Oral mycobiome in community-dwelling elderly and its relation to oral and general health conditions.

OBJECTIVE: Oral fungal infection is generally associated with dysbiosis related to antibiotic use, immunodeficiency, or frailty. However, fungal colonization in a typical population without apparent symptoms and its associated conditions are poorly understood. In this study, oral fungal colonization in community-dwelling and independently living elderly populations was evaluated and factors affecting fungal colonization were analyzed. SUBJECTS AND METHODS: The subjects (410; 181 males and 229 females) were 75-99 years of age; those under prior antibiotic use were excluded. Fungal populations in the saliva were evaluated by PCR-based molecular techniques. Body mass index (BMI), smoking habits, and oral health conditions were examined. RESULTS: Salivary fungal amounts exceeded 104  CFU/ml in 63 (15.4%) of 410 subjects. Candida albicans was most frequently detected (98.4%), followed by Candida glabrata (54.0%), and Candida dubliniensis (38.1%) in those subjects with fungi at 104  CFU/ml or over. Fungi at 104  CFU/ml or over in the presence of C. glabrata or C. dubliniensis was significantly associated with low BMI. CONCLUSIONS: Candida albicans, C. glabrata, and C. dubliniensis dominated the oral mycobiome in Japanese community-dwelling elderly. Lower BMI might signify compromised health status and thus could result in susceptibility to specific candidiasis by C. glabrata and C. dubliniensis.

Posterior teeth occlusion and dysphagia risk in older nursing home residents: a cross-sectional observational study.

The total number of natural teeth was related to swallowing function among older adults; however, limited information is available regarding the impact of occluding pairs of teeth on swallowing function. This study aimed to examine the association between posterior teeth occlusion and dysphagia risk in older nursing home residents. This cross-sectional study included 238 residents aged ≥60 years from eight nursing homes in Aso City, Japan. Swallowing function was evaluated using the modified water swallowing test (MWST); the primary outcome was dysphagia risk (MWST score ≤3). Posterior teeth occlusion was assessed using number of functional tooth units (FTUs), determined based on number and location of the remaining natural and artificial teeth on implant-supported, fixed or removable prostheses. Univariate and multivariate logistic regression analyses were performed to examine the association between posterior teeth occlusion and dysphagia risk, adjusted for the covariates of number of natural teeth, demographic characteristics, comorbidities, physical function, body mass index and cognitive function. Of the 238 subjects, 44 (18·5%) were determined to be at risk of dysphagia based on the MWST scores. The odds ratio (OR) of dysphagia risk decreased in subjects with higher total FTUs [OR = 0·92, 95% confidence interval (CI) 0·87-0·98]. After adjusting for covariates, this association remained significant (OR = 0·90, 95% CI 0·84-0·97). Loss of posterior teeth occlusion was independently associated with dysphagia risk in older nursing home residents. Maintaining and restoring posterior teeth occlusion may be an effective measure to prevent dysphagia.

Swallowing disorders and 1-year functional decline in community-dwelling older adults receiving home care.

The purpose of this study was to clarify the effect of swallowing disorders on functional decline in community-dwelling older adults receiving home care. This was a 1-year follow-up survey of 176 individuals ≥60 years living at home and receiving homecare services, without total dependence in basic daily living activities, in two mid-sized municipalities in Fukuoka, Japan. Functional decline was measured using the Barthel index (BI), and the primary outcome was total dependence in basic daily living activities (BI ≤ 20 points). Swallowing function was assessed using cervical auscultation, and the primary predictor was swallowing disorders. Logistic regression models were used to assess univariate and multivariate associations between baseline swallowing function and functional decline during follow-up. During follow-up 16 (9.1%), the participants became totally dependent in basic daily living activities. The participants with swallowing disorders had 6.41 times higher odds of total dependence in basic daily living activities compared to participants with normal swallowing function. After adjusting for potential confounders, swallowing disorders were significantly associated with higher odds of total dependence in basic daily living activities (odds ratio = 5.21, 95% confidence interval = 1.33-20.44). Regarding swallowing disorders, the corresponding population attributable fraction (%) of the incidence of total dependence in basic daily living activities was 50.4%. The current findings demonstrated that swallowing disorders were associated with greater risk of functional decline in basic daily living activities among older adults living at home and receiving home nursing care. Maintenance and improvement of swallowing function may prevent late-life functional decline.

High-Resolution Detection of Translocation of Oral Bacteria to the Gut.

