Inorganic phosphorus (Pi) in CSF is a biomarker for SLC20A2-associated idiopathic basal ganglia calcification (IBGC1).

INTRODUCTION: Idiopathic basal ganglia calcification (IBGC), also called Fahr's disease or recently primary familial brain calcification (PFBC), is characterized by abnormal deposits of minerals including calcium mainly and phosphate in the brain. Mutations in SLC20A2 (IBGC1 (merged with former IBGC2 and IBGC3)), which encodes PiT-2, a phosphate transporter, is the major cause of IBGC. Recently, Slc20a2-KO mice have been showed to have elevated levels of inorganic phosphorus (Pi) in cerebrospinal fluid (CSF); however, CSF Pi levels in patients with IBGC have not been fully examined. METHODS: We investigated the cases of 29 patients with IBGC including six patients with SLC20A2 mutation and three patients with PDGFB mutation, and 13 controls. The levels of sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and Pi in sera and CSF were determined by potentiometry and colorimetry. Moreover, clinical manifestations were investigated in the IBGC patients with high Pi levels in CSF. RESULTS: The study revealed that the average level of Pi in the CSF of the total group of patients with IBGC is significantly higher than that of the control group, and the levels of Pi in CSF of the IBGC patients with SLC20A2 mutations are significantly higher than those of the IBGC patients with PDGFB mutations, the other IBGC patients and controls. CONCLUSION: Results of this study suggest that the levels of CSF Pi will be a good biomarker for IBGC1.

Gender differences of the influential factors on the mental health condition of teachers in the A university.

The purpose of this research was to investigate the gender differences of the influential factors on the mental health condition among university teachers in the A university in Japan. A questionnaire survey was mailed to 924 university teachers in Japan, with a survey return rate of 43.8% (N=405). The General Health Questionnaire 28 (GHQ-28), Multidimensional Scale of Perceived Social Support (MSPSS), the Japanese version of the Brief Coping Orientation to Problems Experienced (COPE) and the Work Situation Questionnaire (WSQ) developed by the authors were administered to subjects. The GHQ-28 total score and all of sub-score of the woman was significantly higher than men. In the correlated factor of mental health, level of job satisfaction and job control, social support of significant others was observed in the both sexes. However, gender differences was observed in the coping style. Some copings including self-distraction and self-blame were related to the men, but the woman was related to the substance use. University teachers had some gender differences in the factors affecting their mental health condition. In order to improve university teacher's mental health condition, it is necessary to increase their level of job satisfaction and feeling of job control in the workplace. Especially, it was considered women's coping using substance use was important.

Characteristics of bacterial and fungal growth in plastic bottled beverages under a consuming condition model.

Microbial contamination in unfinished beverages can occur when drinking directly from the bottle. Various microorganisms, including foodborne pathogens, are able to grow in these beverages at room temperature or in a refrigerator. In this study, we elucidated the characteristics of microorganism growth in bottled beverages under consuming condition models. Furthermore, we provide insight into the safety of partially consumed bottled beverages with respect to food hygiene. We inoculated microorganisms, including foodborne pathogens, into various plastic bottled beverages and analysed the dynamic growth of microorganisms as well as bacterial toxin production in the beverages. Eight bottled beverage types were tested in this study, namely green tea, apple juice drink, tomato juice, carbonated drink, sport drink, coffee with milk, isotonic water and mineral water, and in these beverages several microorganism types were used: nine bacteria including three toxin producers, three yeasts, and five moulds. Following inoculation, the bottles were incubated at 35°C for 48 h for bacteria, 25°C for 48 h for yeasts, and 25°C for 28 days for moulds. During the incubation period, the number of bacteria and yeasts and visible changes in mould-growth were determined over time. Our results indicated that combinations of the beverage types and microorganism species correlated with the degree of growth. Regarding factors that affect the growth and toxin-productivity of microorganisms in beverages, it is speculated that the pH, static/shaking culture, temperature, additives, or ingredients, such as carbon dioxide or organic matter (especially of plant origin), may be important for microorganism growth in beverages. Our results suggest that various types of unfinished beverages have microorganism growth and can include food borne pathogens and bacterial toxins. Therefore, our results indicate that in terms of food hygiene it is necessary to consume beverages immediately after opening the bottle.

