Mortality after transcatheter versus surgical aortic valve replacement: an updated meta-analysis of randomised trials.

BACKGROUND: To determine whether transcatheter aortic valve implantation (TAVI) improves early (30-day) and midterm (1-year) mortality compared with surgical aortic valve replacement (SAVR), we performed an updated meta-analysis of all the currently available randomised controlled trials (RCTs). METHODS: To identify all RCTs providing both 30-day and 1­year mortality after TAVI versus SAVR, PubMed and ClinicalTrials.gov were searched up to and including July 2019. A risk difference (RD) and its 95% confidence interval were generated using data of prespecified outcomes in both the TAVI and SAVR groups. Study-specific estimates were pooled using inverse variance-weighted averages of RDs in the random-effects model. RESULTS: We identified seven eligible high-quality RCTs including a total of 7631 as-treated patients. Pooled analyses demonstrated significantly lower 30-day (RD -0.60%; p = 0.046) and 1­year all-cause mortality (RD -1.12%; p = 0.03) after TAVI than after SAVR. No funnel plot asymmetry was detected for 30-day and 1­year mortality. Meta-regression analyses indicated that RDs of 30-day and 1­year mortality between TAVI and SAVR were not modulated by mean Society of Thoracic Surgeons Predicted Risk of Mortality score. Bleeding complications at 30 days and 1 year and stage 2/3 acute kidney injury at 30 days were significantly less frequent after TAVI than after SAVR, whereas major vascular complications and new permanent pacemaker implantation at 30 days and 1 year were significantly more frequent after TAVI than after SAVR. CONCLUSION: The best evidence from the present meta-analysis of all the currently available RCTs suggests that TAVI may reduce 30-day and 1­year all-cause mortality compared with SAVR.

Web survey-based selection of controls for epidemiological analyses of a multi-prefectural outbreak of enterohaemorrhagic Escherichia coli O157 in Japan associated with consumption of self-grilled beef hanging tender.

An outbreak of enterohaemorrhagic Escherichia coli O157 occurred in multiple prefectures of Japan in November 2009. We conducted two case-control studies with trace-back and trace-forward investigations to determine the source. The case definition was met by 21 individuals; 14 (66.7%) were hospitalised, but no haemolytic uraemic syndrome, acute encephalopathy or deaths occurred. Median age was 23 (range 12-48) years and 14 cases were male (66.7%). No significant associations with food were found in a case-control study by local public health centres, but our matched case-control study using Internet surveys found that beef hanging tender (or hanger steak), derived from the diaphragm of the cattle, was significantly associated with illness (odds ratio = 15.77; 95% confidence interval, 2.00-124.11). Pulsed-field gel electrophoresis analysis of isolates from patients and the suspected food showed five different patterns: two in faecal and food samples, and another three in patient faecal samples only, although there were epidemiological links to the meat consumed at the restaurants. Trace-back investigation implicated a common food processing company from outside Japan. Examination of the logistics of the meat processing company suggested that contamination did not occur in Japan. We concluded that the source of the outbreak was imported hanging tender. This investigation revealed that Internet surveys could be useful for outbreak investigations.

Spheroid culture enhances osteogenic potential of periodontal ligament mesenchymal stem cells.