Ectopic enrichment of oral microbes in the gut is a notable alteration in gut microbial balance. These microbes are likely delivered from the oral cavity with saliva and food; however, evidence of oral-gut microbial transmission is insufficient and needs further investigation. In this observational study, we examined 144 pairs of saliva and stool samples collected from community-dwelling adults to verify the oral-gut microbial link and identify the relevant influencing factors on the increased abundance of oral microbes within the gut. The bacterial composition of each sample was determined using PacBio single-molecule long-read sequencing of the full-length 16S ribosomal RNA gene and amplicon sequence variant (ASV) analysis. Although the bacterial compositions of salivary and gut microbiota were distinctly different, at least 1 ASV was shared between salivary and gut microbiota in 72.9% of subjects. Shared ASVs accounted for 0.0% to 63.1% (median 0.14%) of the gut microbiota in each subject and frequently included abundant Streptococcus salivarius and Streptococcus parasanguinis. Their total relative abundance in the gut was significantly higher in older subjects or those with dental plaque accumulation. The gut microbiota with ≥5% of shared ASVs displayed a higher abundance of Streptococcus, Lactobacillus, and Klebsiella and a lower abundance of Faecalibacterium, Blautia, Megamonas, and Parabacteroides. Our study presents evidence for the translocation of oral bacteria to the gut in community-dwelling adults and suggests that aging and dental plaque accumulation contribute to an increased abundance of oral microbes in the gut, which might be relevant to the compositional shift in the gut commensals.

Effect of exposure to non-esterified fatty acid on progressive deterioration of insulin secretion in patients with Type 2 diabetes: a long-term follow-up study.

AIM: The aim of the study was to determine whether fasting serum non-esterified fatty acid (NEFA) could be associated with long-term progressive deterioration of insulin secretion in patients with Type 2 diabetes. METHODS: Seventy-seven Japanese patients with Type 2 diabetes (mean BMI 23.3 kg/m(2) ) were followed for 10 years. We measured fasting C-peptide level every 1-2 years. By using the slope of regression line between fasting C-peptide level and duration, we calculated its individual annual decline as an index of insulin secretion. During the follow-up periods of C-peptide, the patients were evaluated for fasting serum non-esterified fatty acid, LDL cholesterol, HDL cholesterol and HbA(1c) levels for the last 8 years. We excluded patients who had renal dysfunction or anti-insulin antibodies from among the insulin-treated patients. Association between the individual annual decline of fasting C-peptide level and related factors were evaluated. RESULTS: The mean individual annual decline of fasting serum C-peptide level was -0.013 ± 0.027 nmol/l/year. Fasting serum non-esterified fatty acid level had no significant difference between the first and the last 2 years of the 8-year observation period of non-esterified fatty acid. Using multiple regression analysis, mean fasting serum non-esterified fatty acid level was associated with the individual annual decline of fasting serum C-peptide level (standardized regression coefficient -0.358, P=0.0056), although other related factors, including HbA(1c) level, were not associated. CONCLUSIONS: Mean fasting serum non-esterified fatty acid level during an 8-year observation was independently associated with long-term progressive deterioration of insulin secretion in Japanese patients with Type 2 diabetes.

Molecular characterization of fungal populations on the tongue dorsum of institutionalized elderly adults.

OBJECTIVES: To characterize the global composition of oral fungal populations in frail elderly adults and to investigate the relationship with their health status. MATERIALS AND METHODS: We investigated the fungal populations on the tongue dorsum in 291 institutionalized elderly adults by molecular PCR-based techniques using internal transcribed spacer regions of nuclear ribosomal DNA. RESULTS: Quantitative PCR analysis showed that fungi were present on the tongue dorsum of 128 subjects at ≥10(4) CFU per sample, and 35 of them exceeded 10(5) CFU per sample. Length heterogeneity-PCR analysis and nucleotide sequence determinations showed that Candida albicans was most frequently detected in those subjects with fungi at ≥10(4) CFU per sample (105 subjects), followed by Candida dubliniensis (78), Malassezia restricta (57), and Candida tropicalis (45). Statistical analysis revealed that those subjects with ≥10(5) CFU of fungi other than C. albicans per sample had an increased risk of fever (≥7 febrile days per 12 months) compared with subjects with <10(5) CFU per sample, after adjustment for other fever-associated confounding factors. CONCLUSIONS: These data demonstrate that the oral cavity of the elderly is inhabited by a diverse array of fungi not limited to typical Candida species and they suggest that the diversity in distribution is associated with health status.