Comparative study of cognitive impairment between medicated and medication-free patients with remitted major depression: class-specific influence by tricyclic antidepressants and newer antidepressants.

Patients with major depressive disorder (MDD) are known to present with cognitive deficits; however, the presence of these deficits in the remitted state have been inconsistent. One of the most important factors potentially contributing to inconsistencies between studies may be the influence of medications. To explore the influence of antidepressants on cognitive performance in remitted MDD, we evaluated memory and executive functions using Wechsler Memory Scale-Revised and Stroop Color and Word Test, and compared performance among 50 medicated (29 treated with tricyclic antidepressants [TCA], 21 treated with selective serotonin reuptake inhibitors or serotonin noradrenalin reuptake inhibitors) and 19 medication-free MDD patients and 31 controls. The results showed that all 3 MDD groups had significantly lower performance for verbal memory compared with controls. Both medicated groups showed significantly lower performance for visual memory compared with controls; however, the medication-free group did not differ from controls. For the executive function, only the TCA group showed a significantly lower performance compared with controls. These results suggest that cognitive impairment remained even in remitted patients with MDD, however, part of this impairment may be influenced by class-specific antidepressant side effects.

Microbial contamination associated with consumption and the growth in plastic bottled beverage.

Plastic bottles enable the storage of unfinished beverages, and most of microbial contamination has occurred in the unfinished beverage that was left. Therefore, we investigated microorganisms in various beverages contaminated by pouring and drinking directly by mouth from the bottle, and analyzed the growth of microorganisms in the beverages at room temperature. In the pouring test, microbial growth was detected in 60 of 320 samples, and 13 bacterial strains, 49 mold strains, and 8 yeast strains were isolated. Molds including Cladosporium spp., Tramets spp., Bjerkandera spp., and Penicillium spp. accounted for the majority of isolated microorganisms. In the drinking test, microbial growth was detected in 181 of 352 samples, and 225 bacterial strains, 27 mold strains and 77 yeast strains were isolated. Bacteria including Streptococcus spp. such as S. salivarius and Staphylococcus spp. such as S. aureus accounted for the majority of isolated microorganisms. Enterotoxin-producing S. aureus and Bacillus cereus were also isolated. The pH of the beverage influenced the growth of bacteria. The Brix values of the beverage did not correlate with the growth of microorganisms. These results revealed that various microorganisms including foodborne pathogens were able to grow in numerous types of beverages and that the storage of unfinished beverage in inappropriate condition, such as the storage at room temperature led microorganism to grow easily in beverage. Therefore, it is necessary to consume beverages as soon as possible after opening the bottle.

Decontamination of Vibrio parahaemolyticus in fish by washing with hygienic seawater and impacts of the high level contamination in the gills and viscera.

The effect of washing in Vibrio parahaemolyticus contaminated and hygienic seawater on fish, and the frequency and level of natural V. parahaemolyticus contamination in fish were investigated. In the first experiment, live horse mackerel was experimentally kept in seawater artificially contaminated with V. parahaemolyticus. After washing in contaminated and hygienic seawater, the contamination in fish was quantitatively analyzed. Washing fish in the seawater contaminated with V. parahaemolyticus increases the contamination level on the surface and in the gills of the fish. Washing in hygienic seawater was effective in reducing the contamination in fish and cutting board surfaces, but not in the gills or viscera. In the second experiment, natural V. parahaemolyticus contamination in various fish caught by us was analyzed. V. parahaemolyticus was detected in 6 of 28 gill samples and 10 of 28 viscera samples of naturally contaminated fish. The means of V. parahaemolyticus level on gills were 3.3 and 3.9 log cfu/g, and those in viscera were 2.6 and 4.4 log cfu/g by culture method and a real-time PCR assay, respectively. These results indicate that the gills and viscera are able to spread the pathogens to fish meat as well as fish surface contamination by washing in the contaminated seawater. Washing with hygienic seawater and control of contamination from gills and viscera are critically important to prevent V. parahaemolyticus infections.

