[A Bibliometric Analysis of Research Paper Productivity of Japanese Pharmacy Schools].

Since the early 2000s, Japan has been frequently noted as being the only country among about 20 major countries where the publication of academic papers has stagnated. During this period, there have been major changes especially with regards to the Japanese pharmacy schools, such as the shift to a six-year schooling system and the rapid increase in the number of private pharmacy schools. However, few studies have focused on academic productivity specifically among pharmacy schools. Therefore, this study analyzed the outputs associated with the publication of peer-reviewed scholarly articles in Scopus search engine per faculty member in pharmacy schools nationwide in 2020. Professors, associate professors, and lecturers were considered as faculty members. The average number of papers published per the faculty member was 3.13 for national and public universities and 1.15 for private universities, with a significant difference between these universities. Dividing the pharmacy schools of private universities into schools established in and after 2003 and schools established before that, the production coefficient of the former was 0.98 and that of the latter was 1.33. Newly established pharmacy schools were thus found to be slightly less productive in terms of published papers than traditional schools. The paper productivity of private university pharmacy schools is stagnant; the increase in the number of private schools that have adopted a six-year schooling system has contributed to large extent to the creation of clinically competent pharmacists, but it has also brought to light concerns related to the decline in basic research capabilities of Japanese pharmaceutical academia.

SIPA1L1/SPAR1 Interacts with the Neurabin Family of Proteins and is Involved in GPCR Signaling.

Signal-induced proliferation-associated 1 (SIPA1)-like 1 (SIPA1L1; also known as SPAR1) has been proposed to regulate synaptic functions that are important in maintaining normal neuronal activities, such as regulating spine growth and synaptic scaling, as a component of the PSD-95/NMDA-R-complex. However, its physiological role remains poorly understood. Here, we performed expression analyses using super-resolution microscopy (SRM) in mouse brain and demonstrated that SIPA1L1 is mainly localized to general submembranous regions in neurons, but surprisingly, not to PSD. Our screening for physiological interactors of SIPA1L1 in mouse brain identified spinophilin and neurabin-1, regulators of G-protein-coupled receptor (GPCR) signaling, but rejected PSD-95/NMDA-R-complex components. Furthermore, Sipa1l1-/- mice showed normal spine size distribution and NMDA-R-dependent synaptic plasticity. Nevertheless, Sipa1l1-/- mice showed aberrant responses to α2-adrenergic receptor (a spinophilin target) or adenosine A1 receptor (a neurabin-1 target) agonist stimulation, and striking behavioral anomalies, such as hyperactivity, enhanced anxiety, learning impairments, social interaction deficits, and enhanced epileptic seizure susceptibility. Male mice were used for all experiments. Our findings revealed unexpected properties of SIPA1L1, suggesting a possible association of SIPA1L1 deficiency with neuropsychiatric disorders related to dysregulated GPCR signaling, such as epilepsy, attention deficit hyperactivity disorder (ADHD), autism, or fragile X syndrome (FXS).SIGNIFICANCE STATEMENT Signal-induced proliferation-associated 1 (SIPA1)-like 1 (SIPA1L1) is thought to regulate essential synaptic functions as a component of the PSD-95/NMDA-R-complex. In our screening for physiological SIPA1L1-interactors, we identified G-protein-coupled receptor (GPCR)-signaling regulators. Moreover, SIPA1L1 knock-out (KO) mice showed striking behavioral anomalies, which may be relevant to GPCR signaling. Our findings revealed an unexpected role of SIPA1L1, which may open new avenues for research on neuropsychiatric disorders that involve dysregulated GPCR signaling. Another important aspect of this paper is that we showed effective methods for checking PSD association and identifying native protein interactors that are difficult to solubilize. These results may serve as a caution for future claims about interacting proteins and PSD proteins, which could eventually save time and resources for researchers and avoid confusion in the field.

Age-dependent impairment of memory and neurofibrillary tangle formation and clearance in a mouse model of tauopathy.

