Predictor of buckwheat allergy in children based on challenge test results: a retrospective observational study in Japan.

Summary: Background. Buckwheat (BW) is a major food allergen and one of the leading causes of food-induced anaphylaxis in Japan. The standard method of diagnosing food allergy is the oral food challenge (OFC). The BW-specific IgE (BW-sIgE) value is used to assess BW allergy but its utility is limited. Aim. The aim of the present study was to identify factors with predictive value for the diagnosis of BW allergy using the OFC. Methods. We evaluated 37 patients who were classified into the positive or negative group according to their OFC results. Results. Ten patients (27.0%) showed objective or persistent, moderate, subjective symptoms during the OFC. The positive group had a significantly higher BW-sIgE/total IgE ratio than the negative group (p less than 0.001), but the total IgE (p = 0.139) and BW-sIgE (p = 0.130) did not differ significantly. Receiver operator characteristic (ROC) analysis showed that the BW-sIgE/total IgE ratio had a larger area under the curve (AUC, 0.885) than BW-sIgE (AUC, 0.667). The statistically optimal cut-off was 0.0058 for the BW-sIgE/total IgE ratio, which corresponded to a clinical sensitivity and specificity of 90.0% and 81.5%, respectively. Conclusions. BW-sIgE/total IgE ratio may be more useful predictor of BW OFC results than BWs-IgE.

NWChem: Past, present, and future.

Specialized computational chemistry packages have permanently reshaped the landscape of chemical and materials science by providing tools to support and guide experimental efforts and for the prediction of atomistic and electronic properties. In this regard, electronic structure packages have played a special role by using first-principle-driven methodologies to model complex chemical and materials processes. Over the past few decades, the rapid development of computing technologies and the tremendous increase in computational power have offered a unique chance to study complex transformations using sophisticated and predictive many-body techniques that describe correlated behavior of electrons in molecular and condensed phase systems at different levels of theory. In enabling these simulations, novel parallel algorithms have been able to take advantage of computational resources to address the polynomial scaling of electronic structure methods. In this paper, we briefly review the NWChem computational chemistry suite, including its history, design principles, parallel tools, current capabilities, outreach, and outlook.

Pioglitazone treatment and cardiovascular event and death in subjects with type 2 diabetes without established cardiovascular disease (JDDM 36).

AIMS: The protective association of pioglitazone with cardiovascular events and death was investigated over 6-years in large-scale type 2 diabetic subjects without established cardiovascular disease in a primary care setting. METHODS: A six-year observational cohort study including 2864 subjects with type 2 diabetes without established cardiovascular disease was performed. The primary endpoint was a composite of first occurrence of cardiovascular disease or death. The effect of pioglitazone use at a baseline year with a Cox proportional hazard model and the time-dependent use in each one-year examination interval with a pooled logistic regression model were analyzed. RESULTS: Baseline use of pioglitazone (n=493) did not show a statistically protective effect on the primary endpoint (n=175), although it tended to reduce the risk (adjusted hazard ratio 0.67 [95% CI: 0.43-1.05]). However, pooled logistic regression analysis indicated a significant protective association of pioglitazone with the primary endpoint (0.58 [0.38 to 0.87] and cardiovascular disease (0.54 [0.33-0.88]), independent of concurrent levels of blood glucose, blood pressure, lipids, albuminuria, and renal function. In particular, this protective association was observed in those with diabetic nephropathy regardless of the daily dose of pioglitazone. Among a total of 898 subjects who took pioglitazone during the period, 43% experienced a discontinuation at least once; however, serious adverse effects were rare. CONCLUSIONS: This observational study indicated a protective association of pioglitazone with cardiovascular disease and death in type 2 diabetic subjects without established vascular disease, particularly those with nephropathy.

Effects of extracellular DNA and DNA-binding protein on the development of a Streptococcus intermedius biofilm.

AIMS: The aim of this study was to clarify the effects of homologous and heterologous extracellular DNAs (eDNAs) and histone-like DNA-binding protein (HLP) on Streptococcus intermedius biofilm development and rigidity. METHODS AND RESULTS: Formed biofilm mass was measured with 0·1% crystal violet staining method and observed with a scanning electron microscope. The localizations of eDNA and extracellular HLP (eHLP) in formed biofilm were detected by staining with 7-hydoxyl-9H-(1,3-dichloro-9,9-dimethylacridin-2-one) and anti-HLP antibody without fixation, respectively. DNase I treatment (200 U ml(-1)) markedly decreased biofilm formation and cell density in biofilms. Colocalization of eHLP and eDNA in biofilm was confirmed. The addition of eDNA (up to 1 µg ml(-1)) purified from Strep. intermedius, other Gram-positive bacteria, Gram-negative bacteria, or human KB cells into the Strep. intermedius culture increased the biofilm mass of all tested strains of Strep. intermedius, wild-type, HLP-downregulated strain and control strains. In contrast, the addition of eDNA (>1 µg ml(-1)) decreased the biofilm mass of all Strep. intermedius strains. CONCLUSIONS: These findings demonstrated that eDNA and eHLP play crucial roles in biofilm development and its rigidity. SIGNIFICANCE AND IMPACT OF THE STUDY: eDNA- and HLP-targeting strategies may be applicable to novel treatments for bacterial biofilm-related infectious diseases.

