Decreased peripheral perfusion measured by perfusion index is a novel indicator for cardiovascular death in patients with type 2 diabetes and established cardiovascular disease.

Cardiovascular disease (CVD) is still the major cause of mortality in patients with type 2 diabetes. Despite of recent therapies, mortality and resources spent on healthcare due to CVD is still important problem. Thus, appropriate markers are needed to predict poor outcomes. Therefore, we investigated the role of peripheral perfusion as an indicator for cardiovascular death in patients with type 2 diabetes and established CVD. This retrospective cohort study included 1080 patients with type 2 diabetes and history of CVD recruited from the outpatient clinic at Matsushita Memorial Hospital in Osaka, Japan. Peripheral perfusion is assessed using the perfusion index (PI), which represents the level of circulation through peripheral tissues. The median age and PI values were 74 years (range: 67-79 years) and 2.6% (range: 1.1-4.3%), respectively. During follow-up duration, 60 patients died due to CVD. The adjusted Cox regression analysis demonstrated that the risk of developing cardiovascular death was higher in the first quartile (Hazard ratio, 6.23; 95% CI, 2.28 to 22.12) or second quartile (Hazard ratio, 3.04; 95% CI, 1.46 to 6.85) of PI than that in the highest quartile (fourth quartile) of PI. PI (per 1% decrease) was associated with the development of cardiovascular death (Hazard ratio, 1.39; 95% CI, 1.16 to 1.68). PI could be a novel indicator of cardiovascular death in patients with type 2 diabetes and established CVD.

Peripheral perfusion, measured by perfusion index, is a novel indicator for renal events in patients with type 2 diabetes mellitus.

Diabetic kidney disease (DKD) is one of the leading causes of end stage renal disease. Despite recent therapies, mortality due to DKD and resources spent on healthcare are important problems. Thus, appropriate markers are needed to predict renal outcomes. Therefore, we investigated the role of peripheral perfusion as an indicator for renal events in patients with type 2 diabetes mellitus. This retrospective cohort study included 566 patients who were admitted to Matsushita Memorial Hospital in Osaka, Japan for type 2 diabetes mellitus. Peripheral perfusion was assessed using perfusion index (PI), which represents the level of circulation through peripheral tissues and was measured on each toe using a Masimo SET Radical-7 (Masimo Corporation, Irvine, CA, USA) instrument. The duration of follow up was 3.0 years. The median age of patients was 70 years (IQR range: 61-77 years) and median PI value was 2.9% (IQR range: 1.8-4.8%). Multiple logistic regression analyses showed that PI (per 1% increase) was associated with an odds ratio of composite of end-stage renal disease (ESRD) and/or doubling of serum creatinine level; n = 40 (odds ratio 0.823 [95% CI: 0.680-0.970]), and composite of ESRD, doubling of serum creatinine level, and renal death and/or cardiovascular death; n = 44 (odds ratio 0.803 [95% CI: 0.665-0.944]). The factors which were statistically significant in univariate analysis and those known to be related factors for renal event were considered simultaneously as independent variables for multiple logistic regression analysis. PI can be a novel indicator for renal events in patients with type 2 diabetes mellitus.

Decreased microcirculatory function measured by perfusion index is predictive of cardiovascular death.

BACKGROUND: The importance of microcirculation for adverse outcomes in the early phase of critical illnesses has been reported. Microcirculatory function is assessed using the perfusion index (PI), which represents the level of circulation through peripheral tissues. We investigated the correlation between PI and cardiovascular death to explore whether it can serve as a predictor of cardiovascular death. METHODS AND RESULTS: This retrospective study included 2171 patients admitted to Matsushita Memorial Hospital in Osaka, Japan, for medical treatment. We measured PI for all patients. To examine the effects of PI on cardiovascular death, a Cox proportional hazard model was used. The median age and PI values were 72 years (range 63-79 years) and 2.7% (range 1.4-4.6%), respectively. During the 3927.7 person-years follow-up period, a total of 54 patients died due to cardiovascular disease. PI was positively correlated with BMI (P < 0.0001) and total cholesterol levels (P = 0.004). PI was negatively correlated with age (P < 0.0001), heart rate (P < 0.0001), and creatinine levels (P < 0.0001). Adjusted Cox regression analyses demonstrated that PI was associated with an increased hazard of cardiovascular death (hazard ratio 0.84; 95% CI; range 0.72-0.99). In addition, compared with patients with a high PI (> 3.7%), those with a low PI (≤ 2.0%) had a significantly increased risk of cardiovascular death. This low PI group had a hazard ratio of 3.49 (95% CI 1.73-7.82). CONCLUSIONS: The PI is a valuable predictor for cardiovascular death in a clinical setting.

