Gesture imitation performance in community-dwelling older people: assessment of a gesture imitation task in the screening and diagnosis of mild cognitive impairment and dementia.

BACKGROUND: Gesture imitation, a simple tool for assessing visuospatial/visuoconstructive functions, is reportedly useful for screening and diagnosing dementia. However, gesture imitation performance in healthy older adults is largely unknown, as are the factors associated with lower performance. To address these unknowns, we examined the gesture imitation performance of a large number of community-dwelling older adults aged ≥65 years in Arao City, Kumamoto Prefecture (southern Japan). METHODS: The examiner presented the participants with eight gesture patterns and considered it a success if they could imitate them within 10 s. The success rate of each gesture imitation was calculated for three diagnostic groups: cognitively normal (CN) (n = 1184), mild cognitive impairment (MCI) (n = 237), and dementia (n = 47). Next, we reorganised the original gesture imitation battery by combining six selected gestures with the following scoring method: if the participants successfully imitated the gestures, immediately or within 5 s, two points were assigned. If they succeeded within 5-10 s, one point was assigned. The sensitivity and specificity of the battery were investigated to detect the dementia and MCI groups. Factors associated with gesture imitation battery scores were examined. RESULTS: Except one complex gesture, the success rate of imitation in the CN group was high, approximately 90%. The sensitivity and specificity of the gesture imitation battery for discriminating between the dementia and CN groups and between the MCI and CN groups were 70%/88%, and 45%/75%, respectively. Ageing, male sex, and a diagnosis of dementia or MCI were associated with lower scores on the gesture imitation battery. CONCLUSION: Gesture imitation tasks alone may not be sufficient to detect MCI. However, by combining gestures with set time limits, gesture imitation tasks can be a low-burden and effective method for detecting dementia, even in community medicine, such as during health check-ups.

GDP-bound Rab27a regulates clathrin disassembly through HSPA8 after insulin secretion.

Clathrin-dependent endocytosis is a key process for secretory cells, in which molecules on the plasma membrane are both degraded and recycled in a stimulus-dependent manner. There are many reports showing that disruption of endocytosis is involved in the onset of various diseases. Recently, it has been reported that such disruption in pancreatic ß-cells causes impaired insulin secretion and might be associated with the pathology of diabetes mellitus. Compared with exocytosis, there are few reports on the molecular mechanism of endocytosis in pancreatic ß-cells. We previously reported that GDP-bound Rab27a regulates endocytosis through its GDP-dependent effectors after insulin secretion. In this study, we identified heat shock protein family A member 8 (HSPA8) as a novel interacting protein for GDP-bound Rab27a. HSPA8 directly bound GDP-bound Rab27a via the ß2 region of its substrate binding domain (SBD). The ß2 fragment was capable of inhibiting the interaction between HSPA8 and GDP-bound Rab27a, and suppressed glucose-induced clathrin-dependent endocytosis in pancreatic ß-cells. The region also affected clathrin dynamics on purified clathrin-coated vesicles (CCVs). These results suggest that the interaction between GDP-bound Rab27a and HSPA8 regulates clathrin disassembly from CCVs and subsequent vesicle transport. The regulatory stages in endocytosis by HSPA8 differ from those for other GDP-bound Rab27a effectors. This study shows that GDP-bound Rab27a dominantly regulates each stage in glucose-induced endocytosis through its specific effectors in pancreatic ß-cells.

Enhanced Contraction of Arterial Smooth Muscle Cell in Skin Artery Is Sensitive to Hyperpolarization Mediated by BKCa Channel in Chronic Constriction Injury Model Rat.

