A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial☆.

BACKGROUND: Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. PATIENTS AND METHODS: The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). RESULTS: A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. CONCLUSIONS: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.

CPNE7 Induces Biological Dentin Sealing in a Dentin Hypersensitivity Model.

Dentin hypersensitivity commonly occurs due to opened dentinal tubules for many reasons. In our previous study, copine 7 (CPNE7) could induce dentin formation for an indirect pulp-capping model in vivo. This study aims to investigate the formation of tertiary dentin when CPNE7 is applied to intentionally exposed dentin with nothing over it in vivo, whether it affects microleakage of the teeth, and the penetration ability of CPNE7 molecules through dentinal tubules in vitro. Cervical dentin areas of 6 maxillary incisors of 5 beagles were exposed to a class V-like lesion, and 1 side of 3 maxillary incisors was adapted with recombinant CPNE7 protein for 5 min as the experimental group. The other side was the control group, and there was no treatment of ethylenediaminetetraacetic acid (EDTA) and CPNE7 after preparation. The defects were exposed without any restorations, and all beagles were sacrificed after 4 wk. The fluid penetration of exposed dentin areas was investigated by a microleakage-testing device and confocal laser scanning microscope. Tertiary dentin formation was confirmed with histological scanning electronic microscopic analysis. Tertiary dentin formation reduces dentinal fluid flow due to occluded tubules or discontinuity with primary or secondary dentin. The in vivo hypersensitivity model with the anterior teeth of beagle dogs showed newly formed tertiary dentin at the dentin-pulp boundary in recombinant CPNE7-treated teeth when compared with the untreated control group in histologic analysis. Scanning electronic microscopic analysis revealed occluded sites with mineral deposition of intratubular dentin. In the permeability test, the mean microleakage value of the CPNE7-treated group was significantly lower than that of the control group (P < 0.05). The tubular penetration of rhodamine B-combined CPNE7 was confirmed under confocal laser scanning microscope. CPNE7 induces formation of tertiary dentin through shallowly exposed dentinal tubules, which decreases dentin permeability.

Dog Sperm Cryopreservation in Glucose-Fructose or Sucrose Supplemented Glycerol-Free Tris: Effect of Post-Thaw Incubation Time on Gene Expression Related to Apoptosis and Motility.

　　OBJECTIVE: The study evaluated the effects of glucose-fructose or sucrose supplementation in glycerol-free Tris (GFT) solution on motility, viability, the level of reactive oxygen species (ROS), as well as the level of apoptosis (BAX and BCL2) and motility (SMCP)-related gene expression of dog spermatozoa. MATERIALS AND METHODS: Spermatozoa (5×107 sperm/ml) were cryopreserved in GFT containing 86 mM glucose and 86 mM fructose (GF-GFT) or 100 mM sucrose (S-GFT). Progressive motility, viability, ROS (H2O2) level and mRNA gene expression of spermatozoa were evaluated 0 h, 3 h or 6 h post-thaw at 24°C. RESULTS: The motility of spermatozoa cryopreserved in GF-GFT was increased throughout the post-thaw incubation time. The motility of spermatozoa cryopreserved in S-GFT was increased at 3 h of post-thaw incubation. The sperm ROS level in the GF-GFT group was inconsistent during the post-thaw incubation time; however, the ROS level in the S-GFT group was gradually increased with progression of the post-thaw incubation period. The post-thaw incubation had no substantial effect on the mRNA expression of the BAX, BCL2, and SMCP genes of spermatozoa in both the GF-GFT and S-GFT groups. CONCLUSION: The supplementation of glucose and fructose improves progressive sperm motility during 6 h of post-thaw incubation while maintaining similar sperm viability. The addition of GF to GFT for cryopreservation and post-thaw incubation would yield more functional spermatozoa for future assisted reproduction practices.

Effects of feeding Original XPC™ to broilers with a live coccidiosis vaccine under industrial conditions: Part 2. Cecal microbiota analysis.

