33,34 In addition to hippocampus, atrophy of prefrontal cortex and amygdala – brain regions that control cognition, mood, and anxiety – has also been

reported in patients with depression or bipolar disorder.35 Evidence from postmortem studies Atrophy of hippocampus or other brain regions could result from loss of cells (neurons or glia) or decreased size of the cell body or neuronal processes. The most extensive studies have been conducted on prefrontal and cingulatc cortex and demonstrate Inhibitors,research,lifescience,medical that the neuronal body size and number of glia is decreased in depressed patients.36-38 There is much less known about the hippocampus and Calcitriol buy additional studies will be required to determine what accounts for the atrophy of hippocampus observed in depressed patients. Postmortem analysis of CREB and BDNF has also provided evidence consistent with a loss of neural plasticity in depression. Levels of CREB arc decreased in the cerebral cortex of depressed Inhibitors,research,lifescience,medical patients or suicide victims.39,40 Levels of BDNF are also decreased in prefrontal

cortex and hippocampus of depressed patients.41 Reduced levels of CREB and BDNF“, two molecular markers of neural plasticity, indicate that the ability of limbic brain structures to mount adaptive responses is compromised in depressed patients. Antidepressant treatment increases neural plasticity Inhibitors,research,lifescience,medical In contrast to the effects of stress, antidepressant treatment results in molecular and cellular responses that demonstrate an increase in neural plasticity. Moreover, these studies have Inhibitors,research,lifescience,medical paved the way for additional studies that demonstrate that antidepressant treatment results in structural

remodeling. In many cases, the effects of antidepressant treatment oppose or reverse Inhibitors,research,lifescience,medical the effects of stress. Taken sellekchem together, these findings provide additional support for the hypothesis that neural plasticity plays a significant role in the treatment, as well as the pathophysiology of mood disorders. The evidence for regulation of neural plasticity at the level of neurogenesis, signal transduction, and gene expression Cilengitide is discussed in the second half of this review. Antidepressant treatment increases adult neurogenesis Neurogenesis is increased by chronic antidepressant administration One of the most surprising discoveries of recent times in the field of depression is that antidepressant treatment regulates neurogenesis in the adult hippocampus (Figures 1 and 2). In contrast to the actions of stress, chronic antidepressant treatment increases the number of newborn neurons in the adult hippocampus of rodents or tree shrews.42,43 The upregulation of neurogenesis is dependent on chronic antidepressant treatment, consistent with the time course for the therapeutic action of antidepressants.

Be that as it may, from a clinical perspective, a combination of all the three parameters of plaque volume, time of plaque progression, and instability indices of plaques is critical. Atherosclerosis selleck inhibitor velocity may show a wide range in future

studies. When a small unstable plaque can rapidly rupture and result in total coronary occlusion and when a large plaque can persist Inhibitors,research,lifescience,medical for a longer time (or at least when it does not lead to complete occlusion), we can easily see the importance of atherosclerosis velocity. Clinically, atherosclerosis velocity vis-à-vis an asymptomatic/sub-acute arterial plaque is a highly unpredictable process. Asymptomatic/sub-acute vulnerable plaques in coronary arteries account for a significant level of acute cardiovascular events.23 Their main risk is associated with their acute rupture, which may result in fatal MI or stroke.23 Recently, the role of microcalcifications embedded in the vulnerable fibrous cap in the development of acute ruptures has been highlighted.24,25 Liang et

al.26 performed an interesting study using intravascular Inhibitors,research,lifescience,medical ultrasound (IVUS) in patients and proved that the occurrence of a http://www.selleckchem.com/products/ABT-888.html microcalcification Inhibitors,research,lifescience,medical in the atherosclerotic plaque fibrous cap considerably increased the risk of the rupture of a vulnerable plaque. IVUS also seems to be capable of quantifying atherosclerotic plaques as well as positive and negative vascular remodeling.27 Intraplaque hemorrhage also has been considered a factor which accelerates sub-clinical atherosclerosis.28-30 Risk Factors and Atherosclerosis Velocity Regarding atherosclerosis velocity, we believe that we should be extremely precise when indicating the impact of risk factors Inhibitors,research,lifescience,medical on all the elements

of atherosclerosis velocity. To our knowledge, there is currently a lack of evidence in terms of the effects of traditional cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, and smoking) on atherosclerosis velocity. The effects of these traditional risk factors have been proved in atherosclerosis development Inhibitors,research,lifescience,medical and progression.31-33 Regardless of the effects of these traditional risk factors on the development of the atherosclerotic plaque, a growing body of evidence demonstrates their impact on rupture-induced occlusion. Mauriello et al.34 analyzed a large number of endarterectomy specimens from symptomatic and asymptomatic patients to explore the association between cardiovascular Anacetrapib risk factors and carotid plaque morphology. The authors succeeded in proving a strong association between hypertension and vulnerable and thrombotic carotid plaques.34 Diabetes mellitus/hyperglycemia-induced oxidative stress/reactive oxygen species is one of the factors that can promote both vascular smooth muscle cell proliferation/migration in atherosclerotic lesions and vascular smooth muscle cell apoptosis, which results in atherosclerotic plaque instability and rupture.

