Odors associated with neonatal experiences with the dam have enhanced anxiolytic effects in rat.

Odor stimuli are widely reported to promote relaxation and reduce anxiety in humans and rodents. However, it remains unclear if this anxiolytic efficacy can be further enhanced by association with positive experiences. Therefore, we compared the effects of a novel odor to a familiar odor previously paired with a positive experience on anxiety-like behaviors in rats. One group of Wistar-Imamichi female and male pups was exposed to an odor stimulus with their dams during postnatal days (PNDs) 8-12, whereas another control group was exposed to perfused air during the same period. Starting on PND 42, all animals were examined in the open field test (OFT) and elevated plus maze (EPM) test during exposure to scent-free air (vehicle), a novel odor, or the positive-familiar odor from postnatal exposure. In the EPM, female rats entered open arms with all 4 paws (complete entry) more frequently and spent more time on open arms during exposure to the positive-familiar odor than during exposure to air or a novel odor, whereas partial open arm entries with forepaws only were increased during exposure to both novel and positive-familiar odors compared to air. In contrast, male rats demonstrated no significant increase in open arm activity during positive-familiar odor exposure, but did show equally reduced grooming frequency during novel and familiar-positive odor exposure in the OFT. Exposure to positive-familiar odors may be an effective and safe method for anxiety reduction, especially in females.

Arginine-Rich Cell-Penetrating Peptide-Mediated Transduction of Mouse Nasal Cells with FOXP3 Protein Alleviates Allergic Rhinitis.

Intranasal corticosteroids are effective medications against allergic rhinitis (AR). However, mucociliary clearance promptly eliminates these drugs from the nasal cavity and delays their onset of action. Therefore, a faster, longer-lasting therapeutic effect on the nasal mucosa is required to enhance the efficacy of AR management. Our previous study showed that polyarginine, a cell-penetrating peptide, can deliver cargo to nasal cells; moreover, polyarginine-mediated cell-nonspecific protein transduction into the nasal epithelium exhibited high transfection efficiency with minimal cytotoxicity. In this study, poly-arginine-fused forkhead box P3 (FOXP3) protein, the "master transcriptional regulator" of regulatory T cells (Tregs), was administered into the bilateral nasal cavities of the ovalbumin (OVA)-immunoglobulin E mouse model of AR. The effects of these proteins on AR following OVA administration were investigated using histopathological, nasal symptom, flow cytometry, and cytokine dot blot analyses. Polyarginine-mediated FOXP3 protein transduction induced Treg-like cell generation in the nasal epithelium and allergen tolerance. Overall, this study proposes FOXP3 activation-mediated Treg induction as a novel and potential therapeutic strategy for AR, providing a potential alternative to conventional intranasal drug application for nasal drug delivery.

Clinical Surveillance of Candidemia at Our Hospital.

Treatment of Candidemia has become increasingly complicated as more and more non-albicans Candida species are being isolated in recent years.We launched an investigation of the species, the MIC value, and the state of administration of antifungal drugs for all the cases with Candida spp. confirmed by blood cultures for the 7-year period from 2012 to 2018 at our hospital. In total, 192 cases were found and 206 strains of Candida species were isolated. Overall, 49.5% of the 206 isolated strains were Candida albicans (102 strains), followed by Candida glabrata (40 strains, 19.4%), and Candida parapsilosis (38 strains, 18.4%). The most frequently used antifungal drug for the initial dose was MCFG (120 cases, 59.2%), while the most frequently switched antifungal agent was L-AMB. Cases with an inappropriate end-of-treatment time represented 58.7% of all the cases.We investigated the Candidemia situation at our hospital for a period of seven years. We believe that it is important for medical institutions to gather detailed data on candidemia at their own hospitals. Likewise, the hospital's Infection Control Team/Antimicrobial Stewardship Team should inform the physicians-in-charge about the appropriate diagnosis and treatment based on the data obtained.

Food hardness influences the progression of age-related hearing loss in mice.