Biological supplements in poultry feed are of continued interest due to the improvements in growth performance, protection from pathogen invasion, and benefits in overall host health. The fermentation metabolites of Diamond V Original XPC™ (XPC) have previously been shown to improve commercial performance and reduce Salmonella in poultry. The current study sought to characterize the cecal microbiota using culture-independent analysis based on 16S rRNA gene in Coccivac-D sprayed broilers supplemented with XPC and/or Salinomycin (SAL). Ross 708 male broilers (n = 640) were assigned to one of 4 treatments: Cocci-vaccine (T1), Cocci-vaccine + XPC (T2), Cocci-vaccine + SAL (in the grower diet only) (T3), and Cocci-vaccine + SAL (in the grower diet only) + XPC (T4). Analysis with a PCR-based denaturing gradient gel electrophoresis (DGGE) indicated a shift in the microbial populations present at the various sampling ages - 16, 28, and 42 days. Phylogenetic analysis indicated further consistency in microbial communities directly related to bird age. Identification of microbial communities present and the assessment of their respective quantities using an Illumina MiSeq indicated treatment with XPC had no significant impact on microbial diversity (Chao1 index, observed operational taxonomic unit (OTU) and phylogenetic diversity (PD) whole tree). Sampling age revealed significantly greater diversity at 16 and 28 d (P < 0.05) as compared to the 42 d for the Shannon diversity index, while showing significantly decreased richness and diversity in the 42 d sampling age (Chao1 and observed OTU; P < 0.05). The results of the current study indicate that the chicken intestinal microbiota are impacted more by temporal changes rather than by the feed additive studied.

Pasture flock chicken cecal microbiome responses to prebiotics and plum fiber feed amendments.

When prebiotics and other fermentation substrates are delivered to animals as feed supplements, the typical goal is to improve weight gain and feed conversion. In this work, we examined pasture flock chicken cecal contents using next generation sequencing (NGS) to identify and understand the composition of the microbiome when prebiotics and fermentation substrates were supplemented. We generated 16S rRNA sequencing data for 120 separate cecal samples from groups of chickens receiving one of 3 prebiotics or fiber feed additives. The data indicated that respective feed additives enrich for specific bacterial community members and modulate the diversity of the microbiome. We applied synthetic learning in microbial ecology (SLiME) analysis to interpret 16S rRNA microbial community data and identify specific bacterial operational taxonomic units (OTU) that are predictive of the particular feed additives used in these experiments. The results suggest that feed can influence microbiome composition in a predictable way, and thus diet may have indirect effects on weight gain and feed conversion through the microbiome.

Effects of feeding Original XPC™ to broilers with a live coccidiosis-vaccine under industry conditions: Part 1. Growth performance and Salmonella inhibition.

Supplementation of poultry diets with Diamond V Original XPC™ (XPC) has been proposed as a means to ameliorate the commonly observed loss of appetite and depression of growth in birds given a live coccidiosis vaccine. A study was conducted to compare the effects on bird performance of a live coccidiosis vaccine in broilers, with and without the dietary inclusion of XPC (1.25 g/kg). Ross 708 male broilers (n = 1,280) were allocated to one of 4 feed treatments: cocci-vaccine (T1), cocci-vaccine + XPC (T2), cocci-vaccine + salinomycin in the grower diet only, (T3), and cocci-vaccine + salinomycin in the grower diet + XPC (T4). Birds consuming diets containing XPC (T2 and T4) and salinomycin (T3) exhibited increased (P < 0.05) feed intake and significantly heavier body weights at 28 d (1.70, 1.74, and 1.67 kg, respectively) and 42 d (3.29, 3.31, and 3.26 kg, respectively). Feed conversion ratio at 28 d was improved (P < 0.05) by adding XPC to diets (T2: 1.47 and T4: 1.44) compared to control diets (T1: 1.50 and T3: 1.47). Salmonella prevalence determined via selective media indicated the inclusion of XPC in the diet resulted in a significant reduction of Salmonella when compared to treatments lacking XPC. Molecular confirmation of Salmonella species indicated S. Kentucky to be present in 38 of the 39 positive samples. Results revealed the ability of XPC in reducing the prevalence of Salmonella. Results from this study also suggest that XPC could be used in conjunction with a live coccidiosis-vaccine to increase growth rate and improve feed conversion of broilers. However, further work is needed to delineate more specific effects directly attributable to XPC.

Effects of dietary mixture of garlic (Allium sativum), coriander (Coriandrum sativum) and probiotics on immune responses and caecal counts in young laying hens.