Insoluble, fibrillar intraneuronal accumulation of the tau protein termed neurofibrillary tangles (NFTs), are characteristic hallmarks of Alzheimer's disease (AD). They play a significant role in the behavioral phenotypes of AD. Certain mice (rTg4510) constitutively express mutant human tau until transgene expression is inactivated by the administration of doxycycline (DOX). The present study aimed to determine the timing of the onset of memory impairment in rTg4510 mice and define the relationship between the extent of memory deficit and the duration of NFT overexpression. In 6-month-old (young) rTg4510 mice, both spatial memory and object recognition memory were impaired. These impairments were prevented by pre-treatment with DOX for 2 months. In parallel, the expression of NFTs decreased in the DOX-treated group. Ten-month-old (aged) rTg4510 mice showed severe impairments in memory performance. Pretreatment with DOX did not prevent these impairments. Increasing levels of NFTs were observed in aged rTg4510 mice. DOX treatment did not prevent tau pathology in aged rTg4510 mice. Expression of the autophagy markers LC3A and LC3B increased in rTg4510 mice, along with an increase in NFT formation. These results suggest that the clearance mechanisms of NFTs are impaired at 10 months of age.

Fracture risk increased by concurrent use of central nervous system agents in older people: Nationwide case-crossover study.

BACKGROUND: Multiple medication use among older patients is reported to increase fracture risk. But this association is unclear in different subgroups and has not been confirmed by a case-crossover study, which can eliminate measurable and unmeasurable time-invariant confounders. OBJECTIVE: To estimate the fragility fracture risk associated with concurrent use of multiple central nervous system (CNS) agents in older patients using a case-crossover design. METHODS: This study targeted almost all patients aged ≥65 years in Japan who incurred fragility fractures from May 2013 to September 2014, based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB Japan). Conditional logistic regression analysis estimated the risk of fragility fracture associated with the daily number of CNS agents, including subgroup analyses stratified by sex, age, and fracture location. RESULTS: For 446,101 patients, the adjusted odds ratios (ORs) of fragility fracture increased almost linearly with number of CNS agents; 0, 0-1, 1-2, 2-3, 3-4, 4-5, and >5: OR reference, 1.21 (95% confidence interval, 1.18-1.23), 1.40 (1.35-1.46), 1.58 (1.49-1.67), 1.89 (1.74-2.05), 1.80 (1.60-2.03), and 1.90 (1.61-2.23; trend p < 0.001), respectively. A similar trend was observed for several subgroups, especially in males and those aged ≥85 years, showing marked linearity. CONCLUSIONS: The increased risk of fragility fracture associated with the use of multiple CNS agents was robust in older people in Japan.

Impairment of cerebellar long-term depression and GABAergic transmission in prion protein deficient mice ectopically expressing PrPLP/Dpl.

Prion protein (PrPC) knockout mice, named as the "Ngsk" strain (Ngsk Prnp0/0 mice), show late-onset cerebellar Purkinje cell (PC) degeneration because of ectopic overexpression of PrPC-like protein (PrPLP/Dpl). Our previous study indicated that the mutant mice also exhibited alterations in cerebellum-dependent delay eyeblink conditioning, even at a young age (16 weeks of age) when neurological changes had not occurred. Thus, this electrophysiological study was designed to examine the synaptic function of the cerebellar cortex in juvenile Ngsk Prnp0/0 mice. We showed that Ngsk Prnp0/0 mice exhibited normal paired-pulse facilitation but impaired long-term depression of excitatory synaptic transmission at synapses between parallel fibres and PCs. GABAA-mediated inhibitory postsynaptic currents recorded from PCs were also weakened in Ngsk Prnp0/0 mice. Furthermore, we confirmed that Ngsk Prnp0/0 mice (7-8-week-old) exhibited abnormalities in delay eyeblink conditioning. Our findings suggest that these alterations in both excitatory and inhibitory synaptic transmission to PCs caused deficits in delay eyeblink conditioning of Ngsk Prnp0/0 mice. Therefore, the Ngsk Prnp0/0 mouse model can contribute to study underlying mechanisms for impairments of synaptic transmission and neural plasticity, and cognitive deficits in the central nervous system.