C57BL/6J and DBA/2J mice are often used for hearing research because of their early onset and progression of age-related hearing loss (AHL). Here, we report that the hardness of the diet affects the progression of AHL in these mice. When C57BL/6J mice and DBA/2J mice were fed a pellet-type or powder-type standard AIN93M diet, the pellet diet significantly promoted AHL. AHL promotion was eliminated by crushing the pellet diet to a powder. Subsequently, when C57BL/6J mice were fed the pellet-type AIN93M diet obtained from three different manufacturers, two of them significantly promoted AHL. The hardness of the diets was measured, and it was found that the two diets that promoted AHL were significantly harder than the other diet. Next, we attempted to reduce diet hardness by replacing some nutritional ingredients with dried eggs or phosphatidylcholine (PC), and we succeeded in obtaining brittle diets with lower hardness values. Then, C57BL/6J mice were bred with brittle diets for 6 months and the promotion of AHL was suppressed to the equivalent level as the powder diet. Furthermore, when senescence-accelerated mice, SAMP8, were fed a brittle diet for one year, the progression of AHL was also suppressed; however, it did not affect other aging indexes, such as mental and physical performance. We also confirmed that a high-fat pellet diet, which is soft even in pellet form, did not promote AHL. Time-restricted feeding (tRF), which is a chrono-nutritional method to delay aging, ameliorated the promotion of AHL by the hard AIN93M pellets in C57BL/6J mice. These results indicate that the physical form and hardness of diets affect the progression of AHL in mouse models.

A flexible sequential learning deficit in patients with Parkinson's disease: a 2 x 8 button-press task.

A 2 x 8 button-press task is a sequential hand movement task in which subjects are required to press eight pairs of buttons as accurately and quickly as possible. The 2 x 8 task allows us to examine flexible sequential learning, more aptly called sequence-unselective learning. Sequence-unselective learning is observed after repeated experiences with the task, when subjects have shown good progress in learning, with new sequences as well as previously learned ones. Although cognitive inflexibility has been reported in patients with Parkinson's disease (PD), there have been few studies investigating their flexibility in sequential learning. We examined PD patients' ability for sequence-unselective learning through the use of a 2 x 8 button-press task. In the first session, PD patients and subjects from the control group performed a sequential 2 x 8 task until the learning criterion was fulfilled (Session 1). After 1 month, they participated in other sessions: one involving the learned sequence (Session 2) and another involving the new sequence (Session 3). We found that PD patients made more errors than the normal control subjects only when learning the new sequence (Session 3) (P < 0.01). In Session 3, control subjects reached the learning target with fewer errors than in the Session 1 (normal sequence-unselective learning), whereas the PD patients did not exhibit such an improvement. Our results revealed a sequence-unselective deficit in PD patients. The deficit may help to emphasize the cognitive and physical inflexibility of PD.

Structured floral arrangement programme for improving visuospatial working memory in schizophrenia.

Several cognitive therapies have been developed for patients with schizophrenia. However, little is known about the outcomes of these therapies in terms of non-verbal/visuospatial working memory, even though this may affect patients' social outcomes. In the present pilot study, we investigated the effect of a structured floral arrangement (SFA) programme, where participants were required to create symmetrical floral arrangements. In this programme, the arrangement pattern and the order of placing each of the natural materials was predetermined. Participants have to identify where to place each material, and memorise the position temporarily to complete the floral arrangement. The schizophrenic patients who participated in this programme showed significant improvement in their scores for a block-tapping task backward version; whereas, non-treated control patients did not show such an improvement. The present results suggest that the SFA programme may positively stimulate visuospatial working memory in patients.

Prefrontal and medial temporal contributions to episodic memory-based reasoning.

Episodic memory retrieval and reasoning are fundamental psychological components of our daily lives. Although previous studies have investigated the brain regions associated with these processes separately, the neural mechanisms of reasoning based on episodic memory retrieval are largely unknown. Here, we investigated the neural correlates underlying episodic memory-based reasoning using functional magnetic resonance imaging (fMRI). During fMRI scanning, subjects performed three tasks: reasoning, episodic memory retrieval, and episodic memory-based reasoning. We identified dissociable activations related to reasoning, episodic memory retrieval, and linking processes between the two. Regions related to reasoning were identified in the left ventral prefrontal cortices (PFC), and those related to episodic memory retrieval were found in the right medial temporal lobe (MTL) regions. In addition, activations predominant in the linking process between the two were found in the left dorsal and right ventral PFC. These findings suggest that episodic memory-based reasoning is composed of at least three processes, i.e., reasoning, episodic memory retrieval, and linking processes between the two, and that activation of both the PFC and MTL is crucial in episodic memory-based reasoning. These findings are the first to demonstrate that PFC and MTL regions contribute differentially to each process in episodic memory-based reasoning.

Differential contributions of the anterior temporal and medial temporal lobe to the retrieval of memory for person identity information.