Decreased microcirculatory function measured by perfusion index is a novel indicator of diabetic kidney disease in patients with type 2 diabetes.

AIMS/INTRODUCTION: Diabetic kidney disease has been considered as an important risk factor of cardiovascular disease. Chronic hypoxia is considered to be the main cause of renal injury. Diminished microcirculatory blood flow could be associated with hypoxia in the kidney. Whether diminished microcirculation is associated with diabetic kidney disease has not yet been reported. Here, we investigated the correlation between microcirculatory function and diabetic kidney disease in patients with type 2 diabetes. MATERIALS AND METHODS: Our cross-sectional study included 574 patients who were admitted to Matsushita Memorial Hospital in Moriguchi, Japan, for type 2 diabetes. Microcirculatory function was assessed using the perfusion index (PI), which represents the level of circulation through peripheral tissues. We measured the PI for all patients. RESULTS: The median age and PI values were 70 years (range 60-77 years) and 2.8% (range 1.6-4.8%). Multiple regression analyses showed that the PI independently correlated with the logarithm of urinary albumin excretion (P = 0.009) and estimated glomerular filtration rate (P = 0.005), respectively. Multiple logistic regression analyses showed that patients with systolic blood pressure (SBP) greater than the median and PI less than or equal to the median (high-low group) had a significantly increased odds of albuminuria compared with those with SBP less than or equal to the median and PI greater than the median (low-high group), and patients with SBP greater than the median and PI less than or equal to the median (high-low group) had a significantly increased odds of estimated glomerular filtration rate <60 mL/min per 1.73 m2 compared with those with SBP less than or equal to the median and PI greater than the median (low-high group) or SBP greater than the median and PI greater than the median (high-high group). CONCLUSIONS: PI could be a novel indicator of diabetic kidney disease in patients with type 2 diabetes.

Plasmon-mediated chemical transformation from alkane to alkene on a silver nanoparticle array under 532 nm excitation.

Surface-enhanced Raman scattering (SERS) spectra of organic compounds, para-methylthiophenol (p-MT), decylamine and 1-butanethiol (1-BT), were measured using a two-dimensional silver nanoparticle array at 532 nm excitation. For p-MT, it was observed that Raman peaks grew at 1580 and 1690 cm-1, which were never observed in the normal Raman spectrum, indicating oxidation from the methyl to carboxyl group. For both decylamine and 1-BT, an intensive SERS peak grew at 1580 cm-1. We measured the time-resolved SERS spectra of 1-BT at the laser intensity of 185 W mm-2 and confirmed that the spectral shapes changed as the total exposure increased. Another SERS peak was also observed at 3050 cm-1 for decylamine and 1-BT. From these results, it was considered that unsaturated bonds were formed in the alkanes, meaning that alkenes were produced from alkanes. Additionally, the SERS spectrum revealed that the chemically transformed alkane possesses a methyl group. The result indicates that dehydrogenation preferentially occurs at the secondary carbons, which is consistent with the stability of radicals on carbon atoms. The laser intensity threshold for plasmon-mediated chemical transformation was experimentally observed to be 2.7 and 40 W mm-2 for p-MT and 1-BT, respectively. The higher laser intensity is necessary for oxidation of alkanes compared with aromatic compounds, which is consistent with the chemical stability of organic compounds.

The perfusion index is a useful screening tool for peripheral artery disease.

The number of people with peripheral artery disease (PAD) has been increasing globally; therefore, it is important to explore more options to screen patients who are at a risk of developing PAD. The perfusion index (PI) represents the degree of circulation through the peripheral tissues and is measured noninvasively. We investigated the correlation between the PI and ankle-brachial index (ABI) to explore whether the PI could be used a screening tool for PAD. This cross-sectional study included 390 patients. We measured the ABI and PI for all patients. The median ABI value was 1.06 (0.92-1.13); the PI was 1.7% (0.9-3.5). The PI was higher in men than in women (P < 0.0001). The PI was positively correlated with the estimated glomerular filtration rate and ABI in both men and women. The sensitivity and specificity of the PI to predict PAD (ABI ≤0.9) were 90.0% and 80.3%, respectively, and the cutoff PI value was 1.5% in men. The sensitivity and specificity of the PI to predict PAD were 82.1% and 79.2%, respectively, and the cutoff PI value was 1.1% in women. PI could be a reliable screening tool for diagnosing PAD because it does not restrict the patient's mobility, can be completed in a short time period, and is associated with reduced costs.

Alogliptin plus voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension.