Bactericidal activity and oral pathogen inactivation by electromagnetic wave irradiation.

AIMS: The aim of this work was to clarify the effects of electromagnetic wave irradiation (EMWI) on oral bacterial pathogens. METHODS AND RESULTS: A Gram-negative (Porphyromonas gingivalis) or Gram-positive (Streptococcus mutans, S. intermedius, Enterococcus faecalis) bacterial suspension was irradiated by EMW apparatus (500-1000 kHz, 5-15 times, 1 s time(-1) ). Quantification of survival bacteria by CFU counting revealed that EMWI exhibited marked bactericidal activity against all tested bacteria and bactericidal activity at 500 kHz increased in an irradiation number-dependent manner. After EMWI at 500 kHz, scanning electron microscopic observations showed that the chain of S. mutans cells was shortened after 5 irradiations and the outlines of bacterial cells (S. mutans and P. gingivalis) were unclear after 5-10 irradiations. EMWI inhibited the inductive effect of S. mutans on pro-inflammatory cytokine production in human monocytes and this inhibitory effect was comparable with that of heat-killed bacteria. Furthermore, using an enzyme activity assay, EMWI partially inactivated the activities of gingipains from P. gingivalis. CONCLUSIONS: These findings demonstrated that EMWI has inactivation and bactericidal activities against single microbial species among four kinds of oral pathogens. SIGNIFICANCE AND IMPACT OF THE STUDY: Electromagnetic wave irradiation may be applicable for medical disinfection and sterilization, such as refractory periapical periodontitis.

Chronic kidney disease categories and renal-cardiovascular outcomes in type 2 diabetes without prevalent cardiovascular disease: a prospective cohort study (JDDM25).

AIMS/HYPOTHESIS: In type 2 diabetic patients at low risk for cardiovascular disease (CVD), the relationship between the clinical course of nephropathy by stage of chronic kidney disease (CKD) and onset of CVD remains unclear. Clarification of this relationship is important for clinical decision-making for both low- and high-risk diabetic patients. METHODS: This 4 year prospective study enrolled 2,954 type 2 diabetic patients with no prevalent CVD, and serum creatinine <176.8 µmol/l. The risk for CVD onset (non-fatal and fatal CVD and stroke, and peripheral arterial disease) was assessed according to CKD stage categorised by urinary albumin-to-creatinine ratio (ACR; mg/mmol) and estimated GFR (eGFR; ml min(-1) 1.73 m(-2)). Association of progression from 'no CKD' stage (ACR <3.5 mg/mmol and eGFR ≥ 90 ml min(-1) 1.73 m(-2)) with risk for CVD onset was also evaluated. RESULTS: During follow-up (median 3.8 years), 89 CVD events occurred. Compared with patients with 'no CKD' as reference, those with ACR ≥ 35.0 mg/mmol with co-existing eGFR 60-89 ml min(-1) 1.73 m(-2) or <60 ml min(-1) 1.73 m(-2) showed increased risk for CVD onset, whereas those with eGFR ≥ 90 ml min(-1) 1.73 m(-2) did not. Those with ACR <3.5 mg/mmol and eGFR <60 ml min(-1) 1.73 m(-2) did not show any increased risk. Among patients with 'no CKD' stage at baseline, those who progressed to ACR ≥ 3.5 mg/mmol during follow-up showed an increased risk compared with those who did not, whereas those who progressed to eGFR <90 ml min(-1) 1.73 m(-2) did not have increased risk. CONCLUSIONS/INTERPRETATION: The risk for CVD was associated with progression of albuminuria stage rather than eGFR stage in type 2 diabetic patients at relatively low risk for CVD.

Low incidence of cardiovascular events in Japanese patients with Type 2 diabetes in primary care settings: a prospective cohort study (JDDM 20).

