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Objective: To evaluate the breed‐characteristic features of cervical intervertebral disc disease (C‐IVDD) and associated vertebral instability in small‐breed dogs and to present the concept of intervertebral disc degeneration and associated instability stage, method of diagnosis, treatment and outcomes. Animals: In total, 307 client‐owned dogs with C‐IVDD treated with spinal cord decompression with or without vertebral stabilization (2000–2021). Methods: Information on age, sex, affected sites, stabilized sites, diagnostic methods for vertebral instability and outcomes were retrieved. The patient's age, affected sites (cranial vs caudal discs), and frequency of vertebral stabilization were compared in six CD and five NCD breed. Multivariable analyses of the chondrodystrophic (CD) vs non‐CD (NCD) groups, and vertebral stabilization (dogs stabilized vs dogs not stabilized) were performed. Results: In total, 222 (72.3%) and 77 (25.1%) were CD and NCD breeds, respectively. Vertebral instabilities were diagnosed based on the survey radiographs with computed tomography/magnetic resonance imaging (n = 2), dynamic myelography (n = 29), intraoperative spinal manipulation (n = 11) or second surgery in dogs with persistent postoperative paraspinal pain (n = 3). Of these dogs, 295 (96.1%) recovered (median follow‐up: 8.5 [range, 1–119] months). Significant differences in age, affected sites and frequency of stabilization were noted among the breeds. Older age and frequent vertebral stabilization were the associated factors for the NCD breed dogs. Male dogs, caudal discs affected (C5–T1) and the NCD breed dogs were risk factors for the dogs with vertebral stabilization. Conclusion: Vertebral stabilization is indicated for small‐breed dogs with cervical disc‐associated vertebral instability. [ABSTRACT FROM AUTHOR]

Objectives: To describe the diagnostic findings, surgical technique and outcomes in seven pugs with thoracolumbar vertebral instability due to articular process anomalies. Materials and Methods: Records (2010 to 2019) of pugs with thoracolumbar vertebral instability associated with articular process anomalies that underwent decompressive laminectomy and vertebral stabilisation were reviewed. Data on preoperative and postoperative neurologic status, diagnostic findings, surgical techniques and outcomes were retrieved. Results: Seven dogs were presented with ambulatory or non‐ambulatory paraparesis. Caudal articular process anomalies (three dogs) and concomitant cranial and caudal articular process anomalies (four dogs) were noted. Myelography (six dogs) or magnetic resonance imaging (one dog) showed none to severe spinal cord compression. Dynamic myelography in six dogs demonstrated nine distinct sites of spinal cord dimension reduction positioned in extension and/or flexion (mean reduction: 16.0%, range: 8.5 to 24.0%). These dynamic compressions were located at sites with articular process anomalies (seven sites) and sites with no articular process anomalies (two sites). Vertebral instability was confirmed by intraoperative spinal manipulation in all dogs. All dogs remained ambulatory with improved (five dogs) or static (two dogs) neurological deficits at the last follow‐up (median: 16 months; range: 1.5 to 66 months). Clinical Significance: Dynamic myelography and/or intraoperative spinal manipulation demonstrated vertebral instabilities at sites with or without articular process anomalies on imaging. Decompressive laminectomy with vertebral stabilisation resulted in long‐term neurological improvement in most dogs. [ABSTRACT FROM AUTHOR]

