Genes for left-handedness: how to search for the needle in the haystack?

Although several genes that determine left-right asymmetry for structural syndromes such as situs inversus have been characterised in recent years (Supp, Witte, Potter, & Brueckner, 1997), there has been little progress in determining which genes or loci predispose to left-right handedness in humans. Linkage analysis has been used widely for the localisation of genes followed by their positional cloning. The complex genetics of handedness is one of the greatest problems for standard linkage analysis. Several genetic models have been proposed for the inheritance of handedness in humans. On the basis of these models, left-handedness can be considered a common single gene trait with a high gene frequency and a non-mendelian inheritance pattern. We report here a possible strategy, using these genetic models, that can be applied for the identification for genes determining handedness in humans.     

Building the toolbox for in vivo glia-to-neuron reprogramming

<正>Unlike regenerative-competent species that possess a remarkable intrinsic capacity to replenish lost neurons and restore neurocircuits spontaneously, the central nervous system in adult mammals lacks the ability to compensate for the neuronal loss caused by neurodegenerative diseases or traumatic injuries resulting in permanent loss of functionality. Inspired by earlier discoveries that radial glia or astrocytes isolated from the postnatal cortex can generate neurons,     

Is epilepsy in the elderly overlooked? An investigation in a home for the aged

The symptoms of epileptic seizures in old patients differ from those in younger patients. Therefore, these seizures may be misinterpreted as symptoms of other "typical" diseases in old people. In an old people's home, we assessed whether a standardized questionnaire is able to reveal undiagnosed epilepsy in the elderly. Reported sudden falls, loss of consciousness, and cramps were the criteria for further diagnostic procedures. We found epilepsy in 11 of 389 study participants. In four of them (1% of the total sample), the epilepsy was newly diagnosed; five more cases remained unclear. Therefore, the total number of epileptic patients might have been even higher. Most of the reported sudden falls and unconsciousness (89%) were due to internal medical or other neurological or orthopaedic causes. Once these have been excluded, the diagnosis of epilepsy should be considered. The results of our pilot study suggest that epilepsy in old people's homes is often unrecognised. Early diagnosis and treatment of epilepsy in the elderly is important to improve prognosis and social consequences for affected persons.     

Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α-synuclein

Increased intracellular levels of α-synuclein are implicated in Parkinson's disease and related disorders and may be caused by alterations in the ubiquitin-proteasome system (UPS) or the autophagy-lysosomal pathway (ALP). A critical question remains how α-synuclein is degraded by neurons in vivo. To address this, our study uses α-synuclein transgenic mice, expressing human α-synuclein or α-synuclein-eGFP under the (h)PDGF-β promoter, in combination with in vivo pharmacologic and multiphoton imaging strategies to systematically test degradation pathways in the living mouse brain. We demonstrate that the UPS is the main degradation pathway for α-synuclein under normal conditions in vivo while with increased α-synuclein burden the ALP is recruited. Moreover, we report alterations of the UPS in α-synuclein transgenic mice and age dependence to the role of the UPS in α-synuclein degradation. In addition, we provide evidence that the UPS and ALP might be functionally connected such that impairment of one can upregulate the other. These results provide a novel link between the UPS, the ALP, and α-synuclein pathology and may have important implications for future therapeutics targeting degradation pathways.     

What matters for life satisfaction in the oldest-old?

The purpose of this study was to examine factors associated with life satisfaction in the oldest-old within a spectrum of psychosocial and health related variables. Scores on the life satisfaction index (LSI-Z) were related to scales and questions regarding, demographics, depression, locus of control, cognitive function, functional capacity (instrumental and personal activities of daily living), self-rated overall health and medically based health, and social network. The sample consisted of 315 participants, aged 80-98 years; (M = 83 years, 66% women). Regression analyses indicated that social network quality, self-rated overall health, sense of being in control of one's life, and depressive symptoms were significantly associated with life satisfaction. There was no gender difference in overall life satisfaction. However, there were different patterns of variables associated with life satisfaction in men and women. Self-rated overall health and depressive symptoms were related to life satisfaction in women, whereas widowhood was significantly associated with lower life satisfaction among men. The results emphasize the need to analyse associates of life satisfaction within a broader context of psychosocial variables and separately for men and women.     

What are the contributing factors for insomnia in the general population?