On the contrary, IBM muscle is characterized by the presence of unique degenerative features and inefficient regenerative properties. Thus, IBM invariably progresses leading to a significant disability. Our studies showing that also from IBM it is possible to isolate cells with a high myogenic potential, such as mesoangioblasts, localized in the perivascular niche and normally not actively producing skeletal muscle, might open new therapeutic strategies of clinical Inhibitors,research,lifescience,medical relevance. However, since mesoangioblasts isolated from IBM muscle fail to normally differentiate into skeletal

muscle, in order to envisage a possible clinical use of autologous mesoangioblasts as muscle regenerative cell therapy, it will be essential to stimulate Inhibitors,research,lifescience,medical in vitro IBM mesoangioblasts to enhance their defective myogenic differentiation. Even more important would be to successfully activate in vivo the endogenous mesoangioblasts present in IBM muscle than inducing them to make new regenerating fibers thus actively counteracting progressive muscle degeneration. To this end, it is of paramount importance the identification of factors (ie. cytokines,

growth factors) produced by muscle or inflammatory cells Inhibitors,research,lifescience,medical and released in the surrounding milieu able to regulate the till differentiation ability of IBM mesoangioblasts. Modulation of such target molecules selectively dysregulated in IBM muscle Inhibitors,research,lifescience,medical to promote myogenic differentiation of endogenous mesoangioblasts appears a more handy approach to enhance muscle regeneration compared to transplantation techniques. Actually, the

use of myogenic stem cells to cure any muscle disorder represents a very difficult challenge and it is now unpredictable whether it will ever come true. However, their safety Inhibitors,research,lifescience,medical as therapeutic tool has been demonstrated (9) and a phase I clinical trial with donor-derived mesoangioblasts is ongoing in DMD patients (26). Nevertheless, major technical problems exist that is necessary to overcome to achieve satisfactory transplantation and engraftment of homogeneous population of myogenic precursors. On one side, in fact, in genetic myopathies it must be demonstrated that muscle reconstitution Drug_discovery with fibers expressing the defective gene will be clinically relevant to thwart progressive muscle weakness and degeneration. On the other side, in acquired diseases of muscle, transplanted stem cells might in turn become target of the same noxae causing the disease, thus frustrating the attempt to significantly contribute to muscle regeneration and counteract the progressive atrophy of treated muscles.

A major drawback for a monolateral right-sided approach was the lack of selleck chemicals opportunity to exclude or occlude the left atrial appendage safely. Since the left atrial appendage is largely responsible for thrombo-embolic events in patients with atrial fibrillation, and can be part of the substrate responsible for atrial fibrillation, it could be preferable to occlude or exclude the left atrial appendage

in a subgroup of atrial fibrillation patients. We therefore developed a technique with a monolateral left-sided Inhibitors,research,lifescience,medical approach for patients when isolation and exclusion of the left atrial appendage were deemed necessary. Freedom of atrial fibrillation at 1 year was 73% for the combined group of right- and left-sided

selleck chemical interventions. A complementary Inhibitors,research,lifescience,medical endocardial approach was performed at 6 months in 18 patients.7 Since the success rate at 2-year follow-up was unsatisfactory,8 we changed the energy source from microwave to monopolar radiofrequency energy. Realizing that the concept of an epicardial box lesion had distinct limitations and was difficult to achieve on a beating heart (epicardial fat, heat-sink effect, power delivery of a monopolar ablation device), we combined Inhibitors,research,lifescience,medical the surgical procedure with a simultaneous endocardial electrophysiology procedure. A single-session hybrid atrial fibrillation procedure was born. For the first time, we could study the effect of an epicardial ablation on the endocardium in a human being as well as see the epicardial effects

