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In this study, we consider cross-sectional interaction models including spatial autoregressive models and peer effects models as special cases. Our model allows the endogenous effect – the effect of others’ outcomes on one’s own outcome – to be nonlinear and nonparametric. For the model estimation, we propose a sieve instrumental variable estimator and establish both its consistency and asymptotic normality. Furthermore, we propose a nonparametric specification test for the linearity of the endogenous effect. Under the null hypothesis of linearity, we show that the test statistic is asymptotically distributed as normal. As an empirical illustration, we focus on the data on regional economic performance investigated by Gennaioli et al. (2013). This empirical analysis highlights the usefulness of the proposed model and method.

This paper studies endogenous treatment effect models in which individuals are classified into unobserved groups based on heterogeneous treatment choice rules. Such heterogeneity may arise, for example, when multiple treatment eligibility criteria and different preference patterns exist. Using a finite mixture approach, we propose a marginal treatment effect (MTE) framework in which the treatment choice and outcome equations can be heterogeneous across groups. Under the availability of valid instrumental variables specific to each group, we show that the MTE for each group can be separately identified using the local instrumental variable method. Based on our identification result, we propose a two-step semiparametric procedure for estimating the group-wise MTE parameters. We first estimate the finite-mixture treatment choice model by a maximum likelihood method and then estimate the MTEs using a series approximation method. We prove that the proposed MTE estimator is consistent and asymptotically normally distributed. We illustrate the usefulness of the proposed method with an application to economic returns to college education.

In this paper, we consider the estimation of a continuous treatment effect model in the presence of treatment spillovers through social networks. We assume that one's outcome is affected not only by his/her own treatment but also by a (weighted) average of his/her neighbors' treatments, both of which are treated as endogenous variables. Using a control function approach with appropriate instrumental variables, in conjunction with some functional form restrictions, we show that the conditional mean potential outcome can be nonparametrically identified. We also consider a more empirically tractable semiparametric model and develop a three-step estimation procedure for this model. The consistency and asymptotic normality of the proposed estimator are established under certain regularity conditions. As an empirical illustration, we investigate the causal effect of the regional unemployment rate on the crime rate using Japanese city data.

Network formation is often characterized by homophily, i.e. the tendency of agents to connect with others who have similar attributes. However, while most agents are homophilous, others could be heterophilous; they aim to create ties with dissimilar agents. This study provides empirical evidence supporting this hypothesis by applying a random coefficient approach to data on the information‐sharing networks of small‐ and medium‐sized Vietnamese enterprises. In particular, we find that firms tend to form heterophilous links with respect to business type and gender ratio. One possible reason for the heterophily is that firms can obtain useful and performance‐improving information from such dissimilar partners.

In this study, we consider linear social interaction models under incomplete information that allow for missing outcome data due to sample selection. For model estimation, assuming that each individual forms his/her belief about the other members' outcomes based on rational expectations, we propose a two-step series nonlinear least squares estimator. Both the consistency and asymptotic normality of the estimator are established. As an empirical illustration, we apply the proposed model and method to National Longitudinal Study of Adolescent Health (Add Health) data to examine the impacts of friendship interactions on adolescents' academic achievements. We provide empirical evidence that the interaction effects are important determinants of grade point average and that controlling for sample selection bias has certain impacts on the estimation results. Supplementary materials for this paper are available online.

This study considers semiparametric spatial autoregressive models that allow for endogenous regressors, as well as the heterogenous effects of these regressors across spatial units. For the model e...

We empirically assess the treatment effects of a place-based policy in Japan and propose a socially desirable and practically feasible treatment assignment rule for the program. To account for heterogeneity of treatment effects, we estimate the conditional average treatment effect for each region using a marginal treatment effects framework and construct treatment rules based on regional characteristics such as demography, degree of suburbanization, and local production network. Our results indicate that targeting cities where the number of household cars and the share of the elderly population are moderate is the most appropriate for improving per-capita income and per-worker retail sales.

This study proposes a method to economically evaluate environmental quality using property auction data. Our approach is consistent with microeconomic auction theory and can directly estimate the value function from the data, a task that is often difficult when using conventional revealed preference methods such as the hedonic approach. We use a method of simulated moments to estimate the value function, which in turn is used to calculate the economic value of environmental quality changes. We apply this method to data on foreclosure property auctions in Tokyo in order to economically evaluate hypothetical improvements in neighborhood fire risks.