Decreased bioelements content in the hair of patients with Fahr's disease (idiopathic bilateral calcification in the brain).

The remarkable calcification of the basal ganglia and cerebellum has been traditionally called Fahr's disease, but this nomenclature is criticized for including heterogeneous diseases. To determine the pattern of some biological metals in the hair of patients with Fahr's disease, we investigated the levels of 24 bioelements in the hair of 28 patients (17 males and 11 females) with Fahr's disease and compared them with those of three age-, sex-, and living region-matched controls (84 controls in total). Interestingly, we found decreases in the levels of several bioelements [calcium (Ca), copper (Cu), iron (Fe), mercury (Hg), iodine (I), nickel (Ni), phosphate (P), lead (Pb), and selenium (Se)] in the hair of patients. This is in contrast to our previous finding of increases of Cu, Fe, zinc (Zn), and magnesium (Mg) in the cerebrospinal fluid (CSF) of patients. The decreased level of Cu in the hair was the most prominent and pathognomonic, while the increased level of Cu in the CSF had been found to be the most significant in patients. More significant correlations between two bioelements in the hair were recognized in patients than controls. Although Fahr's disease has been considered to be a heterogenous entity, the significant tendencies of several bioelements in the hair of patients in this study suggest metabolic disorders of bioelements, especially biometals, on the background. Some transporters, especially P transporter such as PiT2, of bioelements will be involved in the different distribution of bioelements in the body of patients.

Patterns of levels of biological metals in CSF differ among neurodegenerative diseases.

We measured the levels of some biological metals: copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), and zinc (Zn) in the cerebrospinal fluid (CSF) in patients with neurodegenerative diseases (52 patients with amyotrophic lateral sclerosis (ALS)), 21 patients with Alzheimer's disease (AD), and 20 patients with Parkinson's disease (PD) by inductively coupled plasma mass spectrometry (ICP-MS). The diagnoses were additionally supported by neuroimaging techniques for AD and PD. In ALS, the levels of Mg (p<0.01 significant difference), Fe, Cu (p<0.05), and Zn (p<0.10) in CSF were higher than those in controls. Some patients showed very high levels of Cu and Zn before the critical deterioration of the disease. In AD, the levels of Cu and Zn in CSF were significantly higher in patients with late-onset AD (p<0.01). In PD, we found significantly increased levels of especially Cu and Zn in particular (p<0.01) and Mn (p<0.05) in CSF. A multiple comparison test suggested that the increased level of Mg in ALS and that of Mn in PD were the pathognomonic features. These findings suggest that Cu and Zn in particular play important roles in the onset and/or progression of ALS, AD, and PD. Therefore, Cu-chelating agents and modulators of Cu and Zn such as metallothionein (MT) can be new candidates for the treatment of ALS, AD, and PD.

[Proposal of a novel dosing schedule of docetaxel by using alpha1-acid glycoprotein as an index].