of an endocardial ablation, during Inhibitors,research,lifescience,medical the same procedure. Using this approach we could demonstrate that after Inhibitors,research,lifescience,medical epicardial creation of a box lesion with microwave or radiofrequency there was a conduction delay from the pulmonary veins and the posterior wall of the left atrium, but no exit or entrance block. This incomplete epicardial surgical ablation line necessitated a complementary endocardial isolation of one or more pulmonary veins and/or the roof and inferior line. The importance of these findings was Cilengitide twofold: first, we proved that the concept of combining a percutaneous endocardial approach with a thoracoscopic epicardial approach was safe and technically feasible and, secondly, that creation of a continuous transmural box lesion from the epicardium with a monopolar energy source was not possible. Even with satisfactory clinical results, transmurality and continuity of epicardial lesions could not be assured. This could probably explain the relatively low success rate at long-term follow-up. Again we had to change our strategy. We decided to focus first on an antral epicardial isolation of the pulmonary veins.

TOWARD PERFECTION Before aiming at achieving perfection in medical practice, one should admittedly be, or become, an accomplished person. We would like to quote from two non-medical texts of Maimonides, one philosophical—the Guide of the Perplexed—the other ethical—the Eight Chapters. In the Guide (III, 54), Maimonides mentions four categories of perfection (Heb. shelemut). First mentioned is perfection in resources, second, perfection in Inhibitors,research,lifescience,medical health, third, in moral qualities, and, fourth, intellectual excellence. (Maimonides writes that perfection in property

is of little essential value, although most human beings put it at the top of their endeavors. We remember the adage: “Who is rich?—One who is satisfied with what he owns.”7) These categories are cited in a sequence of growing importance. Regarding “perfection in resources,” this does not mean that one

should become wealthy; however, one should be free from financial worries. Maimonides had indeed to cope with this problem: when his brother David, who Vandetanib chemical structure provided for the financial needs of both families, suddenly Inhibitors,research,lifescience,medical perished at sea, Maimonides had to take over that responsibility. According to his own testimony, this caused him to be sick and depressed during a whole year, till he Inhibitors,research,lifescience,medical decided to become a practicing physician. In the Eight Chapters (chapter IV),8 which are an introduction to his commentary on the Fathers’ Aphorisms (Heb. Pirqei Avot), Maimonides advocates adopting the medium line regarding the moral qualities. We quote (my own translation from the Hebrew): Thus, the perfect man [Heb. ha-adam ha-shalem] should constantly call to mind his moral qualities [Heb. midotav], ponder his actions, and control his soul all day long. Each time he feels a propensity Inhibitors,research,lifescience,medical toward some extreme action,

he should at once apply the accurate treatment in order Inhibitors,research,lifescience,medical to stop the progress of that tendency. Maimonides adds that one should always keep in mind one’s moral weaknesses, and treat them in due time, for there is not anybody without shortcomings. In other words, no human being is essentially perfect, not even the biblical Moses; however, everyone should our site strive AV-951 toward being perfect, while trying to control all his actions. Returning to the Guide (I, 34), we shall now examine in what terms Rambam considers the difficulties that undermine philosophical accomplishment. The reasons [for the difficulties] are that a person has, at the beginning [of his studies], very limited capabilities. A man does not own initially full mastership [Heb. shelemuto ha-sofit], although it exists in him virtually [Heb. be-koa]. A lot of tenacity, of determination, and of work is required in order to become fully knowledgeable. In order to attain human perfection (Heb. ha-shelemut ha-enoshit), one has to master logic, the sciences that help in forming reflection, natural sciences (including medicine), and—ultimately—theology.

T2) Ruxolitinib chemical structure analysis of variance (ANOVA) with repeated measures on the second factor. Second, after checking the interrater-reliability for the three different strength ratings, by calculating intraclass correlation coefficients (ICC; Shrout and Fleiss 1979), we compared both groups referred to their average strength in the BDORT (after inducing their anxiety) for both times of measurement. The data were

analyzed using a 2 (group: experimental group vs. control group) Inhibitors,research,lifescience,medical × 2 (time of measurement: T1 vs. T2) ANOVA with repeated measures on the second factor. Third, we compared the experimental group and the control group in relation to the data in the STAI-G, divided into STAI-G-State Inhibitors,research,lifescience,medical and STAI-G-Trait for both times of measurement. Hence, data were analyzed using two 2 (group: experimental group vs. control group) × 2 (time of measurement: T1 vs. T2) ANOVAs with repeated measures on the second factor. Results Intensity of anxiety The ANOVA did not reveal an main effect for time of compound libraries measurement (F(1, 47) = 3844) and for group (F(1, 47) = 0.472). However, there was a significant interaction between time of measurement and

