Annexin A6 is a scaffold for PKCα to promote EGFR inactivation.

Protein kinase Cα (PKCα) can phosphorylate the epidermal growth factor receptor (EGFR) at threonine 654 (T654) to inhibit EGFR tyrosine phosphorylation (pY-EGFR) and the associated activation of downstream effectors. However, upregulation of PKCα in a large variety of cancers is not associated with EGFR inactivation, and factors determining the potential of PKCα to downregulate EGFR are yet unknown. Here, we show that ectopic expression of annexin A6 (AnxA6), a member of the Ca(2+) and phospholipid-binding annexins, strongly reduces pY-EGFR levels while augmenting EGFR T654 phosphorylation in EGFR overexpressing A431, head and neck and breast cancer cell lines. Reduced EGFR activation in AnxA6 expressing A431 cells is associated with reduced EGFR internalization and degradation. RNA interference (RNAi)-mediated PKCα knockdown in AnxA6 expressing A431 cells reduces T654-EGFR phosphorylation, but restores EGFR tyrosine phosphorylation, clonogenic growth and EGFR degradation. These findings correlate with AnxA6 interacting with EGFR, and elevated AnxA6 levels promoting PKCα membrane association and interaction with EGFR. Stable expression of the cytosolic N-terminal mutant AnxA6(1-175), which cannot promote PKCα membrane recruitment, does not increase T654-EGFR phosphorylation or the association of PKCα with EGFR. AnxA6 overexpression does not inhibit tyrosine phosphorylation of the T654A EGFR mutant, which cannot be phosphorylated by PKCα. Most strikingly, stable plasma membrane anchoring of AnxA6 is sufficient to recruit PKCα even in the absence of EGF or Ca(2+). In summary, AnxA6 is a new PKCα scaffold to promote PKCα-mediated EGFR inactivation through increased membrane targeting of PKCα and EGFR/PKCα complex formation.

Clock drawing interpretation scale (CDIS) and neuro-psychological functions in older adults with mild and moderate cognitive impairments.

The clock drawing test (CDT) is an easy to apply, well accepted and reliable test that is widely used to screen for visuo-constructional difficulties in the aged people. Yet, besides visual agnosia and constructional apraxia, executive control influences performances in this task. Execution modalities and rating schemes vary widely, as for the way stimuli are proposed, the time to which the clock is set, and the elements that are considered for scoring. The scoring system we have selected is called clock drawing interpretation scale (CDIS) contains 20 items in 3 areas: visuo-perceptual, attentional and numerical factors. Our aim is to know the meanings of the CDIS total and sub-areas score, investigating the relationships with specific neuropsychological tests, in elderly persons with moderate cognitive impairment. CDIS has been administered to 90 people, aged about 75 years, attending our rehabilitative day hospital or our memory clinic. A neuropsychological battery has been administered to a sample of 47 outpatients, selected by contingence. Respective mean MMSE for the 2 samples are 24 and 25.1 (adjusted for age and education). The score method shows good internal consistency, with Cronbach's a about 0.75, either for total score or for the 3 sub-scores. Both total score and all sub-scores share correlations with mini mental state examination (MMSE), geriatric depression scale (GDS 5-item form), digit-symbol test, phonetic fluency and constructional apraxia tests. Total score and Group A (visuo-perceptive items) correlate also with cancellation attentional matrices, trail making test A and B, Corsi's cubes and Raven's colored matrices. Group B (attention items) and Group C (numerical factors) lack some of these correlations (Pearson correlation coefficients between 0.264 and 0.629). Neither CDIS total score nor sub-scores (except for numerical factors) correlate with verbal learning and memory. CDIS total cores correlates also with the level of education (r=0.418; p=0.001), but not with age. In conclusion, the clock drawing test, scored by the 20-item CDIS, looks as a homogeneous and analytic test, which is focused on visuo-perceptive and executive skills, while it disregards verbal learning and memory, in elderly people with moderate cognitive impairment. Its 3-item groups show good internal consistency; they also plausibly correlate to specific neuropsychological tests. The almost overlapping results of total and visuo-perceptual sub-score come from the way the test is performed and evaluated. The correlation between CDIS and GDS confirms the relevance of mood towards executive functions.

Impaired facial emotion recognition and preserved reactivity to facial expressions in people with severe dementia.

