Immature platelet fraction measurement in patients with chronic liver disease: a convenient marker for evaluating cirrhotic change

Platelet number is often used as an indicator of the severity of liver disease. Although inadequate thrombopoietin production and decreased platelet production have been proposed as major causes of cirrhotic thrombocytopenia, the underlying mechanism has not yet been fully clarified. We examined whether the measurement of the immature platelet fraction (IPF) in thrombocytopenic patients with liver dysfunction is useful as a rapid and noninvasive method for the differential diagnosis of chronic liver diseases. We examined 20 liver cirrhosis patients, 56 patients with chronic hepatitis, 9 patients with fatty liver, and 86 patients without liver disease. The percentage value of IPF (IPF%) was measured using an XE-2100 multiparameter automatic hematology analyzer. Using a receiver operating characteristic curve, we found diagnostic significance of the absolute platelet count and the absolute number of the IPF between cirrhotic patients and noncirrhotic patients, and developed a powerful multivariate discriminant analysis (MDA) function based on the platelet count and the IPF%. The diagnostic accuracy obtained by the MDA function was superior to that obtained by the absolute number of platelets and the IPF. We therefore propose our IPF% measurement for the diagnosis of liver cirrhosis.     

A Structure-Relationship Study of the Uptake of Aliphatic Polyamine Compounds by Rat Intestinal Brush-border Membrane Vesicles

The effects of lipophilicity, ion-diffusion potential and membrane surface potential on the uptake of various aliphatic polyamine compounds by rat intestinal brush-border membrane vesicles (BBMV) have been investigated. A valinomycin-induced potassium-diffusion potential (inside-negative) stimulated the initial uptake of diamine compounds, and good correlation was observed between lipophilicity and the amount of diffusion-potential-dependent transport of the diamines. In contrast, because of their much lower lipophilicity, tri- and tetraamine compounds were not affected by the diffusion potential. Tetracaine, which can make the membrane surface potential more positive, inhibited the transport rate of 1,9-nonanediamine, spermidine and spermine by the BBMV. These data suggest that the transport mechanism of diamines is similar to that of monoamine compounds in respect to its dependence on ion-diffusion potential and on the membrane surface potential. The extent of the effect of ion-diffusion potential on the rate of transport of the diamines was closely related to the lipophilicity of the diamine. In contrast, only the surface potential contributed to the transport mechanism of lower lipophilic tri- and tetraamine compounds.     

Enantioselective Pharmacokinetics of Homochlorcyclizine: Disposition of (+)- and (–)-Homochlorcyclizine after Intravenous and Oral Administration of Racemic Homochlorcyclizine to Rats

Abstract— Concentrations of homochlorcyclizine enantiomers in blood, urine, and tissues of the liver, lung, kidney, brain, heart, spleen, intestine and stomach of rats after drug administration were determined by high-performance liquid chromatography on a chiral stationary phase. After intravenous administration (10 mg kg^?1), homochlorcyclizine was rapidly distributed in many tissues, with the highest concentration in lung. No differences were found between enantiomers in blood concentrations. After oral administration (50 mg kg^?1), the concentrations of the (+)-isomer in nearly all tissues were higher than those of the (–)-isomer. The AUC_0-x values of the (+)- and (–)-isomers differed significantly. The absorption of racemic homochlorcyclizine from rat small intestine was not enantioselective. These results suggested that the different concentrations between enantiomers after oral administration were not caused by enantioselective absorption or distribution but rather by preferential first-pass metabolism of the (–)-isomer in the liver. The enantioselectivity of metabolism was also demonstrated by in-vitro experiments.     

Uptake Mechanism of Trientine by Rat Intestinal Brush-border Membrane Vesicles

The uptake characteristics of trientine by rat intestinal brush-border membrane vesicles were studied. The uptake characteristics of trientine were similar to those of the physiological polyamines with respect to the excessive accumulation in vesicles, the pH dependency, the temperature dependency and the ineffectiveness of K⁺ diffusion potential (inside negative). The initial uptake of trientine was saturable with a K_m value of 1.13 mM, which was larger than that of spermine and spermidine. Furthermore, the uptake rate of trientine was dose-dependently inhibited by spermine and spermidine. Spermine competitively inhibited the uptake of trientine with a K_i value of 18.6 μM, and it was close to the K_m value for spermine (30.4 μM). These data suggested that the uptake of trientine was similar to that of spermine and spermidine in rat small intestinal brush-border membrane vesicles, and these polyamines seem to inhibit the absorption of trientine from the gastrointestinal tract.     