Central Nervous System Agent Classes and Fragility Fracture Risk among Elderly Japanese Individuals in a Nationwide Case-Crossover Design Study.

Central nervous system (CNS) agents cause fractures among the elderly, but fracture risks of a wide range of CNS agent classes have not been analyzed in a study with the same population and definitions of variables. This study aimed to estimate the degree of fragility fracture risk of a wide range of CNS agent classes in elderly Japanese people. A case-crossover design study, with a case window and three control windows of 3 d each, as well as longer windows up to 15 d, was conducted among opioid non-users who lived without hospitalization for ≥13 months and incurred fragility fractures at ≥65 years of age, using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Conditional logistic regression estimated adjusted odds ratios (ORs) of CNS agent classes for fragility fractures for groups including and excluding users of pro re nata CNS agents (PRN-CNS agents) and for windows of 3-15 d. Antiepileptic agents had the highest adjusted ORs, 2.4 (95% confidence interval 2.3-2.5) for the group including PRN-CNS agent users (n = 446101). The next-highest classes were anti-dementia agents 1.5 (1.5-1.6), antipsychotics 1.5 (1.4-1.6), anti-Parkinson agents 1.3 (1.2-1.5), and antidepressants 1.1 (1.1-1.2). Similar ORs were found when PRN-CNS agent users were excluded (n = 352828), and slightly higher ORs were found for longer windows, with almost the same order of classes. Elderly individuals who use antiepileptic agents or a combination of antiepileptic agents and CNS agent classes with the next-highest ORs should be carefully monitored.

mGluR1 in cerebellar Purkinje cells is essential for the formation but not expression of associative eyeblink memory.

Classical eyeblink conditioning is a representative associative motor learning that requires both the cerebellar cortex and the deep cerebellar nucleus (DCN). Metabotropic glutamate receptor subtype 1 (mGluR1) is richly expressed in Purkinje cells (PCs) of the cerebellar cortex. Global mGluR1 knock-out (KO) mice show a significantly lower percentage of conditioned response (CR%) than wild-type mice in eyeblink conditioning, and the impaired CR% is restored by the introduction of mGluR1 in PCs. However, the specific roles of mGluR1 in major memory processes, including formation, storage and expression have not yet been defined. We thus examined the role of mGluR1 in these processes of eyeblink conditioning, using mGluR1 conditional KO (cKO) mice harboring a selective and reversible expression of mGluR1 in PCs. We have found that eyeblink memory is not latently formed in the absence of mGluR1 in adult mouse PCs. However, once acquired, eyeblink memory is expressed even after the depletion of mGluR1 in PCs. We thus conclude that mGluR1 in PCs is indispensable for the formation of eyeblink memory, while it is not required for the expression of CR.

Fragility Fractures in Older People in Japan Based on the National Health Insurance Claims Database.

Fragility fractures associated with age-related bone loss are of urgent concern worldwide because they reduce QOL and pose financial burdens for health care services. Currently, national data in Japan are limited. This study provides quantitative data for older patients throughout Japan who, although otherwise relatively healthy, sustained fragility fractures and were hospitalized for them. The National Database of Health Insurance Claims and Specific Health Checkups of Japan was accessed to target patients aged 65 years or older who sustained fractures between May 2013 and September 2014 and were not hospitalized for at least 13 months prior to fracture. We investigated whether the first fracture sustained was fragility related at any of four locations (proximal humerus, distal radius, vertebra, or femoral neck) and whether it necessitated hospitalization. Fragility fractures were identified in 490138 of 1188754 patients (41.2%, 345980 patients/year; 1 : 4 male-to-female ratio). Regardless of gender, vertebral fractures were most common across the age cohorts studied (43286 males and 162767 females/year), and femoral neck fractures increased markedly with increased patient age. Approximately 80% of patients with femoral neck fractures were hospitalized (62.3% of males, 71.1% of females) compared with up to 10.4% of patients with other fragility fractures. Data provided in this study can be used as a baseline for evaluating the health economy and establishing health policy in Japan.

