YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14.

The Yes-associated protein (YAP) is a transcriptional factor involved in tissue development and tumorigenesis. Although YAP has been recognized as a key element of the Hippo signaling pathway, the mechanisms that regulate YAP activities remain to be fully characterized. In this study, we demonstrate that the non-receptor type protein tyrosine phosphatase 14 (PTPN14) functions as a negative regulator of YAP. We show that YAP forms a protein complex with PTPN14 through the WW domains of YAP and the PPXY motifs of PTPN14. In addition, PTPN14 inhibits YAP-mediated transcriptional activities. Knockdown of YAP sensitizes cancer cells to various anti-cancer agents, such as cisplatin, the EGFR tyrosine kinase inhibitor erlotinib and the small-molecule antagonist of survivin, S12. YAP-targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects.

Alterations of nitric oxide and monoamines in the brain of the EL mouse treated with phenobarbital and zonisamide.

The effects of phenobarbital (PB; doses, 5, 10, and 25 mg/kg, intraperitoneally (i.p.)) and zonisamide (ZNS; doses, 30, 75, and 150 mg/kg, i.p.) on nitric oxide (NO) production, and those of coadministration of PB (5 mg/kg, i.p.) and ZNS (75 mg/kg, i.p.) on monoamines in the brain of the seizure-susceptible EL mouse were investigated. Nitric oxide production was obtained by measuring the combined level of nitrite plus nitrate (NOx). Zonisamide and PB dose-dependently suppressed the seizure of the EL mouse, and coadministration of PB (5 mg/kg) and ZNS (75 mg/kg) induced a greater degree of seizure suppression than treatment with ZNS or PB alone. Although PB (5 mg/kg) had no effect on brain NOx levels, ZNS (150 mg/kg) and coadministration of ZNS (75 mg/kg) and PB (5 mg/kg) decreased NOx levels significantly. Phenobarbital (5 mg/kg) did not influence monoamines, while coadministration of PB (5 mg/kg) and ZNS (75 mg/kg) decreased dihydroxyphenylacetic acid and increased 5-HT concentrations. The effect of the coadministration of two drugs on monoamines were similar to that of ZNS alone. These results suggest that one of the anticonvulsant effects of coadministration of PB and ZNS may be caused by changes in NOx levels.

Influences of caffeine to nitric oxide production and zonisamide concentration in the brain of seizure-susceptible EL mice.

To investigate changes of nitric oxide (NO) productions and zonisamide (ZNS) concentrations in the brain of seizure-susceptible EL mice given caffeine orally, mice were given caffeine (600 microg/mL) solution ad libitum as a drinking fluid for 1-3 weeks. Nitric oxide production in the brain was determined by measuring levels of nitrite plus nitrate (NOx). The brain NOx levels of mice treated with caffeine for 3 weeks were significantly higher than the control. Seizures in mice treated with caffeine for 2 and 3 weeks were not suppressed by ZNS at a dose of 75 mg/kg. Serum ZNS concentrations of mice with caffeine intake for 1-3 weeks were higher than in untreated mice. Conversely, brain ZNS concentrations of mice with caffeine intake for the same periods were significantly lower than in untreated mice. These results suggested that caffeine influenced brain NO production and ZNS concentrations in the seizure susceptibility of EL mice.

Effects of MK-801, dantrolene, and FK506 on convulsive seizures and brain nitric oxide production in seizure-susceptible EL mice.

To clarify the role of nitric oxide (NO) in the pathogenesis of seizures in susceptible EL mice, we investigated effects of three drugs potentially related to NO production, MK-801, dantrolene, and FK506, on convulsive seizures and brain NO metabolites (NOx). MK-801 or dantrolene, but not FK506, suppressed convulsive seizures in EL mice; only MK-801 reduced NOx in the brain. Our results suggested involvement of the N-methyl-D-aspartate receptor-channel complex and intracellular calcium mobilization, but not calcineurin, in the convulsions of EL mice.

