the propellant utilization efficiency was increased, while the accelerator impingement current became negligible.

Flying fish (Teleostei: Exocoetidae) glide at a speed considerably faster than they can travel in water. This phenomenon has been investigated and examined from taxonomic, anatom- ical, aerodynamic and biological standpoints through field observations. However, direct meas- urements of the flight performance of flying fish at the moment of leaping from the water surface have not previously been performed, due to the difficulty of monitoring gliding behavior. In the present study, we used recently developed data loggers capable of recording acceleration on a 3- dimensional axis to directly examine the gliding behavior of the flying fish Cypselurus heterurus doederleini under controlled conditions. Gliding behavior was assessed with the data logger fixed to the fish in 1 of 2 different positions, and positioning was not found to seriously affect leaping performance, as no effects on pitch angle, amplitude of fluctuation in swaying acceleration, stroke cycle frequency, or the duration of acceleration were observed. Pitch angle (20.0 ± 3.3°) and stroke cycle frequency (21.2 ± 4.6 Hz) were found to be lower in the present study than in previous stud- ies that examined gliding behavior in the field. Additionally, the flying fish were estimated to leap from the water surface at speeds of 3.9 to 5.2 m s �1 in our study, which is 38.7 to 51.5% of previ- ously reported maximum swimming speeds determined using stroboscopic filming. Our results suggest that the flying fish in our study may have recognized the capacity of the experimental space and regulated swimming performance before leaping from the water surface.

Background/aims The alarming increase in allergy in the last few decades demands the development of new anti-allergic prevention strategies, and consumption of functional foods (i.e. probiotic Dahi, which has already been proven to enhance immunity by modulation of the gut mucosal immune system) may be one of them. In the present study, we evaluated anti-allergic effects of a Dahi (yogurt) containing probiotic Lactobacillus acidophilus, L. casei and normal Dahi culture Lactococcus lactis biovar diacetylactis (named probiotic Dahi) on ovalbumin induced allergy in mice. Methods Allergy was induced by injecting (i.p.) ovalbumin at 0 and 14 days. Animals were fed with standard diet (control), milk, control Dahi or probiotic Dahi for 21 days. Total and ovalbumin-specific IgE, cytokines and lymphocyte proliferation index were examined after 7, 14 and 21 days. Results Feeding of probiotic Dahi completely suppressed the elevation of total and ovalbumin-specific IgE in the serum of ovalbumin-injected mice. Similarly, splenocytes collected from mice fed with probiotic Dahi entirely lost the total and ovalbumin-specific IgE production property during in-vitro culture. Production of T helper (Th)-1 cell-specific cytokines, i.e. interferon -γ and interleukin (IL)-2, increased, while Th2-specific cytokines, i.e. IL-4 and IL-6, decreased in the supernatant of cultured splenocytes collected from mice fed with probiotic Dahi compared to the other groups. Moreover, ovalbumin-stimulated lymphocyte proliferation was strongly suppressed by feeding of probiotic Dahi in comparison to milk and control Dahi. Conclusions Results of the present study indicate that probiotic Dahi suppressed ovalbumin-induced allergic consequences characterized by decreasing levels of total and ovalbumin-specific IgE and lymphocyte proliferation and skewed ovalbumin-induced Th2-specific immune response towards Th1-specific response.

The GAC→AAC mutation at codon 178 (D178N) of prion protein (PrP) gene ( PRNP ) results in 2 distinct clinicopathologic phenotypes dependent on codon 129 polymorphism of the mutant allele: fatal familial insomnia (FFI) with methionine encoded in codon 129 and familial Creutzfeldt-Jakob disease (CJD) with valine.1,2 However, some D178N patients who had homozygosity for methionine at codon 129 (D178N-129MM) were reported recently to have the CJD phenotype.3–5 The cause for these clinicopathologic diversities is unclear. We report a Japanese son–mother pair who presented with FFI and CJD phenotypes. ### Case reports. #### Patient 1 (proband). A 54-year-old man, born to nonconsanguineous parents, developed dysphagia and loss of appetite. Later, he showed peculiar movement in sleep, followed by insomnia and hypersomnolence. Diplopia, intention tremor, ataxic gait, sleep apnea, fluctuant low-grade fever, tachycardia, hyperhidrosis, constipation, and impotence also followed. He was admitted to hospital 7 months after the onset of symptoms. Neurologic examination showed mild memory disturbance, cerebellar ataxia, myoclonus, brisk deep tendon reflexes, sleep apnea, and dysautonomia. He did not show akinetic mutism. He moved continuously during sleep. EEG showed no periodic synchronous discharge (PSD), and polysomnography showed loss of deep sleep and marked reduction of REM sleep. Brain MRI showed only mild atrophy. In the cerebral cortex and thalamus, hypoperfusion and hypometabolism were detected by SPECT with 99mTc-ECD and PET with 18F-2-fluorodeoxy-d-glucose. He died 13 months after the onset of symptoms. PRNP analysis, with informed consent, on leukocyte DNA showed D178N-129MM. Histologic examination showed spongiform changes limited to the cingulate gyrus and subiculum, and severe neuronal loss and fibrillary gliosis in the centromedian and dorsomedial nucleus of the thalamus and in the inferior olivary nucleus (figure, A, D, and G). Immunohistochemical analysis showed no pathologic PrP (PrPSc) deposition in the cerebral cortex, thalamus, or inferior olivary nucleus. Western blot analysis (WB) showed very …