This study was aimed to propose a novel dosing schedule of docetaxel based on alpha(1)-acid glycoprotein (AGP)as an index. For this purpose, we performed Monte Carlo simulation using a population pharmacokinetic/pharmacodynamic (PPK/PPD) model, which we previously developed to estimate the ANC Nadir distribution after docetaxel administration. AGP values, which were incorporated in PPK/PPD, were sampled from normal distributions (S.D. 44, range from 19 to 259), as various mean levels of 125, 150, 175 and 200 (mg/dl). Monte Carlo simulation was conducted using docetaxel doses of 40, 50 and 60 (mg/m(2)) for each AGP distribution. Simulation was performed 200 times, and distributions of ANC Nadir median were obtained from simulations. We accepted a dose when 20 percentile of the distribution of ANC Nadir median was greater than 500 (counts/microl), in order to avoid the grade 4 neutropenia. From the results of simulations, 40, 50, 60 and 60 doses (mg/m(2)) were recommended for 125, 150, 175, and 200 AGP mean (mg/dl) respectively. Secondly, to evaluate this dosing schedule, we adopted these recommended doses to 16 patients whose ANC Nadir observed is lesser than 500, and simulated the ANC Nadir. The number of patients whose simulated time below ANC=500 was higher than 6 days decreased from 8 to 2, implying that this dosing schedule might be effective to avoid neutropenia induced by docetaxel. In conclusion, we proposed a novel dosing schedule of docetaxel using AGP as an index, which might be effective to avoid neutropenia induced by docetaxel.

Administration of anti-glucagon-like peptide-2 serum suppresses epithelial cell proliferation of the distal small intestine in weanling rats.

We investigated the effects of endogenous glucagon-like peptide-2 (GLP-2) on the development of intestinal mucosa in weanling rats. Three-week-old male weanling Sprague-Dawley rats were administered either anti-GLP-2 or normal rabbit serum every other day for 2 weeks. We then measured length, weight, and bromodeoxyuridine incorporation in the intestine on day 13 following the first injection. Administration of anti-GLP-2 serum significantly inhibited both epithelial proliferation in the distal ileum and elongation of the small intestine. These results suggest that intrinsic GLP-2 contributes to the growth of the small intestine during the weanling period.

alpha-Lactalbumin hydrolysate stimulates glucagon-like peptide-2 secretion and small intestinal growth in suckling rats.

We investigated whether bovine milk constituents influenced glucagon-like peptide (GLP)-2 secretion and intestinal growth in suckling rats. Male Sprague-Dawley rats (14 d old) received i.g. infusions of a milk protein fraction, a lactose solution, or the cream fraction of milk. The serum concentration of GLP-2, but not GLP-1, markedly increased in rats administered milk protein compared with those given the lactose solution or the cream fraction from 60 to 120 min after administration. In another experiment, both casein (CN) and whey protein isolate stimulated GLP-2 secretion at 120 min after administration, but soy protein and ovalbumin did not. Stimulation of GLP-2 secretion by several milk proteins was similar, including alpha-CN, alpha-lactalbumin (alpha-La), and beta-lactoglobulin, in a separate experiment. A hydrolysate of alpha-La obtained by incubation with protease A extracted from Aspergillus oryzae (LaHPA) caused almost twice the GLP-2 release due to intact alpha-La and other alpha-La hydrolysates. Free amino acid concentrations and molecular size distributions did not differ among alpha-La hydrolysates, including LaHPA. In rat pups reared with milk formulae containing alpha-La or LaHPA, LaHPA significantly promoted small intestinal elongation and increased the number of crypt epithelial cells compared with a formula containing intact alpha-La. LaHPA administration also increased the maltase:lactase activity ratio, a marker of maturation of the intestinal mucosa. In conclusion, milk proteins stimulate GLP-2 secretion and contribute to growth and maturation of the small intestine in suckling rats.

Clinical trial simulations for dosage optimization of docetaxel in patients with liver dysfunction, based on a log-binominal regression for febrile neutropenia.