This study was conducted to evaluate the effects of a combined mixture of phytogenic extracts (garlic and coriander) and probiotics on growth performance and immune responses in laying hens based on the results of in vitro studies to screen for immunomodulatory potency of each ingredient. Several parameters of immunomodulatory potency were estimated using lamina propria leucocytes (LPLs) isolated from rat intestinal mucosa tissue. Results show that the combined mixture enhanced LPLs proliferation, increased LPL-mediated cytotoxicity against YAC-1 tumour cells, and decreased lipopolysaccharide (LPS)-induced cytokine production including tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in LPLs. For in vivo study, laying hens (n = 50/each diet group) were fed with control diet, a diet containing antibiotics (0.01% per kg feed) or the combined mixture (0.02% per kg feed) for 21 days. The dietary combined mixture improved egg production (p < 0.05) but not growth performance and carcass traits. Interestingly, the patterns of suppressing plasma IFN-γ productions during inflammation by LPS injection and decreasing caecal E. coli counts in the combined mixture group were comparable to those in the antibiotics group. Taken together, our results suggested that the 0.02% of combined mixture of phytogenic extracts and probiotics as ingredients has potential immunomodulatory effects in laying hens.

Long-term efficacy of biofeedback therapy in patients with dyssynergic defecation: results of a median 44 months follow-up.

BACKGROUND: The beneficial effect of biofeedback therapy (BFT) over a period of more than 2 years has not been studied in a large group of patients. The aim of this study was to evaluate the long-term efficacy of BFT for dyssynergic defecation (DD). METHODS: We evaluated the results for 347 consecutive constipated patients with DD who underwent BFT for a median of five sessions between 2004 and 2009. Initial responses were assessed immediately after the completion of BFT. A responder was defined as a subject with at least a three-point improvement from before to after BFT on an 11-point global bowel satisfaction (GBS) scale, or a two-point improvement if the baseline GBS was more than six points. The probability of remaining a responder was estimated by non-parametric maximum likelihood estimation. KEY RESULTS: The initial response rate to BFT was 72.3% (n = 251), Parkinson's disease and higher baseline GBS scores were associated with initial non-response. The long-term efficacy of BFT was analyzed in 103 patients who were followed up for more than 6 months; the initial effects of BFT were maintained in 85 of the patients (82.5%) during a median of 44 months of follow-up (IQR = 12-68). The probability of remaining a responder was 60% at 2 years, and 58% at 5 years. CONCLUSIONS & INFERENCES: The efficacy of BFT is maintained for more than 2 years after BFT in a considerable proportion of constipated patients with DD. BFT is effective and durable treatment for managing DD.

Effect of diallyl disulfide on acute gastric mucosal damage induced by alcohol in rats.

This study investigated the gastroprotective effects of diallyl disulfide (DADS), a secondary organosulfur compound derived from garlic (Allium sativum L.) on experimental model of ethanol (EtOH)-induced gastric ulcer in rats. The antiulcerogenic activity of DADS was evaluated by gross/histopathological inspection, pro-inflammatory cytokines, and lipid peroxidation with antioxidant enzyme activities in the stomach. DADS (100 mg/kg) was administered by oral gavage 2 h prior to EtOH treatment (5 ml/kg). The animals were killed 1 h after receiving EtOH treatment. Pretreatment with DADS attenuated EtOH-induced gastric mucosal injury, as evidenced by decreased severity of hemorrhagic lesions and gastric ulcer index upon visual inspection. DADS also prevented histopathological alterations and gastric apoptotic changes caused by EtOH. An increase in tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase was observed in the gastric tissues of EtOH-treated rats that coincided with increased serum TNF-α and interleukin 6 levels. In contrast, DADS effectively suppressed production of pro-inflammatory mediators induced by EtOH. Furthermore, DADS prevented the formation of gastric malondialdehyde and the depletion of reduced glutathione content and restored antioxidant enzyme activities, such as catalase, glutathione peroxidase, and glutathione reductase in the gastric tissues of EtOH-treated rats. These results indicate that DADS prevents gastric mucosal damage induced by acute EtOH administration in rats and that the protective effects of DADS may be due to its potent antioxidant and anti-inflammatory activities.

Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines.