Traumatic Brain Injury by Weight-Drop Method Causes Transient Amyloid-ß Deposition and Acute Cognitive Deficits in Mice.

There has been growing awareness of the correlation between an episode of traumatic brain injury (TBI) and the development of Alzheimer's disease (AD) later in life. It has been reported that TBI accelerated amyloid-ß (Aß) pathology and cognitive decline in the several lines of AD model mice. However, the short-term and long-term effects of TBI by the weight-drop method on amyloid-ß pathology and cognitive performance are unclear in wild-type (WT) mice. Hence, we examined AD-related histopathological changes and cognitive impairment after TBI in wild-type C57BL6J mice. Five- to seven-month-old WT mice were subjected to either TBI by the weight-drop method or a sham treatment. Seven days after TBI, the WT mice exhibited significantly lower spatial learning than the sham-treated WT mice. However, 28 days after TBI, the cognitive impairment in the TBI-treated WT mice recovered. Correspondingly, while significant amyloid-ß (Aß) plaques and amyloid precursor protein (APP) accumulation were observed in the TBI-treated mouse hippocampus 7 days after TBI, the Aß deposition was no longer apparent 28 days after TBI. Thus, TBI induced transient amyloid-ß deposition and acute cognitive impairments in the WT mice. The present study suggests that the TBI could be a risk factor for acute cognitive impairment even when genetic and hereditary predispositions are not involved. The system might be useful for evaluating and developing a pharmacological treatment for the acute cognitive deficits.

Data on COA-Cl administration to the APP/PS2 double-transgenic mouse model of Alzheimer׳s disease: Improved hippocampus-dependent learning and unchanged spontaneous physical activity.

We herein present behavioral data regarding whether COA-Cl, a novel adenosine-like nucleic acid analog that promotes angiogenesis and features neuroprotective roles, improves cognitive and behavioral deficits in a murine model for Alzheimer׳s disease (AD). COA-Cl induced significant spatial memory improvement in the amyloid precursor protein/presenilin 2 double-transgenic mouse model of AD (PS2Tg2576 mice). Correspondingly, non-spatial novel object cognition test performance also significantly improved in COA-Cl-treated PS2Tg2576 mice; however, these mice demonstrated no significant changes in physical activity or motor performance. COA-Cl did not change the spontaneous activities and cognitive ability in the wild-type mice.

Patient Preference for Aggressive Medication Therapies with Potentially Stronger Adverse Drug Reactions Revealed Using a Scenario-based Survey.

Some patients do not inform healthcare professionals of adverse drug reactions (ADRs) because they fear termination of aggressive medication therapies. Preferences for aggressive medication therapies may differ between patients and pharmacists. The goal of this study was to estimate whether pharmacists were able to accurately assess patient preference for aggressive medication therapies with potentially stronger ADRs. A cross-sectional study was conducted of hospitalized patients (35 to 74 years of age) receiving oral medications for a chronic disease or systemic chemotherapy at three hospitals in Japan. We estimated the extent of agreement between patient responses and pharmacist predictions using a scenario-based investigation (1) to examine the choice between an aggressive medication therapy and the standard therapy, and (2) to assess increased life expectancy as a result of aggressive medication therapy. The extent of agreement was estimated using the kappa statistic. Of 113 patients, 43 (38.1%) chose the aggressive medication therapy. Pharmacists correctly predicted the choice of 25 (58.1%) of these patients [kappa 0.32 (95% confidence interval 0.15-0.50)]. Of 111 patients, 42 (37.8%) expected one additional life expectancy year. However, pharmacists predicted that as many as 36 (85.7%) of these patients would require more years of added life expectancy before choosing an aggressive medication therapy [kappa 0.24 (0.08-0.40)]. Agreement between patients and pharmacists on the choice of aggressive medication therapy was generally poor. Pharmacists should make an effort to identify patients who might prefer more aggressive medication therapies with potentially stronger ADRs in order to minimize ADR risk.