OBJECTIVE: To compare the efficacy and safety of alogliptin and placebo as add-on therapy in Japanese patients with type 2 diabetes who experienced inadequate glycemic control on voglibose plus diet/exercise therapy. RESEARCH DESIGN AND METHODS: During an 8 week screening phase, patients aged ≥ 20 years were stabilized on voglibose 0.2 mg three times daily plus diet/exercise therapy. Those with HbA1c between ≥ 6.9% and <10.4% were randomly assigned to 12 weeks' double-blind treatment with once daily alogliptin 12.5 or 25 mg, or placebo. The primary endpoint was the change in HbA1c at 12 weeks from baseline. Patients then entered an open-label, 40 week extension trial (patients in the placebo group were randomly allocated to alogliptin 12.5 or 25 mg). CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov ; pivotal trial NCT01263483; Long term trial NCT01263509. RESULTS: Least square mean change in HbA1c after 12 weeks' therapy from baseline (primary endpoint) was significantly greater in the alogliptin 12.5 mg (-0.96%; P < 0.0001) and 25 mg (-0.93%; P < 0.0001) groups compared with placebo (+0.06%). This was associated with statistically significant improvements in other measures of glycemic control, in particular sustained reductions in fasting plasma glucose and postprandial plasma glucose. These benefits were maintained for the duration of the 1 year study and, importantly, they were achieved without detrimental effects on tolerability/safety. In particular, there was no increase in the rate of hypoglycemia and almost no changes in mean body weight. CONCLUSIONS: Addition of once daily alogliptin to voglibose monotherapy in Japanese patients with uncontrolled type 2 diabetes produced clinically significant improvements in glycemic control, and was well tolerated.

Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study.

OBJECTIVE: To compare the efficacy and safety of different dosages of alogliptin with that of placebo and voglibose in drug-naïve Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. RESEARCH DESIGN AND METHODS: In the double-blind, placebo-controlled phase of this two-part study, 480 patients aged ≥20 years with type 2 diabetes mellitus (HbA1c ≥6.9% to <10.4%) were randomized to monotherapy with alogliptin 6.25, 12.5, 25 or 50 mg once daily, placebo, or voglibose 0.2 mg three times daily for a period of 12 weeks. In a subsequent open-label, long-term extension phase, patients continued on the same treatment for an additional 40 weeks (patients in the placebo group were reassigned equally to one of the four alogliptin dosages). MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change in HbA1c from the baseline value at week 12 of treatment. Safety endpoints were the occurrence of adverse events, vital sign measurements, physical examination and ECG findings, and laboratory test results recorded over the entire 52-week period. RESULTS: HbA1c was dose-dependently reduced by alogliptin, and the changes versus baseline were statistically significant with all four dosages in comparison with both placebo and voglibose. In addition, changes in fasting plasma glucose and postprandial plasma glucose AUC(0-2h) values were significantly greater with all four dosages of alogliptin in comparison with placebo. The incidence of adverse events with alogliptin over 52 weeks was not dose-dependent and was lower than with voglibose. Hypoglycemia occurred infrequently and was generally rated as mild. Changes in body weight with alogliptin were minimal (<0.5 kg) and not clinically meaningful. CONCLUSIONS: Alogliptin was well tolerated and dose-dependently improved glycemic parameters in patients with type 2 diabetes inadequately controlled on diet and exercise.

Is the importance of achieving stable disease different between epidermal growth factor receptor tyrosine kinase inhibitors and cytotoxic agents in the second-line setting for advanced non-small cell lung cancer?

BACKGROUND: It is controversial whether achieving stable disease leads to a survival benefit and whether the importance of achieving stable disease differs between cytotoxic agents and molecular targeted agents. To examine these questions, the authors retrospectively reviewed phase II and III studies in the second-line setting for advanced non-small cell lung cancer using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and cytotoxic agents separately. METHODS: The authors chose 45 trials for the chemotherapy group and nine for the EGFR TKI group by searching the PubMed database. All nine trials in the EGFR TKI group concern gefitinib and erlotinib. RESULTS: The median survival time increased 0.0375 month with each 1% increase in stable disease rate (p = 0.039), and each 1% increase in response rate resulted in 0.0744 (p < 0.001) month of median survival time in the analysis combined with both cytotoxic agents and EGFR TKIs. Main and interaction terms for EGFR TKI treatment were not statistically significant. With respect to time to progression, only response rate showed a statistically significant relationship with survival. CONCLUSIONS: To obtain response seems to be more important than to achieve stable disease for both cytotoxic agents and EGFR TKIs, although achieving stable disease is still valuable. The relationship between survival and response or stable disease appears similar for cytotoxic agents and EGFR TKIs.

Asymmetric desymmetrization based on an intramolecular haloetherification: a highly effective and recyclable chiral nonracemic auxiliary, 2-exo-methyl-3-endo-phenyl-5-norbornene-2-carboxaldehyde, for meso-1,3- and meso-1,4-diols.