Pancreatic cancer is the fourth leading cause of cancer death. Gemcitabine is widely used as a chemotherapeutic agent for the treatment of pancreatic cancer, but the prognosis is still poor. Berberine, an isoquinoline alkaloid extracted from a variety of natural herbs, possesses a variety of pharmacological properties including anticancer effects. In this study, we investigated the anticancer effects of berberine and compared its use with that of gemcitabine in the pancreatic cancer cell lines PANC-1 and MIA-PaCa2. Berberine inhibited cell growth in a dose-dependent manner by inducing cell cycle arrest and apoptosis. After berberine treatment, the G1 phase of PANC-1 cells increased by 10% compared to control cells, and the G1 phase of MIA-PaCa2 cells was increased by 2%. Whereas gemcitabine exerts antiproliferation effects through S-phase arrest, our results showed that berberine inhibited proliferation by inducing G1-phase arrest. Berberine-induced apoptosis of PANC-1 and MIA-PaCa2 cells increased by 7 and 2% compared to control cells, respectively. Notably, berberine had a greater apoptotic effect in PANC-1 cells than gemcitabine. Upon treatment of PANC-1 and MIA-PaCa2 with berberine at a half-maximal inhibitory concentration (IC50), apoptosis was induced by a mechanism that involved the production of reactive oxygen species (ROS) rather than caspase 3/7 activation. Our findings showed that berberine had anti-cancer effects and may be an effective drug for pancreatic cancer chemotherapy.

NOD2 Mediates Odontoblast Differentiation and RANKL Expression.

The precise regulation of odontoblast differentiation and osteoclastogenic cytokine expression in human dental pulp cells (HDPCs) is crucial for the pathology of bacteria-related pulpitis. Although the up-regulation of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) has been reported in inflamed human dental pulps, the role of NOD2 in the differentiation of HDPCs remains unclear. Here, we show the involvement of NOD2 in odontoblast differentiation together with osteoclastogenic cytokine expression in HDPCs. Treatment with muramyl dipeptide (MDP), a known NOD2-agonist, significantly inhibited odontoblast differentiation of HDPCs, as revealed by reduced ALP activity, osteoblast/odontoblast marker expression, and mineralized nodule formation. Importantly, the forced down-regulation of NOD2 by small interfering RNA (siRNA) recovered MDP-down-regulated odontoblast differentiation. MDP-elicited suppression of odontoblast differentiation resulted from the increased expression of MKP-1 protein and the subsequent decline of MAPKs phosphorylation, which is a prerequisite for odontoblast differentiation. Furthermore, we found that MDP treatment elevated the expression of osteoclastogenic cytokines in HDPCs, which was also reversed by NOD2 silencing. Analysis of these data, taken together, suggests that the regulation of NOD2 expression upon MDP challenge might serve as an intrinsic mechanism that underlies the hindered dentin formation and accelerated dentin resorption in bacterial infection-mediated pulpitis.

Effect of bovine follicular fluid on reactive oxygen species and glutathione in oocytes, apoptosis and apoptosis-related gene expression of in vitro-produced blastocysts.

The reactive oxygen species (ROS) generated during the in vitro maturation of oocytes affect oocyte maturation and subsequent embryonic development. Bovine follicular fluid (bFF) has an effective antioxidant capacity. This study was conducted to investigate the effects of supplementing oocyte maturation media with bFF from different size classes (3-8 and 9-13 mm) on the glutathione (GSH) and ROS levels of oocytes. Embryonic development and apoptosis, as well as the relative abundance of INFτ, BAX, BCL2 and HSP70 transcripts in blastocysts, were also monitored. Oocytes collected from ovaries were matured in TCM-199 with FBS (control) and 10% 3-8 mm (M), 9-13 mm (L) or a mixture of 3-8 mm and 9-13 mm (M + L) bFF. Glutathione and ROS levels in oocytes after 24 h were assessed by Cell Tracker Blue CMF2HC and DCHFDA staining, respectively. Apoptosis in day-8 blastocysts was assessed by TUNEL staining. The relative abundance of BAX, BCL2, HSP70 and INFτ transcripts was assessed using quantitative real-time polymerase chain reaction (PCR). The GSH level was significantly higher in the L group compared to the other groups (p < 0.05), while the ROS levels in the M group were significantly higher than in the other groups (p < 0.05). The apoptosis levels of blastocysts in the FBS group were significantly higher than those in the M + L group (p < 0.05), although the embryonic development did not differ between the groups. The HSP70 and INFτ expression levels in group M were significantly greater than in the controls (p < 0.05). There was no significant difference in BAX expression between the groups. Supplementation with bFF from various sizes of follicles into the maturation medium was capable of supporting oocyte cytoplasmic maturation by decreasing the ROS. Moreover, bFF subsequently affected antioxidative gene expression, increasing HSP70 and INFτ expressions.