This study was aimed to perform clinical trial simulations to evaluate the dose reduction strategy of docetaxel for Japanese patients with liver dysfunction, which we previously proposed. For this purpose, a log-binominal regression (LBR) was performed for febrile neutropenia (FN) induced by docetaxel in these patients. A LBR analysis was conducted using clinical data from cancer patients treated with docetaxel and incorporated in the subsequent trial simulation. Virtual patients with liver dysfunction were randomly assigned to receive the Japanese standard dose (60 mg/m(2)) or reduced dose (40 or 50 mg/m(2)) of docetaxel. The primary endpoint was overall survival of the reduced dose to the standard dose. The secondary endpoint was the number of patients who experienced FN in response to the two treatment regimens. From the LBR analysis, the performance status and the area under the plasma concentration-time curve (AUC) were selected as covariates associated significantly (p<0.05) with FN occurrence. From the results of the present trial simulation, the median proportion of patients who experienced FN was decreased by about 20% in the reduced dose arm. Non-inferiority criteria, the reduced dose group to the standard dose group were met in 85.5% of the simulated clinical trials with a decrease in the FN frequency. In conclusion, clinical trial simulation models for the efficacy (survival) and toxicity (FN) was first performed in Japanese patients, and the feasibility of docetaxel therapy for liver-dysfunction patients under the dose reduction strategy was supported.

Population pharmacokinetics of docetaxel in patients with hepatic dysfunction treated in an oncology practice.

To investigate the relationship between the degree of liver dysfunction and the pharmacokinetics of docetaxel, a population pharmacokinetic model was developed in an oncology practice without excluding patients with moderate to severe liver dysfunction. Two hundred patients were treated with docetaxel as a single agent or in combination chemotherapy. The plasma concentration-time course data were analyzed using a three-compartment open model with zero-order administration and first-order elimination on the NONMEM program. Sixty-one had elevated transaminase levels, and alkaline phosphatase was elevated in 40. Body surface area, albumin, alpha1-acid glycoprotein, and liver function were found to be significant covariates for the systemic clearance of docetaxel. Compared to patients with normal or minimal impairment of liver function, patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase had 22 and 38% lower clearances, respectively. Goodness-of-fit plots indicated that the model was fitted well with the observed data, and the bootstrap method guaranteed robustness of the model. We developed a population pharmacokinetic model for docetaxel, which can be used in the setting of an oncology practice. Based on the model, dose reduction by approximately 20 and 40% should be considered for patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase, respectively.

The expression of metallothioneins is diminished in the spinal cords of patients with sporadic ALS.

We analyzed the expression of MTs using immunohistochemistry on the spinal cords of patients with ALS (n =12) and controls (n =12). The immunoreactivities of both MT-1/2 and MT-3 stained dominantly in glial cells and were decreased in the spinal cords of patients with ALS, particularly in patients on respirators. The immunoreactivity of MT-1/2 in the ALS groups was significantly reduced compared with controls. In addition, a statistical analysis revealed that the immunoreactivity of MT-3 in astrocytes in the gray matter of the lumbar spinal cord was negatively correlated with the duration of ALS. Both MT-1/2 and MT-3 immunoreactivities were detected mainly in the glias and also detected in some neurons in both control patients and patients with ALS. Interestingly, the patients with MT-3-positive neurons showed definite MT-3-immunoreactive glial reaction around neurons. Previous studies have reported that familial ALS (FALS) model mice (G93A SOD1) crossed with MT-1/2 or MT-3 knock-out mice had accelerated expression of ALS. Judged from these findings, both MT-1/2 and MT-3 play important roles in the progression of ALS. MTs are defensive proteins that can scavenge free radicals; therefore, manipulation of their expression has a strong therapeutic potential for ALS patients.

Logistic regression analysis for febrile neutropenia (FN) induced by docetaxel in Japanese cancer patients.