AIMS: To investigate whether a reduced incidence of cardiovascular disease in Type 2 diabetes can be achieved in a newly recruited cohort following the recently advanced concept of multifactorial treatment and followed in primary care settings as compared with earlier cohorts. METHODS: A prospective study was performed in primary care settings at multiple clinics nationwide in the Japan Diabetes Clinical Data Management (JDDM) study group. Subjects were 2984 patients with Type 2 diabetes without prevalent cardiovascular disease. The main outcome measure was the first event of non-fatal or fatal coronary heart disease, ischaemic stroke or peripheral artery disease, and the incidence was compared with other representative cohorts. RESULTS: There were 90 cardiovascular events over 10,827 person-years of follow-up with a dropout rate of 6%. The incidences (per 1000 person-years, 95% confidence interval) of composite, coronary heart disease, ischaemic stroke and peripheral artery disease in the JDDM study were 8.3 (6.6-10.0), 4.4 (3.2-5.6), 3.1 (2.1-4.2), and 0.7 (0.2-1.2), respectively. Each incidence was lowest in the JDDM study compared with other cohorts (P < 0.01 vs. each cohort). In the JDDM study, significant variables predictive of the occurrence of a cardiovascular event were age, duration of diabetes, HbA(1c), HDL cholesterol and urinary albumin. CONCLUSION: The novel finding of low cardiovascular disease occurrence in this study may be conferred by the feasibility at primary care settings for providing patients with Type 2 diabetes with favourable control of blood glucose, blood pressure and lipids, coupled with unique ethnicity/country factors.

In vivo detection of amyloid ß deposition using ¹9F magnetic resonance imaging with a ¹9F-containing curcumin derivative in a mouse model of Alzheimer's disease.

Amyloid ß (Aß) deposition in the brain is considered the initiating event in the progression of Alzheimer's disease (AD). Amyloid imaging is widely studied in diagnosing AD and evaluating the disease stage, with considerable advances achieved in recent years. We have developed a novel ¹9F-containing curcumin derivative (named FMeC1) as a potential imaging agent. This compound can exist in equilibrium between keto and enol tautomers, with the enol form able to bind Aß aggregates while the keto form cannot. This study investigated whether FMeC1 is suitable as a ¹9F magnetic resonance imaging (MRI) probe to detect Aß deposition in the Tg2576 mouse, a model of AD. In ¹9F nuclear magnetic resonance (NMR) spectra obtained from the whole head, a delayed decreased rate of F ¹9F signal was observed in Tg2576 mice that were peripherally injected with FMeC1 in comparison to wild-type mice. Furthermore, ¹9F MRI displayed remarkable levels of ¹9F signal in the brain of Tg2576 mice after the injection of FMeC1. Histological analysis of FMeC1-injected mouse brain showed penetration of the compound across the blood-brain barrier and binding to Aß plaques in peripherally injected Tg2576 mice. Moreover, the distribution of Aß deposits in Tg2576 mice was in accordance with the region of the brain in which the ¹9F signal was imaged. FMeC1 also exhibited an affinity for senile plaques in human brain sections. These findings suggest the usefulness of FMeC1 as a ¹9F MRI probe for the detection of amyloid deposition in the brain. Furthermore, the properties of FMeC1 could form the basis for further novel amyloid imaging probes.

Association of increased reactive oxygen species production with abdominal obesity in type 2 diabetes.

OBJECTIVE: The close relationship between oxidative stress and abdominal obesity is well known, but the association is unclear in diabetic patients. The aim of this study was to confirm that increased reactive oxygen species (ROS) production is associated with abdominal obesity in diabetic patients. METHODS: ROS production was assayed in Epstein-Barr virus-transformed immortalized lymphoblasts by means of a cypridina luciferin analogue chemiluminescence method. We divided 96 Japanese male diabetic patients into 2 groups: patients with abdominal obesity according to the accepted Japanese criteria (waist circumference is more than 85 cm) (group AO, n = 36); and patients without abdominal obesity (group N, n = 60). Subjects with body mass index (BMI) in the normal range (21 ≤ BMI < 25 kg/m(2)) were then selected and assigned to 2 subgroups (group AOnormal-BMI [n = 13]; and group Nnormal-BMI [n = 35]); ROS production was compared between these 2 subgroups. RESULTS: Stimulation with arachidonic acid (AA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) increased ROS production in lymphoblasts, which was more greatly elevated in lymphoblasts derived from group AO than those from group N. Even in the subjects with normal BMI, AA- and TPA-stimulated ROS production in group AO was significantly higher than that in group N. CONCLUSIONS: These data suggest that increased ROS production is more closely associated with abdominal obesity than high BMI or insulin resistance in diabetic patients.