Nonsteroidal anti-inflammatory drugs (NSAID) sparing effects of glucosamine hydrochloride through N-glycosylation inhibition; strategy to rescue stomach from NSAID damage.

Gastrointestinal or cardiovascular complications limit nonsteroidal anti-inflammatory drugs (NSAID) prescription. Glucosamine hydrochloride (GS-HCl) alternatively chosen, but debates still exist in its clinical efficiency. COX-2 instability through inhibiting COX-2 N-glycosylation of GS-HCl raised the possibility of NSAID sparing effect. Study was done to determine whether combination treatment of glucosamine and NSAID contributes to gastric safety through NSAID sparing effect. IEC-6 cells were stimulated with TNF-α and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and GS-HCl by Western blotting and RT-PCR. C57BL/6 mice injected with type II collagen to induce arthritis were treated with indomethacin alone or combination of reduced dose of indomethacin and GS-HCl after 3 weeks. TNF-α increased the expression of COX-2, iNOS and inflammatory cytokines, but GS-HCl significantly attenuated TNF-α-induced COX-2 expression. Decreased COX-2 after GS-HCl was caused by N-glycosylation inhibition as much as tunicamycin. Combination of reduced dose of indomethacin and GS-HCl significantly reduced the expressions of ICAM-1, VCAM-1, IL-8, IL-1ß, MMP-2, MMP-7, MMP-9, and MMP-11 mRNA as well as NF-κB activation better than high dose indomethacin alone. These NSAID sparing effect of GS-HCl was further proven in collagen-induced arthritis model. Combination of GS-HCl and 2.5 mg/kg indomethacin showed significant protection from gastric damages as well as efficacious anti-arthritic effect. Taken together, COX-2 N-glycosylation inhibition by GS-HCl led to indomethacin sparing effects, based on which combination of GS-HCl and reduced dose of NSAID can provide the strategy to secure stomach from NSAID-induced gastric damage as well as excellent anti-arthritic effects.

Assessment of production performance in 2 breeds of broilers fed prebiotics as feed additives.

Pasture-flock-raised poultry are becoming an increasingly popular product, but only limited options are currently available for maintaining gut health. For these producers, prebiotics are an attractive option because they are generally recognized as safe (GRAS) and can be mixed into the feed and thus do not require adjustments to production protocols. However, if prebiotic treatments reduce production performance, they would not be useful to producers. Thus, the objective of this study was to measure performance of pasture-raised broilers fed 1 of 3 prebiotic treatments. For these trials, 2 breeds of birds were used: Naked Neck slow-growing breeds and Cornish White Rock cross fast-growing breeds. The experimental design was replicated for each breed. A total of 340 birds were split into 4 groups, each group fed one feed additive: 1) galactoligosaccharides (2% wt/wt), 2) fructooligosaccharides (1% wt/wt), 3) plum fibers (1% wt/wt), or 4) no additives. During the 8-wk rearing period, 10 birds from each group were collected and euthanized to take small intestine samples. Histological preparations were made from the small intestine tissue, and 4 measurements of villi height and crypt depth from each cross section were taken. Throughout the study, mortality was monitored and BW measurements were taken at 2-wk intervals. For the Cornish White Rock cross, the group receiving the feed supplemented with fructooligosaccharides had higher (P < 0.05) 8-wk BW than those fed Plum; control and birds fed galactoligosaccharides were intermediate. For the Naked Neck breed, the group receiving the plum fibers had the highest final BW. It appears that all 3 feed supplements offered some protective effect for alterations in villi length and crypt depth due to feed withdrawal, but only for the Naked Neck breed. The data indicate the 3 prebiotics utilized in this study could be used without risk of decreasing production performance, but only for Naked Neck breeds.

The effects of cranio-cervical flexion on activation of swallowing-related muscles.