Although previous studies have suggested the importance of the bilateral anterior temporal (ATL) and medial temporal lobes (MTL) in the retrieval of person identity information, there is little evidence concerning how these regions differentially contribute to the process. Here we investigated this question using functional magnetic resonance imaging (fMRI). Before scanning, subjects learned associations among faces (F), names (N), and job titles (as a form of person-related semantics, S). During retrieval with fMRI, subjects were presented with previously learned and new S stimuli, and judged whether the stimuli were old or new. Successful retrieval (H) trials were divided into three conditions: retrieval of S and associated F and N (HSFN); retrieval of S and associated F (HSF); and retrieval of S only (HS). The left ATL was significantly activated in HSFN, compared to HSF or HS, whereas the right ATL and MTL were significantly activated in HSFN and HSF relative to HS. In addition, activity in bilateral ATL was significantly correlated with reaction time for HSFN, whereas we found no significant correlation between activity in the right MTL and reaction time in any condition. The present findings suggest that the left ATL may mediate associations between names and person-related semantic information, whereas the right ATL mediates the association between faces and person-related semantic information in memory for person identity information. In addition, activation of the right MTL region implies that this area may contribute to a more general relational processing of associative components, including memory for person identity information.

Elderly adults improve verbal fluency by videophone conversations: a pilot study.

We conducted videophone conversations with elderly adults living in a nursing home to discover whether their verbal ability was improved by repeated remote conversations. The control group comprised five elderly adults. The experimental group comprised six elderly adults, including three patients with dementia. They took part in three videophone conversations and their verbal ability was measured before and after the conversations. During the sessions, the participants and volunteers talked about themselves and participated in a quiz. In the experimental group, the mean number of words generated increased from 4.8 to 6.5 after the session (P < 0.05); this increase was not observed in the control group. The experimental group also showed an improvement in words generated after indirect conversations. Videophone conversations appear to have some positive effects on verbal ability and may be beneficial in the cognitive rehabilitation of elderly adults.

Structured Floral Arrangement Program Benefits in Patients With Neurocognitive Disorder.

We attempted to clarify positive benefits in cognitive abilities and motivation during our cognitive intervention [structured floral arrangement (SFA) program] for patients with neurocognitive disorder due to stroke, traumatic brain injury (TBI), and other related disorders. In this SFA program, participants are required to arrange cut flowers and leaves on absorbent foam according to an instruction sheet. In a previous study of patients with schizophrenia, our SFA program encouraged participants and contributed to stimulating their visuospatial process and memory. Here, 27 patients with neurocognitive disorders participated in this study. Sixteen patients were assigned to an SFA-treated group and participated in six sessions during two phases plus to daily activities. Eleven non-treated patients engaged only daily activities during the same period. We compared Apathy Scale scores and neuropsychological scores between the SFA-treated and non-treated patients. Their mean attendance rate was more than 90% during the two phases. SFA-treated patients copied a Rey-Osterrieth complex figure more accurately than non-treated patients (p < 0.05) during the later intervention phase, whereas during the earlier phase, accuracy was comparable between treated and non-treated groups. In the SFA-treated group, recall scores also improved (p < 0.01), and the positive outcomes were maintained for about 3 months (p < 0.05). The Apathy Scale scores did not show significant change in either the SFA-treated or non-treated groups. Our present results suggest that the SFA program encouraged continuous participation to cognitive intervention and was useful for ameliorating dysfunctions in visuospatial memory and recognition in patients with neurocognitive disorder.

Favorite odor induces negative dream emotion during rapid eye movement sleep.

OBJECTIVE: As connections between nightmares and various psychiatric disorders have been reported, the clinical significance of studying dream emotionality is now growing in importance. Because the olfactory bulb connects directly to the amygdala odor presentation may be a crucial tool to study dream emotions. Previous studies have demonstrated that presentation of positive/negative odors during rapid eye movement (REM) sleep affects various aspects of dreaming. Although olfactory perception can be influenced by personal experiences, the role of individual preferences in the effects of olfactory stimuli on dreaming has not yet been clarified. The purpose of the current study was to clarify the effects of odor on dreaming during REM sleep, taking individual preferences into account. METHODS: Phenyl ethyl alcohol (rose-like smell) airflow was presented as an experimental stimulus, and odorless airflow was presented as the control. Participants who like (n = 7) and dislike (n = 8) the odor of phenyl ethyl alcohol were presented air with and without the odor of phenyl ethyl alcohol, respectively, during REM sleep and then awakened to report and rate their dream contents. Thereafter, the transcribed dream reports were rated by independent raters. RESULTS AND CONCLUSIONS: Participants who liked the odor of phenyl ethyl alcohol reported more emotionally negative dreams when they were presented with phenyl ethyl alcohol airflow than that with odorless airflow. In other words, the participant's favorite odor was associated with emotionally negative dreams. These findings could be attributed to the nature of odor perception and the characteristics of brain activities during REM sleep.

Possible role of fatty acids in milk as the regulator of the expression of cytosolic binding proteins for fatty acids and vitamin A through PPARalpha in developing rats.