Objective Although insulin analogs have dramatically changed diabetes treatment, scarce evidence is available on those effects. We aimed to explore whether glycemic control had improved, the use of insulin analogs had been increased, and hypoglycemic events had decreased over time in Japanese pediatric patients with type 1 diabetes (T1D). Methods Glycated hemoglobin A1c (HbA1c) values, proportion of insulin regimens, incidence of severe hypoglycemic events, and pubertal increase in HbA1c were compared in three cohorts of childhood-onset Japanese T1D patients (567 subjects in the 1995 cohort, 754 subjects in the 2000 cohort, and 806 subjects in the 2008 cohort). Results Mean HbA1c values tended to decrease [78.5 mmol/mol (9.33%) in the 1995 cohort, 68.2 mmol/mol (8.39%) in the 2000 cohort, and 61.2 mmol/mol (7.75%) in the 2008 cohort; P

In this paper, we consider sieve instrumental variable quantile regression (IVQR) estimation of functional coefficient models where the coefficients of endogenous regressors are unknown functions of some exogenous covariates. We approximate the unknown functional coefficients by some basis functions and estimate them by the IVQR technique. We establish the uniform consistency and asymptotic normality of the estimators of the functional coefficients. Based on the sieve estimates, we propose a nonparametric specification test for the constancy of the functional coefficients, study its asymptotic properties under the null hypothesis, a sequence of local alternatives and global alternatives, and propose a wild-bootstrap procedure to obtain the bootstrap p-values. A set of Monte Carlo simulations are conducted to evaluate the finite sample behavior of both the estimator and test statistic. As an empirical illustration of our theoretical results, we present the estimation of quantile Engel curves.

Background Glycated albumin is an intermediate glycaemic control marker for which there are several measurement procedures with entirely different reference intervals. We have developed a reference measurement procedure for the purpose of standardizing glycated albumin measurements. Methods The isotope dilution liquid chromatography/tandem mass spectrometry method was developed as a reference measurement procedure for glycated albumin. The stable isotopes of lysine and fructosyl-lysine, which serve as an internal standard, were added to albumin isolated from serum, followed by hydrogenation. After hydrolysis of albumin with hot hydrochloric acid, the liberated lysine and fructosyl-lysine were measured by liquid chromatography/tandem mass spectrometry, and their concentrations were determined from each isotope ratio. The reference materials (JCCRM611) for determining of glycated albumin were prepared from pooled patient blood samples. Results The isotope dilution–tandem mass spectrometry calibration curve of fructosyl-lysine and lysine showed good linearity (r = 0.999). The inter-assay and intra-assay coefficient of variation values of glycated albumin measurement were 1.2 and 1.4%, respectively. The glycated albumin values of serum in patients with diabetes assessed through the use of this method showed a good relationship with routine measurement procedures (r = 0.997). The relationship of glycated albumin values of the reference material (JCCRM611) between these two methods was the same as the relationship with the patient serum samples. Conclusion The Committee on Diabetes Mellitus Indices of the Japan Society of Clinical Chemistry recommends the isotope dilution liquid chromatography/tandem mass spectrometry method as a reference measurement procedure, and JCCRM611 as a certified reference material for glycated albumin measurement. In addition, we recommend the traceability system for glycated albumin measurement.

In 2010, the Japan Diabetes Society decided to introduce the National Glycohemoglobin Standardization Program (NGSP) values into clinical practice. Accordingly, NGSP Certification of Japanese manufacturers of HbA1c-related diagnostic reagents and instruments was initiated in February, 2012, through an NGSP network laboratory, the Asian Secondary Reference Laboratory (ASRL) #1. Traceability to the NGSP reference system can be endorsed by manufacturer certification, as well as by the College of American Pathologists (CAP) survey. Nevertheless, only a few manufacturers participate in the CAP survey in Japan. Thus, proficiency testing (PT) was proposed and executed by ASRL #1. Single-donor whole-blood samples were used for the PT. The participated measurement systems were NGSP certified. Twenty-two laboratories obtained certification through ASRL #1; 2 through the Secondary Reference Laboratory (SRL) #8; and 9 through the SRL #9. The combination plots of the bias data in this PT and in the NGSP certification performed in March and May in 2012 were consistent with each other: mean NGSP values at each level agreed well with the target value. In conclusion, PT using whole blood is useful in endorsing NGSP certification.