Previous our study found that improvement of skin blood flow associated with neuropathic pain using vasodilators is useful for alleviation of neuropathic pain. In this study, we aimed to elucidate the mechanism underlying enhanced vasorelaxation induced by vasodilators, which increase cAMP and cyclic guanosine monophosphate (cGMP), in chronic constriction injury model rat. We assessed vasorelaxation effect of vasodilators by measurement of isometric contraction in isolated plantar artery from chronic constriction injury of sciatic nerve model rats. Nifedipine, a voltage-dependent Ca2+ channel inhibitor, NS1619, Ca2+-activated K+ (BKCa) channel opener, and diazoxide, an ATP-sensitive potassium channel opener, -induced vasorelaxation in ipsilateral plantar artery was enhanced compared to the these in contralateral plantar artery. Sodium nitroprusside (SNP), a nitric oxide (NO) donor, and substance P, a NK1 receptor agonist, caused vasorelaxation in both ipsilateral and contralateral artery. The vasorelaxation induced by SNP and substance P in ipsilateral artery is enhanced compared to the these in contralateral artery. Isoprenaline, a ß adrenoceptor agonist, and salbutamol, a ß2 adrenoceptor agonist, caused strong vasorelaxation in ipsilateral artery but not in contralateral artery. Iberiotoxin, a BKCa channel inhibitor, prominently suppressed the enhanced vasorelaxation induced by SNP, substance P, isoprenaline and salbutamol. In summary, the enhanced contraction of arterial smooth muscle cell in skin artery is sensitive to hyperpolarization in chronic constriction injury model rat. Furthermore, ß adrenoceptor agonist would be a good drug to improve the decreased skin blood flow because it has selective vasorelaxation to ipsilateral plantar artery.

Apigenin Alleviates Endoplasmic Reticulum Stress-Mediated Apoptosis in INS-1 ß-Cells.

The improvement of type 2 diabetes mellitus induced by naturally occurring polyphenols, known as flavonoids, has received considerable attention. However, there is a dearth of information regarding the effect of the trihydroxyflavone apigenin on pancreatic ß-cell function. In the present study, the anti-diabetic effect of apigenin on pancreatic ß-cell insulin secretion, apoptosis, and the mechanism underlying its anti-diabetic effects, were investigated in the INS-ID ß-cell line. The results showed that apigenin concentration-dependently facilitated 11.1-mM glucose-induced insulin secretion, which peaked at 30 µM. Apigenin also concentration-dependently inhibited the expression of endoplasmic reticulum (ER) stress signaling proteins, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) and cleaved caspase-3, which was elevated by thapsigargin in INS-1D cells, with peak suppression at 30 µM. This was strongly correlated with the results of flow cytometric analysis of annexin V/propidium iodide (PI) staining and DNA fragmentation analysis. Moreover, the increased expression of thioredoxin-interacting protein (TXNIP) induced by thapsigargin was remarkably reduced by apigenin in a concentration-dependent manner. These results suggest that apigenin is an attractive candidate with remarkable and potent anti-diabetic effects on ß-cells, which are mediated by facilitating glucose-stimulated insulin secretion and preventing ER stress-mediated ß-cell apoptosis, the latter of which may be possibly mediated by reduced expression of CHOP and TXNIP, thereby promoting ß-cell survival and function.

Comparison of caregiver burden between dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: Caring for patients with dementia with Lewy bodies (DLB) would be more stressful for their caregivers than those with Alzheimer's disease (AD). In this study, we compared levels of caregiver burden and the possible influential factors on the caregiver burden between DLB and AD. METHODS: Ninety-three DLB patients and 500 AD patients were selected from the Kumamoto University Dementia Registry. Caregiver burden, neuropsychiatric symptoms, basic activities of daily living (BADL) and instrumental activities of daily living (IADL) were assessed by the Japanese version of the Zarit Caregiver Burden Interview (J-ZBI), the Neuropsychiatric Inventory (NPI), the Physical Self-Maintenance Scale (PSMS), and the Lawton IADL scale, respectively. RESULTS: Despite the comparable Mini-Mental State Examination score, the J-ZBI score was significantly higher in the DLB group than the AD group (P = 0.012). A stepwise multiple regression analysis revealed that IADL score (ß = -0.23, P = 0.049), PSMS score (ß = -0.31, P = 0.010), disinhibition (ß = 0.22, P = 0.008), and anxiety (ß = 0.19, P = 0.027) were significantly associated with J-ZBI score in DLB. In AD, caregiver's relationship with patient (child) (ß = 0.104, P = 0.005), caregiver's gender (female) (ß = 0.106, P = 0.004), IADL score (ß = -0.237, P < 0.001), irritability (ß = 0.183, P < 0.001), apathy (ß = 0.132, P = 0.001), agitation (ß = 0.118, P = 0.007), and aberrant motor behaviour (ß = 0.107, P = 0.010) were associated with caregiver burden. CONCLUSIONS: Caring for DLB patients caused a higher degree of caregiver burden than AD patients in the same level of cognitive decline. The factors responsible for the caregiver's burden were different between DLB and AD. The caregiver burden for DLB patients was associated with the disability of basic ADL, IADL impairment, anxiety and disinhibition.