Relationship between periodontal condition and arterial properties in an adult population in Japan.

UNLABELLED: Oral Diseases (2010) 16, 781-787 OBJECTIVE: This study addressed the relationship between periodontal condition and second derivative of the finger photoplethysmogram (SDPTG) in Japanese adults. SUBJECT AND METHODS: The Community Periodontal Index (CPI) and SDPTG were recorded in 415 subjects (mean age: 44.0 years). For assessing SDPTG, we mainly focused on the ratio of the absolute value of the height of the early negative 'b' wave and ratio of the late re-decreasing 'd' wave to the height of the initial positive 'a' wave, namely the b/a and d/a ratios. RESULTS: The CPI score was positively correlated with the b/a ratio (P < 0.001), and negatively correlated with the d/a ratio (P < 0.001). Logistic regression analysis showed that subjects with CPI scores ≥ 3 were more likely to have a higher level (male > -0.69, female > -0.64) of b/a ratio (Odds ratio = 1.7, P = 0.026) and lower level (male ≤ -0.29, female ≤ -0.32) of d/a ratio (Odds ratio = 2.2, P =0.001) than those with CPI scores 0-2, after adjusting for age, gender, smoking status, pulse rate and presence of hypertension. CONCLUSION: There was a statistical association between the CPI scores and SDPTG indices in Japanese adults.

Relation of dietary preference to bite force and occlusal contact area in Japanese children.

The purpose of this study was to examine the relationship of dietary preference to bite force and occlusal contact area in Japanese elementary school children. A total of 348 children, aged 7-12 years, from two public elementary schools located in Okayama Prefecture, Japan, participated in the study. Clinical examination included decayed, missing and filled teeth (dmft and DMFT), and total numbers of deciduous and permanent teeth. Bite force and occlusal contact area were measured using a pressure-detecting sheet. Dietary preference was assessed using a questionnaire in which the answers were given in like/dislike form. Mann-Whitney U-test and multiple logistic regression analysis were applied to analyse the data. In multiple logistic regression analysis after adjustment for age, gender and total number of teeth present, children who liked cabbage and celery showed significantly higher bite force (P = 0.05 and P < 0.01, respectively) than those who disliked these. Children who liked cabbage and celery also showed higher occlusal contact area (P < 0.05 and P < 0.01, respectively) than those who disliked these. The Japanese elementary school children who liked hard foods such as cabbage and celery showed higher bite force and higher occlusal contact area than those who disliked these foods. A positive attitude towards harder food items might contribute to healthy development of the masticatory apparatus.

Periodontitis Is Associated with Chronic Obstructive Pulmonary Disease.

Although they are known to share pathophysiological processes, the relationship between periodontitis and chronic obstructive pulmonary disease (COPD) is not fully understood. The aim of the present study was to test the hypothesis that periodontitis is associated with a greater risk of development of COPD, when smoking is taken into account. The analysis in a 5-y follow-up population-based cohort study was based on 900 community-dwelling Japanese adults (age: 68.8 ± 6.3 [mean ± SD], 46.0% male) without COPD aged 60 or older with at least 1 tooth. Participants were classified into 3 categories according to baseline periodontitis severity (no/mild, moderate, and severe). COPD was spirometrically determined by a fixed ratio of <0.7 for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and by FEV1/FVC below the lower limit of normal. Poisson regression was used to calculate the relative risk (RR) of developing COPD according to the severity of periodontitis. The population attributable fraction (PAF) was also calculated. During follow-up, 22 (2.4%) subjects developed COPD. Compared with no/mild periodontitis subjects, a significantly increased risk of COPD occurred among severe periodontitis subjects (RR = 3.55; 95% confidence interval [CI], 1.18 to 10.67), but no significant differences were observed between the no/mild and moderate categories (RR = 1.48; 95% CI, 0.56 to 3.90). After adjustment for potential confounders, including smoking intensity, the relationship between severe periodontitis and risk of COPD remained significant (RR = 3.51; 95% CI, 1.15 to 10.74). Likewise, there was a positive association of periodontitis severity with risk of COPD ( P for trend = 0.043). The PAF for COPD due to periodontitis was 22.6%. These data highlight the potential importance of periodontitis as a risk factor for COPD.

Cell transplantation: differential effects of myoblasts and mesenchymal stem cells.