The ability of decoding the emotional facial expressions may be early damaged in frontotemporal dementia, but relatively well preserved in the Alzheimer's disease (AD). Nevertheless, the data about the relationship of the dementia severity with the ability of recognizing the face emotions are conflicting and insufficient, mainly for the moderate-severe stage of the disease. The present study extends to the existing literature by: (1) assessing people in the moderate and severe stage of dementia, compared with people without cognitive impairment; (2) assessing not only recognition but also reactivity to the facial expression of emotion. The capability of understanding the facial emotions has been evaluated in 79 patients with dementia compared to 64 healthy elderly people. The test consisted in showing them 14 photographic representations of 7 emotions both from male and from female faces, representing happiness, sadness, fear, disgust, boredom, anger and surprise. Patients were asked to observe the face and to recognize the emotion either with a denomination or a description. Then the spontaneous reactivity to the face expressions was videotaped and classified as a congruous or incongruous reaction by two independent observers who showed a good inter-rater reliability. Of the patients, 53% with dementia recognized up to 5 emotions out of 14, while in the healthy controls this number of mean recognition raised to 8.4, a value reached by the patients who scored 16 at MMSE. The most identified emotion is happiness both for the patients and for the controls. In general, positive emotions are better recognized than the negative ones, confirming the literary data. About the reactions to face emotion stimuli, there is no significant difference for any of the face emotion between the control group and the people with dementia. These data show that patients with dementia can recognize and react to facial emotions also in the severe stage of the disease, suggesting the usefulness of a non-verbal, emotional communication and supporting the need for more emotional education for care givers, both relatives and professionals.

Menopausal transition: a possible risk factor for brain pathologic events.

BACKGROUND AND OBJECTIVE: Incidence and prevalence of Alzheimer's disease (AD) are higher in postmenopausal women than in age-matched men. Since at menopause the endocrine system and other biological paradigms undergo substantial changes, we thought to be of interest studying whether (and how) the balance between some biological parameters allegedly neuroprotective (e.g. related to estrogen, dehydroepiandrosterone and CD36 functions) and others considered pro-neurotoxic (e.g. related to glucocorticoid and interleukin-6 activities) vary during lifespan in either sex in either normalcy or neurodegenerative disorders. SUBJECTS AND METHODS: Along with this aim, we evaluated the gene expression levels of estrogen receptors (ERs), glucocorticoid receptors (HGRs), interleukin-6 (IL-6) and CD36, a scavenger receptor of class B allegedly playing a key role in the proinflammatory events associated with AD, in a population of 209 healthy subjects (73M, 106F, 20-91-year old) and 85 AD patients (36M, 49F, 65-89-year old). Results obtained were related to plasma titers of estrogens, cortisol and dehydroepiandrosterone sulfate (DHEAS). Studies were performed in peripheral leukocytes, since these cells (1) are easily obtainable by a simple blood sampling, (2) express many molecules and multiple receptors which are under the same regulatory mechanisms as those operative in the brain and (3) some of them, e.g. monocytes, share many functions with microglial cells. RESULTS: In healthy men all the study parameters were quite stable during lifespan. In women, instead, at menopausal transition, some changes that may predispose to neurodegeneration occurred. In particular, there was (1) an up-regulation of ERs, and a concomitant increase of IL-6 gene expression, events likely due to the loss of the inhibitory control exerted by estradiol (E(2)); (2) an increase of HGR alpha:HGR beta ratio, indicative of an augmented cortisol activity on HGR alpha not sufficiently counteracted by the inhibitory HGR beta function; (3) a reduced CD36 expression, directly related to the increased cortisol activity; and (4) an augmented plasma cortisol:DHEAS ratio, widely recognized as an unfavorable prognostic index for the risk of neurodegeneration. In AD patients of both sexes, the expression of the study parameters was similar to that found in sex- and age-matched healthy subjects, thus indicating their unrelatedness to the disease, and rather a better correlation with biological events. CONCLUSIONS: Menopausal transition is a critical phase of women's life where the occurrence of an unfavorable biological milieu would predispose to an increased risk of neurodegeneration. Collectively, the higher prevalence of AD in the female population would depend, at least in part, on the presence of favoring biological risk factors, whose contribution to the development of the disease occurs only in the presence of possible age-dependent triggers, such as beta-amyloid deposition.

Behavioral and psychotic symptoms of dementia (BPSD) improvements in a special care unit: a factor analysis.