Effects of the curly tail genotype on neuroepithelial integrity and cell proliferation during late stages of primary neurulation

The curly tail (ct/ct) mouse mutant shows a high frequency of delay or failure of neural tube closure, and is a good model for human neural tube defects, particularly spina bifida. In a previous study we defined distinct domains of gene expression in the caudal region of non‐mutant embryos during posterior (caudal) neuropore closure (Gofflot et al. Developmental Dynamics 210 , 431–445, 1997). Here we use BrdU incorporation into S‐phase nuclei to investigate the relationship between cell proliferation and the previously described gene expression domains in ct/ct mutant embryos. The BrdU‐immunostained sections were also examined for abnormalities of tissue structure; immunohistochemical detection of perlecan (an extracellular heparan sulphate proteoglycan) was used as an indicator of neuroepithelial basement membrane structure and function. Quantitation of BrdU uptake revealed that at early stages of neurulation, cell proliferation was specifically reduced in the paraxial mesoderm of all ct/ct embryos compared with wild type controls, but at later stages (more cranial levels) it was increased. Those ct/ct embryos with enlarged posterior neuropore (indicating delay of closure) additionally showed an increased BrdU labelling index within the open neuroepithelium at all axial levels; however, this tissue was highly abnormal with respect to cell and nuclear morphology. It showed cell death and loss of cells from the apical surface, basement membrane defects including increased perlecan immunoreactivity, and increased separation from the underlying mesenchyme and notochord. These observations suggest that the mechanism of delay or failure of neuroepithelial curvature that leads to neural tube defects in curly tail embryos involves abnormalities of neuroepithelial‐mesenchymal interactions that may be initiated by abnormal cellular function within the neuroepithelium. Minor histological and proliferation abnormalities are present in all ct/ct embryos, regardless of phenotype.     

ORIGINAL ARTICLE: Detection of early amnestic mild cognitive impairment without significantly objective memory impairment: a case‐controlled study

Background: We encountered eight early amnestic mild cognitive impairment (aMCI) patients (early MCI group) who did not fulfill the diagnostic criteria for aMCI. We compared the scores of neuropsychological examinations as well as the cerebral metabolic rate for glucose consumption (CMRglc) decrease on ¹⁸F‐FDG PET examination between the early MCI group and 10 aMCI patients (MCI group) or six normal elderly subjects (normal group), to examine whether the current diagnostic criteria can detect early‐stage aMCI. Methods: The three groups underwent Mini‐Mental State Examination (MMSE), Wechsler Adult Intelligence Scale – Third Edition (WAIS‐III), Wechsler Memory Scale Revised (WMS‐R), magnetic resonance imaging and 18F‐fluorodeoxyglucose positron emission tomography (¹⁸F‐FDG PET) examinations. Results: The early MCI group did not show significant memory impairment of 1.0 SD or other cognitive dysfunctions on neuropsychological examinations, and did not fulfill the diagnostic criteria of aMCI. With one‐way anova and Tukey's HSD post‐hoc test, the early MCI group showed the highest scores for WAIS‐III, whereas the MCI group showed the lowest scores for WMS‐R, although there were no significant differences between the early MCI and normal groups. In order to show a discrepancy in scores between WAIS‐III and WMS‐R, we subtracted the scores of WMS‐R from WAIS‐III. Consequently, the normal group showed significantly smaller differences in scores than the other groups, although there were no significant differences between the early MCI and MCI groups. ¹⁸F‐FDG PET recognized a CMRglc decrease in the posterior cingulate gyrus and/or part of the parietotemporal area in both the MCI and early MCI groups, of which the extent and magnitude were weaker in the early MCI group. The normal group did not show a significant CMRglc. Conclusions: The early MCI group should be included in aMCI not only based on the discrepancy between intelligence and memory scores, but also based on the ¹⁸F‐FDG PET findings. The combination of these examinations would make it possible to diagnose early‐stage aMCI.     