Harmine suppresses collagen production in hepatic stellate cells by inhibiting DYRK1B.

Liver fibrosis is a major consequence of chronic liver disease, where excess extracellular matrix is deposited, due caused by the activation of hepatic stellate cells (HSCs). The suppression of collagen production in HSCs is therefore regarded as a therapeutic target of liver fibrosis. The present study investigated effects of harmine, which is a ß-carboline alkaloid and known as an inhibitor of dual-specificity tyrosine-regulated kinases (DYRKs), on the production of collagen in HSCs. LX-2 cells, a human HSC cell line, were treated with harmine (0-10 µM) for 48 h in the presence or absence of TGF-ß1 (5 ng/ml). The expression of collagen type I α1 (COL1A1) and DYRK isoforms was investigated by Western blotting, quantitative RT-PCR, or immunofluorescence. The influence of knockdown of each DYRK isoform on the COL1A1 expression was further investigated. The expression of COL1A1 was markedly increased by treating with TGF-ß1 for 48 h in LX-2 cells. Harmine (10 µM) significantly inhibited the increased expression of COL1A1. LX-2 cells expressed mRNAs of DYRK1A, DYRK1B, DYRK2, and DYRK4, although the expression of DYRK4 was much lower than the others. Knockdown of DYRK1B, but not DYRK1A or DYRK2, with siRNA significantly suppressed TGF-ß1-induced increase in COL1A1 expression. These results suggest that harmine suppresses COL1A1 expression via inhibiting DYRK1B in HSCs and therefore might be effective for the treatment of liver fibrosis.

Asymmetric dimethylarginine accumulation under hyperglycemia facilitates ß-cell apoptosis via inhibiting nitric oxide production.

Low concentrations of nitric oxide (NO) produced by constitutive NO synthase (cNOS) has been shown to suppress apoptosis in pancreatic ß-cells. In the present study, the influence of asymmetric dimethylarginine (ADMA), the major endogenous inhibitor of NOS, on the apoptosis-suppressive effect of NO was investigated. The expression of dimethylarginine dimethylaminohydrolase 2 (DDAH2), an ADMA-metabolizing enzyme, in INS-1 ß-cells and in mouse pancreatic islets was drastically reduced by in vitro exposure to high-concentration glucose (20 mM) and by in vivo treatment of mice with the insulin receptor blocker S661, which resulted in hyperglycemia, respectively. In line with this, a higher ADMA level was observed in INS-1 cells exposed to 20 mM glucose. The treatment of INS-1 cells with ADMA, similarly to with the NOS inhibitor NG-nitro-L-arginine methyl ester, significantly facilitated 20 mM glucose-induced increase in cleaved caspase-3 protein expression. Furthermore, increased protein expression of cleaved caspase-3 and CHOP was observed in INS-1 cells with knockdown of DDAH2. These results suggest that ADMA accumulation through a decrease in DDAH2 expression in ß-cells, which is induced under hyperglycemic conditions, facilitates ß-cell apoptosis through suppression of cNOS-mediated NO production.

Diacylglycerol kinase δ functions as a proliferation suppressor in pancreatic ß-cells.

Although an aberrant reduction in pancreatic ß-cell mass contributes to the pathogenesis of diabetes, the mechanism underlying the regulation of ß-cell mass is poorly understood. Here, we show that diacylglycerol kinase δ (DGKδ) is a key enzyme in the regulation of ß-cell mass. DGKδ expression was detected in the nucleus of ß-cells. We developed ß-cell-specific DGKδ knockout (ßDGKδ KO) mice, which showed lower blood glucose, higher plasma insulin levels, and better glucose tolerance compared to control mice. Moreover, an increased number of small islets and Ki-67-positive islet cells, as well as elevated cyclin B1 expression in the islets, were detected in the pancreas of ßDGKδ KO mice. DGKδ knockdown in the ß-cell line MIN6 induced significant increases in bromodeoxyuridine (BrdU) incorporation and cyclin B1 expression. Finally, we confirmed that streptozotocin-induced hyperglycemia and ß-cell loss were alleviated in ßDGKδ KO mice. Thus, suppressing the expression or enzymatic activity of DGKδ that functions as a suppressor of ß-cell proliferation could be a novel therapeutic approach to increase ß-cell mass for the treatment of diabetes.