S Kawakita1, F Marotta2, Y Naito3, U Gumaste4, S Jain5, J Tsuchiya1, E Minelli21Biokenkyusho Research Laboratory, Shizuoka, Japan; 2WHO-cntr for Biotechnology and Natural Medicine, University of Milan, Milan, Italy; 3Immunology Research Institute and Clinic, Nagoya, Japan; 4Agharkar Research Institute, Pune, Maharashtra, India; 5Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, IL, USA Abstract: The aim of this study was to test the combined effect of a quality-controlled red clover extract (RCE) standardized to contain 40% isoflavones by weight (genistein, daidzein, biochanin A, and formononetin present as hydrolyzed aglycones) together with a modified alkaline supplementation on bone metabolic and biomechanical parameters in an experimental model of surgically-induced menopause. Sprague–Dawley female rats were maintained under controlled standard conditions of light and fed with conventional food of standard calcium content and no alfalfa or soybean components. Rats were randomized into four groups: Group A represented normal rats (sham operated) while three other groups were ovariectomized (OVX) and fed for three months as follows: standard food (group B), 6 mg/kg/day food mixed with RCE (Group C), or given 6 mg/kg/day of RCE plus a modified alkaline supplementation (BP) through a nasogastric tube at a dose of 16 mg (group D). The animals were killed 90 days after surgery. As compared to group B, RCE or RCE + BP treatments brought about significantly higher level of estradiol and mitigated the weight loss of the uterus and improved maximum load of the femoral neck. Osteocalcin level showed an over 65% increase in group B but both RCE and RCE + BP treatments prevented such abnormality with a significantly better result in RCE + BP group which virtually normalized such parameter as well as urinary excretion of DPD. Group C and D reduced the over 20% loss of bone mineral density and bone mineral content/body weight ratio observed in untreated post-ovariectomy group. Untreated ovariectomy caused about 48% decrease of cancellous bone mass in the femoral neck while this abnormality was prevented at similar extent by both RCE and RCE + BP treatments. Ovariectomy determined an over 80% increase of bone alkaline phosphatase (BALP) level but both RCE and RCE + BP treatments significantly mitigated such variable. The BALP decrease yielded by the combined RCE + BP treatment was statistically lower than RCE alone. Taken together these data show that red clover preparation in dosages amenable to clinical practice do improve OVX-induced osteoporosis while a mild metabolic alkalosis might further synergize some therapeutic aspects. Keywords: red clover, alkaline supplementation, osteoporosis, ovariectomy

Salmonella enteritidis infection has received attention during recent years owing to its high prevalence worldwide. In the present study, the protective effect of probiotic dahi (curd) supplemented with Lactobacillus acidophilus and L. casei against Salmonella enteritidis infection in mice is investigated. Seven days pre-feeding with probiotic dahi significantly increased anti- S. enteritidis sIgA (secretary IgA) antibodies and lymphocyte proliferation in S. enteritidis infected mice. IL-2, IL-6 and IFNγ production were significantly increased in supernatant of cultured splenocytes collected from mice pre-fed with probiotic dahi, while IL-4 levels were not changed significantly. Moreover, activities of β-galactosidase and β-glucuronidase, and counts of S. enteritidis in intestine, liver and spleen were decreased, whereas total lactobacilli in faeces were increased in mice pre-fed with probiotic dahi. Pre-feeding of probiotic dahi for 7 days was more effective than 2 days pre-feeding. Thus, the results indicate that, pre-feeding with probiotic dahi ameliorated S. enteritidis infection by stimulating specific and non-specific immune response. Above all, it lowered colonization of gastrointestinal tract as well as translocation of S. enteritidis.