This study considers treatment effect models in which others' treatment decisions can affect one's own treatment and outcome. Focusing on the case of two-player interactions, we formulate treatment decision behavior as a complete information game with multiple equilibria. Using a latent index framework and assuming a stochastic equilibrium selection, we prove that the marginal treatment effect from one's own treatment and that from the partner can be identified separately. Based on our constructive identification results, we propose a two-step semiparametric procedure for estimating the marginal treatment effects using series approximation. We show that the proposed estimator is uniformly consistent and asymptotically normally distributed. As an empirical illustration, we investigate the impacts of risky behaviors on adolescents' academic performance.

This study investigates the identification of parameters in semiparametric binary response models of the form y=1(x′β+v+e>0) when there are nonignorable nonresponses. We propose an estimation procedure for the identified set, the set of parameters that are observationally indistinguishable from the true value β, based on the special regressor approach of Lewbel (2000). We show that the estimator for the identified set is consistent in the Hausdorff metric.

This study considers the estimation of simultaneous binary choice models with social interactions, with particular focus on a bivariate case. Assuming that individuals make binary decisions simultaneously to maximize their overall utility, defined as the sum of utilities from each binary outcome, under incomplete information, we provide a sufficient condition for unique equilibrium, and develop a copula-based maximum likelihood estimator based on the nested fixed-point algorithm. As an empirical analysis, we apply the proposed model and method to National Longitudinal Study of Adolescent Health (Add Health) data in order to investigate the determinants of adolescents’ smoking and drinking behaviors. Our estimation results suggest that smoking and drinking are complementary activities, and that endogenous peer effects are significantly present for smoking behavior, but not for drinking.

This study proposes the use of semiparametric varying-coefficient methods to estimate the preference heterogeneity within stated choice data. Semiparametric varying-coefficient methods have the potential to overcome the disadvantages of conventional random parameter models and latent class models. For binary probit models with varying coefficients, in particular, this study proposes an easy-to-compute local iterative least squares (LILS) approach, based on the expectation–maximization algorithm. The finite sample properties of the LILS estimator are assessed using Monte Carlo experiments. In order to demonstrate the practical usefulness of semiparametric varying-coefficient methods, we present an empirical study, conducting an economic valuation of a landscape with dichotomous choice contingent valuations.

Background: The American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD)/International Diabetes Federation (IDF)/IFCC Consensus Statement on the worldwide standardization of HbA1c states that “… [HbA1c] results are to be reported world-wide in IFCC units … and derived NGSP units … , using the IFCC-NGSP master equation.” Methods: We describe statistical methods to evaluate and monitor the relationships as expressed in master equations (MEs) between the IFCC Reference Measurement procedure (IFCC-RM) and designated comparison methods (DCMs) [US National Glycohemoglobin Standardization Program (NGSP), Japanese Diabetes Society/Japanese Society for Clinical Chemistry (JDS/JSCC), and Mono-S in Sweden]. We applied these statistics, including uncertainty calculations, to 12 studies in which networks of reference laboratories participated, operating the IFCC-RM and DCMs. Results: For NGSP and Mono-S, slope, intercept, and derived percentage HbA1c at the therapeutic target show compliance with the respective MEs in all 12 studies. For JDS/JSCC, a slight deviation is seen in slope and derived percentage HbA1c in 2 of the 12 studies. Using the MEs, the uncertainty in an assigned value increases from 0.42 mmol/mol HbA1c (IFCC-RM) to 0.47 (NGSP), 0.49 (JDS/JSCC), and 0.51 (Mono-S). Conclusions: We describe sound statistical methods for the investigation of relations between networks of reference laboratories. Application of these statistical methods to the relationship between the IFCC-RM and DCMs in the US, Japan, and Sweden shows that they are suitable for the purpose, and the results support the applicability of the ADA/EASD/IDF/IFCC Consensus Statement on HbA1c measurement.