Late-manifestation of attention-deficit/hyperactivity disorder in older adults: an observational study.

BACKGROUND: The age of attention-deficit/hyperactivity disorder onset is usually during the first 12 years of life; however, there have been recent reports of late-onset attention-deficit/hyperactivity disorder. These reports have been limited to that of young adults, and details in older adults remain unknown. As such, we had previously presented the first case report of "very" late-onset attention-deficit/hyperactivity disorder, wherein the symptoms presented in senile age. In this observational study, we aimed to investigate the prevalence and clinical features of such attention-deficit/hyperactivity disorders in older adults visiting our dementia clinic. METHODS: Four hundred forty-six consecutive patients visiting our specialty outpatient clinic for dementia during the 2-year period from April 1, 2015 to March 31, 2017 were included in this study. First, the patients were examined for the presence or absence of dementia in our specialty outpatient clinic for dementia. Those not diagnosed with dementia were examined for the presence or absence of attention-deficit/hyperactivity disorder in our specialty outpatient clinic for developmental disorders. Finally, these patients who were diagnosed with attention-deficit/hyperactivity disorder were investigated in detail to clarify their clinical characteristics. RESULTS: Of 446 patients (246 women and 200 men), 7 patients were finally diagnosed with attention-deficit/hyperactivity disorder. Although these 7 patients were initially suspected to have Alzheimer's disease (considering their age, 6 of these 7 patients were suspected to have early onset Alzheimer's disease), it was found that these symptoms were due to attention-deficit/hyperactivity disorder. These patients had four characteristics in common: (1) they were significantly younger than the complete study population; (2) they predominantly showed inattention-related symptoms; (3) they showed latent manifestation; and (4) they experienced a stressful life event before manifestation. CONCLUSIONS: Our previous case report suggested that very late-onset attention-deficit/hyperactivity disorder patients could be incorrectly diagnosed with dementia. In this observational study, 1.6% of patients who were initially suspected of having dementia were actually diagnosed with attention-deficit/hyperactivity disorder. This study also showed that the "late-onset" described in our previous report would be better described as "late-manifestation." A clinician should consider late-manifestation of attention-deficit/hyperactivity disorder in the differential diagnosis when encountering dementia patients, especially early onset Alzheimer's disease.

Characteristic of process analysis on instrumental activities of daily living according to the severity of cognitive impairment in community-dwelling older adults with Alzheimer's disease.

OBJECTIVES: To clarify the characteristic of impaired and unimpaired Instrumental Activities of daily living (IADL) processes with the severity of cognitive impairment in community-dwelling older adults with Alzheimer's disease (AD) using the Process Analysis of Daily Activity for Dementia (PADA-D). DESIGN: Cross-sectional study. SETTING: 13 medical and care centers in Japan. PARTICIPANTS: 115 community-dwelling older adults with AD. METHODS: The severity of cognitive impairment was classified by Mini-Mental State Examination (20 ≥ mild group, 20 < moderate group ≥ 10, 10 < severe group), and IADL scores and eight IADL items in PADA-D were compared among three groups after adjusting for covariates. Rate of five feasible processes included in each IADL of PADA-D was compared. RESULTS: IADL score showed a decrease in independence with the severity of AD except for Use modes of transportation and Managing finances, which was especially pronounced in Shopping (F = 25.58), Ability to use the telephone (F = 16.75), and Managing medication (F = 13.1). However, when the PADA-D was examined by process, some processes that were impaired and unimpaired with the severity of cognitive impairment were clear. For example, Plan a meal was impaired (ES = 0.29) with the severity, but Prepare the food was not in Cooking performance. CONCLUSIONS: We suggested that detailed process analysis in IADLs can clarify the characteristic of processes that are impaired and unimpaired with the severity of cognitive impairment in older adults with AD living in the community. Our findings may be useful for rehabilitation and care in IADL to continue living at home.