Data on amyloid precursor protein accumulation, spontaneous physical activity, and motor learning after traumatic brain injury in the triple-transgenic mouse model of Alzheimer׳s disease.

This data article contains supporting information regarding the research article entitled "Traumatic brain injury accelerates amyloid-ß deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer׳s disease" (H. Shishido, Y. Kishimoto, N. Kawai, Y. Toyota, M. Ueno, T. Kubota, Y. Kirino, T. Tamiya, 2016) [1]. Triple-transgenic (3×Tg)-Alzheimer׳s disease (AD) model mice exhibited significantly poorer spatial learning than sham-treated 3×Tg-AD mice 28 days after traumatic brain injury (TBI). Correspondingly, amyloid-ß (Aß) deposition within the hippocampus was significantly greater in 3×Tg-AD mice 28 days after TBI. However, data regarding the short-term and long-term influences of TBI on amyloid precursor protein (APP) accumulation in AD model mice remain limited. Furthermore, there is little data showing whether physical activity and motor learning are affected by TBI in AD model mice. Here, we provide immunocytochemistry data confirming that TBI induces significant increases in APP accumulation in 3×Tg-AD mice at both 7 days and 28 days after TBI. Furthermore, 3×Tg-AD model mice exhibit a reduced ability to acquire conditioned responses (CRs) during delay eyeblink conditioning compared to sham-treated 3×Tg-AD model mice 28 days after TBI. However, physical activity and motor performance are not significantly changed in TBI-treated 3×Tg-AD model mice.

Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2.

Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses. Behavioral assays revealed an autism-like phenotype including stereotypy, aberrant social interactions, and impaired memory. In vivo voltage-sensitive dye imaging, facilitating comparison with fMRI studies in autism, revealed widespread increases in cortical spontaneous activity and intracortical functional connectivity. These results suggest that mutations in MDGA2 contribute to altered cortical processing through the dual disadvantages of elevated excitation and hyperconnectivity, and indicate that perturbations of the NRXN-NLGN pathway in either direction from the norm increase risk for autism.

Ameliorative effect of membrane-associated estrogen receptor G protein coupled receptor 30 activation on object recognition memory in mouse models of Alzheimer's disease.

Membrane-associated estrogen receptor "G protein-coupled receptor 30" (GPR30) has been implicated in spatial recognition memory and protection against neuronal death. The present study investigated the role of GPR30 in object recognition memory in an Alzheimer's disease (AD) mouse model (5XFAD) by using novel object recognition (NOR) test. Impairment of long-term (24 h) recognition memory was observed in both male and female 5XFAD mice. Selective GPR30 agonist, G-1, ameliorated this impairment in female 5XFAD mice, but not in male mice. Our study demonstrated the ameliorative role of GPR30 in NOR memory impaired by AD pathology in female mice.

Traumatic brain injury accelerates amyloid-ß deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer's disease.

Several pathological and epidemiological studies have demonstrated a possible relationship between traumatic brain injury (TBI) and Alzheimer's disease (AD). However, the exact contribution of TBI to AD onset and progression is unclear. Hence, we examined AD-related histopathological changes and cognitive impairment after TBI in triple transgenic (3×Tg)-AD model mice. Five- to seven-month-old 3×Tg-AD model mice were subjected to either TBI by the weight-drop method or a sham treatment. In the 3×Tg-AD mice subjected to TBI, the spatial learning was not significantly different 7 days after TBI compared to that of the sham-treated 3×Tg-AD mice. However, 28 days after TBI, the 3×Tg-AD mice exhibited significantly lower spatial learning than the sham-treated 3×Tg-AD mice. Correspondingly, while a few amyloid-ß (Aß) plaques were observed in both sham-treated and TBI-treated 3×Tg-AD mouse hippocampus 7 days after TBI, the Aß deposition was significantly greater in 3×Tg-AD mice 28 days after TBI. Thus, we demonstrated that TBI induced a significant increase in hippocampal Aß deposition 28 days after TBI compared to that of the control animals, which was associated with worse spatial learning ability in 3×Tg-AD mice. The present study suggests that TBI could be a risk factor for accelerated AD progression, particularly when genetic and hereditary predispositions are involved.