BACKGROUND: Cellular transplantation has emerged as a novel therapeutic option for treatment of ventricular dysfunction. Both skeletal myoblasts (SM) and mesenchymal stem cells (MSC) have been proposed as ideal cell for this aim. The aim of this study is to compare the efficacy of these cells in improving ventricular function and to evaluate the different histological findings in a rat model of severe post-infarct ventricular dysfunction. METHODS: Myocardial infarction was induced in Wistar rats by left coronary occlusion. Animals with resulting ejection fraction (EF) lower than 40% were included. Heterologous SM were obtained by lower limb muscle biopsy and MSC by bone marrow aspiration. Nine days after infarction, rats received intramyocardial injection of SM (n=8), MSC (n=8) or culture medium, as control (n=11). Echocardiographic evaluation was performed at baseline and after 1 month. Histological evaluation was performed after HE and Gomori's trichrome staining and immunostainig against desmin, fast myosin and factor VIII. RESULTS: There was no difference in baseline EF and left ventricular end diastolic (LVEDV) and systolic volume (LVESV) between all groups. After 1 month a decrease was observed in the EF in the control group (27.0+/-7.10% to 21.46+/-5.96%, p=0.005) while the EF markedly improved in SM group (22.66+/-7.29% to 29.40+/-7.01%, p=0.04) and remained unchanged in the MSC group (23.88+/-8.44% to 23.63+/-10.28%, p=0.94). Histopathology identified new muscular fibers in the group that received SM and new vessels and endothelial cells in the MSC. CONCLUSION: Skeletal myoblasts transplantation resulted in myogenesis and improvement of ventricular function. In contrast, treatment with mesenchymal stem cells resulted in neoangiogenesis and no functional effect.

Minor segmental wall motion abnormalities detected in patients with Chagas' disease have adverse prognostic implications.

Recent data from our laboratory have shown that patients with the indeterminate form of Chagas' disease can have impairment of left ventricular contractility, as evaluated by the slope of the left ventricle end-systolic pressure-dimension relationship. We also showed that Chagas' disease patients with minimal baseline wall motion abnormalities detected by two-dimensional echocardiography have more intense contractility impairment when compared to patients with the indeterminate form of the disease without this abnormality. The prognostic implications of these findings have not been established. We evaluated 59 patients (37-76 years, mean = 55 years) with different clinical forms of Chagas' disease, who had normal left ventricular global systolic function at baseline (57.6 +/- 6.9%) and who had at least one additional echo during clinical follow-up (0.4-17.6; mean 4.6 years). Group 1 consisted of 14 patients with minor baseline left ventricle wall motion abnormalities and group 2 consisted of 45 patients without these abnormalities. During follow-up, global left ventricle systolic function deterioration was observed in 10 group 1 patients (71.4%) and in only 10 group 2 patients (22.2%; P < 0.005). Age and duration of follow-up were not independent determinants of left ventricular function deterioration in these patients. The present data indicate that mild segmental left ventricular wall motion abnormalities are associated with worsening of systolic function in Chagas' disease patients who have normal baseline global systolic performance.

Cell transplantation after the coculture of skeletal myoblasts and mesenchymal stem cells in the regeneration of the myocardium scar: an experimental study in rats.

UNLABELLED: In myocardial infarction and Chagas's disease, some physiopathological aspects are common: cardiomyocyte loss due to ischemia leads to a reduction of contractility and heart function. Different cells have been proposed for cellular cardiomioplasty. OBJECTIVE: Our goal was to evaluate the method of co-culture of skeletal muscle (SM) and mesenchymal stem cells (MSC) for cell therapy of heart failure in Chagas's disease (CD) and myocardium postinfarction (MI). METHODS: For MI, 39 rats completed the study at 1 month. Seventeen rats received cell therapy into the scar and 22 rats only medium. For CD, 15 rats completed the study at 1 month including 7 that received cell therapy and eight followed the natural evolution. All animals underwent ecocardiographic analysis at baseline and 1 month. Left ventricular, ejection fraction, end systolic, and end dyastolic volume were registered and analyzed by ANOVA. The co-culture method of SM and MSC was performed at 14 days (DMEM, with 15% FCS, 1% antibiotic, IGF-I, dexamethasone). Standard stain analysis was performed. RESULTS: For MI ejection fraction in the animals that received the co-cultured cells increased from 23.52+/-8.67 to 31.45+/-8.87 (P=.006) versus the results in the control group: 26.68+/-6.92 to 22.32+/-6.94 (P=.004). For CD, ejection fraction in animals that received the co-cultured cells increased from 31.10+/-5.78 to 53.37+/-5.84 (P<.001) versus the control group values of 36.21+/-3.70 to 38.19+/-7.03 (P=0.426). Histopathological analysis of the animals receiving co-cultured cells demonstrated the presence of myogenesis and angiogenesis. CONCLUSION: The results validated the product of SM and MSC co-cultures for treatment of diseases.