BPSD are very frequent, so that 90% of demented patients have at least one. BPSD are troublesome both for elders with dementia and for caregivers, fostering the institutionalization. Yet, BPSD may vary as long as the disease progresses, and may fluctuate in the short run, either spontaneously or by pharmacological as well as non-pharmacological interventions. The aim of the study was to investigate by factor analysis possible groupings among the modifications occurring in BPSD, during the stay in a special care unit (SCU). BPSD were rated through the neuropsychiatric inventory (NPI); frequency x severity scores were calculated for any single BPSD at entry and at discharge: the differences were analyzed using factor analysis. The sample comprised 214 demented persons, 65.4% females; of mean age 79.6 years; Overall entry score of NPI was 46.1+/-20.7; NPI overall mean difference at discharge=-30.4+/-20.3. BPSD factor analysis on frequency x severity crude baseline scores resulted in 4 groups: 1 (agitation+irritability+aberrant motor activity+disinhibition); 2 (delusions+hallucinations); 3 (anxiety+dysphoria); 4 (apathy+euphoria). When differences (discharge frequency x severity-entry frequency x severity) for each BPSD scores were factor analyzed, grouping was rather similar: (i) agitation+irritability; (ii) delusions+hallucinations; (iii) anxiety+dysphoria+aberrant motor activity; (iv) euphoria+disinhibition; (v) apathy. In our sample, BPSD improved during the stay in the SCU. These improvements followed trajectories that looked plausible and were consistent with baseline groupings, by factor analysis.

Estrogen receptor alpha and APOEepsilon4 polymorphisms interact to increase risk for sporadic AD in Italian females.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects both sexes, with a higher prevalence in women. Declining estrogen levels after menopause may render estrogen target neurons in the brain more susceptible to age or disease-related processes such as AD. To investigate the role of two single nucleotide polymorphisms in the first intron of the ER-alpha gene, denominated PvuII and XbaI, and their interaction with the known AD susceptibility gene APOE, we examined 131 patients with sporadic AD and 109 healthy control subjects. In multinomial logistic regression analysis, a significantly increased risk of sporadic AD because of interaction between the ER-alpha p allele and APOE epsilon4 allele was observed in women, taking subjects who had neither the p allele nor epsilon4 as reference [odds ratio (OR) 7.24; 95% CI, 2.22-23.60]. For women carrying the ER-alpha x allele together with APOE epsilon4, the risk of sporadic AD was similarly elevated (OR 8.33; 95% CI, 1.73-40.06). The data suggest that the p and x alleles of polymorphic ER-alpha gene interact synergistically with the APOE epsilon4 allele to increase the risk of AD in women but not in men in this Italian cohort.

The impact of cognitive impairment on the rehabilitation process in geriatrics.

A study has been carried out in our geriatric rehabilitation wards, to know better the role of cognitive dysfunction in treatment outcome and processing, mainly functional recovery and comorbidity. We analyzed 478 frail inpatients, 2/3 of them were females, aged 78.7 + 9.2 years, consecutively admitted to the unit. Assessment of cognitive function was performed by the mini mental state examination (MMSE), of functional status by Barthel index (BI), of co-morbidity by cumulative illness rating scale (CIRS) both at the admission and discharge for each patient, together with the usual clinical parameters and social outcome. More than one people in three lived alone and showed some communication problems; one in seven needed modifications in food preparation or nutritional system;more than one in five had pressure sore >/= 2 (EPUAP = European Pressure Ulcers Advisory Panel classification). The mean (+/- SD) levels of the admitted were: MMSE = 20 +/- 7.2; BI total score = 45.5 +/- 28.9; CIRS class = 4 +/- 2, CIRS severity score = 1.9 +/- 0.4. Of the patients, 74.5% were discharged to home. Mean functional gain was 20 points at BI: 65.6 +/-30.7; MMSE improved to 21.6 +/- 7.1 (p = 0.00005 for both comparisons, by Wilcoxon test).MMSE was positively correlated to BI (r = 0.6, p = 0.0005) and negatively correlated (p =0.0005) to CIRS comorbidity (r = -0.33) and severity (r = -0.26), and to age (r = -0.38, p =0.0005) both at admission and at discharge. MMSE at admission was correlated neither to functional gain, nor to improvement of clinical indicators, nor to measures of functional and clinical efficiency. MMSE at discharge showed similar results. In a stepwise multiple correlation analysis, taking the gain in BI as the dependent variable, while BI, serum albumin level, MMSE, CIRS severity and comorbidity indexes at admission as independent variables, MMSE together with BI admission total score and CIRS severity index retained a strong association with functional gain, whilst admission serum albumin levels and CIRSindex lost it. Consistently with some literary data, we showed the actual possibility of functional and clinical gains for people cared in a geriatric rehabilitation ward, all through a wide range of MMSE score, including subnormal scores. Poor cognitive status bears heavily on frailty, but does not hamper the outcomes of genuine rehabilitative efforts in geriatrics.

Measurement on Tinetti test: instrumentation and procedures.

A measurement system and associate signal processing procedures for quantifying subject's performance during the performance-oriented assessment of balance as defined in Tinetti test (TT) is described. It is based on two inclinometers measuring trunk inclination in two orthogonal planes. Signals from the transducers are acquired by a PC through A/DC board. Signal processing consists in computing morphological parameters describing the main features of subject movement during the different TT maneuvers. The system is simple, cheap, user friendly, causes no discomfort to the patient and can easily be modified to comply with either new requirements or the needs of other performance tests dealing with trunk movement. Preliminary results of measurements on both normals and patients suggest the viability of this approach and the possibility of discriminating normal from abnormal performance, based on the values of the morphological parameters.