Correlation between Surgical Manipulations and the Variation of Surgeon's Heart Rate in Brain Surgery: Technical Note

For improvement of surgical performance and safety, we record surgeries by video cameras. However, analysis of the video records is time consuming. To help this task, we are developing methods to automatically mark up significant time points in the surgery. As a possible mean for the marking, we focused on the surgeon''s heart rate. During a craniotomy of an intracranial glioma, we recorded the surgeon''s electrocardiogram using a telemeter and measured the R-to-R interval (RRI). We detected the stable state of heart rate as a peak-to-peak RRI of less than 5% of the mean of RRI data from 15 consecutive heartbeats. We also quantified the frequency of brain touches by the surgeon under the surgical microscope. We examined the association between the stability of surgeon''s heart rate and the brain touches using a chi-square test. As the result, the stable state of surgeon''s heart rate was associated with the brain touches (p < 0.05, odds ratio 5.1). We edited a one-minute digest video of the surgery based on only the heart rate data, and it was sufficient to understand how the surgery was preceded.     

Clinical effects of high oral dose of donepezil for patients with Alzheimer's disease in Japan

Background:  Donepezil 10 mg/day gained approval in Japan in August 2007 for the treatment of cognitive dysfunction in advanced Alzheimer's disease.
Methods:  We evaluated the efficacy and adverse effects of donepezil when the dose was increased to 10 mg/day in 61 Japanese patients with Alzheimer's disease. Cognitive function was evaluated using the Revised Hasegawa Dementia Scale and mini-mental state examination at the day before starting, and at 4, 8 and 24 weeks after starting donepezil 10 mg/day. The relationship with apolipoprotein E4 was also investigated.
Results:  The Revised Hasegawa Dementia Scale and mini-mental state examination scores were not statistically significantly different at any time after starting donepezil 10 mg/day. It can be anticipated that donepezil 10 mg/day will especially inhibit deterioration of cognitive function in advanced Alzheimer's disease. The incidence of adverse events was 11.5%, lower than the rate of 40% or higher recorded during previous clinical trials.
Conclusions:  The progression of cognitive dysfunction could be inhibited by increasing the dose of donepezil to 10 mg/day. It was suggested that longer-term treatment with 5 mg/day might lead to fewer adverse events when the dose is increased to 10 mg/day.     

Predictors of diabetic end‐stage renal disease in Japan

SUMMARY: Diabetes mellitus (DM) has been the leading cause of incident dialysis in Japan since 1998, according to the Japanese Society for Dialysis Therapy (JSDT). In particular, the number of male DM dialysis patients is increasing. DM is becoming a worldwide epidemic in both developed and developing countries. Strategies to detect individuals at high‐risk of developing CKD and end‐stage renal disease (ESRD) are needed that can be implemented on a population‐basis. Among the commonly measured variables, dipstick urinalysis (proteinuria, haematuria), blood pressure, serum creatinine, body mass index (BMI), and serum uric acid are significant predictors of ESRD. Recently, we evaluated the effect of DM as a risk factor of developing ESRD. DM was diagnosed when the fasting plasma glucose (FPG) was 126 mg/dL or more in participants (n = 78529) of the 1993 screening program in Okinawa. The prevalence of DM was 5.2%. The odds ratio (95% CI) of DM for developing ESRD was 3.098 (1.738–5.525, P = 0.0001) after adjusting for possible confounding variables. Early detection and treatment of DM might prevent DM‐related ESRD. We examined 7125 non‐DM screenees who underwent a 1‐day health check between April 1997 and March 1998. They were followed‐up until March 2000 to determine whether they developed DM. Over the 2 years, the cumulative incidence of DM was 2.3%, 2.9% in men and 1.3% in women. Proteinuria was the most robust predictor of the development of DM; the adjusted relative risk (95% CI) was 1.90 (1.14–3.17). Obesity, per se, is also recognized as a risk factor for developing proteinuria. The higher the BMI, the higher the risk of developing ESRD; the adjusted odds ratio (95% CI) was 1.273 (1.121–1.446, P = 0.0002) for men. Other than being overweight (BMI = 25.0 kg/m²), a smoking habit was a significant predictor of developing proteinuria. The prevalence of obesity and DM is increasing in Japan. It is possible that the impact of obesity and complications of DM are different among races and ethnicities. Public relations regarding the risk of DM and its complications are especially important in Asian countries. Asians have more fat than non‐Asians, even at the same BMI levels. Knowledge of the predictors of DM‐ESRD is crucial as a first step toward prevention. Consistent with this notion, initiatives on the management of CKD and ESRD were recently organized in Japan and internationally.