OBJECTIVE AND BACKGROUND: Human periodontal ligament mesenchymal stem cells (hPDLMSCs) are reported to be responsible for homeostasis and regeneration of periodontal tissue. Although hPDLMSCs are commonly cultured in monolayers, monolayer cultures have been reported as inferior to 3-dimensional cultures such as spheroids, which are spherical clusters of cells formed by self-assembly. The aim of this study was to examine the osteogenic phenotype of spheroids of hPDLMSCs, compared with monolayer cultures of hPDLMSC, in vitro and in vivo. MATERIAL AND METHODS: Spheroids were formed using microwell chips that were tagged with polyethylene glycol. Mesenchymal stem cell (MSC) markers in hPDLMSC spheroids were examined by flow cytometer. Real-time polymerase chain reaction analysis was examined to measure the expressions of stemness markers and osteogenesis-related genes in monolayer and spheroid-cultured hPDLMSCs. Immunofluorescence analysis was performed to confirm protein expressions of stemness markers in PDLMSC spheroids. Nodule formation assay, alkaline phosphatase (ALP) activity assay and transplantation assay in a mouse calvarial defect model were performed to confirm the osteogenic potential of hPDLMSC spheroids. To elucidate the mechanism of spheroid culture enhanced osteogenesis in hPDLMSCs with osteoinductive medium (OIM), a small interfering RNA (siRNA) assay targeted with secreted frizzled-related protein 3 (SFRP3) was examined. The levels of SFRP3 expression in monolayer and spheroid-cultured hPDLMSCs with OIM were measured by real-time polymerase chain reaction and western blotting analysis. ALP gene expression and ALP activity were examined in SFRP3-deficient hPDLMSC spheroids. RESULTS: The hPDLMSC spheroids expressed MSC markers, which were similar to hPDLMSCs grown in monolayer cultures. Intriguingly, the protein and mRNA expressions of transcription factors that regulate "stemness" were significantly increased in hPDLMSC spheroids, compared with hPDLMSCs in monolayer cultures. Nodule formation by hPDLMSCs was significantly increased in spheroid cultures grown with OIM, compared with monolayer-cultured hPDLMSCs. ALP activity and expression of osteogenesis-related genes were also significantly enhanced in hPDLMSC spheroids, compared with monolayer cultures. Treatment with hPDLMSC spheroids significantly enhanced new bone formation in a murine calvarial defect model, compared with hPDLMSCs in monolayer culture. Finally, to elucidate mechanisms by which spheroid culture enhances ALP activation in hPDLMSCs grown with OIM, an siRNA assay was used to manipulate expression of SFRP3, a Wnt signaling antagonist. Knockdown of SFRP3 suppressed ALP gene expression in hPDLMSCs grown in OIM; further, it suppressed ALP activity in spheroid culture. These data suggest that the enhancement of osteogenic potential in hPDLMSC spheroids is regulated through SFRP3-mediated ALP activation. CONCLUSION: Spheroid cultures of hPDLMSCs may be a novel and useful tool in regenerative medicine.

IgA Antibodies Against Gliadin and Tissue Transglutaminase in Dogs With Chronic Enteritis and Intestinal T-Cell Lymphoma.

Molecular clonality analysis of T-cell receptor (TCR) genes for diagnosing T-cell lymphoma is widely used in veterinary medicine. However, differentiating chronic enteritis (CE) from intestinal lymphoma is challenging because of the incompatibility between histopathologic and clonality analysis results. On the basis of findings that canine intestinal T-cell lymphoma and celiac disease share some common features, we conducted serologic examinations in combination with histopathologic and T-cell receptor clonality analyses in 48 dogs diagnosed with either CE or intestinal lymphoma. Immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies against gliadin and tissue transglutaminase (tTG) were quantitatively measured using ELISA. The conditions were classified according to the histopathologic diagnosis, clonality analysis, and combined histopathologic/clonality analysis. Histopathologic analysis showed that dogs with intestinal lymphoma were likely to have high levels of serum IgA antibodies against gliadin and tTG, and serum IgG antibodies against tTG. No correlation between the diagnosed groups and control group was observed in the results of the clonality analysis and histopathologic/clonality analysis. It is interesting that dogs with intestinal lymphoma had a higher serum IgA titer against gliadin and tTG than did dogs with CE. These results suggest an association between repetitive inflammatory stimulation by gliadin peptides and subsequent intestinal lymphoma in dogs.

Inhibition of gingipains and Porphyromonas gingivalis growth and biofilm formation by prenyl flavonoids.