Abstract: Background: The aim of this study was to investigate whether the lamellar and lateral structure of intercellular lipid of stratum corneum (SC) can be evaluated from millimeter‐sized SC (MSC) by X‐ray diffraction. Materials and Methods: A 12 mm × 12 mm SC sheet from hairless mouse was divided into 16 pieces measuring 3 mm × 3 mm square. From another sheet, 4 pieces of ultramillimeter‐sized SC (USC:1.5 mm × 1.5 mm square) were prepared. Small and wide‐angle X‐ray diffraction (SAXD and WAXD) measurements were performed on each piece. For MSC and USC, changes in the lamellar and lateral structure after the application of d‐limonene were measured. Results: The intensity of SAXD peaks due to the lamellar phase of long periodicity phase (LPP) and WAXD peaks due to the lateral hydrocarbon chain‐packing structures varied in MSC and USC pieces, although over the 12 mm × 12 mm SC sheet. These results indicated that the intercellular lipid components and their proportion appeared nearly uniform. Application of d‐limonene on MSC and USC piece with strong peaks in SAXD and the WAXD resulted in the disappearance of peaks due to the lamellar phase of LPP and decrease in peak intensity for the lateral hydrocarbon chain‐packing structures. These changes are consistent with normal‐sized sample results. Conclusion: We found that the selection of a sample piece with strong diffraction peaks due to the lamellar and lateral structure enabled evaluation of the SC structure in small‐sized samples by X‐ray diffraction. [ABSTRACT FROM AUTHOR]

Background and purpose: Many epidemiological studies of Guillain−Barré syndrome (GBS) and Fisher syndrome (FS) have been conducted in Europe and America. In contrast, epidemiological studies are rare in Asia where the GBS subtypes differ from those in Western countries. This study was undertaken to clarify the incidence of GBS and FS in a local area in Japan as well as their seasonal trends. Method: Seventy‐one GBS and 37 FS patients were recorded from 2006 to 2015 in an area of approximately 1.5 million inhabitants in Japan. The incidence, seasonal trends and clinical features of GBS and FS were examined. Results: The incidence rate of GBS was 0.42 cases per 100 000 person‐years and that of FS was 0.22 cases per 100 000 person‐years. The incidence of GBS increased with age and FS affected predominantly patients aged from 45 to 64 years old. There was some seasonal clustering of acute motor axonal neuropathy (AMAN) and FS in spring and summer, but it was not significant. AMAN and FS patients had a high frequency of preceding infection (AMAN, 68% gastrointestinal infection; FS, 65% upper respiratory infection). Antecedent respiratory infection was significantly associated with FS as an outcome. Serum antibodies to ganglioside GM1 were detected in 71% of AMAN patients and antibodies to GQ1b were detected in 81% of FS patients. Conclusions: Our study offers evidence of a lower incidence of GBS and a higher incidence of FS in a local area in Japan than in Western countries. [ABSTRACT FROM AUTHOR]

Aims Neurofibrillary tangles (NFTs), a cardinal pathological feature of neurodegenerative disorders, such as Alzheimer's disease (AD) are primarily composed of hyper-phosphorylated tau protein. Recently, several other molecules, including flotillin-1, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] and cyclin-dependent kinase 5 (CDK5), have also been revealed as constituents of NFTs. Flotillin-1 and PtdIns(4,5)P2 are considered markers of raft microdomains, whereas CDK5 is a tau kinase. Therefore, we hypothesized that NFTs have a relationship with raft domains and the tau phosphorylation that occurs within NFTs. Methods We investigated six cases of AD, six cases of other neurodegenerative diseases with NFTs and three control cases. We analysed the PtdIns(4,5)P2-immunopositive material in detail, using super-resolution microscopy and electron microscopy to elucidate its pattern of expression. We also investigated the spatial relationship between the PtdIns(4,5)P2-immunopositive material and tau kinases through double immunofluorescence analysis. Results Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 μm in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons. These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase-3 β and spleen tyrosine kinase. Conclusions These observations suggest that clusters of raft-derived vesicles that resemble GVD bodies are substructures of pretangles other than PHFs. These tau kinase-bearing vesicles are likely involved in the modification of tau protein and in NFT formation. [ABSTRACT FROM AUTHOR]

