Comparative Analysis of Gene Expression Profiles in the Adipose Tissue of Obese Adult Mice With Rapid Infantile Growth After Undernourishment In Utero.

Rapid infantile growth (RG) markedly increases the risk of obesity and metabolic disorders in adulthood, particularly among neonates born small. To elucidate the molecular mechanisms by which RG following undernourishment in utero (UN) contributes to the deterioration of adult fat deposition, we developed a UN mouse model using maternal energy restriction, followed by RG achieved by adjustments to 4 pups per litter soon after birth. A high-fat diet (HFD) was fed to weaned pups treated or not (Veh) with tauroursodeoxycholic acid (TU). UN-RG pups showed the deterioration of diet-induced obesity and fat deposition, which was ameliorated by TU. We performed a microarray analysis of epididymal adipose tissue and two gene enrichment analyses (NN-Veh vs UN-RD-Veh and UN-RG-Veh vs UN-RG-TU). The results obtained identified 4 common gene ontologies (GO) terms of inflammatory pathways. In addition to the inflammatory characteristics of 4 GO terms, the results of heatmap and principal component analyses of the representative genes from 4 GO terms, genes of interest (GOI; Saa3, Ubd, S100a8, Hpx, Casp1, Agt, Ptgs2) selected from the 4 GO terms, and immunohistochemistry of macrophages collectively suggested the critical involvement of inflammation in the regulation of fat deposition in the responses to UN and TU. Therefore, the present results support the 'Developmental Origins of Metaflammation', the last word of which was recently proposed by the concept of metabolic disorders induced by low-grade systemic inflammation.

Developmental Origins of Metaflammation; A Bridge to the Future Between the DOHaD Theory and Evolutionary Biology.

Metabolic syndrome refers to obesity-associated metabolic disorders that increase the risk of type 2 diabetes, coronary diseases, stroke, and other disabilities. Environmental imbalance during the early developmental period affects health and increases susceptibility to non-communicable diseases, including metabolic syndrome, in later life; therefore, the Developmental Origins of Health and Disease (DOHaD) theory was established. According to the DOHaD theory, the hypothesis of the energy-saving 'Thrifty Phenotype' in undernourished fetuses is one of the well-accepted schemes as a risk of developing metabolic syndrome. This phenotype is evolutionarily advantageous for survival of the fittest in a hangry environment after birth, a strong selection pressure, but increases the risk of developing metabolic syndrome under an obesogenic diet according to the 'Mismatch' hypothesis. Increasing evidences support that chronic inflammation pathophysiologically connects obesity to metabolic disorders in metabolic syndrome, leading to the concept of 'Metaflammation'. 'Metaflammation' in humans is proposed to originate from the evolutionary conservation of crosstalk between immune and metabolic pathways; however, few studies have investigated the contribution of evolutionary maladaptation to the pathophysiology of 'Metaflammation'. Therefore, it is promising to investigate 'Metaflammation' from the viewpoint of selective advantages and its 'Mismatch' to an unexpected environment in contemporary lifestyles, in consideration of the principal concept of evolutionarily conserved nutrient sensing and immune signaling systems.

Placental pathology predicts infantile neurodevelopment.

The aim of present study was to investigate the association of placental pathological findings with infantile neurodevelopment during the early 40 months of life. 258 singleton infants were enrolled in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study) whose placentas were saved in our pathological division. To assess the infantile neurodevelopment, we used Mullen Scales of Early Learning (gross motor, visual reception, fine motor, receptive language, expressive language) at 10, 14, 18, 24, 32, and 40 months. For obtaining placental blocks, we carried out random sampling and assessed eleven pathological findings using mixed modeling identified 'Accelerated villous maturation', 'Maternal vascular malperfusion', and 'Delayed villous maturation' as significant predictors of the relatively lower MSEL composite scores in the neurodevelopmental milestones by Mullen Scales of Early Learning. On the other hand, 'Avascular villi', 'Thrombosis or Intramural fibrin deposition', 'Fetal vascular malperfusion', and 'Fetal inflammatory response' were significant predictors of the relatively higher MSEL composite scores in the neurodevelopmental milestones by Mullen Scales of Early Learning. In conclusion, the present study is the first to report that some placental pathological findings are bidirectionally associated with the progression of infantile neurodevelopment during 10-40 months of age.

Circulating microRNA-15b-5p as a biomarker for asthma-COPD overlap.