Relationship between preoperative anxiety and onset of delirium after cardiovascular surgery in elderly patients: focus on personality and coping process.

BACKGROUND: Postoperative delirium is associated with increased mortality. Therefore, it is important to manage delirium during the entire perioperative period. Preoperative anxiety is associated with poor prognosis in postoperative patients who have undergone cardiovascular surgery. This study aims to investigate the relationship between preoperative anxiety and onset of delirium after cardiovascular surgery in elderly patients (aged 65 years or older), considering the individual psychological characteristics, such as personality and stress coping skills in response to anxiety, as confounding factors. METHODS: This prospective study included patients aged >65 years in a preoperative state before undergoing cardiovascular surgery. Subjects were divided into two groups based on whether they experienced postoperative delirium, or not. We compared clinical and demographic factors, preoperative psychiatric and psychological factors, and intraoperative and perioperative physical factors between the control and delirium groups. Multiple imputations were used to account for missing data. RESULTS: Out of 168 subjects enrolled in this study, 26 (15.5%) developed postoperative delirium. Univariate analysis showed significant differences in age (P = 0.027), cognitive function (P = 0.007), agreeableness (P = 0.029), and the Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score (P = 0.023) between the delirium and control groups. Multiple logistic regression analysis did not identify a significant association between preoperative anxiety and the onset of postoperative delirium. However, age (odds ratio (OR) = 1.114, P = 0.018), agreeableness (OR = 0.555, P = 0.008), and the APACHE-II score (OR = 1.227, P = 0.008) were identified as risk factors for postoperative delirium. CONCLUSION: Agreeableness, one of the personality traits associated with preoperative anxiety, appears to be involved in the development of postoperative delirium as an independent psychological factor, regardless of age or physical factors.

Differences by cognitive impairment in detailed processes for basic activities of daily living in older adults with dementia.

BACKGROUND: Impairment of activities of daily living in patients with dementia has a fundamental and lasting impact on their quality of life and requires a detailed assessment. This study investigated to clarify characteristic of basic activities of daily living (BADL) processes with the severity of cognitive impairment in community-dwelling older adults with dementia using the Process Analysis of Daily Activity for Dementia (PADA-D). METHODS: Participants were recruited from outpatient departments of 24 hospitals, daycare centres, and home rehabilitation services in Japan. The severity of cognitive impairment was determined using the Mini-mental State Examination (mild: score ≥ 20; moderate: 10 ≤ score < 20; severe: score < 10). Patient's BADL were assessed according to the PADA-D by observation of the occupational therapist and interviews with family members. Basic information and the scores of BADL items of the PADA-D were compared between the three groups. Subsequently, we compared the percentage of independent or non-independent processes included in the sub-items of BADL in the PADA-D. RESULTS: A total of 143 patients were included in the analysis. Performance on BADL was shown to decrease significantly with increasing severity of cognitive impairment. The percentage of all BADL processes performed ranged from 58% to 100% in mild, 38% to 97% in moderate, and 0% to 88% in severe. Some of the processes included in BADL of PADA-D showed no significant differences in independence between the three groups. DISCUSSION/CONCLUSION: Most BADL processes differed with respect to different independence rates depending on the severity of cognitive impairment of the older adults with dementia. However, some BADL processes were not associated with the severity of cognitive impairment. Our findings may suggest that a detailed BADL assessment of patients with dementia is useful in terms of caregiver education to avoid excessive caregiving and in predicting BADL impairment.

Renoprotective Effects of a Novel Receptor-Interacting Protein Kinase 2 Inhibitor, AS3334034, in Uninephrectomized Adriamycin-Induced Chronic Kidney Disease Rats.