Abnormal behavior of residents in a long-term care facility and the associated stress of care staff members.

To survey the factors associated with abnormal behavior in 99 elderly residing in a special nursing home, we investigated the relationships between abnormal behavior and depression as well as impairments in cognition and activities of daily living (ADL), and the stress level of 28 care staff members. The clinical criteria for grading of dementia (intellectual level), the Cornell scale for depression in dementia (CSDD), the dementia behavior disturbance (DBD) scale, and rating of performance of ADL were used to assess behavioral and psychiatric symptoms in the elderly patients. Stress levels of care staff members were assessed using the 'burnout' scale. The DBD scale score correlated with the intellectual level, CSDD score, and three categories of ADL (urinary continence, faecal continence, and comprehension of conversation). The DBD scale score correlated negatively with one category of ADL (eating) in men, but did not correlate with ADL in women. No correlation was found between the burnout scale scores of care staff and either their age or work schedules. Present results showed that abnormal behavior in special nursing home residents correlated with depression as well as cognitive impairment. It is believed that the treatment and management of depression will decrease abnormal behaviors and improve their quality of life in special nursing home residents.

A solvent used for antiepileptic drugs increases serum and brain zonisamide concentrations in seizure-susceptible el mice.

Effects of a solvent mixture commonly used to dissolve antiepileptic drugs on the anticonvulsive effect as well as serum and brain concentrations of zonisamide (ZNS), a sulfonamide derivative, were investigated. The solvent mixture consisted of propylene glycol (PG, 40%) and ethanol (10.5%) in saline (PES). Intraperitoneal administration of ZNS at 25, 50, and 75 mg/kg dissolved in PES suppressed seizures in the EL strain of mice more effectively than the same doses of ZNS in saline. Serum and brain concentrations of the drug were significantly higher with PES than with saline as the vehicle for administration. At a dose of 75 mg/kg ip, both serum and brain ZNS concentrations in mice treated with ZNS in PES remained significantly higher than concentrations in mice treated with ZNS in saline from 1 to 6 hours after injection. PES mixtures including PG may not be suitable solvents for antiepileptic drugs in experiments investigating anticonvulsive effects.

Age-related alterations of nitric oxide production in the brains of seizure-susceptible EL mice.

We evaluated age-related changes in nitric oxide (NO) production in the brains of EL mice, a strain highly susceptible to seizures. A group of EL(s) mice were tossed up weekly to induce convulsive seizures, while in a nonstimulated EL(ns) group induction of convulsive seizures was avoided. Brain levels of nitrite plus nitrate (NOx) in EL(ns) mice were significantly higher than in nonstimulated mice at 10 days, and also higher than levels at 15 and 50 weeks in either EL(s) or EL(ns) mice. A significantly higher number of NO-producing cells were demonstrated in the hippocampus and parietal cortex by staining for nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase in EL(s) mice at the ages of 15 and 50 weeks than in EL(ns) mice at the age of 6 weeks. In EL(ns) mice, significantly fewer neurons showed NADPH-diaphorase staining in the hippocampus, striatum and parietal cortex at the age of 50 weeks than at 6 weeks. The present results suggest that whole-brain NOx levels in EL(ns) and EL(s) mice and numbers of NADPH-diaphorase-positive neurons in EL(ns) mice decreased with aging, while increasing of numbers of such neurons in EL(s) mice were assumed to develop in compensation for reduction in whole-brain NOx levels.

Effects of combined administration of zonisamide and valproic acid or phenytoin to nitric oxide production, monoamines and zonisamide concentrations in the brain of seizure-susceptible EL mice.