Toxoplasmic encephalitis represents a rare, but often fatal infection after allogeneic hematopoietic stem cell transplantation. Polymerase chain reaction ( PCR)-based preemptive therapy is considered promising for this disease, but is not routinely applied, especially in low seroprevalence countries including Japan. We encountered 2 cases of toxoplasmic encephalitis after transplantation that were successfully treated. The diagnosis of toxoplasmic encephalitis in these cases was confirmed by PCR testing when neurological symptoms were observed. Both patients received pyrimethamine and sulfadiazine treatments within 2 weeks of the development of neurological symptoms, and remained free of recurrence for 32 and 12 months. These results emphasized the importance of the PCR test and immediate treatment after diagnosis for the management of toxoplasmic encephalitis. [ABSTRACT FROM AUTHOR]

The present study investigates the human leucocyte antigen ( HLA) allele and haplotype frequencies in Japanese population. We carried out the frequency analysis in 5824 families living across Japanese archipelago. The studied population has mainly been typed for the purpose of transplant, especially the hematopoietic stem cell transplantation ( HSCT). We determined HLA class I (A, B, and C) and HLA class II ( DRB1) using Luminex technology. The haplotypes were directly counted by segregation. A total of 44 HLA-A, 29 HLA-C, 75 HLA-B, and 42 HLA-DRB1 alleles were identified. In the HLA haplotypes of A-C-B- DRB1 and C-B, the pattern of linkage disequilibrium peculiar to Japanese population has been confirmed. Moreover, the haplotype frequencies based on family study was compared with the frequencies estimated by maximum likelihood estimation ( MLE), and the equivalent results were obtained. The allele and haplotype frequencies obtained in this study could be useful for anthropology, transplantation therapy, and disease association studies. [ABSTRACT FROM AUTHOR]

Despite the outstanding results generally obtained with imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), some patients show a poor molecular response. To evaluate the relationship between steady-state trough plasma IM concentration (IM-Cmin) and clinical response in CML patients, we integrated data from six independent Japanese studies. Among 254 CML patients, the mean IM-Cmin was 1,010.5 ng/ml. Importantly, IM-Cmin was significantly higher in patients who achieved a major molecular response (MMR) than in those who did not (P = 0.002). Multivariate analysis showed that an MMR was associated with both age (odds ratio (OR) = 0.97 (0.958-0.995); P = 0.0153) and with IM-Cmin (OR = 1.0008 (1.0003-1.0015); P = 0.0044). Given that patients with IM-Cmin values >1,002 ng/ml had a higher probability of achieving an MMR in our large cohort (P = 0.0120), the data suggest that monitoring of IM levels in plasma may improve the efficacy of IM therapy for CML patients. [ABSTRACT FROM AUTHOR]

Objective: We examined the effects of rosiglitazone treatment on profiles of adipocytokines levels, postprandial insulin and glucose excursion, lipids levels, comparing with those of pioglitazone treatment in patients with type 2 diabetes mellitus (T2DM). Methods: Changes in body weight, haemoglobin A1c (HbA1c), glucose/insulin/C-peptide/free fatty acid (FFA) during 75 g oral glucose tolerance test (OGTT), HDL-/LDL-cholesterol, triglyceride (TG) and adipocytokines [tumour necrosis factor (TNF)-α, leptin and adiponectin] were measured in T2DM patients treated with rosiglitazone, 8 mg/day (n = 35), or pioglitazone, 45 mg/day (n = 21), for 3 months. Results: After rosiglitazone or pioglitazone treatment, HbA1c (8.6–7.2 vs. 8.3–6.9%, rosiglitazone vs. pioglitazone), fasting plasma glucose (190–144 vs. 178–140 mg/dl), fasting FFA (729–595 vs. 641–526 μEq/l), mean plasma glucose-OGTT (292–229 vs. 285–233 mg/dl) and mean FFA-OGTT (580–430 vs. 488–377 μEq/l) decreased similarly and all were statistically significant (p < 0.01). The insulinogenic index (ΔI0–120/ΔG0–120) (0.19–0.30 vs. 0.17–0.26) and Matsuda index of insulin sensitivity (2.0–3.1 and 2.7–4.3) increased (p < 0.01) similarly, despite increase in body weight (85–88 vs. 81–84 kg). TNF-α (3.8–3.4 vs. 5.2–4.5 pg/ml) decreased (p < 0.05) and adiponectin (6.3–17.8 vs. 7.1–16.4 μg/ml) increased (p < 0.01), while leptin did not change following either treatment. After rosiglitazone treatment, plasma HDL-cholesterol (34–38 mg/dl) and LDL-cholesterol (103–120 mg/dl) increased (p < 0.01), while TGs (177–167 mg/dl) did not change significantly. After pioglitazone treatment, plasma HDL-cholesterol (34–37 mg/dl) increased (p < 0.05), while LDL-cholesterol (104–105 mg/dl) did not change and TGs (153–106 mg/dl) decreased (p < 0.01). Conclusions: Rosiglitazone and pioglitazone have similar beneficial effects on glycaemic control insulin sensitivity, insulin secretion and plasma adipocytokine levels. However, pioglitazone has a more beneficial effect on the plasma lipid profile than rosiglitazone. [ABSTRACT FROM AUTHOR]