Renal inflammation is a final common pathway of chronic kidney disease (CKD), and its progression can be used to effectively gauge the degree of renal dysfunction. Inflammatory mechanisms contribute to glomerulosclerosis and tubulointerstitial fibrosis, which are hallmarks of CKD leading to end-stage renal disease. Receptor-interacting protein kinase 2 (RIP2) is largely committed to nucleotide-binding oligomerization domain signaling as a direct effector and transmits nuclear factor-κB (NF-κB)-mediated proinflammatory cytokine production. In the present study, we hypothesized that if inflammation via RIP2 and NF-κB signaling plays an important role in renal failure, then the anti-inflammatory effect of RIP2 inhibitors should be effective in improving CKD. To determine its pharmacologic potency, we investigated the renoprotective properties of the novel RIP2 inhibitor AS3334034 [7-methoxy-6-(2-methylpropane-2-sulfonyl)-N-(4-methyl-1H-pyrazol-3-yl)quinolin-4-amine] in uninephrectomized adriamycin-induced CKD rats. Six weeks' repeated administration of AS3334034 (10 mg/kg, once daily) significantly reduced urinary protein excretion and prevented the development of glomerulosclerosis and tubulointerstitial fibrosis. In addition, AS3334034 showed beneficial effects on renal function, as demonstrated by a decrease in levels of plasma creatinine and blood urea nitrogen and attenuation of a decline in creatinine clearance. Furthermore, AS3334034 significantly attenuated inflammation, renal apoptosis, and glomerular podocyte loss. These results suggest that the RIP2 inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect and is therefore potentially useful in treating patients with CKD. SIGNIFICANCE STATEMENT: The receptor-interacting protein kinase 2 (RIP2) inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect, suggesting that the nucleotide-binding oligomerization domain-RIP2 axis might play a crucial role in the pathogenesis of inflammatory kidney diseases. AS3334034 is expected to be potentially useful in the treatment of patients with chronic kidney disease.

IgM response is a prognostic biomarker of primary biliary cholangitis treated with ursodeoxycholic acid and bezafibrate.

BACKGROUND AND AIM: Primary biliary cholangitis (PBC) patients who are refractory to ursodeoxycholic acid (UDCA) are at risk for progression to cirrhosis and liver failure. Bezafibrate could be an alternative second-line therapeutic option in these patients. This study aimed to evaluate the long-term outcome(s) of combined UDCA and bezafibrate therapy in UDCA-refractory PBC patients and identify prognostic factors. METHODS: Among 445 patients treated with UDCA, 150 patients inadequately responded to UDCA monotherapy and received long-term UDCA plus bezafibrate (median, 15 years). Data from these patients were used for this retrospective analysis. RESULTS: Combination therapy resulted in significant improvements in serum biochemistry and liver transplantation risk estimated using the UK-PBC-risk and the GLOBE scores. The cumulative normalization rates of alkaline phosphatase, gamma-glutamyltransferase, and immunoglobulin M (IgM) were significantly higher in patients without cirrhosis-related symptoms or liver-related events than in those with them. Overall, IgM constantly emerged as a significant factor associated with cirrhosis-related symptoms and liver-related events at all time points. Cumulative survival rates were significantly lower in patients with IgM ≥ 240 mg/dL than in patients with IgM < 240 mg/dL. Thus, normalization of IgM levels was a good surrogate predictor of long-term prognosis. None of the patients discontinued combination therapy due to any adverse events during the follow-up period. CONCLUSIONS: Our findings point to the beneficial effects of long-term UDCA plus bezafibrate combination therapy for UDCA-refractory PBC patients, and IgM response can be a useful predictive biomarker of long-term clinical outcomes.

Relationship between executive dysfunction and neuropsychiatric symptoms and impaired instrumental activities of daily living among patients with very mild Alzheimer's disease.