Task-specific enhancement of hippocampus-dependent learning in mice deficient in monoacylglycerol lipase, the major hydrolyzing enzyme of the endocannabinoid 2-arachidonoylglycerol.

Growing evidence indicates that the endocannabinoid system is important for the acquisition and/or extinction of learning and memory. However, it is unclear which endocannabinoid(s) play(s) a crucial role in these cognitive functions, especially memory extinction. To elucidate the physiological role of 2-arachidonoylglycerol (2-AG), a major endocannabinoid, in behavioral and cognitive functions, we conducted a comprehensive behavioral test battery in knockout (KO) mice deficient in monoacylglycerol lipase (MGL), the major hydrolyzing enzyme of 2-AG. We found age-dependent increases in spontaneous physical activity (SPA) in MGL KO mice. Next, we tested the MGL KO mice using 5 hippocampus-dependent learning paradigms (i.e., Morris water maze (MWM), contextual fear conditioning, novel object recognition test, trace eyeblink conditioning, and water-finding test). In the MWM, MGL KO mice showed normal acquisition of reference memory, but exhibited significantly faster extinction of the learned behavior. Moreover, they showed faster memory acquisition on the reversal-learning task of the MWM. In contrast, in the contextual fear conditioning, MGL KO mice tended to show slower memory extinction. In the novel object recognition and water-finding tests, MGL KO mice exhibited enhanced memory acquisition. Trace eyeblink conditioning was not altered in MGL KO mice throughout the acquisition and extinction phases. These results indicate that 2-AG signaling is important for hippocampus-dependent learning and memory, but its contribution is highly task-dependent.

Implicit Memory in Monkeys: Development of a Delay Eyeblink Conditioning System with Parallel Electromyographic and High-Speed Video Measurements.

Delay eyeblink conditioning, a cerebellum-dependent learning paradigm, has been applied to various mammalian species but not yet to monkeys. We therefore developed an accurate measuring system that we believe is the first system suitable for delay eyeblink conditioning in a monkey species (Macaca mulatta). Monkey eyeblinking was simultaneously monitored by orbicularis oculi electromyographic (OO-EMG) measurements and a high-speed camera-based tracking system built around a 1-kHz CMOS image sensor. A 1-kHz tone was the conditioned stimulus (CS), while an air puff (0.02 MPa) was the unconditioned stimulus. EMG analysis showed that the monkeys exhibited a conditioned response (CR) incidence of more than 60% of trials during the 5-day acquisition phase and an extinguished CR during the 2-day extinction phase. The camera system yielded similar results. Hence, we conclude that both methods are effective in evaluating monkey eyeblink conditioning. This system incorporating two different measuring principles enabled us to elucidate the relationship between the actual presence of eyelid closure and OO-EMG activity. An interesting finding permitted by the new system was that the monkeys frequently exhibited obvious CRs even when they produced visible facial signs of drowsiness or microsleep. Indeed, the probability of observing a CR in a given trial was not influenced by whether the monkeys closed their eyelids just before CS onset, suggesting that this memory could be expressed independently of wakefulness. This work presents a novel system for cognitive assessment in monkeys that will be useful for elucidating the neural mechanisms of implicit learning in nonhuman primates.

Effect of endurance for adverse drug reactions on the preference for aggressive treatments in cancer patients.