Bilateral primary choroidal melanoma treated with bilateral plaque radiotherapy: a report of three cases.

PURPOSE: To report three cases of bilateral primary choroidal melanoma treated with bilateral plaque radiotherapy. METHODS: Retrospective, single-center case series. RESULTS: Case 1: In 1981, a 50-year-old man was diagnosed with a 5-mm-thick choroidal melanoma in the right eye (OD) and treated with plaque radiotherapy. In 1994, a 6.8-mm-thick choroidal melanoma in the left eye (OS) was treated with plaque radiotherapy. Final visual acuity was light perception OD and 20/20 OS at 24 years follow-up. Case 2: In 1983, a 53-year-old woman was diagnosed with a 3.5-mm-thick choroidal melanoma OS and treated with plaque radiotherapy. In 2001, an enlarging 2.5-mm-thick choroidal melanoma OD was treated with plaque radiotherapy. Final visual acuity was 20/30 OD and 20/20 OS at 22 years follow-up. Case 3: In 2001, a 92-year-old man was diagnosed with a 7.9-mm-thick choroidal melanoma OD treated with plaque radiotherapy. In 2003, an enlarging 2.8-mm-thick juxtapapillary choroidal melanoma was treated with plaque radiotherapy. Final visual acuity was 20/70 OD and 20/60 OS at 2.5 years follow-up. No patient showed ocular melanocytosis. Stable tumor regression was achieved in all six eyes. Metastatic disease did not develop in any case over 16 years of follow-up. CONCLUSIONS: Monitoring of both eyes of patients with uveal melanoma is important for the remote possibility of melanoma in the second eye. In these three patients, plaque radiotherapy allowed for preservation of the globes and some vision.

Swallowing Function and Nutritional Status in Japanese Elderly People Receiving Home-care Services: A 1-year Longitudinal Study.

OBJECTIVES: Malnutrition is a serious health concern for frail elderly people. Poor oral function leading to insufficient food intake can contribute to the development of malnutrition. In the present study, we explored the longitudinal association of malnutrition with oral function, including oral health status and swallowing function, in elderly people receiving home nursing care. DESIGN: Prospective observational cohort study with 1-year follow-up. SETTING: Two mid-sized cities in Fukuoka, Japan from November 2010 to March 2012. PARTICIPANTS: One hundred and ninety-seven individuals, aged ≥ 60 years, living at home and receiving home-care services because of physical disabilities, without malnutrition. MEASUREMENTS: Oral health status, swallowing function, taking modified-texture diets such as minced or pureed foods, nutritional status, cognitive function, and activities of daily living were assessed at baseline. The associations between malnutrition at 1-year follow-up and these related factors were analyzed using a logistic regression model. RESULTS: Swallowing disorders [risk ratio (RR): 5.21, 95% confidence interval (95% CI): 1.65-16.43] were associated with malnutrition. On the other hand, oral health status did not have a direct association with malnutrition. CONCLUSION: Swallowing disorders may be associated with the incidence of malnutrition in elderly people receiving home-care. The findings indicate that maintaining swallowing function may contribute to the prevention of malnutrition in frail elderly people.

Association of the prohormone convertase 2 gene (PCSK2) on chromosome 20 with NIDDM in Japanese subjects.

Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3. PC2 is a type II proinsulin-processing enzyme, and it cleaves the proinsulin molecule on the COOH-terminal side of dibasic peptide, Lys64-Arg65, which joins the C-peptide and the A-chain domains. We have previously cloned and characterized the exon-intron organization of the human PC2 gene (gene symbol PCSK2), localized this gene to human chromosome 20 band p11.2 by fluorescence in situ hybridization, and identified a simple tandem-repeat DNA polymorphism (STRP) in intron 2 of the form (CA)n, suitable for genetic studies. Since non-insulin-dependent diabetes mellitus (NIDDM) is associated with increased secretion of proinsulin and proinsulin-like molecules, we conducted a case-control study to determine whether a genetic variation in PCSK2 might contribute to the development of NIDDM. The study population consisted of 152 Japanese NIDDM subjects and 102 normal healthy nondiabetic control subjects matched for age and body mass index. The subjects were genotyped at the STRP in intron 2, and the results indicated a significant difference (P = 0.004) in the overall allele frequency distribution between the two groups. The A1 allele was found more frequently in NIDDM than in nondiabetic subjects (11 vs. 4%, P = 0.0068). The NIDDM patients were divided into two subgroups according to the presence or absence of the A1 allele.(ABSTRACT TRUNCATED AT 250 WORDS)