Fatty acids in milk are thought to play an important role in intestinal maturation and gene expression in the postnatal small intestine. In this study, we determined the jejunal mRNA levels, in rats, of peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARdelta which are nuclear receptors for fatty acids. We also measured expression of their target genes during the postnatal period, namely liver type fatty acid-binding protein (L-FABP) and cellular retinol-binding protein, type II (CRBPII). The mRNA levels of PPARalpha, L-FABP and CRBPII, but not PPARdelta, gradually increased during the suckling period and then sharply declined to a low level at the end of the weaning period. Rat pups at 17 d of age, weaned to a high-fat diet, showed significantly greater mRNA levels of PPARalpha, L-FABP and CRBPII than those weaned to a low-fat diet. Oral administration of PPARalpha ligand, WY14,643 during four consecutive days of the weanling period caused a parallel increase in the mRNA levels of PPARalpha, L-FABP and CRBPII genes. Furthermore, caprylic acid and oleic acid, which are major components of fatty acids in milk, induced jejunal PPARalpha, L-FABP and CRBPII gene expression. Our results suggest that fatty acids in milk may play a pivotal role in maintaining an enhanced level of expression of L-FABP and CRBPII genes in the small intestine, presumably by acting as inducers of PPARalpha gene expression.

Disappearance of memory fragments in patients with Alzheimer's disease: evidence from a longitudinal study of visual priming.

Previous studies suggested that perceptual memory as indexed by visual priming is normal in patients with Alzheimer's disease (AD). However, these studies did not specifically test the long-term effects of visual priming, which may differ significantly between Alzheimer's patients and normal subjects. To test this possibility, we examined long-term visual priming in AD patients, 1 hour, 1 month, and 3 months after training. Our results indicated a significant difference in visual priming between AD patients and normal subjects after 3 months, but not 1 month. For AD patients, there was a strong positive correlation between the 3-month priming effect and the Mini-Mental State Examination (MMSE) scores-severely demented patients were less likely to exhibit priming after 3 months. It appears that severe cortical degeneration may render AD patients unable to consolidate their perceptual memories. Our results suggest that lack of visual priming in AD patients is linked to the inability to maintain fragmented perceptual memories.

Learning-related changes of brain activation in the visual ventral stream: an fMRI study of mirror reading skill.

A previous neuroimaging study has indicated that the visual dorsal stream may contribute to accurate reading of mirror-reversed words. However, the role of the visual ventral stream in the learning of mirror reading skill remains ambiguous. In the present fMRI study, we investigated learning-related changes in brain activation in the visual ventral stream in a mirror reading task. Subjects participated in three successive runs of the mirror reading task, in each of which they were asked to read mirror-reversed words and normal words as accurately and as quickly as possible. The behavioral data for the mirror reading condition showed significant improvement in reaction time but not in performance accuracy across the three runs. The activation data showed different learning-associated patterns related to the right and left visual ventral streams. On the right side, activity related to the reading of mirror stimuli was significantly greater than that related to normal stimuli in the first run only, whereas on the left side it was greater in all runs. Additional correlation analysis between response time data and percentage signal changes only in the mirror reading condition showed significant correlation on the right visual ventral stream in the first run only, whereas that on the left visual ventral stream was found only in the third run. The dissociable response between the right and left visual ventral streams may reflect learning-related changes in reading strategy and may be critical in improving the speed of reading mirror-reversed words.

Programmed Cell Death Progresses Differentially in Epidermal and Mesophyll Cells of Lily Petals.

In the petals of some species of flowers, programmed cell death (PCD) begins earlier in mesophyll cells than in epidermal cells. However, PCD progression in each cell type has not been characterized in detail. We separately constructed a time course of biochemical signs and expression patterns of PCD-associated genes in epidermal and mesophyll cells in Lilium cv. Yelloween petals. Before visible signs of senescence could be observed, we found signs of PCD, including DNA degradation and decreased protein content in mesophyll cells only. In these cells, the total proteinase activity increased on the day after anthesis. Within 3 days after anthesis, the protein content decreased by 61.8%, and 22.8% of mesophyll cells was lost. A second peak of proteinase activity was observed on day 6, and the number of mesophyll cells decreased again from days 4 to 7. These biochemical and morphological results suggest that PCD progressed in steps during flower life in the mesophyll cells. PCD began in epidermal cells on day 5, in temporal synchrony with the time course of visible senescence. In the mesophyll cells, the KDEL-tailed cysteine proteinase (LoCYP) and S1/P1 nuclease (LoNUC) genes were upregulated before petal wilting, earlier than in epidermal cells. In contrast, relative to that in the mesophyll cells, the expression of the SAG12 cysteine proteinase homolog (LoSAG12) drastically increased in epidermal cells in the final stage of senescence. These results suggest that multiple PCD-associated genes differentially contribute to the time lag of PCD progression between epidermal and mesophyll cells of lily petals.