Diet is one of the important factors that modulate immune responses. In the present study, we have examined the capacity of dietary lipids to modify immune responses in mice and we have investigated the contribution of glycolipid-reactive natural killer T (NKT) cells in this process. Mice fed, high fat diet (HFD; 21.2% fat, 0.20% cholesterol) for 3 weeks, as compared with mice fed standard fat diet (SFD; 4.3% fat, 0.03% cholesterol), showed significantly reduced interferon-γ production in sera at 6 or 12 h after intraperitoneal injection of an NKT cell ligand, α-galactosylceramide. In contrast, production of interleukin-13 was significantly higher at 2 and 6 h in HFD fed mice compared with mice on SFD. No difference was detected in the serum interleukin-4 levels between these two groups of animals. The proportion of NKT cells in spleen and liver was reduced in mice fed HFD compared with those on SFD. In addition, activation of NKT cells assessed by up-regulation of CD69 was suppressed specifically in liver from mice fed HFD. Recall responses of conventional T cells and delayed-type hypersensitivity (Th1 type) against ovalbumin were significantly suppressed in mice fed HFD in comparison with those fed SFD. This suppression was not observed in CD1d−/− mice, suggesting that NKT cells in mice fed HFD played a role in suppressing Th1 responses. Taken together, our findings suggest a critical link between NKT cells, dietary lipid and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Peripheral edema, mild weight gain, and anemia are often observed in type II diabetic patients treated with thiazolidinediones (TZDs). Small decreases in hemoglobin (Hb) and hematocrit (Hct) appear to be a class effect of TZDs and are generally attributed to fluid retention, although experimental data are lacking. We analyzed 50 patients with type II diabetes mellitus undergoing either placebo or pioglitazone (PIO, 45 mg/day) for 16 weeks. Before and after therapy, we measured Hb/Hct and used 3H2O and bioimpedance to quantitate total body water (TBW), extracellular water, and fat-free mass. The majority (89%) of the increment in body weight was accounted for by increased body fat. Hb and Hct fell significantly in the PIO group (−0.9±0.2 g/dl, −2.4±0.5%, both P<0.0001), without change in TBW. A decline in white blood cell (−0.8±0.1 × 103/mm3, P<0.0001) and platelet (−15±6 × 103/mm3, P<0.02) counts was seen after PIO. In conclusion, the small decreases in Hb/Hct observed after 16 weeks of PIO treatment cannot be explained by an increase in TBW. Other causes, such a mild marrow suppressive effect, should be explored.Clinical Pharmacology & Therapeutics (2007) 82, 275–281; doi:10.1038/sj.clpt.6100146; published online 14 March 2007 [ABSTRACT FROM AUTHOR]

