Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion is among the strongest known genetic risk factors for neuropsychiatric disorders, including autism and schizophrenia. Brain imaging studies have reported disrupted large-scale functional connectivity in people with 22q11 deletion syndrome (22q11DS). However, the significance and biological determinants of these functional alterations remain unclear. Here, we use a cross-species design to investigate the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. We find that LgDel mice, an established mouse model of 22q11DS, exhibit age-specific patterns of functional MRI (fMRI) dysconnectivity, with widespread fMRI hyper-connectivity in juvenile mice reverting to focal hippocampal hypoconnectivity over puberty. These fMRI connectivity alterations are mirrored by co-occurring developmental alterations in dendritic spine density, and are both transiently normalized by developmental GSK3ß inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous hyper- to hypoconnectivity reconfiguration occurs also in human 22q11DS, where it affects hippocampal and cortical regions spatially enriched for synaptic genes that interact with GSK3ß, and autism-relevant transcripts. Functional dysconnectivity in somatomotor components of this network is predictive of age-dependent social alterations in 22q11.2 deletion carriers. Taken together, these findings suggest that synaptic-related mechanisms underlie developmentally mediated functional dysconnectivity in 22q11DS.

Alternatives to animal experimentation for hormonal compounds research.

Alternatives to animal testing and the identification of reliable methods that may decrease the need for animals are currently the subject of intense investigation worldwide. Alternative testing procedures are particularly important for synthetic and natural chemicals that exert their biological actions through binding nuclear receptors, called nuclear receptors-interacting compounds (NR-ICs), for which research is increasingly emphasizing the limits of several models in the accurate estimation of the physiological consequences of exposure to these compounds. In particular, estrogen receptor interacting compounds (ER-ICs) have a great impact on human health from the therapeutic, nutritional, and toxicological point of view due to the highly permissive nature of the estrogen receptors towards a large number of natural and synthetic compounds. Similar to in vitro systems, recently generated animal models (e.g., animal models generated for the study of estrogen receptor ligands) may fulfill the 3R principles: refine, reduce, and replace. If used correctly, NR-regulated models, such as reporter mice, xenopus, or zebrafish, and models obtained by somatic gene transfer in reporter systems, combined with imaging technologies, may contribute to strongly decreasing the overall number of animals required for NR-IC testing and research. With these models, flexible and highly standardized parameters and reporter marker quantification can be obtained. Here, we highlight the need for the substitution of currently used testing models with more appropriate ones that can reproduce the features and reactivity of specific mammalian target tissue/organs. We consider the promotion of this advancement a research priority bearing scientific, economic, social, and ethical relevance.

Estrogen receptor-mediated transcriptional activity of genistein in the mouse testis.

Here we show that genistein, through an estrogen receptor-mediated action, modulates gene expression in the mouse testis throughout development. Genistein passed from the lactating mother to the suckling offspring at levels sufficient to activate gene expression in the testis of the pups. Testis are already responsive to genistein as well as to estradiol at day 14.5 of fetal development. Activation of luciferase correlates with an activation of cell proliferation. In conclusion, our results show that genistein affects reproductive organs of male mice at all developmental ages.

[Ethics and dementia: a three years' experience of a French "Alzheimer's ethico-clinic workshop"]. / Ethique et démence: une expérience de trois ans de l'Espace éthique Alzheimer grenoblois.

There is a growing interest concerning ethical questions. This ethical need is the more important in the field of dementia. Indeed, the ethical concerns related to this field are highly specific, which leaves some of our questions without pertinent answers. METHODS: After three years of experience, it is a good time to assess the Alzheimer ethico-clinic workshop created by a French memory centre (in Grenoble) and encouraged by the French national Alzheimer disease plan. RESULTS: Since their implementation, we have recorded 24 monthly coordination meetings, 10 of which have been held through videoconferences with various participants. Most of the time during the workshops, clinical situations that are experienced in our daily activities are brought up by one of us and then exposed for collective discussion. If no practical situation is available, we organize the meetings through critical readings of texts of law or through comments on articles dealing with Ethics. We retain four main ethical topics: the information given to the patient and his family, the acceptance of the person, the balance of benefits/risks and one's individual ethics as opposed to the ethics of a group. At this point in time, we are pleased with the organization of these workshops and feel that they meet our expectations. Thanks to the diverse experiences and activities of each participant, the discussions on Ethics are of high quality. PROSPECTIVES: As a place of shared discussions/thoughts, these ethical workshops could constitute a reference to be used when making decisions in complex situations. Other than the importance of the ethical questions that are raised, it should encourage open-minded attitudes and enrich the actions of each of us by making us more aware of the ethical concerns in daily situations. Finally, these workshops could be a field of research for theses, dissertations and answer the training and research needs of a memory centre.

Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner.

The soy isoflavone genistein targets adipose tissue and elicits physiological effects that may vary based on dietary intake. We hypothesized that the adipose effects of genistein are dose and gender dependent. Four-week-old C57BL/6 male and female mice received daily oral doses of genistein (50-200,000 microg/kg.d) or 17beta-estradiol (E2) (5 microg/kg.d) for 15 d or a diet containing 800 ppm genistein. Genistein increased epididymal and renal fat pad and adipocyte size at doses up to 50,000 microg/kg.d or at 800 ppm in the diet in males but not in females. The alteration in adipocity correlated with changes in peripheral insulin resistance. These treatments increased genistein serum concentrations from 35+/-6 to 103+/-26 nM 12 h after treatment and lowered plasma triglycerides and cholesterol levels. The 200,000 microg/kg.d genistein dose decreased adipose tissue weight similarly to E2. This genistein dose down-regulated estrogen receptor (beta more than alpha) and progesterone receptor expression and induced estrogen-dependent adipose differentiation factors; it did not change expression of the minimal consensus estrogen-responsive element in ERE-tK-LUC mice, which was positively modulated in other tissues (e.g. the lung). E2 down-regulated almost all examined adipogenic factors. Gene microarray analysis identified factors in fat metabolism and obesity-related phenotypes differentially regulated by low and high doses of genistein, uncovering its adipogenic and antiadipogenic actions. The lower dose induced the phospholipase A2 group 7 and the phospholipid transfer protein genes; the 200,000 microg/kg.d dose inhibited them. The antiadipogenic action of genistein and down-regulation of adipogenic genes required the expression of ERbeta. In conclusion, nutritional doses of genistein are adipogenic in a gender-specific manner, whereas pharmacological doses inhibited adipose deposition.

[How can psychological help be provided for the patient/caregiver tandem home?]. / Pour un soutien pychothérapique à domicile du couple patient/aidant.

INTRODUCTION: Elderly people and their family helpers are often isolated at home and do not have access to the professional psychological help that they require. For an elderly population, the trips to consulting rooms are difficult, tedious and expensive. Besides, maintaining a patient at home is heavy to manage for close relatives because of the organization, financial issues and above all the risk of psychological burnout. The literature shows us that psychological assistance is more common at distance from home, in hospitals, in special institutions or specific organizations. However, there is a clear need of help at home. We propose to develop psychological assistance at home for the patient/helper tandem in cases of dementia. This prospective study reports three different cases. METHOD: This study is a qualitative pilot study. Participants characteristics: patients were diagnosed with severe dementia, assistance showed deep fatigue of the helper, both members of the tandem lived at home, age above 69 years, the eed for nursing care at home. THERAPEUTIC ASSESSMENT: The psychological clinician acts after proposing his helpand not on a clear request from the patient. He will meet his patient 7 times during 4 months. The meetings always take place in the same place and last 45 minutes. Confidentiality during the meeting is explained and guaranteed so the patient can speak openly. EVALUATION: An independent psychologist assessed the monitoring in the hospital. Our methodology included two assessments: the first, assessing the task of the helper before the evaluation and the second taking into account a new measurent of the task and the opinions of the participants following a semi-directed interview. The evaluation of the task was performed using Zarit's scale. The evaluation was also based on the clinical observation of the psychologist. RESULTS: Organization of the monitoring: one meeting per week was sufficient for all participants with a minimal duration of 45 minutes. The fact that the meetingsrook place at home was appreciated, because of their simple and convenient organization. The patient/helper tandems in those suffering from advanced dementia could only have taken place in the home because transport any where else would have beent too difficult for them. The sessions during this research study were free of charge. Two out of three participants were ready to pay so long as the study could continue. The managers were bothered a few times by phone calls and/or unexpected visits, invitations for a cup of tea and requests for a small service (like mailing a letter). Assistance for the caregiver: all the caregivers declared that assistance was a personal improvement in a period of doubt, loss of self-confidence and isolation. Furthermore, clinical observation of the therapeutic assistance appears to show that psychological help at home could lead to the improved psychological function of the helper. This was emphasized when we established the limits of the caregiver/patient relationship. We observed a better balance in the input of investing and de-investing and better acceptance of the identity modifications which were required for the caregiver. Assistance for the patient: we believe that this sort of intervention has positive effects on the patients themselves. This care at home protects the destructurated identity of the patients and their intimity. Moreover, intrapsychic tension can be lowered by being shared with the psychologist. Assessment of the burden: among the three patients who wete studied, the burden was unaltered in one case (43/88; 43/88), significantly improved in one case (41/88; 24/88) and remained light in one case (18/88; 16/88). DISCUSSION: We discovered that Zarit's test showed some limits. The time to complete the test is quite long and tedious for caregivers. Some questions are too direct and can put the caregivers in a guilty position. The mini Zarit version with only seven items, appears more satisfactory because it's shorter and provokes less guilt. The other point concerns the therapeutic frame at home. The usually represents all the constants of the therapeutic process including the role of the psychologist and all the items that refer to space, time, management of the timetable, payement and interruptions in care. Could the fact of being at home be harmful for the therapeutic process? Of course, the place of residence is less neutral than a office in an institution and the superposition of the frame of life and of the therapeutic frame raises lots of questions for the psychologist: entering a private house is like entering a private life, which is not without consequences on the follow-up. We are here far from a classical frame of therapeutic interviews, so the frame must be clearly defined. CONCLUSION: This prospective study leads us to the conclusion that the superposition of the frame of life and of the therapeutic frame represents a limit to psychotherapy but is not exclusive of psychological support at home. As a supplement to this face to face follow up at home, we could imagine other ways of providing such psychological support, by phone or by telemedicine for instance. Could the new technologies of communication help to compensate the lack of means in favour of the caregivers at home? Although these new technologies are more dedicated to institutions than to providing care at home, could they not be helpful for organizing psychological help at home? However, in order to validate such devices, they need to be fried and assessed at home.