BACKGROUND AND OBJECTIVE: Porphyromonas gingivalis is considered a major pathogen of chronic periodontitis, which also may be implicated with systemic diseases such as atherosclerosis. Secreted cysteine proteases, gingipains Rgp and Kgp, are essential for P. gingivalis virulence. Some polyphenols and flavonoids are known to inhibit gingipain activity and interfere with biofilm formation by P. gingivalis. Many bioactive compounds have been isolated from Epimedium species, but availability of these compounds on gingipains and P. gingivalis is still unclear. Therefore, the aim of this study was to evaluate natural products from medical plants to develop a new therapeutic agent against periodontal disease. MATERIAL AND METHODS: Prenylated flavonoids were isolated from Epimedium species plant using column chromatographies. The inhibitory effect of the prenylated flavonoids against protease activity of gingipains were examined using purified gingipains and fluorogenic substrates. Anti-P. gingivalis activity was evaluated to analyze planktonic growth and biofilm formation in brain heart infusion medium in the presence of the prenylated flavonoids. RESULTS: We isolated 17 prenylated flavonoids (Limonianin, Epimedokoreanin B, etc.) from Epimedium species. We found that some prenylated flavonoids inhibited gingipain activity in a non-competitive manner with Ki values at µm order. The prenylated flavonoids also hindered growth and biofilm formation of P. gingivalis, in a manner independent of gingipain inhibition by the compounds. CONCLUSION: The results indicated an inhibitory effect of the prenylated flavonoids against P. gingivalis and would provide useful information for future development of periodontitis treatment that suppresses gingipains, P. gingivalis growth and biofilm formation.

No associations between five polymorphisms in COMT gene and migraine.

OBJECTIVES: The pathophysiology of migraine headaches is not clearly understood yet. The dopaminergic system has been hypothesized to be involved in migraine pathogenesis. The aim of this study was to investigate catechol-O-methyltransferase (COMT) polymorphisms and chronic headaches. We analyzed five single nucleotide polymorphisms (SNPs) in COMT. MATERIALS & METHODS: The study population consisted of 71 patients with migraine with aura, 152 patients with migraine without aura, 86 patients with tension-type headache, and 191 healthy controls. The selected polymorphic markers included one causing His62His (rs4633) and two non-synonymous SNPs, Ala72Ser and Val158Met (rs6267, rs4680 respectively). Two other non-polymorphic SNPs (rs6270, rs740602) were examined. RESULTS: We found no significant differences in any genotypes, allele frequencies, or haplotypes among the patient groups and controls. CONCLUSIONS: Our results indicate that the five polymorphisms in COMT have no association with migraineurs in Western Japan. The possibility that segments elsewhere in the gene may contain a mutation responsible for modifying the expression of COMT or the activity of the enzyme is important. We cannot conclusively exclude the entire COMT gene from being involved in migraine pathogenesis.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

Gingival epithelial cells support osteoclastogenesis by producing receptor activator of nuclear factor kappa B ligand via protein kinase A signaling.

BACKGROUND AND OBJECTIVE: Periodontal disease is dental plaque-induced inflammatory disease of the periodontal tissues that results in bone loss in the affected teeth. During bone resorption, receptor activator of nuclear factor kappa B ligand (RANKL) is an essential factor that regulates osteoclastogenesis. Recently, we found that gingival epithelial cells (GECs) in periodontal tissue produce RANKL, the expression of which is regulated by tumor necrosis factor-α and protein kinase A signaling. In this study, we asked whether RANKL-producing GECs induce bone marrow macrophages (BMMs) to form osteoclasts in a co-culture system. MATERIAL AND METHODS: Ca9-22 GECs and osteoclast precursor BMMs were co-cultured with or without the protein kinase A signaling activator forskolin or inhibitor H89 to examine whether the RANKL-producing GECs could be induced to form osteoclasts, as determined using a pit formation assay. RESULTS: Osteoclasts formed spontaneously in co-cultures of Ca9-22 cells and BMMs, even in the absence of RANKL. The cells were cultured on bone slices for 14 d, at which time resorption pits were observed. Forskolin treatment significantly increased osteoclast numbers in these co-cultures, but forskolin alone did not induce osteoclast formation by BMMs. CONCLUSION: GECs producing RANKL are able to support osteoclastogenesis in an in vitro co-culture system using GECs and BMMs, in a process promoted by forskolin.

Clinical assessment and prevalence of parkinsonism in Japanese elderly people.