We tested the effects of cranio-cervical flexion (CCF) on activation of swallowing-related muscles while swallowing liquid in a sample of 45 healthy volunteers. Activation following CCF movement was examined across two positions (supine and sitting) and, three pressure levels and two different postures were examined in each condition, respectively. When CCF was applied, activation of swallowing-related muscles was significantly increased compared to the neutral neck position, and such findings were found across both the supine and sitting positions. Also in the supine position, when the pressure level of the stabilizer was escalated, there was a significant difference in the activity of the swallowing-related muscles compared to the baseline level. In conclusion, our results suggest that CCF may be a viable method to enhance the effectiveness of swallowing-related muscles by changing neck position. When CCF is applied, the stability of the deep flexor muscles must be secured first after which superficially located muscles may better assist swallowing with less effort.

The differential profiles of withdrawal symptoms induced by morphine and beta-endorphin administered intracerebroventricularly in mice.

In the present study, withdrawal symptoms induced by morphine or ß-endorphin administered intracerebroventricularly (i.c.v.) were compared in ICR mice. Naloxone (10mg/kg) was post-treated intraperitoneally (i.p.) 3h after either a single or repeated (1 time/day for 3 days) i.c.v. injections with opioids. Withdrawal symptoms such as jumping frequency, diarrhea, weight loss, rearing, penile licking and paw tremor were observed for 30 min immediately after naloxone treatment. Withdrawal symptoms (jumping, diarrhea, weight loss, rearing, penile licking and paw tremor) observed in the group treated with morphine was persistently increased during 3 days. On the other hand, withdrawal symptoms such as diarrhea, weight loss and rearing in ß-endorphin-treated group were increased after a single injection with ß-endorphin, but gradually decreased after the repeated injection. Furthermore, no jumping behavior, penile licking and paw tremor in ß-endorphin-treated group were observed throughout the whole period of time. In addition, the hypothalamic changes of several signal molecules such as pERK, pCaMK-IIα, c-FOS and pCREB expression were observed during the presence or absence of withdrawal responses induced by morphine or ß-endorphin administered once or repeatedly. Both hypothalamic pCaMK-IIα and c-FOS expressions were increased by naloxone treatment in acutely administered morphine group, whereas only pCaMK-IIα expression was elevated by naloxone treatment in repeatedly administered morphine group. In contrast with the findings in morphine-treated group, only pCaMK-IIα expression was decreased by naloxone treatment in repeatedly administered ß-endorphin group. Our results suggest that profiles of the withdrawal symptoms induced by morphine and ß-endorphin administered supraspinally appear to be differentially regulated. The pCaMK-IIα and the c-FOS protein expression may play important roles for the regulation of naloxone-precipitated withdrawal symptoms such as jumping, diarrhea, weight loss, rearing, penile licking and paw tremor induced by morphine-treated group, whereas the phosphorylation of hypothalamic pCaMK-IIα appears to be involved only in the regulation of naloxone-precipitated withdrawal symptoms such as diarrhea, weight loss and rearing in ß-endorphin-treated group.

Diagnostic sensitivity of culture and drug resistance patterns in Korean patients with intestinal tuberculosis.

SETTING: It is challenging to differentiate between intestinal tuberculosis (ITB) and Crohn's disease in areas where TB is still prevalent. The use of diagnostic tools and verifying the drug resistance patterns of ITB can be helpful for its correct diagnosis. OBJECTIVE: To determine the diagnostic sensitivity of a culture assay using colonoscopic biopsy specimens and the drug resistance patterns of Mycobacterium tuberculosis isolated from ITB. DESIGN: Data from 400 patients diagnosed with ITB were retrospectively analysed. RESULTS: Of the 400 patients, 170 (42.5%) were males; the median age at diagnosis was 40 years. The sensitivity of culture was 44.1% (145/329). Resistance to at least one anti-tuberculosis drug was identified in 13 (17.6%) and multidrug-resistant TB (MDR-TB) was diagnosed in two (2.7%) of the 74 patients for whom drug susceptibility testing was performed. Including M. tuberculosis isolated from respiratory specimens, the proportion of MDR-TB was 4.4% (5/113); previous anti-tuberculosis treatment was an independent risk factor for MDR-TB (26.7% vs. 1.0%, P < 0.01). CONCLUSION: Culture of colonoscopic biopsy specimens shows substantial diagnostic sensitivity; the frequency of MDR-TB is higher in previously treated cases than in new cases.