Background: The IFCC Reference Measurement System for hemoglobin (Hb)A1c (IFCC-RM) has been developed within the framework of metrologic traceability and is embedded in a network of 14 reference laboratories. This paper describes the outcome of 12 intercomparison studies (periodic evaluations to control essential elements of the IFCC-RM).Methods: Each study included: unknown samples (to test individual network laboratories); known samples (controls); recently manufactured calibrators (to check calculated assigned value); stored calibrators (to test stability) and a calibration-set (to calibrate the IFCC-RM). The unknown samples are measured by use of the IFCC-RM and the designated comparison methods [DCMs; the National Glycohemoglobin Standardization Program (NGSP) in the US, Japanese Diabetes Society/Japanese Society for Clinical Chemistry (JDS/JSCC) in Japan, and Mono-S in Sweden] are used to investigate the stability of the Master Equation (ME), the relationship between IFCC-RM and DCMs.Results: A total of 105 IFCC-RM data sets were evaluated: 95 were approved, 5 were not, and for 5 no data were submitted. Trend analysis of the MEs, expressed as change in percentage HbA1c per year, revealed 0.000% (NGSP, not significant), −0.030%, (JDS/JSCC; significant) and −0.016% (Mono-S; not significant). Evaluation of long-term performance revealed no systematic change over time; 2 laboratories showed significant bias, 1 poor reproducibility. The mean HbA1c determined by laboratories performing mass spectrometry (MS) was the same as the mean determined by laboratories using capillary electrophoresis (CE), but the reproducibility at laboratories using CE was better. One batch of new calibrators was not approved. All stored calibrators were stable.Conclusion: A sound reference system is in place to ensure continuity and stability of the analytical anchor for HbA1c.

Although insulin analogs have dramatically changed diabetes treatment, scarce evidence is available on those effects. We aimed to explore whether glycemic control had improved, the use of insulin analogs had been increased, and hypoglycemic events had decreased over time in Japanese pediatric patients with type 1 diabetes (T1D).Glycated hemoglobin A1c (HbA1c) values, proportion of insulin regimens, incidence of severe hypoglycemic events, and pubertal increase in HbA1c were compared in three cohorts of childhood-onset Japanese T1D patients (567 subjects in the 1995 cohort, 754 subjects in the 2000 cohort, and 806 subjects in the 2008 cohort).Mean HbA1c values tended to decrease [78.5 mmol/mol (9.33%) in the 1995 cohort, 68.2 mmol/mol (8.39%) in the 2000 cohort, and 61.2 mmol/mol (7.75%) in the 2008 cohort; P .0001]. The proportion of patients who received basal-bolus treatment tended to increase with statistical significance, as did the proportion on insulin analogs. The incidence of severe hypoglycemic events (events/100 patients/y) had decreased (19.1 in the 2000 cohort and 8.7 in the 2008 cohort; P = .02). The pubertal increase in HbA1c tended to decrease [males, 12.0 mmol/mol (1.10%) in 1995, 9.4 mmol/mol (0.85%) in 2008, and 9.4 mmol/mol (0.86%) in 2008; P = .55; females, 14.0 mmol/mol (1.28%) in 1995, 10.3 mmol/mol (0.94%) in 2000, and 4.2 mmol/mol (0.38%) in 2008; P = .0003].Glycemic control and incidence of severe hypoglycemic events were chronologically improved, especially in female adolescents.

In this study, we consider linear social interaction models under incomplete information that allow for missing outcome data due to sample selection. For model estimation, assuming that each individual forms his/her belief about the other members' outcomes based on heterogeneous rational expectations, we propose a two-step series nonlinear least squares estimator. Both consistency and asymptotic normality of the estimator are established. As an empirical illustration, we apply the proposed model and method to National Longitudinal Study of Adolescent Health (Add Health) data in order to examine the impacts of friendship interactions on adolescents' academic achievements. We provide empirical evidence that the interaction effects are important determinants of grade point average, and that controlling for sample selection bias has certain impacts on the estimation results, particularly on the endogenous interaction effects.