BACKGROUND: Parkinsonism is often observed in the elderly. To clarify the prevalence of parkinsonism-associated diseases and conditions, we conducted a population-based study in a rural island town in western Japan, Ama-cho. METHODS: Participants included 924 subjects aged 65 years or older residing in the town. Between 2008 and 2011, participants were assessed via standardized neurological examination scales, and Brain MRIs were carried out in 2010. Based on the results of assessment using the modified Unified Parkinson's Disease Rating Scale and a standardized neurological examination, participants were diagnosed as having parkinsonism or mild parkinsonian signs (MPS), or as displaying normal motor conditions (M-normal). RESULTS: Of the 729 participants screened, 70 subjects were diagnosed as having parkinsonism, corresponding to a crude prevalence rate of 9.6% (95% CI, 7.9-11.3%), while 167 MPS subjects (22.9%) and 492 subjects experiencing M-normal (67.5%) were observed. Parkinsonism was found in association with various diseases such as Vascular parkinsonism, Lewy body disease, Alzheimer's disease (AD), and idiopathic normal-pressure hydrocephalus. Among the subjects with dementia, the proportion with parkinsonism was higher in the non-AD dementia group. CONCLUSION(S): Parkinsonism occurs in association with several diseases in elderly people. Parkinsonism was also found to be commonly associated with cognitive impairment.

Pathologic Features of Colorectal Inflammatory Polyps in Miniature Dachshunds.

The histopathologic characteristics of colorectal inflammatory polyps that formed in Miniature Dachshunds were compared with those of other colorectal proliferative lesions, including adenomas and adenocarcinomas. Fifty-three colorectal polypoid lesions were histopathologically classified into inflammatory polyps (26 cases), adenoma (18 cases), and adenocarcinoma (9 cases). All 26 dogs that were diagnosed with inflammatory polyps were Miniature Dachshunds, indicating that colorectal inflammatory polyps exhibit a marked predilection for this breed. The inflammatory polyps had complex histopathologic features and were classified into 3 stages based on their epithelial composition. In early stage (stage 1), the polyps tended to exhibit a thickened mucosa containing hyperplastic goblet cells, dilated crypts filled with a large amount of mucus, and mild lymphocyte and macrophage infiltration. In later stages (stages 2 and 3), more severe neutrophil infiltration, interstitial mucus accumulation, granulation tissue, and occasional osteoid tissue were seen. Also, a few small foci of dysplastic epithelial cells were detected. The hyperplastic goblet cells, which were a major component of the epithelium of the inflammatory polyps, were positive for cytokeratin 20 (CK20), while the dysplastic epithelial cells found in inflammatory polyps (stage 3) and the tumor cells of the adenomas and adenocarcinomas were negative for CK20. These CK20-negative epithelial cells exhibited cytoplasmic and nuclear immunoreactivity for beta-catenin. In addition, the epithelial cells in the inflammatory polyps demonstrated significantly higher cyclooxygenase 2 and fibroblast growth factor 2 expression than did those of the adenomas and adenocarcinomas, suggesting that the arachidonate cascade is involved in the development of colorectal inflammatory polyps in miniature dachshunds.

Tumor necrosis factor-α enhances RANKL expression in gingival epithelial cells via protein kinase A signaling.

OBJECTIVE AND BACKGROUND: Periodontitis is an inflammatory disorder of the supporting tissue of teeth, which is composed of gingival soft tissue, cementum covering the tooth root, alveolar bone and periodontal ligament. The receptor activator of nuclear factor kappa B ligand (RANKL) is known to be an essential factor for osteoclastogenesis. Recent clinical studies indicate that levels of RANKL in the gingival crevicular fluid are increased while levels of its decoy receptor, osteoprotegerin (OPG), are decreased in patients with periodontitis. Although the gingival sulcus is composed of gingival tissue, RANKL and OPG expression in gingival epithelial cells is not fully understood. The aim of this study is to investigate the expression of RANKL and OPG in gingival tissue and which factors regulate RANKL expression in gingival epithelial cells. MATERIAL AND METHODS: Reverse transcriptase polymerase chain reaction analysis, western blotting and immunohistochemistry were performed to confirm RANKL and OPG expression in gingival epithelial cells (GECs) and in gingival tissue. Immunostaining was also examined to confirm tumor necrosis factor (TNF)-α and TNF receptor type 1 (TNFR1) expression in gingival tissue. Ca9-22 cells, a human gingival epithelial cell line and human primary GECs were treated with TNF-α. Ca9-22 cells were treated by antibodies against TNF receptors, an inhibitor and an activator of protein kinase A (PKA) signaling and inhibitors of p38, Erk and NF-κB signaling to examine TNF-α-RANKL signaling pathways. RESULTS: RANKL mRNA and protein were expressed in GECs. Immunohistochemistry also showed RANKL expression in gingival tissue. On the other hand, the reverse transcriptase polymerase chain reaction and immunohistochemistry assay showed that GECs did not express OPG. In addition, TNF-α and TNFR1 proteins were expressed in junctional epithelium. TNF-α increased RANKL expression in GECs. TNF-α-induced RANKL expression was inhibited by an antibody against TNFR1 and an inhibitor of PKA signaling. Surprisingly, forskolin, a PKA activator, increased TNF-α-induced RANKL expression. CONCLUSION: RANKL, TNF and TNFR1 were coexpressed in junctional epithelium of gingival tissue. TNF-α induced RANKL expression via TNFR1 and PKA signaling in GECs of junctional epithelium.