Coriandrum sativum L. protects human keratinocytes from oxidative stress by regulating oxidative defense systems.

BACKGROUND: Oxidative radicals are major environmental causes of human skin damage. Oxidative defense factors, including nuclear factor erythroid-derived 2-related factor 2 (Nrf2), are centrally involved in repairing skin cells or protecting them from oxidative damage. Coriandrum sativum L. (coriander; CS) is a commonly consumed food and a traditional phytomedicine in Asia and Europe. In this study, we examined the protective effects of a standardized CS leaf extract against oxidative stress in human HaCaT keratinocytes. METHODS AND RESULTS: CS significantly and dose-dependently protected cells against reduced cell viability caused by H2O2-induced damage, as assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Other assays demonstrated that CS protected HaCaT cells by increasing the levels of glutathione and activities of oxidative defense enzymes, such as superoxide dismutase and catalase. Moreover, it increased the expression of activated Nrf2, which plays a crucial role in protecting skin cells against oxidative stress. CONCLUSION: These results suggest that CS protects human keratinocytes from H2O2-induced oxidative stress through antioxidant effects.

Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group.

PURPOSE: To evaluated the efficacy and safety of sorafenib in patients with advanced gastrointestinal stromal tumors (GIST) who failed to previous standard treatments. EXPERIMENTAL DESIGN: Thirty-one patients with measurable metastatic GIST who failed both imatinib and sunitinib were accrued. Sorafenib was administered orally at 400 mg twice daily until disease progression or development of intolerance. The primary endpoint was disease control rate (response + stable disease, DCR) at 24 weeks. RESULTS: Sorafenib was well tolerated, with hand-foot skin reaction, fatigue, hypertension, and abdominal pain being the most frequent adverse events. The relative dose intensity of sorafenib during the first 6 months was >80%. Four patients achieved partial response (response rate 13%, 95% CI 1-25%), and 16 (52%) had stable disease. DCR at 24 weeks was measured as 36% (95% CI 19-52%). Median progression-free and overall survivals were 4.9 and 9.7 months, respectively. Progression-free survival of patients with prior use of nilotinib (P = .0085) and with primary genotypes other than KIT exon 11 mutation (P = .0341) was significantly shorter than that of patients without. CONCLUSIONS: Sorafenib showed antitumor activity in this population of imatinib and sunitinib pretreated GIST. With sorafenib, about one third of patients can maintain disease control for more than 24 weeks.

Doppler ultrasound to detect pulpal blood flow changes during local anaesthesia.

AIM: To examine whether Doppler ultrasound can detect changes in pulpal blood flow after infiltration anaesthesia. METHODOLOGY: Changes in pulpal blood flow in maxillary central incisor teeth of 18 patients (mean age 26.7 years, 13 men, five women) after infiltration anaesthesia were examined. Before infiltration anaesthesia, the pulpal blood flow was measured using Doppler ultrasound. A local anaesthetic solution containing 2% lidocaine with 1:80,000 epinephrine was injected into the submucosa above the experimental tooth. The Doppler ultrasound test was carried out at 5, 10, 20, 30, 45 and 60 min after infiltration. The parameters were Vas (maximum linear velocity, cm s(-1) ), Vam (average linear velocity, cm s(-1) ) and Vakd (minimum linear velocity, cm s(-1) ), which are indicators of the level of blood flow. The mixed procedure at the 95% confidence interval was used to examine the changes in pulpal blood flow after the injection. RESULTS: The linear velocity profiles (Vas, Vam, and Vakd) decreased sharply 5 min after anaesthesia and then reduced continuously for 30 min. The maximum degree of blood flow reduction in Vas, Vam and Vakd was 58%, 83% and 82%, respectively. After 30 min, the linear velocities increased gradually. The Vam returned to the pre-anaesthesia state at 60 minutes but the Vas and Vakd did not recover completely. CONCLUSIONS: Doppler ultrasound can detect changes in pulpal blood flow after infiltration anaesthesia. In the future, Doppler ultrasound can be used as a tool for measuring pulpal blood flow.