PURPOSE: Cancer patients receiving chemotherapy will sometimes conceal their discomfort, but an excessive endurance for adverse drug reactions (ADRs) can lead to a poorer prognosis. The aim of this study was to clarify the association between ADR endurance and a preference of cancer patients for aggressive treatments. METHODS: A cross-sectional study was undertaken of inpatients under 75 years of age receiving injectable systemic chemotherapy or oral chronic medications at hospitals in Japan. Subjects were asked to respond to a validated questionnaire to assess the extent of their ADR endurance and whether they would choose a novel, more aggressive therapy if their life expectancy was estimated at 2 years. RESULTS: Study participants were separated into the chemotherapy group (n = 36) and the non-chemotherapy group (n = 78). In the chemotherapy group, patients who had moderate ADR endurance scores were more likely to choose the new therapy (0-33, 34-67, and 68-100 points: 0.0, 54.5, and 27.3 %; χ (2) test, p = 0.15). Additionally, every patient on long-term chemotherapy (≥3 years) had high ADR endurance scores but did not choose the new, riskier treatment. In the non-chemotherapy group, the proportion of those choosing the new therapy was linearly associated with higher ADR endurance scores (25.9, 38.2, and 64.7 %; p = 0.04). CONCLUSION: Cancer patients may prefer aggressive therapies, even when self-estimations of ADR endurance are not very high, especially if they have been receiving chemotherapy for a short period of time. These patients should be observed with great caution.

[A community electronic prescription system connecting physicians, pharmacists, and patients, and utilization of clinical information].

We tested a community electronic prescription system (K-CHOPS/PPISS) that we developed in Kagawa, Japan, which connects the prescribing physicians, pharmacists at community pharmacies, and patients through a community data center server. Physicians can send prescriptions, diagnoses, and laboratory data to the datacenter. Pharmacists in community pharmacies can access their patients' information through the datacenter and can return corrected prescriptions and reports containing guidance and adverse events to the hospital or clinic where the prescription was issued. Patients can then see their dispensed medications on their PCs, cellular phones, and smart phones. Additionally, patients can input medication-taking records, allergy and adverse drug reactions (ADR), any over-the-counter drug and supplements that they take, and their physical condition through the devices. The system enables pharmacists to appropriately advise and monitor ADR based on patient clinical data and enables physicians to accurately know the medications handed to patients and advisories issued by the pharmacists. Further, physicians and pharmacists can see the patients' condition which they entered on their devices if the patients agree. These would be helpful for avoiding ADR. The information accumulated in the data center can be potentially utilized for evaluation of the effectiveness and ADR of medications and for development of innovative medication. Discussion of the pros and cons for such utilization is needed.

Age-dependent impairment of eyeblink conditioning in prion protein-deficient mice.

Mice lacking the prion protein (PrP(C)) gene (Prnp), Ngsk Prnp (0/0) mice, show late-onset cerebellar Purkinje cell (PC) degeneration because of ectopic overexpression of PrP(C)-like protein (PrPLP/Dpl). Because PrP(C) is highly expressed in cerebellar neurons (including PCs and granule cells), it may be involved in cerebellar synaptic function and cerebellar cognitive function. However, no studies have been conducted to investigate the possible involvement of PrP(C) and/or PrPLP/Dpl in cerebellum-dependent discrete motor learning. Therefore, the present cross-sectional study was designed to examine cerebellum-dependent delay eyeblink conditioning in Ngsk Prnp (0/0) mice in adulthood (16, 40, and 60 weeks of age). The aims of the present study were two-fold: (1) to examine the role of PrP(C) and/or PrPLP/Dpl in cerebellum-dependent motor learning and (2) to confirm the age-related deterioration of eyeblink conditioning in Ngsk Prnp (0/0) mice as an animal model of progressive cerebellar degeneration. Ngsk Prnp (0/0) mice aged 16 weeks exhibited intact acquisition of conditioned eyeblink responses (CRs), although the CR timing was altered. The same result was observed in another line of PrP(c)-deficient mice, ZrchI PrnP (0/0) mice. However, at 40 weeks of age, CR incidence impairment was observed in Ngsk Prnp (0/0) mice. Furthermore, Ngsk Prnp (0/0) mice aged 60 weeks showed more significantly impaired CR acquisition than Ngsk Prnp (0/0) mice aged 40 weeks, indicating the temporal correlation between cerebellar PC degeneration and motor learning deficits. Our findings indicate the importance of the cerebellar cortex in delay eyeblink conditioning and suggest an important physiological role of prion protein in cerebellar motor learning.