This study considers the estimation of spatial autoregressive models with censored dependent variables, where the spatial autocorrelation exists within the uncensored latent dependent variables. The estimator proposed in this paper is semiparametric in the sense that the error distribution is not parametrically specified and can be heteroscedastic. Under a median restriction, we show that the proposed estimator is consistent and asymptotically normally distributed. A set of Monte Carlo simulations is conducted to evaluate the finite sample performance of the estimator. As an empirical illustration, we investigate the determinants of household burglary risk in the Tokyo metropolitan area.

Background: The Committee on Standardization of Laboratory Testing Related to Diabetes Mellitus of the Japan Diabetes Society (JDS) previously recommended use of the primary calibrator (JDS Lot 1) prepared by the former Committee for Standardization of Glycohemoglobin for standardizing the measurement of haemoglobin A1c (HbA1c). Owing to the depletion of vials of Lot 1 in March 2001, the present committee certified a new reference material, Lot 2, now distributed by the Health Care Technology Foundation (HECTEF). The standardization programme for HbA1c measurement in Japan is currently based on Lot 2, which has values assigned from within Lot 1; the Lot 1 values were consensus values based on assays by laboratories in the Japanese national quality control programme. In this study, for the purpose of international comparison and standardization, Lot 2 was assayed by the JDS reference laboratories, the National Glycoprotein Standardization Program (NGSP) in the USA, and by reference laboratories approved by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Method: The HbA1c values of JDS Lot 2 were transferred from those assigned to Lot 1 using KO500, a high-resolution HPLC method, at three laboratories approved by the JDS committee. Subsequently, vials of JDS Lot 2 were shipped to and assayed by the NGSP in the USA and 10 IFCC reference laboratories. Result: The JDS-assigned HbA1c values (from Lot 1) are 4.04 for Level 1, 5.38 for Level 2, 7.32 for Level 3, 9.88 for Level 4, and 12.63 for Level 5, all expressed as a percentage of total haemoglobin. The values obtained by NGSP and the IFCC laboratories gave the following formulas: NGSP value (%) = JDS value (%) + 0.3%; IFCC value (%) = 1.068 x JDS value (%) -1.741%. Conclusion: Although the values obtained by the IFCC laboratories are significantly lower than the values assigned to Lot 2 by the JDS, the relationship is linear. In addition, standardization of HbA1c based on JDS Lot 2 is currently at a satisfactory level in Japan. As a result, the reassignment of values for Lot 2 to agree with the IFCC values should be relatively easy and will be done after all relevant parties agree to the change.

A method was developed for the quantification of 3, 4-dihydroxyphenylglycol (DHPG), 4-hydroxy-3-methoxymandelic acid (VMA), 4-hydroxy-3-methoxyphenylglycol (MHPG). The separation and determination of these compounds in biological samples were previously thought to be very difficult. In this work the separation has been well achieved by high-performance liquid chromatography on a reversed-phase column using three mobile phases with a step-wise gradient elution mode. The condition for coulometric detection has been developed for an effective determination of these compounds. In the analysis of the rat-brain tissue, DHPG, VMA and MHPG were separated and determined successfully. The average levels of DHPG, VMA, and MHPG in nine different rat-brain tissue samples were 11.8±0.57, 2.13±0.13 and 6.77±1.84ng/g wet brain, respectively. Simultaneously, their precursors DOPA, DA, NE, DOPAC, HVA, 3MT and NMN, and indolamine 5HT and its metabolite 5HIAA may also be determined by the same chromatographic run.

A new method of high-performance liquid chromatographic three-potential electrochemical detection was developed and applied for determining DA, DOPA, NE, E, 3MT, DOPAC, HVA, MHPG, DEP, 5HT and 5HIAA in rat-brain tissue. The proposed method employed a coulometric electrochemical detector coupled with a conditioning cell and a dualelectrode analytic cell. Three individual potentials were applied to the electrodes in order to oxidize-reduce the analytes. This detection system could effectively avoid interfering substance peaks, and could accurately quantify eleven components of catecholamines and serotonin as well as metabolites. The present method showed normal linearity with quantity injection of the standards; the detection limit was 0.17-1.22pg for all analytes of interest. In a measurement of neuroamines in rat-brain, the recovery of all target components averaged 74.5%.