A new chiral auxiliary, a 3-endo-phenyl norbornene aldehyde derivative, which is a crystalline, very stable, and easily handled, was developed for the desymmetrization of meso-1,3- and meso-1,4-diols. The key step of the method, an intramolecular bromoetherification, proceeded in a highly diastereoselective manner. A four-step sequence, 1) acetalization, 2) intramolecular bromoetherification followed by acid hydrolysis, 3) protection of the alcohol, and 4) retrobromoetherification, transformed the meso-diols into optically active derivatives. The 3-endo-phenyl norbornene aldehyde derivative was simultaneously reformed and could be used repeatedly. This is the first chemical example of a single auxiliary that is applicable for highly enantioselective desymmetrization of meso-1,3- and meso-1,4-diols; to the best of our knowledge, this is the best chemical method available for the desymmetrization of meso-1,4-diols.

[Explicit memory for type font of words in source monitoring and recognition tasks].

We investigated whether people can consciously remember type fonts of words by methods of examining explicit memory; source-monitoring and old/new-recognition. We set matched, non-matched, and non-studied conditions between the study and the test words using two kinds of type fonts; Gothic and MARU. After studying words in one way of encoding, semantic or physical, subjects in a source-monitoring task made a three way discrimination between new words, Gothic words, and MARU words (Exp. 1). Subjects in an old/new-recognition task indicated whether test words were previously presented or not (Exp. 2). We compared the source judgments with old/new recognition data. As a result, these data showed conscious recollection for type font of words on the source monitoring task and dissociation between source monitoring and old/new recognition performance.

[Self-reference effect in an independence/remember-know procedure].

The self-reference effect was examined using the IRK (independence/remember-know, Jacoby, 1998) procedure. In the learning phase, participants were asked to rate trait words in one of the three ways of encoding: self-reference, semantic, and physical. In the test phase, they were told to use a word-stem as a cue to recall studied words, if they could not recall, to complete stems with the first word that came to mind. Furthermore, participants were to classify the completed words into those they "remembered," those they "knew," or "new." Estimates derived from the IRK procedure showed the self-reference effect only for the intentional memory (i.e., the "remembered" items), but not for the automatic memory. Results suggested that the self-reference effect is due to intentional use of memory.

Kinetically controlled optical resolution of racemic norbornene aldehyde derivatives.

A new method for obtaining optically pure 5-norbornene 2-endo-aldehyde derivatives was developed. The reaction of a diastereomeric mixture of the ene acetals 2 and 2', derived from racemic norbornene aldehydes (+/-)-1 and chiral nonracemic (S,S)-hydrobenzoin 7, with NBS (0.5-0.6 eq.) in the presence of H(2)O proceeded in a kinetically controlled manner to give the optically pure hydroxy aldehydes 3 along with the intact ene acetals 2'. Both compounds 3 and 2' were converted into the optically pure norbornene aldehydes 1 and ent-1, respectively. This method opens the way to produce various types of 5-norbornene 2-endo-aldehydes with 3-exo- or 3-endo-substituents in optically pure forms.

[Working memory for movement patterns: a direct comparison of memory spans for body and hand movements in dual-task situations].

In this experiment, 36 participants engaged in one of three span tasks; digit span, body movement span, or hand movement span task, in which they were asked to remember visually presented sequences of digits, whole body movement patterns, or hand movement patterns, respectively. As in a standard memory span procedure, the items within each sequence were recalled in order. Participants were presented with increasingly longer sequences of the items, and span score was defined as the number of items in the longest sequence a participant could recall perfectly. The span tasks were tested under three concurrent task conditions; no concurrent task control, concurrent articulation task, and concurrent body-related movement task. The concurrent movement task interfered with performance on both body movement and hand movement span tasks, but not on the digit span task, while the concurrent articulation task interfered with performance on all of the three span tasks. It is suggested that memory for movement patterns, which is involved in the body and band movement spans, would be mediated by a common motor-processing system.

Efficient lipase-catalyzed enantioselective desymmetrization of prochiral 2,2-disubstituted 1,3-propanediols and meso 1,2-diols using 1-ethoxyvinyl 2-furoate.

An efficient lipase-catalyzed desymmetrization of prochiral 2,2-disubstituted 1,3-propanediols was developed using 1-ethoxyvinyl 2-furoate 1b, for which the well-known method using vinyl or isopropenyl acetate has had limited success due to low reactivity and easy racemization of the products through acyl group migration. The reagent 1b is highly reactive and converts various prochiral 1,3-diols to the monoesters having a chiral quaternary carbon center with 82-99% ee. These products were stable against racemization under acidic conditions, and their furoyl groups were compatible with oxidative conditions. Prolonging the reaction time led to the kinetic resolution of the monoesters resulting in an increase of their optical purity. The similar desymmetrization of meso cis-1,2-cycloalkanediols gave the monoesters with 82-97% ee without racemization.