Adverse clinical events in dependent long-term nursing home residents.

OBJECTIVE: To assess the occurrence, type, and burden of adverse clinical events (ACE) among residents of chronic facilities. An ACE is any acute or subacute change in health status suggesting acute or subacute illness. DESIGN: Survey with face-to-face functional assessment and 3-month retrospective chart review. STUDY POPULATION: One hundred six continuing-care residents with a minimum length of stay of 4 months at an Italian chronic care facility. MEASUREMENTS: Functional assessment and chart review-based classification of ACE burden on care management according to a clinical-functional Severity Rating Scale. MAIN RESULTS: Functional dependence, dementia and concurrent clinical problems were common. Two hundred seventy-three ACEs were detected. Eighty-nine percent of residents experienced at least one ACE. Only 21% of ACEs could be managed by simple medical intervention and monitoring within 1 day; in 23% there was need for more complex care management; 7% of the latter ACEs resulted in residual (new) functional impairment. Cardiovascular and gastrointestinal systems were most commonly involved in ACEs. Neurological ACEs were the most frequent category leading to new functional impairment (22%). ACE occurrence/burden was higher in male residents (P < 0.01) and strongly associated with the number of concurrent medical problems (P < 0.001). Neither cognitive nor functional dependence levels were related to ACE occurrence. CONCLUSIONS: This description of the burden on care management resulting from acute and subacute changes in clinical and functional status of chronic patients emphasizes the continuing and unpredictable nature of medical attention required in a nursing home or chronic care facility. ACEs occur far more frequently among the elderly than is generally recognized. Thus a high level of medical and nursing skill is necessary in chronic care facilities.

[Biochemical and hematological indices of alcohol consumption in the aged]. / Indici biochimici ed ematologici di assunzione alcoolica nell'anziano.

Tre gamma-GT, SGOT, SGPT, urate and triglyceride levels and the mean cell volume were suggested to be markers of alcohol intake in the adult. The value of these markers for the old and the very old (over 80) were investigated. Three groups of different ages of heavy drinkers (under 50, 60-70 over 80) were examined. The highest number of alterations was found in the under 50 group; the lowest in the over 80 (P less than 0.01; chi square M X N method). The mean values in this last group and the number of alterations were similar to those found in a group of no-drinkers of the same age. These markers of alcohol uptake are considered to be of less value for the aged people.

[Blood lipids and alcohol consumption in the aged]. / Lipidi ematici ed assunzione di alcool nell'anziano.

In order to clarify the importance of chronic alcohol uptake in modifying the plasmal lipid levels in the aged people, two groups of males were examined. The people in the two groups had same mean age, and smoking habits (under 10 cigarettes a day) and received the same free ward diet, but had a different alcohol uptake; one group drank more than 150 g of ethanol a day and the other group less than 50 g. The almost only vehicle of ethanol was the red wine. No differences were found among the two groups neither for the cholesterol nor for total lipids, nor for triglycerides. This confirmed that for the aged people it cannot be spoken of an "alcohol induced iperlipemia".

[Alkaline urine in the aged]. / Le urine alcaline negli anziani.

Considering the frequent finding of alkalinity in the urines of elderly people of both sexes, we can propose many hypothesis among which the most probable seems a latent renal failure with secondary hyperparathyroidism and consequent alkalinization of the urines. We can presume that such a frequent alkalinity of the urines in old subjects has an important role in the frequent infectious of the urinary tract of elderly people.

[Proteinuria in the aged]. / La proteinuria negli anziani.

The Authors for a better knowledge of the senile kidney have studied the urinary proteins of a group of elderly people resident in a geriatric institute. For instance they have noted the percentage of proteinuria in the urine of 313 patients (M and F) with various pathology, making also an electrophoresis of the urinary proteins. They put in evidence that the subjects with proteinuria were older than others, without proteinuria, and noted the high incidence of the infectious diseases of the urinary tract in these patients. In a second time the urine of 247 apparently healthy elderly people has been studied. Through an accurate examination (that is comprehensive of some serum parameters and a comparison with subjects without proteinuria) the Authors discussed a way of growing old defined "with biological trouble".

[Alcohol, blood lipids and advanced age]. / Alcool, lipidi ematici ed età avanzata.

The problem of the alcohol induced hyperlipemia in men is still in discussion. The Authors have tested the plasma lipid values of elderly subjects, known as a "good drinkers" in relation to abstemious males of equal age. No significant differences were found in the plasma lipid values of the good drinkers compared with those of the abstemious patients.