Evaluation of lophine derivatives as L-012 (luminol analog)-dependent chemiluminescence enhancers for measuring horseradish peroxidase and H2O2.

8-Amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4(2H,3H)dione (L-012) was recently synthesized as a new chemiluminescence (CL) probe; the light intensity and the sensitivity of L-012 are higher than those of other CL probes such as luminol. Previously, our group developed four lophine-based CL enhancers of the horseradish peroxidase (HRP)-catalyzed CL oxidation of luminol, namely 2-(4-hydroxyphenyl)-4,5-diphenylimidazole (HDI), 2-(4-hydroxyphenyl)-4,5-di(2-pyridyl)imidazole (HPI), 4-(4,5-diphenyl-1H-imidazol-2-yl)phenylboronic acid (DPA), and 4-[4,5-di(2-pyridyl)-1H-imidazol-2-yl]phenylboronic acid (DPPA), and showed that DPPA was suitable for the photographic detection of HRP. In this study, we replaced luminol with L-012 and evaluated these as L-012-dependent CL enhancers. In addition, to detect HRP and/or H2O2 with higher sensitivity, each detection condition for the L-012-HRP-H2O2 enhanced CL was optimized. All the derivatives enhanced the L-012-dependent CL as well as luminol CL; HPI generated the highest enhanced luminescence. Under optimized conditions for HRP detection, the detection limit of HRP was 0.08 fmol. By contrast, the detection limit of HRP with the enhanced L-012-dependent CL using 4-iodophenol, which is a common enhancer of luminol CL, was 1.1 fmol. With regard to H2O2 detection, the detection limits for enhanced CL with HPI and 4-iodophenol were 0.29 and 1.5 pmol, respectively. Therefore, it is demonstrated that HPI is the most superior L-012-dependent CL enhancer.

Overexpression of the activated form of the AtAREB1 gene (AtAREB1ΔQT) improves soybean responses to water deficit.

Abscisic acid-responsive element binding protein (AREB1) is a basic domain/leucine zipper transcription factor that binds to the abscisic acid (ABA)-responsive element motif in the promoter region of ABA-inducible genes. Because AREB1 is not sufficient to direct the expression of downstream genes under non-stress conditions, an activated form of AREB1 (AREB1ΔQT) was created. Several reports claim that plants overexpressing AREB1 or AREB1ΔQT show improved drought tolerance. In our studies, soybean plants overexpressing AREB1ΔQT were characterized molecularly, and the phenotype and drought response of three lines were accessed under greenhouse conditions. Under conditions of water deficit, the transformed plants presented a higher survival rate (100%) than those of their isoline, cultivar BR 16 (40%). Moreover, the transformed plants displayed better water use efficiency and had a higher number of leaves than their isoline. Because the transgenic plants had higher stomatal conductance than its isoline under well-watered conditions, it was suggested that the enhanced drought response of AREB1ΔQT soybean plants might not be associated with altered transpiration rates mediated by ABA-dependent stomatal closure. However, it is possible that the smaller leaf area of the transgenic plants reduced their transpiration and water use, causing delayed stress onset. The difference in the degree of wilting and percentage of survival between the 35S-AREB1ΔQT and wildtype plants may also be related to the regulation of genes that protect against dehydration because metabolic impairment of photosynthesis, deduced by an increasing internal CO2 concentration, was not observed in the transgenic plants.