This study was undertaken to elucidate the anticonvulsive effects of zonisamide (ZNS: 25, 50, and 75 mg/kg, intraperitoneal [i.p.]), which was coadministered with valproic acid (VPA: 25, 50, and 100 mg/kg, i.p.), or phenytoin (PHT: 10, 25, and 50 mg/kg, i.p.) to ZNS concentration, nitric oxide metabolites (NOx levels), and monoamines in the brain of the EL mouse, a strain highly susceptible to seizures. NOx levels were obtained from measuring of combined level of nitrite plus nitrate. Coadministration of ZNS with VPA or PHT suppressed convulsive seizures more effectively than with treatment of ZNS alone. Both serum and brain concentrations of ZNS tended to increase as the dose of VPA or PHT was increased. While coadministrations of ZNS (75 mg/kg) and VPA or PHT at any dose did not change brain and serum NOx levels, those altered brain monoamine contents. These results suggested that anticonvulsive effect of coadministrations of ZNS and VPA or PHT were caused by changes of monoamines rather than changes of NO metabolites.

The effect of alcohol on convulsions and nitric oxide levels in seizure-susceptible el mice.

To evaluate the influences of ethanol intake on convulsive seizures and brain nitric oxide (NO) production, EL mice, a strain highly susceptible to seizures, were given a 10% ethanol solution ad libitum. In mice consuming ethanol for 4, 8, and 12 weeks, seizures were not suppressed by zonisamide (75 mg/kg ip). Brain NO metabolite levels in mice after 12 weeks of consumption were significantly lower than those in control mice and those consuming ethanol for 4 weeks. Numbers of NADPH diaphorase-positive neurons in the hippocampal formation and parietal cortex of mice consuming for 4 and 12 weeks were significantly higher than in controls. These results suggested that increasing of numbers of NADPH diaphorase-positive neurons in the hippocampal formation and parietal cortex were assumed to develop in compensation for reduction in whole-brain NO metabolite levels of EL mice exposed to ethanol.

Nitric oxide production is decreased in the brain of the seizure susceptible EL mouse.

To investigate nitric oxide production in the brain of the EL mouse, an inbred mutant strain of the ddY mouse that is susceptible to convulsive seizures, we measured whole brain nitric oxide metabolites, and counted the number of nitric oxide-producing cells in the parietal cortex and striatum. Nitric oxide metabolites in the brain and serum were determined by measuring levels of nitrite plus nitrate. Nitric oxide-producing cells were demonstrated histochemically by staining for nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase. Levels of nitrite plus nitrate in the whole brain were significantly lower than those of the control mice, although levels of nitrite plus nitrate in the serum did not differ between groups. There were significantly fewer NADPH-diaphorase-positive cells in the parietal cortex and striatum of the EL mouse compared to the ddY controls. These results suggest that lower nitric oxide production in the brain may be related to the susceptibility of the EL mouse to convulsive seizures.

Gender of demented patients and specific family relationship of caregiver to patients influence mental fatigue and burdens on relatives as caregivers.

OBJECTIVES: To survey the burden and psychological problems of family caregivers of demented people. DESIGN: All scores were compared according to gender of the demented patients and which family members were the caregivers. SETTING: Outpatients clinic at the university hospital and the day service system for the elderly. PATIENTS: Sixty-two demented patients living at home and family members acting as caregivers. MEASURES: Cognitive function, activities of daily living (ADL) and behaviour of demented patients were rated using the Hasegawa scale, the ADL scale and the dementia behaviour disturbance (DBD) scale. Caregiver's burden and mental fatigue were rated using a burden scale and a general health questionnaire (GHQ). RESULTS: Caregiver burden correlated negatively with the Hasegawa score and positively with the GHQ and DBD scores. Caregiver burden, GHQ and DBD for male patients were significantly higher than for females. Little difference was evident for caregiver burden scale or patient DBD between spouses and offspring as caregiver, but the GHQ score for spouses was significantly worse than that for offspring. CONCLUSIONS: The difficulty of caregivers in supporting the daily life of demented family members correlated with patients' cognitive impairment, abnormal behaviour and ADL status, and caregivers' difficulty resulted in mental fatigue. Caregivers' relative isolation from friends, attributable to their caregiving responsibility, did not correlate with the demented person's cognitive impairment or ADL status.