The prohormone convertase enzyme 2 (PC2) is essential for processing pro-islet amyloid polypeptide at the NH2-terminal cleavage site.

Impaired processing of pro-islet amyloid polypeptide (proIAPP), the precursor of the beta-cell peptide islet amyloid polypeptide (IAPP) (amylin), has been implicated in islet amyloid formation in type 2 diabetes. The prohormone convertase enzymes PC3 (also known as PC1) and PC2 are localized to beta-cell secretory granules with proIAPP and proinsulin and are responsible for proinsulin processing. To determine whether PC2 might be essential for proIAPP processing, we performed Western blot analysis of freshly isolated islets from normal mice and mice lacking active PC2. As expected, the primary species of IAPP immunoreactivity in islets from wild-type mice was fully processed (4-kDa) IAPP, with only small amounts of the 8-kDa precursor (unprocessed proIAPP) present. Islets from heterozygous PC2 null mice were identical to wild-type animals, suggesting that half the normal complement of PC2 is sufficient for normal proIAPP processing. By contrast, in islets from homozygous PC2 null mice, the predominant IAPP-immunoreactive form was of intermediate size (approximately 6 kDa), with no detectable mature IAPP and slightly elevated amounts of the 8-kDa precursor form present. Thus, in the absence of PC2, proIAPP processing appears to be blocked at the level of a proIAPP conversion intermediate. Immunofluorescence of pancreas sections and immunoblotting using antisera raised to the NH2- and COOH-terminal flanking regions of mouse proIAPP demonstrated that the 6-kDa intermediate form was an NH2-terminally extended proIAPP conversion intermediate (processed only at the COOH-terminus). These data indicate that PC2 is essential for processing of proIAPP at the NH2-terminal cleavage site in vivo and that PC3 is likely only capable of processing proIAPP at the COOH-terminal cleavage site.

Homeostasis model assessment is a reliable indicator of insulin resistance during follow-up of patients with type 2 diabetes.

OBJECTIVE: To investigate the usefulness of the homeostasis model assessment as an index of insulin resistance (HOMA-IR) for evaluating the clinical course of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The usefulness of HOMA-IR and its relationship with insulin resistance assessed by the hyperinsulinemic-euglycemic clamp study (clamp IR) were evaluated in 55 Japanese patients with type 2 diabetes before and after treatment. The patients were subjected to diet (approximately 1,440-1,720 kcal/day) and exercise therapy (walking 10,000 steps daily) for 6 weeks during their hospitalization. RESULTS: Univariate regression analysis disclosed a significant correlation between log-transformed HOMA-IR and log-transformed clamp IR before (r = -0.613, P < 0.0001) and after ( = -0.734, P < 0.0001) treatment. Neither the slopes (-0.71 +/- 0.12 vs. -0.79 +/- 0.09, F = 0.25, P = 0.61) nor the intercepts (y-intercept = 1.67 vs. 1.70, x-intercept = 2.36 vs. 2.15, F = 0.02, P = 0.88) of the regression lines between HOMA-IR and clamp IR were significantly different before and after treatment. There was a significant correlation between the decrease in log-transformed HOMA-IR and the increase in clamp IR during treatment (r = -0.617, P < 0.0001). CONCLUSIONS: HOMA-IR may constitute a useful method not only for diagnosing insulin resistance, but also for follow-up during the treatment of patients with type 2 diabetes.

Cancer whole-genome sequencing: present and future.