Aims Type 2 diabetes is preceded by a symptom-free period of impaired glucose tolerance (IGT). Pancreatic B-cell function decreases as glucose intolerance develops. In many patients with IGT, fasting blood glucose is within normal limits and hyperglycaemia occurs only postprandially. We examined whether pancreatic B-cell function changes during acute hyperglycaemia induced by oral glucose loading. Methods We calculated the insulinogenic index (I.I.) as an indicator of pancreatic B-cell function and measured serum levels of thioredoxin, a marker of cellular redox state, and 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative stress, during a 75-g oral glucose tolerance test (OGTT) in 45 subjects [24 patients with normal glucose tolerance (NGT), 14 with IGT and seven with Type 2 diabetes]. Results Thioredoxin levels decreased after glucose loading [66.1 ± 23.7, *59.3 ± 22.4, *49.3 ± 21.2 and *37.7 ± 18.0 ng/ml, fasting (0 min) and at 30, 60 and 120 min, respectively; * P < 0.001 vs. fasting]. In contrast, concentrations of 8-OHdG peaked at 30 min and then gradually decreased (0.402 ± 0.123, *0.440 ± 0.120, †0.362 ± 0.119 and †0.355 ± 0.131 ng/ml, * P < 0.05 vs. fasting, † P < 0.01 vs. 30 min). The insulinogenic index correlated with the change in thioredoxin levels ( r = 0.34, P < 0.05). However, there was no relationship with the change in 8-OHdG levels from 0 to 30 min. Conclusions Hyperglycaemia in response to oral glucose impairs pancreatic B-cell function with decreasing thioredoxin levels. The augmented oxidative stress induced by hyperglycaemia may affect the cellular redox state. These findings strongly suggest that repeated postprandial hyperglycaemia may play an important role in the development and progression of diabetes mellitus. [ABSTRACT FROM AUTHOR]

A 10-year-old German shepherd dog was presented with a severe abdominal distension. At necropsy, whitish and firm mass was observed in the mesentery with metastases in the pericardium and pleura. The intestinal serosa was thickened and stiff. Histologically, the tumours were composed of a biphasic population of cells, which reacted with cytokeratin, vimentin and Wilms’ tumour 1 protein antibody. Ultrastructural examination revealed numerous microvilli, abundant rough endoplasmic reticulum, numerous desmosomes and bundles of microfilament. The tumour was classified as biphasic mesothelioma of peritoneal origin. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that the elevated C-reactive protein (CRP) levels are associated with body fat, especially visceral adipose tissue, but most of them were investigated in Westerners who had higher body mass index (BMI) than Asians. To investigate the association between CRP concentrations, parameters of visceral obesity, the insulin resistance syndrome and carotid atherosclerosis in healthy Japanese who had a lower BMI than Westerners. We explored the relationships between fatness and visceral obesity parameters [by anthropometry, bioelectrical impedance analysis and abdominal computed tomography (CT)] and CRP (high sensitivity) and examined their associations with components of insulin resistance syndrome, interleukin-6 (IL-6), tissue necrosis factor-α (TNF-α) and intima-media thickness (IMT) of common carotid arteries (CCAs) by ultrasonograms in 116 healthy Japanese subjects. In crude regression analyses, CRP was significantly associated with measures of obesity. After adjustment for age, gender and smoking, the association with CRP was stronger for parameters of visceral obesity (waist circumference, waist-to-hip ratio and visceral adipose tissue accumulation) than for other parameters of obesity. IL-6 and TNF-α were not associated with CRP. Blood pressure (BP), metabolic variables and CCA-IMT were also significantly associated with CRP. But, after being adjusted for age, gender, smoking and BMI, BP and high-density lipoprotein cholesterol (HDLc) were significantly associated. CRP level is associated with visceral adipose tissue and is significantly associated with the components of insulin resistance syndrome in healthy Japanese subjects. These data support a possible role of visceral adipose tissue in inflammation component of atherosclerosis, and further studies are needed to study the mechanism of CRP elevation caused by visceral adipose tissue. [ABSTRACT FROM AUTHOR]