Quantitative deconvolution of unresolved chromatographic peaks by multi-channel electrochemical detection was successfully performed. An electrochemical detector with four cells was employed. A regenerated current-voltage spectrum of three analyte components was obtained and used for peak deconvolution of the unresolved chromatographic peak. The overlapped peaks of three components, 5-hydroxyindole-3-acetic acid (5HIAA), deoxyepinephrine (DEP) and 3,4-dihydroxyhydrocinnamic acids (DHCA), was deconvoluted into the respective peaks of the components. The recoveries were 100.2% (5HIAA), 99.2% (DEP) and 99.7% (DHCA). This method could be used for the analysis of overlapped peaks in high-performance liquid chromatography with electrochemical detection.

Effective and efficient planning and development of residential environments require clarifying the nature of residential preferences. In reality, residential preferences are heterogeneous, so the standard econometric models that assume only one type of preference are not optimal. In this study, conjoint choice experiment methods are employed with a mixed logit approach. The findings reveal significant heterogeneity with regard to some residential attributes. The determinants of preference heterogeneity were also investigated by conducting regression analyses on the attributes that were valued heterogeneously. Overall, the relationships observed between the explanatory variables and the heterogeneity in the valuations were understandable. However, coefficient of determination values for each model were low, indicating that the bulk of preference heterogeneity results from unobservable factors.

Absence of skin conductance response (SCR) and failure of its habituation are psychophysiological signs observed in most schizophrenics. In the present experiments, skin conductance activity was studied in rats before and after intraventricular administration of 6-hydroxydopa (6-OHdopa), a neurotoxin that selectively destroys noradrenaline nerve terminals and induces denervation supersensitivity at the synapse. All intact rats studied (n = 32) showed SCR and its habituation to repeated auditory stimuli (500 Hz, 90 dB, 1 sec, 20 times). They also showed some spontaneous fluctuation (SF) of the skin conductance. In the early stage following the 6-OHdopa (100 micrograms) administration (n = 16), it was noted that the SCR disappeared and the SF were markedly reduced in frequency (p less than 0.001). From the third day to the fourth week after this treatment, there was some recovery of the SF rate, and the SCR tended to reappear with a marked slowing down of its habituation. Eight weeks after the treatment, the majority (11/16) of the 6-OHdopa rats showed habituation failure of the SCR (p less than 0.005); vehicle-treated rats (n = 16) did not show these alterations. Estimation of catecholamine concentration after the experiment confirmed the selective depletion of brain noradrenaline. These results suggest that destruction of the noradrenergic fibers after the 6-OHdopa treatment and denervation supersensitivity which developed later are the cause of the nonresponding and nonhabituating changes of SCR, respectively.

A chromatographic method utilizing a carboxymethylated poly(vinyl alcohol) resin for a more accurate determination of stable haemoglobin A1c (St-A1c) has been developed. The complete separation between St-A1c, labile HbA1c (L-A1c) and HbF was achieved by gradient elution with sodium chloride in phosphate buffer. This high resolution permits accurate quantitation of St-A1c, even in the presence of high levels of HbF or L-A1c. In 142 subjects with normal fasting plasma glucose and normal response to a 75-g oral glucose tolerance test, the reference interval of St-A1c was 2.80–3.98%.

The measurement of glycated hemoglobin is central in the monitoring of glycemic control in patients with diabetes. There are at least 30 different laboratory assays commercially available to measure the proportion of HbA1c in blood. In 1995 the IFCC established a Working Group (IFCC WG-HbA1c) to achieve international standardization of HbA1c measurement. The main achievements can be summarized as follows: a) a reference measurement procedure has been established with purified primary calibrators; b) a network of reference laboratories has been developed worldwide; and c) work has begun on implementation of traceability to the IFCC reference system. The IFCC WG-HbA1c recognizes the recommendation of the IFCC-IUPAC Committee on Nomenclature, Properties and Units that the analyte measured by the IFCC reference measurement procedure has been defined as betaN1-deoxyfructosyl-hemoglobin and that the recommended measurement units are mmol/mol. The IFCC WG-HbA1c recommends maintaining the use of the name HbA1c in clinical practice.