[Life satisfaction in 28 intellectually gifted persons aged 65 and over]. / Satisfaction de vie de 28 surdoués parvenus à 65 ans et plus.

OBJECTIVE: To date, no French studies have been published concerning intellectually gifted elderly people (over 65 years of age), although they represent more than 200,000 people in France. METHOD: This paper reports the results of a study conducted with members of the Mensa Association, whose membership is open to those who have scored very highly on IQ tests (scores of 132 or higher). Twenty-eight gifted elderly people (aged between 65 and 86 years) were assessed using a life satisfaction index (Neugarten Scale). The results were compared with those obtained from a sample of 394 elderly people who participated in the lcare study, which is recognised as a reference study. RESULTS: Our study indicates that gifted elderly people have significantly higher rates of life satisfaction (past, present and future) than normal elderly people. DISCUSSION: The Neugarten index revealed the great life satisfaction in this population. However, several biases should be taken into account: size of the sample, recruitment method and life satisfaction assessment. Despite these limits, the results of this study are of certain interest since there is little data on follow-up and aging of intellectually gifted people in the literature.

Teleconsultation in psychology: the use of videolinks for interviewing and assessing elderly patients.

Although elderly people are one of the major target groups for telemedicine applications, they remain under-represented in studies of teleconsultation. Videolinks appear to be easily used by many elderly people as a means of communicating with health-care staff, including psychologists and doctors. To date, studies of psychometric teleconsultation have been confined to screening tests, or have used very small numbers of patients. There is a need to examine the reliability of more complex psychometric batteries and to use larger samples of older people. Some recommendations for conducting clinical interviews and psychometric tests are presented, based on clinical experience and a review of the literature. The importance of ergonomic considerations, patient comfort and professional preparation are explained.

[Interaction of soda lime and halogenated anesthetics]. / Interazioni tra calce sodata ed anestetici alogenati.

The increased use of soda lime for low flow anaesthesia leads to some problems related to the interaction with halogenated agents. These agents may be absorbed by soda lime or degradated according to their water content. Halothane and enflurane, in contact with soda lime, produce some metabolites, but their concentration is low when compared to their own lethal concentration. Sevoflurane degradates to four compounds. Compound A may reach a value between 13.3-42.1 ppm in the inspired fraction: these values are 50-100 times lower than the toxic concentrations. Isoflurane and desflurane are degradable at very low extent. Some case reports of unexpected high carboxyhemoglobin levels during anaesthesia indicate the possibility of CO production from soda lime and baralyme when halogenated agents are used. This reaction occurs only with anaesthetics containing CHF2-moiety (isoflurane, enflurane and desflurane) and when some specific factors make soda lime or baralyme completely dry. Low flow anaesthesia preserves the moisture content of the soda lime and protects from carbon monoxide production, by increasing water content in the circle.

[Scoring and validation of the Clock Face Test in psychometric assessment of elderly subjects]. / Cotation et validation du test du cadran de l'horloge en psychométrie chez le sujet âgé.

