Both hypo- and hyperglycaemia are associated with increased fracture risk in Japanese people with type 2 diabetes: the Fukuoka Diabetes Registry.

AIM: The impact of glycaemic control on fracture risk is controversial, which may be due to the possible presence of hypoglycaemia. The aim of this study was to separately investigate the impacts of severe hypoglycaemia and poor glycaemic control on fracture risk in people with type 2 diabetes. METHODS: Overall, 4706 Japanese participants (2755 men and 1951 postmenopausal women) with type 2 diabetes (mean age 66 years) were followed prospectively (a median of 5.3 years; follow-up rate, 97.6%), and were stratified by severe hypoglycaemia status and glycaemic control. The primary outcome was fractures at any anatomic site. RESULTS: Fractures occurred in 662 participants (249 men and 413 women). The age- and sex-adjusted incidence rates (expressed per 1000 person-years) were: 71.2 (multiple episodes of severe hypoglycaemia), 43.1 (one episode), 25.2 [HbA1c < 53 mmol/mol (< 7%) without severe hypoglycaemia], 28.7 [HbA1c 53 to < 64 mmol/mol (7% to < 8%) without severe hypoglycaemia], 27.7 [HbA1c 64 to < 75 mmol/mol (8% to < 9%) without severe hypoglycaemia] and 40.5 [HbA1c ≥ 75 mmol/mol (≥ 9%) without severe hypoglycaemia]. Multivariate-adjusted hazard ratios (95% confidence intervals) for fractures were 2.24 (1.56, 3.21) in those with multiple episodes of severe hypoglycaemia, and 1.42 (1.04, 1.95) in those with HbA1c ≥ 75 mmol/mol (≥ 9%) without severe hypoglycaemia, compared with those with HbA1c < 53 mmol/mol (< 7%) without severe hypoglycaemia. CONCLUSIONS: Both severe hypoglycaemia and poor glycaemic control were significantly related to an increased risk of fracture in people with type 2 diabetes, although severe hypoglycaemia conferred a stronger risk.

Association between eating rate and obesity: a systematic review and meta-analysis.

BACKGROUND: The association between eating rate and obesity has recently been reported. However, the findings remain inconclusive. OBJECTIVES: We undertook a systematic review with a meta-analysis of published epidemiological studies to provide a reliable close estimate of the association between eating rate and obesity. METHODS: A comprehensive search of MEDLINE, EMBASE and CINAHL was conducted to identify studies that reported quantitative estimates for indices of obesity based on the category of eating rate. Interventional studies or studies conducted using children as subjects were excluded. Two independent researchers extracted the data. A summary estimate was calculated using a random-effects model, and subgroup analyses were conducted to identify sources of heterogeneity. RESULTS: Data from 23 published studies were eligible for inclusion. The mean difference in body mass indices (BMIs) between individuals who ate quickly and those who ate slowly was 1.78 kg m(-2) (95% confidence interval (CI), 1.53-2.04 kg m(-2)). The pooled odds ratio of eating quickly on the presence of obesity was 2.15 (95% CI, 1.84-2.51). There was evidence of significant quantitative heterogeneity in the magnitudes of the association across studies (I2=78.4%, P-value for heterogeneity <0.001 for BMI, I2=71.9%, P-value for heterogeneity <0.001 for obesity), which may be partially explained by differences in the type of study population (a weaker association was observed for BMI in diabetic patients). CONCLUSIONS: Eating quickly is positively associated with excess body weight. Further studies are warranted to determine whether interventions to slow the speed of eating are effective for weight control.

Impact of eating rate on obesity and cardiovascular risk factors according to glucose tolerance status: the Fukuoka Diabetes Registry and the Hisayama Study.