Influence of BMI, Age and duration of diabetes mellitus on glycaemic control with twice-daily injections of biphasic insulin aspart 30 versus multiple daily injections of insulin aspart (JDDM 18): retrospective reanalysis of a 6-month, randomized, open-label, multicentre trial in Japan.

BACKGROUND AND OBJECTIVE: Good glycaemic control in patients with diabetes mellitus often requires insulin supplementation therapy. Recent developments of analogue insulin and premixed formulations have increased the therapeutic options for patients who need such therapy. This study aimed to retrospectively clarify appropriate treatment regimens according to age, body mass index (BMI) and duration of diabetes in Japanese patients with type 2 diabetes previously entered in an open-label, randomized trial that compared convenience-oriented biphasic insulin aspart 30 versus multiple injections of insulin aspart with or without NPH insulin. METHODS: Japanese insulin-naïve patients were randomized to receive either biphasic insulin aspart 30 twice daily or insulin aspart three times daily with or without multiple injections of NPH insulin for a treatment period lasting 6 months. RESULTS: Reduction of glycosylated haemoglobin (HbA(1c)) at the end of 6 months was not different in the two treatment groups irrespective of BMI, age and duration of diabetes. However, the achievement rate of HbA(1c) <7.0% was significantly higher in patients with a BMI <25 kg/m2 in the multiple-injection group and tended to be higher in patients with a diabetes duration <10 years in the twice-daily injection group. CONCLUSION: Twice-daily injections of biphasic insulin aspart 30 may be more suitable for obese patients whereas multiple injections of insulin aspart with or without NPH insulin may be preferable for those with a longer duration of diabetes.

Roles of TLR2, TLR4, NOD2, and NOD1 in pulp fibroblasts.

Pulp fibroblasts express various pro-inflammatory mediators leading to marked infiltration of inflammatory cells in the progression of pulpitis. We hypothesized that pulp fibroblasts play roles in the recognition of invaded caries-related bacteria and the subsequent innate immune responses. We found clear expressions of TLR2, NOD1, and NOD2 and a faint expression of TLR4 in human dental pulp fibroblasts (HDPF) by RT-PCR and flow cytometry. We also observed that various pro-inflammatory mediators, including cytokines, chemokines, adhesion molecules, prostaglandin E(2) and its key enzyme COX-2, not iNOS or caspase-1, were markedly up-regulated by stimulation with these TLR and NOD agonists. More over, the NOD2 agonist acted synergistically with the TLR2, not the TLR4, agonist to stimulate the production of pro-inflammatory mediators in HDPF. These findings indicate that TLR2, TLR4, NOD2, and NOD1 in HDPF are functional receptors, and NOD2 is a modulator of signals transmitted through TLR2 in pulpal immune responses, leading to progressive pulpitis.

Periodic metallo-dielectric structure in diamond.

Intense ultrashort light pulses induce three dimensional localized phase transformation of diamond. Photoinduced amorphous structures have electrical conducting properties of a maximum of 64 S/m based on a localized transition from sp(3) to sp(2) in diamond. The laser parameters of fluence and scanning speed affect the resultant electrical conductivities due to recrystallization and multi-filamentation phenomena. We demonstrate that the laser-processed diamond with the periodic cylinder arrays have the characteristic transmission properties in terahertz region, which are good agreement with theoretical calculations. The fabricated periodic structures act as metallo-dielectric photonic crystal.

Differences in clinical course between dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND AND PURPOSE: To investigate whether there may be differences in the clinical course and changes in cognitive progression between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). METHODS: We compared the time from the first visit to endpoints (discontinuation of visits because of admission, death, or institutionalization) between 56 patients with DLB and 111 patients with AD. Mini-Mental State Examination (MMSE) scores of patients were every 12 months examined up to 60 months. RESULTS: Dementia with Lewy bodies had a significantly shorter time to reaching endpoints than those with AD (median time; 40 months vs. 52 months, P < 0.0001). The proportion of admission (or death) was significantly higher in DLB than in AD (30% vs. 14%, P < 0.05), while the difference in institutionalization in nursing homes did not reach statistical significance (25% vs. 17%). Rates of longitudinal MMSE score decline for DLB and AD groups were equivalent. CONCLUSION: Dementia with Lewy bodies had a greater risk of admission (or death) because of most commonly fall-related injuries and bronchopneumonia than AD, but the two groups did not differ in rate of cognitive decline.

Attenuated radial augmentation index is associated with successful long-term antihypertensive treatment.