group (F(1, 47) = 9.26, P < 0.008, η² = 0.16). For T1, the mean values of anxiety did not differ significantly between both groups. Inhibitors,research,lifescience,medical However, the interaction indicated that the mean values of anxiety decreased in the experimental group from the first to Inhibitors,research,lifescience,medical the second time of measurement and the mean values of anxiety in the anxiety condition were as far as possible unchanged (see Fig. ​Fig.22). Figure 2 Likert Scale (LS) for the intensity of anxiety in the experimental group (EG) and the control group (CG) for time of measurement 1 (T1) and time of measurement 2 (T2). Physical task First, the interrater-reliability coefficients were acceptable

for all judges (ranging from 0.90 to 0.96 and averaging 0.93) for both times of measurement. The subsequent 2 (group: experimental group vs. control group) × 2 (time of measurement: Inhibitors,research,lifescience,medical T1 vs. T2) ANOVA yields a main effect for time of measurement (F(1, 48) = 13.44, P < 0.001, η² = 0.21) but not for group (F(1, 48) = 3.20). In addition, we found a significant interaction between group and time of measurement (F(1, 48) = 12.96, P < 0.001, η² = 0.21). Figure ​Figure33 shows that the mean data for strength (after the anxiety induction) increased in the experimental group from T1 to T2 and the strength in the control group was as far as possible unchanged from T1 to T2. Figure Carfilzomib 3 Mean strength rating and standard errors for the emotion anxiety in the experimental group (EG) and in the control group (CG) for time of measurement 1 (T1) and time of measurement 2 (T2). STAI-G-State The ANOVA revealed no significant main effect for group (F(1, 48) = 1.74) or for time of measurement (F(1, 48) = 0.54). However, we found a significant interaction between group and time of measurement (F(1, 48) = 5.73, P < 0.022).

TTA was ≤ 10 minutes for 854 http://www.selleckchem.com/products/SB-203580.html patients (70.8%) and ≤ 15 minutes for 998 (82.8%). Triage duration was less than 5 minutes for 645 patients (53.5%). Table ​Table22 shows the mean RTP time and fractile response rates

for each CTAS level. All category I patients met the set CTAS standard, however, this was not so in the other 4 categories. Figure 1 Mean waiting time from registration to being seen by physician in the emergency department by triage category. Table 2 Comparison of physician response times in study with CTAS response time objectives. In our study sample, 81 patients (6.7%) were hospitalized, 118 patients (9.8%) LWBS and 1007 (83.5%) were discharged. Of the 118 patients who LWBS, 11.9% were Level III, 20.3% were Level Inhibitors,research,lifescience,medical IV and 67.8% were Level V. The median time these patients waited before leaving was 133.0 minutes (95% CI, 119.9 – 153.2 min). The median ED LOS was 144 minutes for the study sample as a whole. Figure ​Figure22 shows an increase in LOS with triage acuity. Figure 2 Mean length of stay in the emergency department by triage category. Discussion Inhibitors,research,lifescience,medical Our data assessed triage performance, timeliness of care, and length of stay in ED. It evaluated the feasibility and validity of the CTAS outside of Canada. Our results show an indirect relationship between CTAS somehow acuity level and RTP: as CTAS acuity Inhibitors,research,lifescience,medical level increased, RTP decreased and LOS increased. ED patients who left the ED without being

seen were of low CTAS acuity levels. The majority of our ED patients were category IV and V (75.7%), which is in line with the percentage of CTAS IV and V in the Principality of Andorra ED of 76.82% [9]. The lower percentage of levels Inhibitors,research,lifescience,medical I & II (0.6%) could be due to many reasons such as random

errors, or assigning a patient an inappropriate low triage level. This is not a trauma hospital and, hence, this could be another reason leading to low percentages of levels I & II. Tables ​Tables11 and ​and22 demonstrate the RTP time generally increased as triage acuity fell. Although this is expected, fractile response rates were actually higher in levels Cilengitide IV and Inhibitors,research,lifescience,medical V (61% and 83% respectively), than in level III (36%). This lower fractile response rate could be due to a variety of reasons including space limitations, eligibility for care at this hospital, ED volume, or language spoken. Bias and prejudice might also play a role in this lower response rate. Our data also showed that, for the most critically ill patients (level I&II), RTP was rapid and LOS was greatest, which are in line with CTAS objectives. This is expected because these patients required more time and manpower resources for the care and management of their critical condition, thus, contributing to a prolonged LOS in the ED (Figure ​(Figure22 and Table ​Table11). Hospitalization rate is a marker of the severity of illness. Hospital admission rate through our ED, in this study, was 6.