AIMS/HYPOTHESIS: Medical nutrition therapy plays a critical role in the prevention and treatment of type 2 diabetes. However, appropriate measures of eating behaviours, such as eating rate, have not yet been clearly established. The aim of the present study was to examine the associations among eating rate, obesity and cardiovascular risk factors. METHODS: A total of 7,275 Japanese individuals aged ≥40 years who had normal fasting glucose levels, impaired fasting glucose or diabetes were divided into four groups according to self-reported eating rate: slow, medium, relatively fast and very fast. The associations between eating rate and various cardiovascular risk factors were investigated cross-sectionally. RESULTS: The proportions of participants who were obese or who had elevated waist circumference levels increased progressively with increases in eating rate (p for trend <0.001), regardless of glucose tolerance status. These associations remained significant after adjustment for potential confounders, namely, age, sex, total energy intake, dietary fibre intake, current smoking, current drinking and regular exercise (p for trend <0.001). Blood pressure and lipid levels also tended to increase in association with eating rate. HbA(1c) rose significantly as eating rate increased, even after multivariate adjustment, including BMI, in diabetic patients on insulin therapy (p = 0.02), whereas fasting plasma glucose did not increase significantly. CONCLUSIONS/INTERPRETATION: Our findings suggest that eating rate is associated with obesity and other cardiovascular risk factors and therefore may be a modifiable risk factor in the management of cardiovascular risk factors and diabetes.

An easily implemented method for abbreviation expansion for the medical domain in Japanese text. A preliminary study.

BACKGROUND: One of the barriers for the effective use of computerized health-care related text is the ambiguity of abbreviations. To date, the task of disambiguating abbreviations has been treated as a classification task based on surrounding words. Application of this framework for languages that have no word boundaries requires pre-processing to segment a sentence into separate word sequences. While the segmentation processing is often a source of problem, it is unknown whether word information is really requisite for abbreviation expansion. OBJECTIVES: The present study examined and compared abbreviation expansion methods with and without the incorporation of word information as a preliminary study. METHODS: We implemented two abbreviation expansion methods: 1) a morpheme-based method that relied on word information and therefore required pre-processing, and 2) a character-based method that relied on simple character information. We compared the expansion accuracies for these two methods using eight medical abbreviations. Experimental data were automatically built as a pseudo-annotated corpus using the Internet. RESULTS: As a result of the experiment, accuracies for the character-based method were from 0.890 to 0.942 while accuracies for the morpheme-based method were from 0.796 to 0.932. The character-based method significantly outperformed the morpheme-based method for three of the eight abbreviations (p < 0.05). For the remaining five abbreviations, no significant differences were found between the two methods. CONCLUSIONS: Character information may be a good alternative in terms of simplicity to morphological information for abbreviation expansion in English medical abbreviations appeared in Japanese texts on the Internet.

General asymmetric hydrogenation of hetero-aromatic ketones

trans-RuCl(2)[(R)-xylbinap][(R)-daipen] or the S,S complex acts as an efficient catalyst for asymmetric hydrogenation of hetero-aromatic ketones. The hydrogenation proceeds with a substrate-to-catalyst molar ratio of 1000-40000 to give chiral alcohols in high ee and high yield. The enantioselectivity appears to be little affected by the properties of the hetero-aromatic ring. This method allows for asymmetric synthesis of duloxetine, an inhibitor of serotonin and norepinephrine uptake carriers.

Selective hydrogenation of benzophenones to benzhydrols. Asymmetric synthesis of unsymmetrical diarylmethanols

[reaction: see text] trans-RuCl2[P(C6H4-4-CH3)3]2(NH2CH2CH2NH2) acts as a highly effective precatalyst for the hydrogenation of a variety of benzophenone derivatives to benzhydrols that proceeds smoothly at 8 atm and 23-35 degrees C in 2-propanol containing t-C4H9OK with a substrate/catalyst ratio of 2000-20000. Use of a BINAP/chiral diamine Ru complex effects asymmetric hydrogenation of various ortho-substituted benzophenones and benzoylferrocene to chiral diarylmethanols with consistently high ee.

Enantioresolution and absolute stereochemistry of omicron-substituted diphenylmethanols

omicron-Substituted diphenylmethanols were enantioresolved by the method of chiral dichlorophthalic acid amide, yielding enantiopure alcohols. Their absolute configurations were unambiguously determined by X-ray crystallography of chiral dichlorophthalate esters.

Localized expression of aromatase in human vascular tissues.