A Shiga toxin-producing Escherichia coli O157 outbreak associated with consumption of rice cakes in 2011 in Japan.

In May 2011, an outbreak of Shiga toxin-producing Escherichia coli (STEC) O157 was reported from Yamagata Prefecture, Japan. Investigations, including a case-control study, revealed that the outbreak was linked to two varieties of rice cakes produced by a local manufacturer between 2 and 7 May. Active and passive surveillance identified 136 suspected cases, 142 confirmed cases, 26 asymptomatic cases, and 25 secondary cases. While no environmental samples taken from the manufacturing premises tested positive for STEC, other than a stool sample taken from one employee, on-site and epidemiological investigations indicated that STEC was introduced during the manufacturing process of rice cakes rather than through contamination of raw materials. This was the first reported outbreak of STEC associated with cakes and confectionery in Japan, which indicates that contamination and outbreaks of STEC can occur in any food unless proper precautions are taken.

Depression and cognitive impairment in patients with mild parkinsonian signs.

OBJECTIVES: Mild parkinsonian signs (MPS) are reported to be associated with increased risk of dementia, Parkinson's disease, parkinsonism, and vascular lesions of white matter and are also a significant predictor of mortality. Although more than 20% of subjects aged 60 years and older suffer from MPS in Japan, it is often unrecognized and underestimated by patients and medical physicians. We used neuropsychological methods to examine cognitive function and depressive symptoms in subjects with MPS. METHODS: We performed a population-based study in Ama-cho, a rural island town in western Japan. Participants included 951 subjects aged 65 years and older, 613 of whom completed all questionnaires, neurological examinations, and neuropsychological assessments and were included in the data analysis. Subjects were assessed for depression and subjective cognitive impairment using the Geriatric Depression Scale (GDS-15), Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and modified Unified Parkinson's Disease Rating Scale (mUPDRS). RESULTS: Of the 613 participants, 143 were diagnosed with MPS. GDS scores were significantly higher in the MPS group compared with the motor control group, while MMSE scores were significantly lower. CONCLUSIONS: We demonstrated that MPS correlate with both depressive symptoms and cognitive impairment.

Prognostic value of increased intraepithelial lymphocytes and lymphocytic clonality in dogs with chronic enteropathy or small-cell lymphoma.

The clinical significance of severe infiltration of small intraepithelial lymphocytes (IEL) and the results of polymerase chain reaction for antigen receptor rearrangement (PARR) in dogs with chronic enteropathy (CE) and small-cell lymphoma (SCL) are controversial. This cohort study aimed to evaluate the prognostic significance of the IEL and PARR results in dogs with CE or SCL. Although definitive diagnostic histopathological criteria for SCL in dogs have yet to be established, dogs with the histopathological findings of severe IEL infiltration were diagnosed with SCL in this study. One hundred and nineteen dogs were recruited, with 23 dogs classified as having SCL and 96 dogs as having CE. The positive rate of PARR was 59.6 % (71/119) in the duodenum and 57.7 % (64/111) in the ileum. Subsequently, three dogs with SCL and four dogs with CE developed large-cell lymphoma (LCL). The median overall survival (OS) of dogs with SCL was 700 days (range, 6-1410 days), and that of dogs with CE was not reached. In the log-rank test, shorter OS was observed in cases with histopathological SCL (P = 0.035), clonal TCRγ rearrangement in the duodenum (P = 0.012), and clonal IgH rearrangement in the ileum (P < 0.0001). The Cox proportional hazards model adjusted for sex and age showed that histopathological SCL (hazard ratio [HR] 1.74; 95 % confidence interval [CI], 0.83-3.65), duodenal clonal TCRγ rearrangement (HR, 1.80; 95 % CI, 0.86-3.75), and ileal clonal IgH rearrangement (HR, 2.28; 95 % CI, 0.92-5.70) could shorten overall survival, although their 95 % CIs included 1.0. These results indicate that severe IEL infiltration could be a useful histopathological feature for diagnosing SCL, and clonality-positive results could be a negative prognostic factor in dogs with CE. Furthermore, the development of LCL should be carefully monitored in dogs with CE and SCL..

Influence of calcium channel blockers in patients with gastrointestinal disease in Japanese community pharmacies.