Kainic and domoic acids differentially affect NADPH-diaphorase neurons in the mouse hippocampal formation.

We investigated changes in numbers of nitric-oxide-producing cells in the hippocampal formation, striatum, and temporal cortex of mice 24 h after intraperitoneal administration of kainic acid (5, 10, 15, and 20 mg/kg) or domoic acid (1, 2, and 4 mg/kg). Nitric-oxide-producing cells were demonstrated histochemically by staining for nicotinamide adenine dinucleotide phosphate diaphorase. Nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons in the dentate gyrus and the subiculum did not change in number following administration of kainic acid or domoic acid at any dose. Positive neurons in the CA3 region of mice treated with kainic acid or domoic acid at any dose were significantly fewer than in controls. Although the numbers of positive neurons in the CA1/CA2 regions did not differ from those of controls at any of the four doses of kainic acid, positive cells in the CA1/CA2 were significantly more numerous than in controls at any dose of domoic acid. Although no significant differences in the numbers of positive neurons in the striatum were apparent between controls and any of the four doses of kainic acid, domoic acid significantly decreased the numbers of such cells. These results suggest that systemically administered kainic acid and domoic acid affect differentially nitric-oxide-producing cells in the hippocampal formation.

Influence of dietary zinc on convulsive seizures and hippocampal NADPH diaphorase-positive neurons in seizure susceptible EL mouse.

Adequate, high and deficient dietary levels of zinc (Zn) were compared in seizure-susceptible EL mice with respect to convulsions and to nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase-positive hippocampal neurons. Diaphorase positivity is associated with nitric oxide (NO) production. Convulsive seizures in the EL mice given the various diets did not differ over 1-4 weeks, but convulsions in EL mice given the Zn-deficient diet for 4 weeks were more effectively suppressed by injection of zonisamide (ZNS) (75 mg/kg intraperitoneally) than in mice receiving high- or adequate-Zn diet for the same period. Numbers of NADPH diaphorase-positive neurons in the CA1/CA2 region of the hippocampal formation were significantly higher in mice given the Zn-deficient diet for 4 weeks than in mice fed adequate Zn. Mice receiving the high-Zn diet for the same period had significantly fewer NADPH diaphorase-positive neurons in the subiculum than mice with adequate Zn. These results suggest that Zn deficiency inhibits convulsive seizures of EL mice, and that dietary Zn influences numbers of NO producing neurons in the hippocampal formation.

Mental status of the elderly receiving home health services and the associated stress of home helpers.

One hundred and ninety elderly people receiving home health service were investigated. The intellectual levels, depressive state evaluated by the Cornell scale for depression in dementia (CSDD) scale, abnormal behaviors evaluated by the dementia behavior disturbance (DBD) scale, and activities of daily living (ADL) were examined. These assessments were performed by 72 skilled home helpers who also assessed the severity of their own level of stress using the Burnout scale. The intellectual level and mood-related signs, based on the CSDD scale, of the elderly living with families or with a spouse were diminished significantly as compared to the elderly living alone. The elderly living with families also performed worse on all ADL categories except for visual acuity as compared to the elderly living with a spouse or living alone. There was no significant correlation between the Burnout scale score and age or frequency of working as a home helper. These results suggest that elderly people living with families as compared to the elderly living with a spouse or living alone have greater mental health needs as well as more profound physical limitations.

Deep venous thrombosis of the leg due to psychiatric stupor.