The atheroprotective effects of estrogen are well established and the presence of an estrogen receptor in vascular tissues has recently been reported. Therefore, we investigated the localization of the estrogen-producing enzyme aromatase in vascular tissues to assess the possible contribution of endocrine, paracrine, and autocrine modes of action. Aromatase was found in human vascular smooth muscle cells (SMCs) but not in endothelial cells on in situ hybridization. These observations were further supported by quantitative analysis of aromatase mRNA and the activity in 15 human vascular specimens. Only trace levels of expression were detected in the 3 infants examined, whereas 0.0088 to 0.0806 amol/ microg RNA of aromatase mRNA and 12.9 to 122.3 fmol. h-1. mg-1 protein of the activity were detected in 12 of the adult individuals. The switching of tissue-specific exon 1 of the human aromatase gene was also observed in some cases. Aromatase was found to be expressed only in cultured SMCs and not in cultured endothelial cells of human aorta and pulmonary artery and to be regulated through dexamethasone and the signaling pathways of protein kinase A and C. Study results revealed the localized expression of aromatase in vascular SMCs, which indicated a possible direct action of locally produced estrogen in an autocrine or paracrine manner, with possible cross talk between smooth muscle and endothelial cells.

[The classification and analysis of the blood pathway in left ventricular cavity observed by left ventricular contrast echocardiography].

We can observe and analyse the blood pathway in left ventricular cavity by contrast echocardiography using sonicated albumin, because it can be through the pulmonary capillaries. I. The observational classification of the blood pathway in left ventricular cavity. Group I: The contrast medium comes to the apex directly from the mitral orifice. Group II: The contrast medium comes to the apex along the posterior wall forming the spiral flow and turns back to the outflow tract. Group III: The contrast medium is found like a fireworks only at the apex. II. The factors associated with the blood pathway in left ventricular cavity. 1. Abnormality of left ventricular wall motion, 2. The form of left ventricular cavity, 3. Early diastolic peak velocity of the transmitral flow, 4. A/E, 5. Left ventricular function.

Major role of the CYP2C isozymes in deamination of amphetamine and benzphetamine: evidence for the quinidine-specific inhibition of the reactions catalysed by rabbit enzyme.

1. The cytochrome P450 isozymes involved in the deamination of amphetamine (AP) and benzphetamine (BZP) have been studied in liver microsomes from rabbit and rat using isozyme-specific inhibitors. 2. Metabolism of BZP in rat yielding phenylacetone and formaldehyde was moderately inhibited by testosterone and chloramphenicol. N-Debenzylation was thought to be P450-dependent, but all inhibitors except for a non-specific inhibitor, SKF-525A, failed to inhibit this reaction. 3. In rabbit, quinidine and testosterone were potent inhibitors of both BZP deamination and dealkylation. Deamination of AP in rabbit was extensively inhibited only with quinidine. 4. AP deamination with purified rabbit CYP2C3, which was previously identified as the major isozyme responsible for this metabolism, was extensively inhibited with quinidine, previously thought to be a specific inhibitor of CYP2D. 5. These results strongly support the notion that the CYP2C isozymes play a major role in the deamination of both AP and BZP, but not for N-debenzylation of BZP in rat. However, on the basis of different sensitivities toward inhibitors, multiple isozymes seem to be involved in BZP deaminations in both species.

Deamination of amphetamines by cytochromes P450: studies on substrate specificity and regioselectivity with microsomes and purified CYP2C subfamily isozymes.

Deamination or oxidative cleavage of the carbon-nitrogen bond in various phenylisopropylamines was examined in liver microsomes from rabbits and rats, and in reconstituted systems containing CYP2C subfamily isozymes. Kinetic studies of phenylacetone formation from six amphetamine (AP) derivatives, catalyzed by rabbit liver microsomes, indicated that AP had the highest apparent affinity (lowest K(m)) and increasing the size of the substituent on the nitrogen atom decreased the affinity. The values of maximal velocity increased with increasing size of the substituent. Experiments with purified CYP2C3 from rabbit liver gave similar results: this enzyme showed the highest activity for phenylacetone formation from benzphetamine (BZP) and showed lower activities with compounds having smaller nitrogen substituents. Based on these results, we conclude that among a series of AP derivatives, the parent phenylisopropylamine has the highest affinity for rabbit liver deaminase, where as BZP has the highest turnover. However, the intrinsic clearance (Vmax/K(m)) values for the individual reactions tended to be comparable. The rates of BZP and deprenyl N-demethylation by rat CYP2C11 and 2C13 were far greater than those of the reactions at other N-alpha-positions. This result indicated that rat CYP2C enzymes have a more rigid regioselectivity than rabbit CYP2C3 for the deamination/N-dealkylation of phenylisopropylamines.