BACKGROUND: It remains unclear how to characterize different subtypes of asthma and chronic obstructive pulmonary disease (COPD). We previously described serum periostin and chitinase-3-like protein 1 (YKL-40) as useful markers for asthma-COPD overlap (ACO). MicroRNAs (miRNAs) are now recognized as markers for identifying the pathophysiological features in several diseases. This study aimed to identify circulating miRNAs that could discriminate patients with ACO from patients with asthma or COPD. METHODS: This study included two independent cohorts. First, we screened 84 miRNAs for expression levels in patients with ACO (n = 6) or asthma (n = 6) using a quantitative real-time PCR array. The miRNAs showing at least a 2-fold difference in the discovery phase were analyzed in 30 patients each with asthma, COPD, or ACO in the replication phase. The diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve (AUROC). RESULTS: Nine miRNAs were identified in the discovery phase. Five of these miRNAs (miR-148a-3p, miR-15b-5p, miR-223-3p, miR-23a-3p, and miR-26b-5p) had lower levels in ACO patients and could discriminate between ACO patients and patients with either asthma or COPD. miR-15b-5p was the most accurate miRNA for the discrimination of patients with ACO (AUROC, 0.71). Moreover, the combined assessment of miR-15b-5p, serum periostin, and YKL-40 (AUROC, 0.80) improved diagnostic accuracy for ACO compared with the combined model of periostin and YKL-40 (AUROC, 0.69). CONCLUSIONS: Circulating miR-15b-5p is a potential marker for identifying patients with ACO. By elucidating the molecular pathways controlled by miRNAs, we may better understand the pathophysiology of ACO.

Impact of Gene Expression Associated with Glucocorticoid-Induced Transcript 1 (GLCCI1) on Severe Asthma and Future Exacerbation.

Genetic variations in glucocorticoid-induced transcript 1 (GLCCI1) have been associated with the response to corticosteroid treatment. However, the associations of GLCCI1 polymorphisms or gene expression with the prognosis of asthma and pathophysiological factors related to steroid insensitivity remain unclear. We sought to investigate the associations of GLCCI1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and histone deacetylase 2 (HDAC2) mRNA expression levels and the GLCCI1 rs37973 polymorphism with asthma severity and future exacerbation in patients with asthma. Subjects included 25 patients with severe asthma and 127 patients with nonsevere asthma. mRNA expression levels in peripheral blood mononuclear cells were measured and evaluated as predictors of severe asthma using receiver operating characteristic (ROC) analysis. The hazard ratios of the mRNA expression levels for time to first exacerbation in the 1-year follow-up period were calculated. GLCCI1, Nrf2, and HDAC2 mRNA expression levels were significantly lower in patients with severe asthma than in patients with nonsevere asthma and could predict severe asthma with an area under the ROC curve of 0.68, 0.71, and 0.65, respectively. In contrast, no relationship was found between the GLCCI1 rs37973 polymorphism and severe asthma. The hazard ratios for asthma exacerbation in patients with low GLCCI1, Nrf2, and HDAC2 mRNA expression levels were 3.24 (95% confidence interval, 1.42-7.40), 3.13 (1.37-7.16), and 2.98 (1.22-7.25), respectively. Patients with severe asthma could be distinguished by lower GLCCI1, Nrf2, and HDAC2 mRNA levels in peripheral blood cells, and all of these gene signatures could predict future asthma exacerbations.

Tumor budding is an independent prognostic marker in early stage oral squamous cell carcinoma: With special reference to the mode of invasion and worst pattern of invasion.

Pathologically proven regional lymph node metastasis affects the prognosis in early stage oral cancer. Therefore we investigated invasive tumor patterns predicting nodal involvement and survival in patients with clinically node-negative T1 and T2 oral squamous cell carcinoma (cT1,2N0M0 OSCC). Ninety-one cases of cT1,2N0M0 OSCC treated with transoral resection of the primary tumor were assessed based on 3 types of invasive tumor patterns on histopathologic and pancytokeratin-stained immunohistological sections: the mode of invasion, worst pattern of invasion (WPOI), and tumor budding. The correlations among invasive tumor patterns, regional metastasis, and disease-free survival were analyzed. Of the 91 cases, 22 (24%) had pathologically proven regional metastasis. The mode of invasion (p<0.01) and tumor budding (p<0.01) were associated with regional metastasis as well as lymphovascular invasion (p = 0.04) in univariate analysis. In logistic regression analysis, however, tumor budding was the only independent predictor of regional metastasis (hazard ratio (HR) = 3.05, 95% confidence interval (CI) = 0.29-5.30, p<0.01). All three invasive patterns, the mode of invasion, WPOI, and tumor budding, were found to be significant predictors of 5-year disease-free survival (p<0.01, p = 0.03, and p<0.01, respectively) as well as lymphovascular invasion (p = 0.02) and perineural invasion (p = 0.02). A final model for Cox multivariate analysis identified the prognostic advantage of the intensity of tumor budding (HR = 2.19, 95% CI = 1.51-3.18, p<0.01) compared with the mode of invasion and WPOI in disease-free survival. Our results indicate that the intensity of tumor budding may be a novel diagnostic biomarker, as well as a therapeutic tool, for regional metastasis in patients with cT1,2N0M0 OSCC. If the pancytokeratin-based immunohistochemical features of more than five buds, and a grade 4C or 4D mode of invasion are identified, careful wait-and-see follow-up in a short period with the use of imaging modalities is desirable. If there are more than ten buds, a grade 4D mode of invasion, or WPOI-5 in the same section, wide resection of the primary tumor with elective neck dissection should be recommended.