WHAT IS KNOWN AND OBJECTIVE: Calcium channel blockers (CCBs), which have been widely used for the treatment of hypertension and angina pectoris, decrease lower oesophageal sphincter pressure and, as a result, can exacerbate gastrointestinal disease. In a previous study, increased risk of exacerbation of gastrointestinal disease among elderly patients following treatment with CCBs was identified. The prevalence of gastrointestinal diseases has increased in elderly patients, and it is possible that treatment with CCBs may have undesirably influenced this increase. The change in risk of gastrointestinal disease can be estimated by analysing changes in the prescription of antisecretory drugs as an outcome of exacerbation of gastrointestinal disease caused by CCBs. METHODS: It was hypothesized that patients who were prescribed CCBs would also change their use of antisecretory drugs. From September 2005 to August 2009, a dynamic retrospective cohort study was performed at five community pharmacies in Nagasaki, Japan, to assess alteration of antisecretory drug therapy following treatment with CCBs. Correlations with alterations of antisecretory drug therapy were determined by the Cox proportional hazards model. RESULTS AND DISCUSSION: The proposed study included 260 patients who were prescribed CCBs and 155 controls. During the study period, 53 patients were prescribed CCBs and 13 controls altered their antisecretory drug therapy; the hazard ratio was 2·22 (95% CI 1·25-4·26). WHAT IS NEW AND CONCLUSION: Calcium channel blocker treatment of patients with gastrointestinal disease was associated with alteration in frequency of prescription and an increase in dosage of antisecretory drugs. For clinical management of hypertension, alternative antihypertensive drugs may be considered for patients with gastrointestinal diseases. Further studies are required to determine the influence of CCB therapy on gastroesophageal diseases, suggested by the increase in use of antisecretory drugs.

Regulatory mechanisms in the pathways of cartilage and bone formation.

Three transcription factors of the Sox family have essential roles in different steps of the chondrocyte differentiation pathway. Because the transcription factor Cbfa1, which is needed for osteoblast differentiation, also stimulates hypertrophic chondrocyte maturation, it links the chondrocyte and osteoblast differentiation pathways in endochondral bone formation. Signaling molecules, including Indian Hedgehog, PTHrP and FGFs, also establish essential links either between these pathways, between steps in these pathways or between signaling molecules and transcription factors, so that a more comprehensive view of endochondral bone formation is emerging.

Rapid selection of complement-inhibiting protein variants in group A Streptococcus epidemic waves.

Serotype M1 group A Streptococcus strains cause epidemic waves of human infections long thought to be mono- or pauciclonal. The gene encoding an extracellular group A Streptococcus protein (streptococcal inhibitor of complement) that inhibits human complement was sequenced in 1,132 M1 strains recovered from population-based surveillance of infections in Canada, Finland and the United States. Epidemic waves are composed of strains expressing a remarkably heterogeneous array of variants of streptococcal inhibitor of complement that arise very rapidly by natural selection on mucosal surfaces. Thus, our results enhance the understanding of pathogen population dynamics in epidemic waves and infectious disease reemergence.

Expression of fibrosis-related genes in canine chronic hepatitis.

Molecular regulation of fibrosis in chronic canine hepatitis is poorly understood. The authors employed quantitative polymerase chain reaction (PCR) to determine the expression levels of genes reported to be related to fibrosis in other species (human, mouse, and rat) and to elucidate the relationship of these genes with the degree of fibrosis and the presence or absence of ascites and/or jaundice in dogs with hepatitis. Nine fibrosis-related genes were assayed: PDGFB, PDGFD, MMP2, TIMP1, THBS1, COL1A1, COL3A1, TGFB1, and TGFB2. Liver samples of 15 dogs with chronic hepatitis and 4 healthy control dogs were obtained via laparoscopic biopsy and subjected to histologic and quantitative PCR analyses. The expression of all 9 genes showed significant positive correlation (P<.01, r>.70) with the degree of fibrosis. Furthermore, the expression levels of all genes except TGFB1 were significantly higher (P<.05) in dogs with hepatic failure-related symptoms (ascites/jaundice). Results suggest that these 9 genes are integral to the development of fibrosis in canine chronic hepatitis.