Anti-vaccinia virus effect of M13 bacteriophage DNA.

Single-stranded DNA derived from M13 phage was evaluated for antiviral activity in mice infected with vaccinia virus. M13 DNA at a dose as low as 16.7 mg/kg was effective in reducing the number of tail lesions caused by vaccinia virus by more than 90%. A single administration of M13 DNA 1 day before infection was sufficient to reduce significantly the number of tail lesions caused by vaccinia virus. Denatured eukaryotic nucleic acids such as calf thymus DNA and human placenta DNA were not effective. A mixture of nucleotides prepared according to the nucleotides composition of M13 DNA was also ineffective. Within 4 h after the administration of M13 DNA, the serum interferon (IFN, predominantly type beta) titer rose from undetectable levels to as much as approximately 700 IU/ml. IFN was detectable for up to 12 h after the administration of M13 DNA. IFN titers as high as 1050 IU/ml were detected in vitro when M13 DNA was added to spleen cultures. We conclude that at least part of the antiviral activity of M13 DNA can be explained on the basis of IFN induction.

M13 bacteriophage DNA inhibits duck hepatitis B virus during acute infection.

We investigated effects of various DNAs on duck hepatitis B virus replication in vivo. One-day-old ducks were infected intravenously with DHBV. Various DNAs were then injected intravenously, and duck hepatitis B virus levels were followed for up to 20 days after the inoculation. When M13 bacteriophage DNA (M13 DNA), heat-denatured Escherichia coli DNA or phi X 174 phage DNA was injected intravenously at a dose of 2.45 mg/kg body wt daily for 10 days, a significant decrease of serum duck hepatitis B virus DNA was detected within 10 days. The efficacy was twice that reported with antisense DNA on a weight basis and far more than that reported on a molar basis. M13 DNA was superior, on the basis of effective dose, to acyclovir as an anti-duck hepatitis B virus agent. On treatment with M13 DNA, serum 2-5 A synthetase level was increased five to six times, suggesting that the antiviral effect of M13 DNA is at least partly due to induction of endogenous interferon, which in turn induces 2-5 A synthetase. No significant inhibitory effect on replication of duck hepatitis B virus was demonstrated by DNAs obtained from herring testes, herring sperm, salmon testes, human placenta or calf thymus. On discontinuation of M13 DNA injection on day 10, duck hepatitis B virus reappeared in the serum at later time points. Digestion of M13 DNA with S1 nuclease resulted in marked reduction of antiviral activity. These results show that M13 DNA, not its digested product, has potent antiviral activity.

Theoretical foundation on a noninvasive estimation for viscoelastic mechanical property of blood vessels by ultrasonic Doppler effect.

The method used in this paper is developed to estimate the degree of viscoelasticity of the blood vessel wall in a noninvasive mechanical method. In this proposed method, we can obtain an output waveform connected with mechanical behavior of blood vessels by using Ultrasonic Doppler Effect Sensory (UDES). Characterizing parameters on this waveform are established to estimate the mechanical properties of blood vessels. By analyzing the characteristics of these parameters, we attempt to estimate the viscoelastic property of blood vessels. Previously, it was found that these parameters are related to viscoelastic mechanical properties of materials. In this paper, we carried out computer analysis on the mechanical viscoelastic model and compared the theoretical behavior of blood vessels with the experimental output waveform by UDES. From these results, it was proved that values of these parameters connect with the change of the viscoelastic mechanical property of blood vessels. Therefore, the characterizing parameters of experimental output waveforms can be used to estimate the viscoelastic property of blood vessels in a noninvasive method.

Algorithm of the noninvasive diagnosis method on the atherosclerosis by ultrasonic Doppler effect.