A case of periodontitis in a young adolescent Japanese girl with Down's syndrome is presented in this report. The patient received a monthly preventive course of dental care consisting of mechanical plaque control and oral hygiene instruction. After 2.5 years she recovered from progression of periodontal disease both clinically and microbiologically. The importance of clinical care for periodontitis in Down's syndrome patients is discussed. [ABSTRACT FROM AUTHOR]

Background The regulation of transgene expression is a key issue for the development of safe gene therapy. Various strategies have been used to regulate protein production at the levels of transgene expression, transcription, translation, and secretion. Neutralization following secretion is another important backup system to prevent super-therapeutic levels of a protein from being expressed by gene transfer. Methods We tested whether the soluble human erythropoietin receptor (EpoR)/IgG1Fc could neutralize the rat Epo at the post-secretory level and suppress erythrocytosis. Results To assess whether soluble human EpoR could bind rat Epo in vitro, we used the Epo-dependent human leukemic cell line, AS-E2. EpoR/IgG1Fc significantly inhibited the growth of AS-E2 cells in Epo-containing medium. To test this neutralization effect of EpoR/IgG1Fc in vivo, we first transferred pCAGGS-Epo into rat muscle by in vivo electroporation, confirmed erythropoiesis for 3 weeks, and then delivered EpoR/IgG1Fc by liver-targeted gene transfer via tail-vein injection with hydrodynamics-based transfection. Reticulocyte counts and hematocrit levels in rats that received pCAGGS-EpoR/IgG1Fc injections were significantly lower than in rats that received pCAGGS-EpoR, pCAGGS-IgG1Fc, or no injection. Conclusions These results demonstrate that liver-targeted pCAGGS-EpoR/IgG1Fc transfer by tail-vein injection with hydrodynamics-based transfection is useful for neutralizing Epo delivered by in vivo electroporation. This backup strategy at the level of post-secretion could facilitate the clinical application of gene therapy in the future. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background The repeated application of glucocorticoids (GC) on the skin augmented the inflammatory response of both allergic and irritant contact dermatitis in our studies. Objective In order to further clarify the mechanism of such an augmentation of contact hypersensitivity (CHS), we investigated the modulatory effects of cytokines in the epidermis after the administration of GC at challenged sites in CHS. Methods Diflucortolone valerate was applied to BALB/c mice on alternate days for a total of nine times. On day 12, they were contact sensitized with dinitrofluorobenzene (DNFB). Next, on day 17, one day after the last application of GC, they were challenged with DNFB on the ear. The whole challenged ear lobes were removed after a hapten challenge and then were analysed by the RT-PCR method or underwent an immunohistochemical analysis. To clarify the modulatory effects of cytokines in vivo, DNFB sensitized mice pre-treated with GC were injected with rIL-10, IL-1 receptor antagonist (ra) and anti-IL-1α monoclonal antibody (mAb) and thereafter were challenged with DNFB. Results A RT-PCR analysis has demonstrated IL-10 mRNA to be detected in the challenged skin of non-GC-pretreated mice but not in that of GC-pre-treated mice after challenge. On the other hand, the expression of IL-lα mRNA in the challenged skin of mice pretreated with GC was more strongly detected that that in mice without GC-pretreatment. Furthermore, an immuno-histochemical analysis in the challenge showed the expression of IL-10 in the skin showed the expression of IL-10 in the challenged epidermis of the non-GC-pretreated mice but not in the GC-pretreated mice and IL-lα was also strongly expressed in the epidermis of the GC-pretreated mice. A subcutaneous injection of anti-IL-lα mAb or IL-1 ra inhibited the augmented CHS reaction in the GC-pretreated mice. A subcutaneous injection of rIL-10 also inhibited the augmentation of the CHS reaction in the GC-pretreated... [ABSTRACT FROM AUTHOR]