OBJECTIVES: Patients with Alzheimer's disease (AD) experience a gradual loss in their ability to perform instrumental activities of daily living (IADLs) from the early stage. A better understanding of the possible factors associated with IADL decline is important for the development of effective rehabilitation and support programs for patients with AD. Thus, we examined the relationships between comprehensive cognitive functions and neuropsychiatric symptoms and IADLs in patients with very mild AD. METHODS: In total, 230 outpatients with probable AD were recruited from the Memory Clinic at Kumamoto University Hospital between May 2007 and October 2016. All patients scored ≥21 points on the Mini-Mental State Examination at the first assessment. Relationships between the subdomains of the Lawton IADL scale and neuropsychological/neuropsychiatric tests were examined by multiple regression analysis. All analyses were performed separately in men and women. RESULTS: In female patients, scores on the Frontal Assessment Battery were significantly associated with telephone use ability, shopping, and ability to handle finances. Apathy scores in the Neuropsychiatric Inventory (NPI) were associated with telephone use ability, housekeeping, responsibility for own medications, and ability to handle finances. NPI agitation scores were associated with food preparation and housekeeping. Geriatric Depression Scale scores were associated with telephone use ability and ability to handle finances. In male patients, only NPI apathy scores were associated with telephone use ability. CONCLUSIONS: These results suggest the importance of properly assessing executive function, depression, and apathy at interventions for impaired IADLs among female patients with very mild AD.

Late-onset attention-deficit/hyperactivity disorder as a differential diagnosis of dementia: a case report.

BACKGROUND: Although adult attention-deficit/hyperactivity disorder has recently gained increased attention, few reports on attention-deficit/hyperactivity disorder in the pre-elderly or elderly have been published. Here, we present the case of a patient with attention-deficit/hyperactivity disorder who gradually developed dementia-like symptoms as she aged, which initially made her condition difficult to distinguish from early onset Alzheimer's disease. This report illustrates that some types of attention-deficit/hyperactivity disorder may be misdiagnosed as dementia. CASE PRESENTATION: The patient was a 58-year-old woman. Although she presented with a tendency for inattentiveness and forgetfulness since childhood, she did not have a history of psychiatric disorders prior to consultation. Around the age of 52 years, her inattentiveness and forgetfulness gradually progressed, and at 57 years of age, she became inattentive and forgetful that it interfered with her work and daily life. For example, she forgot meetings with important clients and transferred money to the wrong bank account; these failures resulted in poor management of her company. At home, she experienced increasing difficulties with remembering prior commitments with her family and misplacing items, which her family members noticed. With the encouragement of her family and employees, who worried that she was suffering from dementia, she visited our memory clinic, whereby she was suspected of having early onset Alzheimer's disease. However, neuropsychological tests and brain imaging evaluations did not reveal any significant abnormalities. After dismissing various possible diagnoses, including dementia, other organic diseases, mood disorders, and delirium, we diagnosed her with attention-deficit/hyperactivity disorder. Treatment with 18 mg of methylphenidate was initiated, and significant improvements in her symptoms were observed within a few days; for example, she stopped losing her things, was able to concentrate for long durations, and could complete more tasks than she could before treatment. Since initiating treatment, she has returned to work and has been able to perform her daily activities without difficulty. CONCLUSIONS: This case supports that some patients with late-onset attention-deficit/hyperactivity disorder may gradually develop dementia-like symptoms during the pre-elderly and elderly stages of life. Therefore, clinicians should consider late-onset attention-deficit/hyperactivity disorder as a differential diagnosis of some types of dementias.

TRPV2 channels mediate insulin secretion induced by cell swelling in mouse pancreatic ß-cells.

ß-Cell swelling induces membrane depolarization, which has been suggested to be caused at least partly by the activation of cation channels. Here, we show the identification of the cation channels. In isolated mouse pancreatic ß-cells, the exposure to 30% hypotonic solution elicited an increase in cytosolic Ca2+ concentration ([Ca2+]c). The [Ca2+]c elevation was partially inhibited by ruthenium red, a blocker of several Ca2+-permeable channels including transient receptor potential vanilloid receptors [transient receptor potential cation channel subfamily V (TRPV)], and by nicardipine, but not by the depletion of intracellular Ca2+ stores with thapsigargin and caffeine. The hypotonic stimulation also increased insulin secretion from isolated mouse islets, which was significantly suppressed by ruthenium red. Expression of TRPV2 and TRPV4 was confirmed in mouse pancreatic islets and the MIN6 ß-cell line by RT-PCR, Western blot, and immunohistochemical analyses. However, neither 4α-phorbol 12,13-didecanoate nor GSK1016790A, TRPV4 activators, showed any apparent effect on [Ca2+]c in isolated mouse ß-cells or in MIN6 cells. In contrast, probenecid, a TRPV2 activator, induced an increase in [Ca2+]c in MIN6 cells, which was attenuated by ruthenium red. Moreover, the [Ca2+]c elevation induced by 30% hypotonic stimulation was significantly reduced by knockdown of TRPV2 with siRNA and by tranilast, a TRPV2 inhibitor. The knockdown of TRPV2 also decreased insulin secretion induced by the hypotonic stimulation. In addition, glucose-stimulated insulin secretion was also significantly reduced in the TRPV2-knockdown MIN6 cells. These results suggest that osmotic cell swelling activates TRPV2 in mouse ß-cells, thereby causing membrane depolarization and subsequent activation of voltage-dependent Ca2+ channels and insulin secretion.