Biochemical and functional characterization of transiently expressed in neural precursor (TENP) protein in emu egg white.

A protein transiently expressed in the neural precursors of developing tissues (TENP) was found to be present in emu (Dromaius novaehollandiae) egg white as one of the major proteins. Nucleotide analysis of its encoding cDNA revealed a sequence of 452 amino acids including a 19 amino acid peptide signal. Phylogenetic analysis determined that emu TENP was clustered within the bactericidal/permeability-increasing protein (BPI) superfamily together with other avian TENPs. RT-PCR analysis revealed that the emu TENP gene was highly expressed in the magnum of the oviduct, indicating that TENP is a major egg white component. Emu TENP was purified by anion exchange chromatography and ammonium sulfate fractionation. Unlike BPI, emu TENP exhibited antibacterial activity against Gram-positive bacteria, including Micrococcus luteus and Bacillus subtilis, but not against Gram-negative bacteria such as Escherichia coli and Salmonella Typhimurium. The results suggest that emu TENP is a potent novel antibacterial protein with a spectrum distinct from that of BPI.

Assessment of the shape of the inferior alveolar canal as a marker for increased risk of injury to the inferior alveolar nerve at third molar surgery: a prospective study.

PURPOSE: Morphologic evaluation of computed tomographic images is an important assessment tool before surgical removal of the lower third molar (LM3). The aim of this study was to ascertain whether the shape of the inferior alveolar canal (IAC) is a reliable predictor for inferior alveolar nerve (IAN) injury during M3 surgery. MATERIALS AND METHODS: This prospective study assessed samples with a high risk of IAN injury during M3 surgery based on orthopantomographic examination. The predictor variables were demographic factors (patient's age and gender), anatomic factors (angulation of the tooth), and radiographic factors (cortication status, buccolingual position, shape of the IAC, number of roots, and root shape). The outcome variable was IAN injury. The relation between predictor and outcome variables was analyzed using the Fisher exact test and a logistic regression model. RESULTS: One hundred sixty-nine LM3s (115 patients) were analyzed. IAN injury was observed in 12 of 115 patients and 13 of 169 LM3s (7.7%). All 13 cases with IAN injury exhibited absence of cortication. A dumb-bell-shaped IAC was considered a useful predictor for IAN injury (sensitivity, 69.2%; specificity, 84.6%). In cases with absence of cortication, logistic regression analysis indicated that a dumb-bell-shaped IAC was closely related to IAN injury (P = .005). CONCLUSION: The cortication status and shape of the IAC are reliable predictors for IAN injury at M3 surgery. Cases exhibiting absence of cortication and a dumb-bell-shaped IAC should be recognized as presenting a high risk of IAN injury at M3 surgery.

Clinical significance of computed tomographic assessment and anatomic features of the inferior alveolar canal as risk factors for injury of the inferior alveolar nerve at third molar surgery.

PURPOSE: To assess the clinical features of the inferior alveolar canal (IAC) using computed tomography (CT) and to analyze the significance of CT examination at third molar surgery. MATERIALS AND METHODS: A retrospective cohort study was performed involving 99 patients (145 teeth). The relationship between cortication status, buccolingual position, and shape of the IAC on the CT image and inferior alveolar nerve (IAN) injury after third molar surgery were statistically analyzed. RESULTS: The shape of the IAC was categorized into 3 groups: round/oval, teardrop, and dumbbell. IAN injury was observed in 7 of 145 cases (4.8%). All 7 cases exhibited absence of cortication; 3 were dumbbell shape and 4 were round/oval. According to logistic regression analysis of cases with absence of cortication, IAC shape was closely related to IAN injury. CONCLUSIONS: These results suggest that assessment of the IAC shape and cortication status at third molar surgery may be clinically useful.