Lack of a systematic assessment of insomnia has led to large variations in its reported prevalence in the general population. This study aims to provide new guidelines to assess insomnia prevalence. A cross-sectional telephone survey using the Sleep-EVAL system was done with 24,600 general population-based subjects 15 years and older representative of general populations (France, the UK, Germany, Italy, Portugal, and Spain) consisting of 251,405,391 inhabitants. The overall participation rate was 81.0%. Within the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) symptomatology for insomnia, 27.2% (95% confidence interval: 26.6–27.8%) of the sample reported difficulty initiating sleep (DIS) (10.1%) or maintaining sleep (DMS) (disrupted sleep (DS): 18.0%; early morning awakening (EMA): 10.9%) or nonrestorative sleep (NRS) (8.9%) at least three times per week; 48.5% of them were concomitantly suffering of a DSM-IV sleep/mental disorder. A factor analysis identified several variables strongly related to each of the major factors of insomnia allowing: (1) The narrowing of the definition of insomnia: the prevalence of insomnia decreased to 16.8% with 64.5% of insomnia subjects having a DSM-IV sleep/mental disorder; (2) The identification of a sleep-deprived (voluntary or not) group without insomnia symptoms, representing 2.1% (1.9–2.3%) of the sample. Interestingly, the latter group closely matched the definition of insufficient sleep syndrome as described by the International Classification of Sleep Disorders (ICSD). Using more delineated criteria to assess insomnia increases the recognition of subjects complaining about sleep. Classifications should be amended to improve the correct identification of insomnia. Sleep-deprived subjects should also not be neglected.     

Dopamine agonists: the treatment for Parkinson's disease in the XXI century?

Levodopa combined with a peripheral dopa-decarboxylase inhibitor (DCI) has been considered the therapy of choice for Parkinson's disease (PD). Levodopa is nearly always effective, but has a high incidence of adverse effects with long term use, including response fluctuations (on/off phenomena) and dyskinesias. Dopaminergic agonists, acting directly at the receptor level, would be able to decrease the incidence of these motor complications.In progressive neurodegenerative diseases, such as PD, modification of the rate of disease progression (often referred to as neuroprotection) is currently a highly debated topic. Increased oxidative stress is thought to be involved in nigral cell death, that is characteristic of PD. This oxidative stress may be further exacerbated by levodopa therapy. These mechanisms have been proven in vitro and animal models, but it's relevance in humans remains speculative.Based on the considerations above, the emerging therapeutic strategies for PD advocate early use of dopamine agonists in the treatment of PD. A number of recent well-controlled studies have proven the efficacy of dopamine agonists used as monotherapy. Moreover, as predicted by animal studies, on the long term, dopaminergic agonists induce significantly less motor complications than levodopa.In the last 2years, three new dopamine agonists have been launched, including ropinirole, pramipexole and cabergoline. These new agonists have been added, as therapeutical options to well-established drugs, like pergolide, bromocriptine or talipexole. The recently launched compounds have proven efficacy in monotherapy and as adjunctive therapy to levodopa. Unfortunately, only a very limited amount of comparative data among the different agonists is available. Pergolide has proven to be a superior drug to bromocriptine as adjunctive therapy to levodopa in a significant number of studies and is considered the gold standard dopamine agonist. Nevertheless, none of the recently launched compounds has compared itself against pergolide.A comparison of monotherapy trials is difficult, because of differences in design and populations. In a recently completed trial pergolide was statistically significantly better than placebo in all the efficacy parameters tested, with 57% of pergolide treated patients improving over 30% in the motor section of the UPDRS, as compared to 17% in the placebo arm. Interestingly, these results were obtained in the absence of any other antiparkinsonian drug during the trial. Recent monotherapy trials done with ropinirole and pramipexole achieved also significant improvements as monotherapy, but in these cases selegeline, a drug that causes a symptomatic improvement in PD, was allowed as co-medications during the trial. Not all trials used the same efficacy measures, i.e. monotherapy trials with pergolide and ropinirole used a "responder" based analysis (responder were all patients that improved 30% or more on the motor section of UPDRS), as well as a baseline to endpoint improvement in motor scores. Pramipexole monotherapy trials used only the latter approach, which is clinically less powerful than a responder analysis.Even with the difficulties mentioned above, all the recent trials with dopamine agonists have proven that these drugs are a useful symptomatic long term treatment for PD with or without levodopa and that the early use of dopamine agonists reduces the incidence of motor complications as compared to levodopa.     