Summary Objectives: This paper illustrates a high speed clinical data retrieving system, from 10 years of data of operating hospital information system for the purposes of research, evidence creation, patient safety, etc., even incorporating time sequence of causal relations. Methods: Total of 73,709,298 records of 10 years at Hamamatsu University Hospital (as of June 2008) are sent from HIS to retrieval system in HL7 v2.5 format. Hierarchical variable length database is used to install them. Results: A search for “listing patients who were prescribed Pravastatin (Mevalotin and generic drugs, any titer)” took 1.92 seconds. “Pravastatin (any) prescribed and recorded AST >150 within two weeks” took 112.22 seconds. Searching conditions can be set to be more complex, connected by Boolean operator and/or. This system called D*D is in operation at Hamamatsu University Hospital since August 2002. It is used for 48,518 times (monthly average of 703 searches). Neither searching, nor background export of data from HIS caused delay of routine operating CPOE. Conclusions: Search database outside of routine operating CPOE, with daily export of order data in HL7 v2.5 format, is proved to provide excellent search environment without causing trouble. Hierarchical representation gives high-speed search response, especially with time sequence of events.

The Japan Arteriosclerosis Longitudinal Study-Existing Cohorts Combine (JALS-ECC) is a pooled study based on individual participant data from existing prospective cohort studies in Japan. Its purpose was to consider associations between risk factors and cardiovascular disease (CVD) outcomes, as well as differences between subgroups, defined by age, gender or geographical region, which could not be detected in the smaller samples.Individual records for 66,691 participants in 21 cohort studies were pooled, accounting for a total of 575,628 person-years. From this data, there were 409 deaths attributed to stroke and 169 deaths attributed to coronary heart disease (CHD). Total stroke and CHD events were 1,478 and 178, respectively. Of the 1,424 total stroke events with a reported stroke subtype, 975 were classified as ischemic, 267 as hemorrhagic, and 178 as subarachnoid hemorrhage.The JALS-ECC collected data from existing cohort studies covering a diverse Japanese population, which has provided information about the effects of modifiable factors on the risks of the CVD. Such information should provide a reliable basis for establishing prevention strategies.

The aging process is paralleled by two- to fourfold increases in plasma/serum levels of inflammatory mediators, such as cytokines and acute-phase proteins. In this study we assessed the inflammatory profile and polymorphism of healthy elderly subjects and the influence of a nutraceutical supplement. Forty elderly, generally healthy subjects were recruited, divided into two matched groups, and given either a fermented papaya preparation 9 g/day by mouth or the same amount of placebo. Treatments were carried out in a cross-over manner with a 3-month supplementation period followed by a 6-week washout period between treatments. Ten healthy young subjects served as controls. Interleukin-6 (IL-6) promoter -174 G/C polymorphism genotype was determined together with blood levels for redox status, proinflammatory cytokines, high sensitivity C-reactive protein, and serum 70 kDa heat shock protein (Hsp70) concentrations. Tumor necrosis factor-alpha and IL-6 were higher in elderly subjects (P < 0.05 versus young controls). The concentration of Hsp70 inversely correlated with markers of inflammation in -174 G/C-negative subjects (r = 0.62, P < 0.05). Nutraceutical intervention normalized the inflammatory parameters (P < 0.05) with a rise of Hsp70 (P < 0.05). This suggests that healthy elderly individuals may have a proinflammatory profile playing as a downregulating factor for inducible Hsp70, particularly if -174 G/C-negative. A nutraceutical intervention seems able to beneficially modulate such a phenomenon.

Energy dispersive X-ray diffraction measurements have been carried out for liquid Ge1−xSix alloys (x = 0.0, 0.3, 0.5, 1.0) using synchrotron radiation at SPring-8. We measured the X-ray diffraction spectra of liquid Ge and Si up to a high temperature range, (liquid Ge from 1270 to1870 K and liquid Si from 1680 to 2020 K), liquid Ge0.7Si0.3 at 1620 K, and liquid Ge0.5Si0.5 at 1540, 1590, 1670 and 1720 K. The total structure factors of the liquid Ge–Si alloys have a characteristic shoulder on the high-wave-vector side of the first peak. We deduced a pair distribution function from the Fourier transform of the observed structure factor, which was weakly dependent on the temperature. The nearest-neighbor coordination number of liquid Ge–Si alloys is close to that of pure liquid Ge and Si. The first peak of the pair distribution function moved to a shorter distance with increasing Si concentration. These results may indicate that the atomic radii of the Si and Ge atoms in the pure liquid are preserved in the liquid alloys.