We report the cases of two patients with psychiatric stupor who developed venous thrombosis. A 29-year-old schizophrenic woman had been hospitalized in psychiatric institutions three times because of stupor associated with auditory hallucinations and thought blocking. These symptoms recurred and she was admitted to our hospital with deep venous thrombosis of her left leg. The other patient was a 67-year-old woman with depression. She had also suffered from insomnia. Following admission to our hospital, she developed a depressive stupor complicated by deep venous thrombosis of her left leg. Both cases were treated with sodium heparin and urokinase, and completely resolved. It is well known that dehydration, infection and decubitus ulcers are important physical complications of psychiatric stupor, but there have been few reports of deep venous thrombosis as a physical complication of stupor.

A study of the quality of life in elderly people using psychological testing.

To study factors which influence the quality of life (QOL) in the elderly, we investigated the relationship between scores on the modified Philadelphia Geriatric Center (JPGC) Morale Scale and various other psychological tests in 51 elderly people residing in a long-term care facility. The JPGC Morale Scale score correlated with the scores for all sections of the Japanese version of the Cornell Medical Index (JCMI), but not with those for the Mini Mental State Examination, the Kohs block design test, the Bender Gestalt test and the activities of daily living (ADL). Both somatic and psychotic symptoms on the JCMI were correlated with the dementia behaviour disturbance scale score and walking ability according to the ADL. Subjects were further divided into four groups according to Fukamachi's neurotic discriminative diagram based on the JCMI. Scores for most sections of somatic and psychotic symptoms on the JCMI were elevated in proportion to the degree of neurotic tendencies in the elderly. These results indicate that the QOL of the elderly is influenced by subjective symptoms, but not by the degree of cognitive impairment or the ADL.

Abnormal behavior of elderly people residing in institutions of medical and social welfare systems.

We investigated factors correlated with abnormal behavior in the elderly residing in a special nursing home (group A) and a psychiatric hospital (group B) using the dementia behavior disturbance scale, the mini mental state examination, the Japanese version of the Philadelphia Geriatric Center morale scale, and the ADL assessment scale. The cognitive function of group B was decreased compared with that of group A, but most activities of daily living (ADL) in the latter group were disrupted compared with those in the former. Only a few categories of ADL correlated with abnormal behavior in group A, whereas cognitive function, quality of life, and most categories of ADL correlated with abnormal behavior in group B. These results suggest that factors correlated with abnormal behavior in the elderly differ within institutions of medical and social welfare systems.

Alcohol intake decreases brain Zonisamide concentration in inbred EL mice.

This study was undertaken to evaluate the effect of ethanol intake on the anticonvulsive effects of Zonisamide (ZNS), a sulfonamide derivative. EL mice, which are highly susceptible to seizures, were given a 10% ethanol solution ad lib for 1-4 weeks. In mice given ethanol for 4 weeks, seizures were not suppressed by ZNS at a dose of 75 mg kg-1, i.p. Serum ZNS concentrations following ethanol consumption for 1-4 weeks were higher than in untreated mice; however, brain ZNS concentrations following ethanol consumption were lower than those in untreated mice. These results suggest that alcohol intake decreases the brain concentration of ZNS, but not the serum concentration.

Age differences of psychiatric inpatients presenting with physical complications.

We reviewed the records of 292 inpatients in the psychiatric ward of Kagoshima University Hospital who were referred from other medical facilities over a 5-year period in order to clarify age differences in the reason for referral. Patients were classified into groups of physically and mentally ill individuals based on indications for admission. Both groups were further divided into four subgroups based on age. The incidence of inpatients with physical illnesses increased with age. Conditions related to pregnancy, childbirth and the puerperium occurred at high frequency in female patients in the 20- to 39-year-old subgroup. Individuals in the 40- to 59-year-old and in the > or = 60 years subgroups suffered more frequently from neoplasms. The proportion of patients manifesting a defective state in all age subgroups with the exception of the under 19-year-old subgroup was significantly higher in the physical illness group than in the mental illness group. The proportion of patients in a depressive state in the > or = 60 years subgroup was significantly higher in the mental illness group than in the physical illness group. Hence, it is necessary to find a method to be able to cope with psychiatric patients with physical complications to solve this problem.