Background: In 2001, the Committee on Standardization of Laboratory Testing Related to Diabetes Mellitus of the Japan Diabetes Society (JDS) prepared and certified a new reference material for haemoglobin A1c (HbA1c), Lot 2. The standardization programme for HbA1c measurement in Japan is currently based on Lot 2, although some laboratories still use the previous material (Lot 1). The values assigned to Lot 2 were based on the consensus values for Lot 1 and should give the same results. Therefore, there should be no difference in the measured values no matter which calibrators are used. The Committee conducted a domestic survey in order to confirm this relationship. Method: In November 2002, four samples for HbA1c assay were sent to 795 laboratories as part of a national survey in Japan. Assays were performed using the laboratories' routine clinical methods. The coefficients of variation (CVs) of the reported values from all laboratories for the samples were calculated in order to determine the current level of standardization in Japan. Results: The overall CVs in the measured values for the four samples ranged from 2.7% to 4.0%. Values from laboratories using calibrators based on Lots 1 and 2 were similar. Conclusion: The present state of standardization for the routine measurement of HbA1c in Japan, as indicated by the 2002 survey, is excellent. This should aid in the eventual conversion of Lot 2 to IFCC-based values from the results of the 2002 national HbA1c survey.

HbA1C is the stable glucose adduct to the N-terminal group of the beta-chain of HbA0. The measurement of HbA1c in human blood is most important for the long-term control of the glycaemic state in diabetic patients. Because there was no internationally agreed reference method the IFCC Working Group on HbA1c Standardization developed a reference method which is here described. In a first step haemoglobin is cleaved into peptides by the enzyme endoproteinase Glu-C, and in a second step the glycated and non-glycated N-terminal hexapeptides of the beta-chain obtained are separated and quantified by HPLC and electrospray ionisation mass spectrometry or in a two-dimensional approach using HPLC and capillary electrophoresis with UV-detection. Both principles give identical results. HbA1c is measured as ratio between the glycated and non-glycated hexapeptides. Calibrators consisting of mixtures of highly purified HbA1c and HbA0 are used. The analytical performance of the reference method has been evaluated by an international network of reference laboratories comprising laboratories from Europe, Japan and the USA. The intercomparison studies of the network showed excellent results with intra-laboratory CVs of 0.5 to 2% and inter-laboratory CVs of 1.4 to 2.3%. Possible interferences have been carefully investigated. Due to the higher specificity of the reference method the results are lower than those generated with most of the present commercial methods which currently are calibrated with unspecific designated comparison methods. The new reference method has been approved by the member societies of the International Federation of Clinical Chemistry and Laboratory Medicine and will be the basis for the future uniform standardization of HbA1c routine assays worldwide.

1. 1. Effects of acute methamphetamine administration on spacing and locomotor activity were investigated in paired rats using a computer-assisted automated video-analysis method. 2. 2. Both 0.1 and 1 mg/kg of methamphetamine significantly increased the spacing in comparison with saline. This alteration in behavioral interaction by methamphetamine may serve as one of the animal models of social withdrawal. 3. 3. A significant increase in locomotor activity was found after 1 mg/kg of methamphetamine. 0.1 mg/kg dosage was accompanied by a locomotor change of a lesser degree and shorter duration. 4. 4. The difference with respect to the dose dependency and the time course indicates that the changes in these two behavioral indices by methamphetamine may have different underlying mechanisms.

Pharmacological studies on neuroleptics and amphetamine strongly suggest that some dysfunction of the central catecholamine system may play a key role in the pathogenesis of schizophrenia. Our previous studies have demonstrated that intraventricular administration of 6-hydroxydopamine, a selective neurotoxin of the catecholamine neuron, can reproduce schizophrenia-like abnormalities in the skin conductance activity. In the present experiments, effects of pharmacological modulation of the central noradrenergic activity were studied in rats. Stimulation of the central noradrenergic activity by yohimbine (0.6 mg/kg, i.m.) slowed down the habituation of the skin conductance response (SCR) and increase the spontaneous fluctuation of the skin conductance (SF), while inhibition of the activity by clonidine (0.06 mg/kg, i.m.) accelerated or obliterated the SCR and decreased the SF frequency. If the functional significance of the central noradrenergic system lies in vigilance control, the present results are consostent with classical theory in psychophysiology: the habituation rate of SCR and the frequency of SF are correlated well with each other and both indices reflect arousal level. The disorder of the system should produce not only these psychophysiological abnormalities but also psychological disturbances; i.e., overarousal and underarousal syndromes. Therefore, the dysfunction of the noradrenergic system might constitute an essential aspect of schizophrenic disorder.