Recent explosive advances in next-generation sequencing technology and computational approaches to massive data enable us to analyze a number of cancer genome profiles by whole-genome sequencing (WGS). To explore cancer genomic alterations and their diversity comprehensively, global and local cancer genome-sequencing projects, including ICGC and TCGA, have been analyzing many types of cancer genomes mainly by exome sequencing. However, there is limited information on somatic mutations in non-coding regions including untranslated regions, introns, regulatory elements and non-coding RNAs, and rearrangements, sometimes producing fusion genes, and pathogen detection in cancer genomes remain widely unexplored. WGS approaches can detect these unexplored mutations, as well as coding mutations and somatic copy number alterations, and help us to better understand the whole landscape of cancer genomes and elucidate functions of these unexplored genomic regions. Analysis of cancer genomes using the present WGS platforms is still primitive and there are substantial improvements to be made in sequencing technologies, informatics and computer resources. Taking account of the extreme diversity of cancer genomes and phenotype, it is also required to analyze much more WGS data and integrate these with multi-omics data, functional data and clinical-pathological data in a large number of sample sets to interpret them more fully and efficiently.

Prognosis of uveal melanoma based on race in 8100 patients: The 2015 Doyne Lecture.

A retrospective, nonrandomized, interventional case series of 8100 patients with uveal melanoma were evaluated for melanoma-related metastasis based on patient race. The patient race was Caucasian (n=7918, 98%), Hispanic (n=105, 1%), Asian (n=44, <1%), or African American (n=33, <1%). On the basis of race (Caucasian, Hispanic, Asian, and African American), significant differences were noted in mean age at presentation (58, 48, 44, and 52 years; P<0.001), distance of posterior tumor margin to foveola (5, 5, 6, and 4 mm; P<0.001), distance of posterior tumor margin to optic disc (5, 5, 6, and 4 mm) (P<0.001), tumor base (11, 12, 12, and 13 mm; P<0.001), tumor thickness (5.4, 7.1, 6.5, and 7.5 mm; P<0.001), intraocular hemorrhage (10, 14, 11, and 24%; P=0.02), and rupture of Bruch's membrane (20, 27, 39, and 36%; P=0.001). On the basis of multivariate analysis, the rate of metastasis increased with increasing age (P<0.001), ciliary body location (P<0.001), increasing tumor base (P<0.001), increasing tumor thickness (P<0.001), pigmented tumor (P=0.001), subretinal fluid (P=0.001), intraocular hemorrhage (P=0.045), and extraocular extension (P=0.036). Kaplan-Meier estimates of metastasis at 3, 5, and 10 were 8, 15, and 25% in Caucasians; 13, 13, and 13% in Hispanics; 4, 4, and 36% in Asians; and 8, 8, and 8% in African Americans. Compared with Caucasians, despite relative risk for metastasis of 0.31 for African Americans, 0.73 for Hispanics, and 1.42 for Asians, there was no statistical difference in metastasis, or death from uveal melanoma based on race. In summary, uveal melanoma showed similar prognosis for all races.

Abrogation of protein convertase 2 activity results in delayed islet cell differentiation and maturation, increased alpha-cell proliferation, and islet neogenesis.

To date, the role of pancreatic hormones in pancreatic islet growth and differentiation is poorly understood. To address this issue, we examined mice with a disruption in the gene encoding prohormone convertase 2 (PC2). These mice are unable to process proglucagon, prosomatostatin, and other neuroendocrine precursors into mature hormones. Initiation of insulin (IN) expression during development was delayed in PC2 mutant mice. Cells containing IN were first detected in knockout embryos on d 15 of development, 5 d later than in wild-type littermates. However, the IN(+) cells of d 15 PC2 mutant mice coexpressed glucagon, as did the first appearing beta-cells of controls. In addition, lack of PC2 perturbed the pattern of expression of transcription factors presumed to be involved in the determination of the mature alpha-cell phenotype. Thus, in contrast to controls, alpha-cells of mutant mice had protracted expression of Nkx 6.1 and Pdx-1, but did not express Brn-4. Islets of adult mutant mice also contained cells coexpressing insulin and somatostatin, an immature cell type found only in islets of the wild-type strain during development. In addition to the effects on islet cell differentiation, the absence of PC2 activity resulted in a 3-fold increase in the rate of proliferation of proglucagon cells during the perinatal period. This increase contributed to the development of alpha-cell hyperplasia during postnatal life. Furthermore, the total beta-cell volume was increased 2-fold in adult mutants compared with controls. This increase was due to islet neogenesis, as the number of islets per section was significantly higher in knockout mice compared with wild-type mice, whereas both strains had similar rates of IN cell proliferation. These results indicate that hormones processed by PC2 affected processes that regulate islet cell differentiation and maturation in embryos and adults.