Is the parietal lobe necessary for recollection in humans?

An intriguing puzzle in cognitive neuroscience over recent years has been the common observation of parietal lobe activation in functional neuroimaging studies during the performance of human memory tasks. These findings have surprised scientists and clinicians because they challenge decades of established thinking that the parietal lobe does not support memory function. However, direct empirical investigation of whether circumscribed parietal lobe lesions might indeed be associated with human memory impairment has been lacking. Here we confirm using functional magnetic resonance imaging that significant parietal lobe activation is observed in healthy volunteers during a task assessing recollection of the context in which events previously occurred. However, patients with parietal lobe lesions that overlap closely with the regions activated in the healthy volunteers nevertheless exhibit normal performance on the same recollection task. Thus, although the processes subserved by the human parietal lobe appear to be recruited to support memory function, they are not a necessary requirement for accurate remembering to occur.     

Melatonin and the time window for the expression of the α8 nicotinic acetylcholine receptor in the membrane of chick retinal cells in culture

We have previously shown that melatonin influences the development of α8 nicotinic acetylcholine receptor (nAChR) by measurement of the acetylcholine-induced increase in the extracellular acidification rate (ECAR) in chick retinal cell cultures. Cellular differentiation that takes place between DIV (days in vitro) 4 and DIV 5 yields cells expressing α8 nAChR and results in a significant increase in the ECAR acetylcholine-induced. Blocking melatonin receptors with luzindole for 48 h suppresses the development of functional α8 nAChR. Here we investigated the time window for the effect of melatonin on retinal cell development in culture, and whether this effect was dependent on an increase in the expression of α8 nAChR. First, we confirmed that luzindole was inhibiting the effects of endogenous melatonin, since it increases 2-[¹²⁵I] iodomelatonin (23 pM) binding sites density in a time-dependent manner. Then we observed that acute (15, 60 min, or 12 h) luzindole treatment did not impair acetylcholine-induced increase in the ECAR mediated by activation of α8 nAChR at DIV 5, while chronic treatment (from DIV 3 or DIV 4 till DIV 5, or DIV 3.5 till DIV 4.5) led to a time-dependent reduction of the increase in the acetylcholine-induced ECAR. The binding parameters for [¹²⁵I]-α-bungarotoxin (10 nM) sites in membrane were unaffected by melatonin suppression that started at DIV 3. Thus, melatonin surges in the time window that occurs at the final stages of chick retinal cell differentiation in culture is essential for development of the cells expressing α8 nAChR subtype in full functional form.     

Should the guidelines for monitoring serum cholesterol levels in the elderly be re-evaluated?

Elevated circulating cholesterol can have profound effects on the health of an individual. Such excess cholesterol can promote coronary artery disease, production and accumulation of β-amyloid in the brain, and possibly Alzheimer’s disease (AD). In a clinical trial evaluating the benefit of a cholesterol-lowering drug in the treatment of AD, mean cholesterol levels at baseline among individuals participating in the trial were found to be relatively high. Based on this observation we suggest that cholesterol levels should be actively monitored in the elderly, as many individuals with AD are over 65 years of age and therefore excluded by currently accepted guidelines.     

When is the appropriate time for surgical intervention of the herniated lumbar disc in the adolescent?

Symptomatic lumbar disc herniation in the adolescent is uncommon. The appropriate treatment in this particular age group is not clear. We conducted a retrospective review of the medical, surgical, and radiological records of six adolescents with symptomatic lumbar disc herniation who underwent microdiscectomy after failed conservative therapy. The mean follow-up was 13 months. All patients improved quickly and returned to their normal activity levels. We suggest that severe pain resulting from a herniated lumbar disc, even without any neurological deficit, is an indication for microdiscectomy in adolescents so that these patients return to full-time education and normal activities as soon as possible.     

Independence: a new criterion for the analysis of the electromagnetic fields in the global brain?

The impressive increase in the understanding of some basic processing in the human brain has recently led to the formulation of efficient computational methods, which when applied in the design of better signal processing tools, provides a deeper and clearer view to study the functioning of the human brain. The recently developed independent component analysis (ICA) has been shown to be an efficient tool for artifact identification and extraction from electroencephalographic and magnetoencephalographic recordings. In addition, ICA has been applied to the analysis of brain signals evoked by sensory stimuli. Extensions of the basic ICA methodology have also been employed to reveal otherwise hidden information. This paper reviews our recent results in this field.