In spite of extensive studies over the last 2 decades to find direct evidence in support of the dopamine hypothesis of schizophrenia, no undisputed experimental data has been obtained. In contrast, estimation of noradrenalin (another major catecholamine) and its metabolites in postmortem brain and in the cerebrospinal fluid appears to be producing consistent results. To understand the meaning of this change for the pathogenesis of the illness, we have carried out animal experiments in which reproducibility of schizophrenic signs and symptoms by noradrenergic dysfunction, and treatability of the disorder by modulation of noradrenergic activity were studied. First, psychophysiological signs in skin conductance responsiveness (nonhabituating or nonresponding change) and smooth pursuit eye movement (spiky or stepwise pursuit) could be reproduced by enhancing or suppressing central noradrenergic activity. Behavioral abnormalities resembling schizophrenic symptoms are known to be reproducible by over- or underactivity of the system (overarousal or underarousal syndrome). Secondly, the action of various drugs capable of modulating schizophrenic symptoms was analyzed in relation to noradrenergic activity. Haloperidol, in particular, had a potent suppressing effect on skin conductance activity (spontaneous fluctuation rate and habituation rate) when administered chronically, suggesting its inhibitory action on noradrenergic activity.

A "normalized map" of human plasma proteins, which illustrated the standard distribution pattern of the proteins, was prepared by comparing eight two-dimensional electrophoretic gels of normal human plasma. Phenotypes of several plasma proteins were detected. The pI and molecular weight of each spot in the normalized map were calculated and 84 spots out of 128 were identified or tentatively identified as known plasma proteins by several methods including micro amino acid analysis of the proteins extracted from the stained gel pieces. Human cerebrospinal fluid and urine protein patterns were compared with the normalized map and the positions of proteins characteristic of each body fluid sample were determined.

An unexpected prolongation of retention was observed in an experiment on the retention behaviour of latex beads in constant field sedimentation field-flow fractionation (SFFF). The prolongation depended on the type and concentration of detergent used in the solvent stream, and also on the size of the solute particulates. These facts suggested that retention in SFFF strongly depends on the state of the interface between the column surface and the solvent stream. On application of Stern's electrical double-layer diffusion model to the state of the surface border of the column wall, the prolongation of retention behaviour was well explained. As a result, an additional modification to the SFFF retention equation can be made, and the empirical equation, 1/ R = Cd + Dd + E, is proposed, where R is the retention ratio, C , D and E are functional parameters determined by the type and concentration of detergents used in the solvent stream and d p is the particle diameter.

Computer enhanced spectroscopic separation technique has been applied to identification of coeluted components in supercritical fluid chromatography by using an ultraviolet photodiode array multichannel detector. The powerful function such as peak deconvolution procedure has successfully offered thespectroscopic complete separation for even partially or completely coeluted components in super critical fluid chromatography.

A highly efficient proportioning device for versatile gradient elution in high-performance liquid chromatography is described, which can be used with an existing, conventional, one-piston reciprocating pump. The device consists of two constant-pressure solvent reservoirs, two air-traps, a three-way magnetic valve, a mixing chamber and an air-damper. Any desired gradient can be performed by setting the solvent composition—time profile on the signal generator that controls the three-way magnetic valve digitally. Solvents from two reservoirs are introduced into the three-way magnetic valve through each air-trap and are proportioned. The solvent from the valve is led to the mixing chamber, to which an air-damper is connected. The compositional fluctuations of the delivered solvent are minimized by the air-damper. Solvent profiles are produced with an error of less than 0.5% when compared to the designated compositions in the step mode.

Quantitative deconvolution of a chromatographic peak with extremely low UV absorption (less than 0.005 A.U.) is demonstrated for the analysis of an anaesthetic (ketamine) in rabbit serum. One ketamine metabolite, nor-ketamine, was deconvoluted from a completely fused peak in the three-dimensional chromatogram by using a highly sensitive multi-wavelength UV detector. After injection of ketamine, the nor-ketamine level in the serum increased to 3 μg/ml, calculated as ketamine, in 120 min.