PURPOSE: Fever occurring in a neutropenic patient remains a common life-threatening complication of cancer chemotherapy, and febrile neutropenia (FN) is recognized as a dose-limiting factor (DLF) in cancer chemotherapy. The aim of this study is to evaluate the significant covariate associated with the risk of FN occurrence in Japanese patients. METHODS: A stepwise logistic regression was conducted using data from Japanese cancer patients treated with docetaxel. Based on those results, an equation was established which predicts the probability of FN occurrence. RESULTS: From the result of a stepwise multivariate logistic regression analysis, performance status factor (PS*), which is set to 1 if performance status factor is 2 or 3, and to 0 otherwise and area under the plasma concentration versus time curve (AUC) were selected as covariates significantly associated (p < 0.05) with FN occurrence. The obtained equation to predict the probability (P) of docetaxel-induced FN occurrence is P = 1/[1 + exp{-(1.29 x AUC + 1.41 x PS* -3.52)}]. A receiver operating characteristic (ROC) curve analysis revealed that the best cut-off value of FN probability to differentiate between the presence and absence of FN was 0.61. CONCLUSIONS: An equation was developed to predict the probability of FN occurrence for Japanese patients treated with docetaxel. It was found that FN may not occur when the probability of FN occurrence calculated by the predictive equation is less than 0.61. Therefore, the predictive equation for FN occurrence may be used for selecting the appropriate dose to avoid the occurrence of FN.

Norovirus infections in symptomatic and asymptomatic food handlers in Japan.

Noroviruses are the leading cause of outbreaks of gastroenteritis in the world. At present, norovirus genogroup II, genotype 4 (GII/4), strains are the most prevalent in many countries. In this study we investigated 55 outbreaks and 35 sporadic cases of norovirus-associated gastroenteritis in food handlers in food-catering settings between 10 November 2005 and 9 December 2006 in Japan. Stool specimens were collected from both symptomatic and asymptomatic individuals and were examined for norovirus by real-time reverse transcription-PCR; the results were then confirmed by sequence analysis. Norovirus was detected in 449 of 2,376 (19%) specimens. Four genogroup I (GI) genotypes and 12 GII genotypes, including one new GII genotype, were detected. The GII/4 sequences were predominant, accounting for 19 of 55 (35%) outbreaks and 16 of 35 (46%) sporadic cases. Our results also showed that a large number of asymptomatic food handlers were infected with norovirus GII/4 strains. Norovirus GII had a slightly higher mean viral load (1 log unit higher) than norovirus GI, i.e., 3.81 x 10(8) versus 2.79 x 10(7) copies/g of stool. Among norovirus GI strains, GI/4 had the highest mean viral load, whereas among GII strains, GII/4 had the highest mean viral load (2.02 x 10(8) and 7.96 x 10(9) copies/g of stool, respectively). Importantly, we found that asymptomatic individuals had mean viral loads similar to those of symptomatic individuals, which may account for the increased number of infections and the predominance of an asymptomatic transmission route.

Population pharmacokinetic and pharmacodynamic analysis for time courses of docetaxel-induced neutropenia in Japanese cancer patients.

The present study describes a population pharmacokinetic and pharmacodynamic (PK/PD) analysis based on data obtained from cancer patients treated with docetaxel at the National Cancer Center Hospital East in Japan. Docetaxel was infused intravenously over 1 h every 3 weeks, and time courses of absolute neutrophil counts (ANC) for a total of 395 observations (62 patients) were analyzed using a semimechanistic-physiological PK/PD model in the NONMEM program. The prominent feature of our PK/PD model is that it has the capability to predict a temporary increase in ANC. Among 10 patient factors, alpha(1)-acid glycoprotein was selected as a significant covariate for drug effect as the increase in alpha(1)-acid glycoprotein was negatively correlated with the drug effect. Goodness-of-fit plots indicated that the model fitted well with the observed data, and the bootstrap method guaranteed robustness of the model. In conclusion, we developed a novel population PK/PD model that can adequately analyze ANC profiles after docetaxel administration in oncology practice, where temporary but consistent increases in ANC were observed.

Development and evaluation of the e-learning teaching materials for surgical nursing training.

We investigated e-learning teaching materials with a questionnaire for 55 nursing students. Students thought the materials easy to use. In addition, the teaching materials which we developed gave them the confidence of thinking, "I can do it". We affect training by imaging a nursing procedure and think anxiety to training to be be relieved. However, load of PC became high in these teaching materials to display of two motion pictures simultaneously in one screen, so it would be necessary to produce the teaching materials considered transmission rate.