Previously we proposed Acoustical Imaging and Processing Method to measure the viscoelastic property of the blood vessels of a canine and the related materials using Ultrasonic Doppler Effect Measurement. Furthermore, its theoretical foundation was presented. In this paper, this method is applied to measure the viscoelastic mechanical property, that is, the mechanical degradation of human blood vessels by a percutaneous noninvasive method. Based on these results, we proposed the algorithm of the noninvasive estimation method on the viscoelastic mechanical property of the blood vessel by using Doppler Effect Sensor. This method makes it possible to discriminate the blood vessel with arteriosclerosis from a normal blood vessel. Clinical applications were successfully performed using our developed computer software based on our proposed algorithm.

CAE software for the noninvasive diagnosis method on the atherosclerosis by ultrasonic Doppler effect.

Previously, we developed the noninvasive estimation method on the viscoelastic deterioration of the blood vessel and related materials by using Ultrasonic Doppler Effect Sensor and we presented its theoretical foundation. Furthermore, we applied this method to discriminate the human blood vessels with atherosclerosis from normal blood vessels, as the viscoelastic deterioration under in vitro condition and proposed the algorithm for its diagnosis. In the present paper, we propose the software for personal computer (AORTA) for clinical diagnosis on the atherosclerosis within a few minutes by using Ultrasonic Doppler Effect Sensor based on this algorithm. Using this software, we clinically applied this method to patients with atherosclerosis and normal people. It enables us to discriminate the atherosclerotic blood vessels from those of the normal blood vessel within several minutes. By using this system, it is found that the normal human blood vessel has elastic property. When the blood vessel becomes atherosclerotic, it deteriorates in elasticity and shows the viscoelastic property. This system evaluates noninvasively the viscoelastic property of the blood vessel and the degree of the atherosclerosis.

In vitro cytostatic effect of TNF (tumor necrosis factor) entrapped in immunoliposomes on cells normally insensitive to TNF.

The cytostatic activity of TNF entrapped in novel immunoliposomes with a specific antibody against target cells is described. A two step conjugation method was used for the preparation of these targeted immunoliposomes. In the first step, liposomes containing N-4-(p-maleimidophenyl)butyryl phosphatidylethanolamine (MPB-PE) were conjugated with a goat anti-mouse IgG Fab' fragment which recognizes the Fc portion of a mouse antibody against the target cell markers. In the second step, the mouse antibody against human tumor cells was conjugated to the liposomes. Using these targeted immunoliposomes, we demonstrated that cells usually insensitive to TNF such as Daudi cells, MT-2 cells and T-24 cells could become sensitive to TNF in vitro. The cytostatic activity of these immunoliposomes was blocked by the addition of a lysosomotropic agent such as NH4Cl or chloroquine. Significant uptake of 125I-TNF into T-24 cells was observed when these immunoliposomes were used, and this uptake of TNF was inhibited by cytochalasin B or chloroquine. Free 125I-TNF was not taken up by these cells.

Hybrid concept on the mechanical test method of small caliber blood vessel.

A mechanical test on small caliber blood vessel is difficult because the strength is very low and the dimension is very small. In the present paper a multifunctional axial test apparatus design is proposed. This has the characteristics such that the load cell and the environmental container for the specimen are built up in terms of cassette, respectively, and thus both are easy to equip and take off, that is, easy to replace. Also, the test methodology by internal pressure for small caliber blood vessels has been proposed. By using both of these methodologies, the characteristics of the mechanical behavior of small caliber blood vessels, such as compliance, stress relaxation, and viscoelastic property have been clarified. An attempt has been made on the application of this method to a clinical case.

A novel metabolite of strychnine, 22-hydroxystrychnine.

1. An unknown metabolite of strychnine termed M-5 was isolated, from an incubation mixture using guinea pig liver microsomes, by repeated preparative t.l.c. 2. The structure of M-5 was shown to be 22-hydroxystrychnine by mass, n.m.r. and i.r. spectrometry. 3. 22-Hydroxystrychnine is a stable enol, a unique metabolite possessing a hydroxyl group on the double bond of the alicylic moiety.