Pulse wave analysis was performed in apparently normal volunteers (n=164) and in essentially hypertensive patients without cardiovascular complications (n=171) using a newly developed non-invasive pulse wave measurement device (HEM-9010AI). Our results suggest that early wave reflections measured by radial augmentation index (AIr) are enhanced in volunteers with systolic blood pressure (SBP) >or= 160 mm Hg compared with the volunteers with their SBP<160 mmHg (98+/-18 vs 88+/-12, P<0.05). Furthermore, AIr is lower in hypertensive patients with long-term antihypertensive treatment than in those with short-term treatment (84+/-10 vs 89+/-13, P<0.01).

Caries-related bacteria and cytokines induce CXCL10 in dental pulp.

UNLABELLED: Marked infiltration of inflammatory cells, such as activated T-cells, is observed in the progression of pulpitis; however, little is known about the mechanism of their recruitment into pulpal lesions. It has been recently demonstrated that CXC chemokine ligand 10 (CXCL10) chemoattracts CXC chemokine receptor 3 (CXCR3)-positive activated T-cells. We therefore examined whether CXCL10 is involved in the pathogenesis of pulpitis. CXCL10 mRNA expression levels in clinically inflamed dental pulp were higher than those in healthy dental pulp. Immunostaining results revealed that CXCL10 was detected in macrophages, endothelial cells, and fibroblasts in inflamed dental pulp, and that CXCR3 expression was observed mainly on T-cells. Moreover, cultured dental pulp fibroblasts produced CXCL10 after stimulation with live caries-related bacteria, peptidoglycans, and pro-inflammatory cytokines. In contrast, heat-killed bacteria did not induce CXCL10 secretion. These findings suggest that CXCL10-CXCR3 may play an important role in the pulpal immune response to caries-related bacterial invasion. ABBREVIATIONS: CXCL10, CXC chemokine ligand 10; CXCR3, CXC chemokine receptor 3; IFN, interferon; FBS, fetal bovine serum; LTA, lipoteichoic acid; PGN, peptidoglycan; IL, interleukin; TNF, tumor necrosis factor; PBS, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay; CCL, C-C chemokine ligand; TLR, Toll-like receptor; NOD, nucleotide oligomerization domain; HDPF, human dental pulp fibroblasts.

Deep gray matter hyperperfusion with occipital hypoperfusion in dementia with Lewy bodies.

Although decreased occipital perfusion is a characteristic feature of dementia with Lewy bodies (DLB), not all patients with DLB show a significant decreased perfusion in the occipital lobe. We explored characteristics of perfusion changes to improve the identification of DLB, in addition to occipital hypoperfusion. Statistical image analysis of single photon emission computed tomography data was performed on 22 patients with DLB and 25 patients with Alzheimer's disease (AD). A significant decreased perfusion in the occipital lobe was found in 16 patients with DLB (72%) and three patients with AD (12%), while a significant increased perfusion in the deep gray matter (striatum and/or thalamus) was found in 18 patients with DLB (81%) and eight patients with AD (31%), respectively. Either occipital hypoperfusion or deep gray matter hyperperfusion was found in 21 patients with DLB (95%), while in nine patients with AD (35%), indicating a sensitivity of 95% and a specificity of 65% in discriminating DLB from AD. Our results suggest that the addition of deep gray matter hyperperfusion to occipital hypoperfusion may be useful in the clinical differentiation of DLB and AD.

Time and cost involved in the care of newly registered patients with diabetes mellitus and other lifestyle diseases at diabetes clinics in Japan (JDDM 4).

AIMS: To study the time and cost involved in the care of newly registered outpatients with Type 2 diabetes mellitus (DM), compared with patients with hypertension and/or hyperlipidaemia (HTL). METHODS: A total of 313 patients with DM and 58 patients with HTL without diabetes were registered on their first visits to 11 diabetes clinics across Japan. The time and cost involved in their care was recorded over the following 5 months. RESULTS: In the first 3 months, there was an extensive time commitment to both groups. The time spent by physicians was 1.5 times longer for DM than for HTL. The total care time spent by all the care providers for DM was twice that for HTL. The cost of DM care was twice that for HTL, with the cost of medicines excluded. However, half of the cost for DM was for laboratory tests. When these were excluded, and the remaining cost divided by the time spent, the amount for DM was half of that for HTL. Over the 5 months, mean glycated haemoglobin (HbA(1c)) in DM patients improved from 8.0% to 6.5%, and 72% of DM patients achieved the glycaemic target of HbA(1c) < or = 6.5%. CONCLUSIONS: DM care in a diabetes clinic requires a great deal more time and resources than HTL to achieve the best outcome. An educational system for self care, presently lacking in the primary care setting in Japan, would improve glycaemic control for DM patients in the community.