AIMS: To propose an original evaluation and validation of the Clock Face Test (CFT). METHOD: Outpatients; 163 elderly people, aged over 65 years. Factory analysis, Student's test. RESULTS: The test shows a positive correlation with Folstein's MMSE (r = 0.769) and Signoret's BEC 96 (r = 0.644), a good specificity (75% with MMSE; 79% with BEC 96) and a good sensitivity (87% with MMSE; 74% with BEC 96). Four factors are identified by factory analysis; 74% of the variancy is explained by the first three factors. CONCLUSION: The CFT is a valid tool, easy to conduct. Several applications are possible for diagnosis, psychometric control and therapeutic trials.

Psychological impact of a remote psychometric consultation with hospitalized elderly people.

Teleconsultation is a potentially useful approach to the psychological assessment of elderly patients. We assessed the psychological impact of a videolinked psychometric consultation in a sample of hospitalized elderly people. The 15 patients, none of whom had a psychiatric history, participated in a video-consultation and a conventional face-to-face consultation. The mean age of the patients was 88 years. Each consultation consisted of a preliminary interview with a psychologist and two psychometric tests which evaluated the patient's cognitive function (the Mini-Mental State Examination and the Clock Face Test). A second psychologist, who acted as an observer, assessed the patients' attitudes to the two types of consultation. Although most patients (11 of the 15) expressed a preference for the face-to-face consultation, the video-consultations were judged to be acceptable by the patients and the psychologists. The experience of teleconsultation could be improved by practice on the consultant's part and by some technical modifications. Finally, some differences in test scores were observed and further work is required to evaluate the reliability of different psychometric tests when used by videolink.

"Telepsychometry": a remote psychometry consultation in clinical gerontology: preliminary study.

OBJECTIVE: Evaluation of the clinical feasibility of remote psychometric consultation with elderly patients. METHODS: Remote consultation with six women and four men (average age 87) was compared with a standard consultation. An interview and two psychometric tests were used: the Mini-Mental Status Examination (MMSE) and the Clock Face Test (CFT), which were administered by a clinical psychologist and controlled by a psychologist observer who remained in the room with the patient. The experimental setting consisted of two rooms linked by a coaxial cable. Each room was equipped with a camera, television screen, and microphone. The clinician was able to operate the mobile camera in the patient's room by remote control. The clinician was assisted by a computer, which helped to focus on standardized points. A video camera recorded the consultation for documentation purposes. RESULTS: Decreased performance was observed in the remote versus the standard consultation for both tests (MMSE: p = 0.008; CFT: p = 0.006). Physiologic hearing loss may have been responsible for a fall in the patients' attention. CONCLUSION: Remote psychometric consultation can be applied successfully to the psychological examination of elderly patients provided that communication problems are solved.

The Italian SEPSIS study: preliminary results on the incidence and evolution of SIRS, sepsis, severe sepsis and septic shock.

This prospective, multicenter, epidemiological study was carried out in 99 Italian ICUs, distributed throughout the country, from April 1993 to March 1994. In the study, we applied the new ACCP/SCCM classification system for sepsis (SIRS, sepsis, severe sepsis and septic shock) and determined the prevalence, incidence, evolution and outcome of these categories in critically ill patients. The preliminary analysis of 1101 patients showed that on admission SIRS accounted for about half of the diagnoses (52%) with sepsis, severe sepsis and septic shock accounting for 4.5%, 2.1% and 3% of patients, respectively. Patients with severe sepsis or septic shock more frequently had high SAPS scores than patients without sepsis. Mortality rates were similar in patients with SIRS (26.5%) and without SIRS or infection (24%), but rose to 36% in patients with sepsis, to 52% in those with severe sepsis and to 81.8% in those with septic shock. Sepsis, severe sepsis and septic shock were more common in patients with medical diagnoses, and neither severe sepsis nor septic shock was observed in trauma patients. With respect to evolution, the incidence of septic shock was progressively higher in patients admitted with more severe "sepsis-related" diagnoses, while only a trivial difference in rates of incidence was observed between SIRS patients and those admitted without SIRS or any septic disorder (nil). The breakdown of the various ACCP/SCCM "sepsis-related" diagnoses at any time during the study was: SIRS in 58% of the population, sepsis in 16.3%, severe sepsis in 5.5% and septic shock in 6.1%. It seems reasonable to expect from the final evaluation of our study answers to the questions raised by the ACCP/SCCM Consensus Conference about the correlations between "sepsis-related" diagnosis, severity score, organ dysfunction score and outcome.