Deficits in long-term retention of learned motor skills in patients with cortical or subcortical degeneration.

We investigated the acquisition and long-term retention of new skills in patients with cortical (Alzheimer's disease, AD) and subcortical (progressive supranuclear palsy, PSP; Parkinson's disease, PD) degeneration. The motor skill task performance of the PD and PSP patients improved with training, but the improvement disappeared within a few months, whereas AD patients retained learned skills for 3-18 months. The results of our experiments show that subcortical dysfunction induces a retention deficit for newly learned motor skills. Our present study suggests that a normal striatum is necessary for the formation of long-lasting motor skills, and that the striatum plays an important role as a motor skill consolidation system.

Residential maze as a task for testing rats' maze learning ability: effects of hippocampal lesions and cholinergic receptor antagonists.

We investigated whether rats can learn mazes by a procedure in which rats were left in the maze (residential maze) in groups for 1 h a day. Water and food locations, which served as the start and goal boxes respectively in the test trial, were at the opposite ends of the maze. On the test trial conducted everyday before the residence period, animals put in the start box showed a significant decrease of the error response into the blind alleys and running time to reach the goal box. Systemic administration of scopolamine (0.25, 0.5 mg/kg), a muscarinic receptor antagonist, dose-dependently increased the number of errors, but mecamylamine, a nicotinic receptor antagonist, had no effect. Bilateral hippocampal lesions retarded both the acquisition and retention of this maze learning. The results suggest that this residential maze procedure is useful for testing maze learning ability in rats.

[Longitudinal study of procedural memory in patients with Alzheimer-type dementia].

We never forget how to ride a bicycle, and it is thought that procedural memories are retained for a long time. Recently, it was reported that patients with dementia of the Alzheimer type(DAT) could not only acquire, but also retain, long-lasting procedural memories. Previous group studies had shown procedural memory retention times of only 1 month in DAT patients, while amnesic patients and healthy people could retain such memories for 12 months. The relationship between the ability to retain procedural memory and the stage of the disease is not clear, as to date there has been no longitudinal study of procedural memory retention in DAT patients. Thus, we examined DAT patients' ability to retain long-term procedural memories (after 1, 5 and 20 months), and analyzed the relationship between procedural memory ability and the progress of disease. Motor-type procedural memory was examined using the mirror tracing task and the bi-manual coordinated tracing task. All three of the DAT patients showed improvement in their performance. The time required for the tracing was reduced between trials, and the improvement did not disappear between sessions, or rather, their times further decreased in subsequent sessions. Even the most severe DAT patient (Mini Mental State Examination(MMSE) score of 4) was able to acquire the procedural memory and retain it for at least 3 months. Furthermore, one of the subjects showed retention of the procedural memory at 20 months. Our results suggest that DAT patients can retain procedural memories for extended periods, with no relationship between retention ability and disease progression. It is possible for even severely demented patients to acquire and retain motor-type procedural memories. Cognitive rehabilitation in DAT appears to be effective, and it is possible for DAT patients to learn new things. It may be that DAT patients can ameliorate their quality of life by using retained procedural memory.

[Neural basis of procedural memory].

Procedural memory is acquired by trial and error. Our daily life is supported by a number of procedural memories such as those for riding bicycle, typing, reading words, etc. Procedural memory is divided into 3 types; motor, perceptual, and cognitive. Here, the author reviews the cognitive and neural basis of procedural memory according to these 3 types. It is reported that the basal ganglia or cerebellum dysfunction causes deficits in procedural memory. Compared with age-matched healthy participants, patients with Parkinson disease (PD), Huntington disease (HD) or spinocerebellar degeneration (SCD) show deterioration in improvements in motor-type procedural memory tasks. Previous neuroimaging studies have reported that motor-type procedural memory may be supported by multiple brain regions, including the frontal and parietal regions as well as the basal ganglia (cerebellum); this was found with a serial reaction time task (SRT task). Although 2 other types of procedural memory are also maintained by multiple brain regions, the related cerebral areas depend on the type of memory. For example, it was suggested that acquisition of the perceptual type of procedural memory (e.g., ability to read mirror images of words) might be maintained by the bilateral fusiform region, while the acquisition of cognitive procedural memory might be supported by the frontal, parietal, or cerebellar regions as well as the basal ganglia. In the future, we need to cleary understand the neural "network" related to the procedural memory.