[Clinical investigation of bisphosphonate-related osteonecrosis of the jaws].

We examined the clinical features of bisphosphonate(BP)-related osteonecrosis of the jaws(BRONJ), a serious complication resulting from intravenous BP treatment for multiple myeloma and malignant tumors with bone metastasis. We retrospectively reviewed the medical records of 36 patients who received intravenous BP therapy for the above-mentioned conditions, at Sapporo Medical University Hospital between July 2006 and October 2008. BP therapy caused BRONJ in 7 of 24 patients, but did not affect the bones of the other 17 patients. The other 12 of the 36 patients involved in the study were prescribed BP only after they had undergone an oral examination and treatment for dental inflammation. Of these patients, 7 developed BRONJ with BP treatment, after tooth extraction or acute dental inflammation. Treating dental inflammation before prescribing BP prevented the development of BRONJ. BRONJ is highly intractable and does not resolve with the standard treatment for osteomyelitis. Therefore, preventive therapy, which can be achieved by cooperation between medical doctors and dentists, is currently the most effective strategy for BRONJ. Conservative treatment with antibiotics may also be useful for maintaining or improving the quality of life of BRONJ patients.

[A detection of very mild Alzheimer's disease and MCI by memory complaints and deterioration of IADL in a questionnaire for a memory clinic].

BACKGROUND AND PURPOSE: There have been very few studies trying to explain about daily life features of patients with very mild Alzheimer disease (AD) and of those with mild cognitive impairment (MCI). The purpose of this study was 1) to clarify characteristics of very mild AD and MCI in their daily life, and 2) to examine items in a questionnaire that can be useful for detecting subjects of suspected AD. SUBJECTS AND METHODS: Subjects were 111 patients of the memory clinic in National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Japan; 39 normal range, 28 MCI, and 44 very mild AD. On their first visits, they were asked to fill out a questionnaire consisted of 103 items. Thirty five items in a questionnaire were selected, 15 memory-complaint items and 20 items of instrumental activities of daily living (IADL), and examined retrospectively. At first we compared each set of groups using the chi-square test. Then a logistic regression analysis was used to observe which items contributed to judge a person to be suspected of AD. And further, sensitivity and specificity for discriminating between an AD suspected and a normal range were examined. RESULTS: None of the items showed statistical significance between MCI group and very mild AD group. Then, we combined these two groups into one group (n = 72), and made comparison between this new group and normal range group (n = 39). There were 18 items that showed statistical significance between the two groups. And five of them, 'dysfunction of memory: noticed by others', 'dysfunction of memory: getting worse', 'unable to utilize the memorandum', 'forget incidents occurred a few days ago' and 'unable to locate unfamiliar places' showed significantly high odds ratio in judgment on a person to be suspected of AD. In addition to preceding 5 items we adopted two items, 'dysfunction of memory: unnoticeable by her/himself' and 'unable to manage household expenses', which were not included in the logistic regression analysis, but were essential for the discrimination between the two groups. The sum of score of these 7 items showed high specificity and sensitivity for dividing between the two groups. CONCLUSION: These findings indicated that an exploration of memory complaints and deteriorations of IADL was useful for the detection of MCI and very mild AD, especially 7 items described above could be used as a simple questionnaire for the elderly.

Heterogeneity and tissue specificity of tropomyosin isoforms from four species of bivalves.

Heterogeneity and tissue specificity of tropomyosin isoforms obtained from four species of bivalves (Scapharca broughtonii (ark shell), Mytilus galloprovincialis (mussel), Atrina pectinata (surf clam) and Crassostrea gigas (Pacific oyster)), were examined. Tropomyosins were extracted from translucent and opaque portions of posterior adductor muscle, respectively, and cardiac muscle of each bivalve. There were two tropomyosin isoforms in the ark shell, the surf clam and the Pacific oyster. They were designated as TMa and TMb. In the ark shell, TMa was the common isoform and TMb was specific for the opaque portion of the adductor muscle. In the surf clam, TMb was the common isoform present in all tissues. TMa was found only in the translucent portion of muscle. In the Pacific oyster, TMb was the major component in both portions of adductor muscle and TMa was the major component in cardiac muscle, although both tropomyosins were included in all tissues. The mussel had only one tropomyosin.