OBJECTIVE: Acute radiation of the small intestine causes an immediate and potentially reversible effect on the sensitive regenerative epithelium of the intestinal mucosa while markedly altering the overall intestinal ecosystem. The aim of the present study was test a novel probiotic mixture formulation (Microflorana-F) in an experimental model of acute radiation enteritis with particular interest in endotoxinemia and bacterial translocation. MATERIALS AND METHODS: Male Wistar rats allocated to three groups were fed for 7 days with: (A) a standard balanced diet; (B) a standard diet with the addition of 1 mL t.i.d. of Microflorana-F and (C) the same probiotic but after heat inactivation. Under ketamine anesthesia, abdominal irradiation was performed at a single dose rate of 20 Gy. Sham-radiated healthy rats served as a control (D). Standard food and active/inactive probiotic supplementation schedule was maintained throughout the study period. When they were killed 14 days later a midline laparotomy and a medium sternotomy was carried out. The mesenteric lymph nodes, whole spleen and liver samples as well as blood, the portal vein and bile samples were cultured. Endotoxinemia was also measured. RESULTS: Early deaths (1 week) occurred mostly in rats fed standard food or inactivated probiotic. The endotoxin level significantly increased in irradiated rats fed standard food and inactivated probiotic while supplementation with the active form of the probiotic mixture significantly improved such parameters (P < 0.05). After radiation injury, mesenteric lymph nodes and portal blood were the samples most frequently yielding bacterial growth. Treatment with only the active form of probiotic significantly reduced the incidence of bacterial contamination in all samples. CONCLUSIONS: These data suggest that the manipulation of gut ecosystem by biologically effective probiotic preparations might be a worthwhile therapeutic and preventive tool in radiation-induced enteritis.

Background and Aim: Oxidative DNA damage occurs as an early event in hepatitis C virus (HCV) infection and is an indication of the potential for carcinogenesis. The aim of this study was to test a novel antioxidant/immunomodulator in patients with HCV-related cirrhosis. Methods: The study group consisted of 50 patients with HCV-related cirrhosis with transaminase values less than twofold increased (alanine aminotransferase [ALT]

Summary A new type of inherited chondrodysplasia is described in Japanese Brown cattle, but the basic defects of the epiphyseal growth plate (EGP) in the limb long bones, and proliferation and differentiation of the chondrocytes in the EGP, are not yet understood. In the present study, the EGPs of the limb long bones in eight cases of chondrodysplasia and four normal (control) cattle were examined histologically and immunohistochemically. In the control cattle, proliferative chondrocytes (PCs) and hypertrophic chondrocytes (HCs) were arranged in columns parallel to the long axis of the bone, and HCs were situated on the metaphyseal side of the EGP. In all the affected cattle, many chondrocytes with a hypertrophic appearance were detected in the inner areas of the central portion of the EGP. The PC columns were short and arranged irregularly. Bone tissue and small blood vessels were found frequently in these areas. Six affected cattle showed complete EGP-closure. Backscattered electron (BSE) imaging showed that the calcified cartilage matrix was restricted to the lower region of the hypertrophic zone (HZ) of the EGP in the control cattle, while the calcified cartilage matrix and bone tissue were scattered in the inner areas of the EGP in all the chondrodysplastic cattle. Immunohistochemistry revealed type X collagen in the HCs and cartilage matrix of the HZ in the control cattle. In all the affected cattle, type X collagen was detected in apparently hypertrophic chondrocytes in the inner areas of the EGP. Type II collagen was detected in the entire EGP in all the affected cattle, as in the controls. BrdU (5-bromo-2’-deoxyuridine), injected intravenously 1 h before euthanasia was detected in many PCs in the EGP in the control cattle; none, however, was detected in the central portion of the EGP in any affected animal. These observations indicate that differentiation into HCs and calcification of cartilage matrix occur in the inner areas of the central portion of the EGP in chondrodysplasia of Japanese Brown cattle. Differentiation into the HCs at this abnormal site may be caused by the inadequate proliferation and disorganization of the PCs. Premature EGP-closure, observed commonly in chondrodysplasia of Japanese Brown cattle, was thought to be caused by replacement of the calcified cartilage in the inner areas of the EGP by bone tissue.