Differentiation-inducing factor-1 prevents hepatic stellate cell activation through inhibiting GSK3ß inactivation.

Differentiation-inducing factor-1 (DIF-1), a morphogen produced by the cellular slime mold Dictyostelium discoideum, is a natural product that has attracted considerable attention for its antitumor properties. Here, we report a novel inhibitory effect of DIF-1 on the activation of hepatic stellate cells (HSCs) responsible for liver fibrosis. DIF-1 drastically inhibited transdifferentiation of quiescent HSCs into myofibroblastic activated HSCs in a concentration-dependent manner, thus conferring an antifibrotic effect against in the liver. Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, showed any effect on the inhibition of HSC activation by DIF-1. In contrast, TWS119, a glycogen synthase kinase 3ß (GSK3ß) inhibitor, attenuated the inhibitory effect of DIF-1. Moreover, the level of inactive GSK3ß (phosphorylated at Ser9) was significantly reduced by DIF-1. DIF-1 also inhibited nuclear translocation of ß-catenin and reduced the level of non-phospho (active) ß-catenin. These results suggest that DIF-1 inhibits HSC activation by disrupting the Wnt/ß-catenin signaling pathway through dephosphorylation of GSK3ß. We propose that DIF-1 is a possible candidate as a therapeutic agent for preventing liver fibrosis.

Dual effect of reduced type I diacylglycerol kinase activity on insulin secretion from MIN6 ß-cells.

The role of type I diacylglycerol kinases (DGKs) in the regulation of insulin secretion was investigated in MIN6 ß-cells. In intracellular Ca2+ concentration ([Ca2+]i) measurement experiments, 1 µM R59949, a type I DGK inhibitor, and 10 µM DiC8, a diacylglycerol (DAG) analog, amplified 22.2 mM glucose-induced [Ca2+]i oscillations in a protein kinase C (PKC)-dependent manner, whereas 10 µM R59949 and 100 µM DiC8 decreased [Ca2+]i independent of PKC. High concentrations of R59949 and DiC8 attenuated voltage-dependent Ca2+ channel currents. According to these results, 22.2 mM glucose-stimulated insulin secretion (GSIS) was potentiated by 1 µM R59949 but suppressed by 10 µM of the same. The DGKα inhibitor R59022 showed a similar dual effect. Conversely, DiC8 at 10 and 100 µM potentiated GSIS, although 100 µM DiC8 decreased [Ca2+]i. These results suggest that DAG accumulated through declined type I DGK activity shows a dual effect on insulin secretion depending on the degree of accumulation; a mild DAG accumulation induces a PKC-dependent stimulatory effect on insulin secretion, whereas an excessive DAG accumulation suppresses it in a PKC-independent manner, possibly via attenuation of VDCC activity.

IRR is involved in glucose-induced endocytosis after insulin secretion.

Endocytosis after insulin secretion plays a pivotal role in the regulation of insulin secretion in pancreatic ß-cells. Our recent study suggested that EPI64, a GTPase activating protein for Rab27a, contributes to the regulation of glucose-induced endocytosis, which is mediated by the GDP-bound form of Rab27a. Here, we identified insulin receptor-related receptor (IRR) as an EPI64-interacting protein. Knockdown of IRR inhibited glucose-induced uptake of transferrin, a marker of endocytosis, translocation of the guanine-nucleotide-exchange factor ARNO to the plasma membrane, and generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3). These results suggest that IRR functions upstream of PIP3 generation and controls endocytosis after insulin secretion.