It is possible that, as genes involved in psychiatric disorders become elucidated, endophenotypes reflected in underlying selleck chemical Volasertib disturbances, and genetically defined disorders, may come to correspond more closely to true diseases. The classical method of identifying a disorder, for most of the history of psychiatry, was for the influential psychiatrist to discern and describe disorders based on his or her selleck chem inhibitor clinical experience,

with little attempt at precise definition or method-based research. The main method of forming diagnoses in modern psychiatric nosology has been by committee Inhibitors,research,lifescience,medical agreement, based sometimes on quite limited empirical, research. Diagnostic criteria are then defined by listing certain symptoms, to define the number necessary for the diagnosis, with duration of time, other requirements,

and exclusions. In DSM-IV, eight symptoms are listed as qualifying for major depression, with a requirement that at least five be present, including at least one of two core symptoms, together with duration Inhibitors,research,lifescience,medical of 2 weeks or more, presence of clinically significant distress or impairment of function, with absence respectively of mixed episode, direct Inhibitors,research,lifescience,medical effects of a drug of abuse, a medication or other substance, or of a general medical condition, or of bereavement, and for depressive disorder, of bipolar disorder or certain other psychotic diagnoses. For dysthymia, fewer symptoms are required, but for a longer period of 2 years, and from a shorter list of eligible symptoms. For ICD-10 depressive episode, the definitions in the clinical criteria are not tightly specified, but they are well specified in the separate Research Criteria, where they tend to be more restrictive than in the

clinical criteria. The Research Criteria are less used, and the existence of two different Inhibitors,research,lifescience,medical sets of criteria in the classification causes some obvious problems. Eligible symptoms for depressive episode are the same as in DSM-IV, with the addition of one further symptom, loss of confidence Inhibitors,research,lifescience,medical or selfesteem, with the number of symptoms required to be present depending on the severity of the episode, and a third symptom, fatigue, placed as eligible with the two other core symptoms, rather than in the additional list. There is an identical minimum length, of 2 weeks, and somewhat similar excluding criteria, but without specifying bereavement. The list of eligible symptoms for dysthymia is Dacomitinib longer, with three required. The core symptoms The core symptoms of depression, of which at least one is required in DSM-IV, are depressed mood, and loss of interest or pleasure. The further eligible symptom in ICD-10 is decreased energy or fatigability, but, since two core symptoms must be present, in effect depressed mood or loss of interest/pleasure are required in this schema also. The reason for the addition of decreased energy to the core is not clear. These core symptoms reflect the view that depressive disorder is essentially a disorder of mood or affect.

2012). Similarly, in the present study, LQ treatment significantly decreased the number of reactive astrocytes in the spinal cord and

CC of pre-, early post-, and peak-EAE mice. Such www.selleckchem.com/products/MG132.html findings point to an immunomodulatory mechanism through which LQ acts to uphold OL health and blunt demyelinating effects of EAE. Notwithstanding, LQ’s mechanisms of action are still being investigated. LQ is a small molecule that passively enters all cell types. A direct effect of LQ on astrocytes via modulation of NF-κB to reduce inflammatory Inhibitors,research,lifescience,medical response, or an indirect effect on various cell types and increase in growth factors, may contribute to cell survival, axon myelination, and neuroprotection in EAE and MS (Aharoni et al. 2012; Bruck et al. 2012; Thone et al. 2012). One of the many neurotrophic factors inhibitor Cisplatin essential for neuronal function and myelination is BDNF. During EAE, BDNF mRNA and protein are significantly decreased, specifically in neurons, though higher immunoreactivity is observed in reactive astrocytes and immune cells around Inhibitors,research,lifescience,medical the lesions (Linker et al. 2010). A recent study showed that LQ treatment

during EAE restores BDNF expression to normal levels (Aharoni et Inhibitors,research,lifescience,medical al. 2012). Similarly, a significant elevation of serum BDNF levels in relapse remitting MS (RRMS) patients receiving LQ therapy was observed (Thone et al. 2012). BDNF/tyrosine kinase receptor B (TrkB)-stimulated intracellular signaling is critical for neuronal survival, morphogenesis, plasticity, normal OL development, and axon myelination (Hetman et al. 1999; Linker et al. 2009; Numakawa et al. 2010; Vondran et al. 2010; Xiao et al. 2010; VonDran et al. 2011). LQ treatment-induced increase Inhibitors,research,lifescience,medical in BDNF and modulation of immune and astrocyte cell signaling could be responsible for improvement in OL proliferation/and survival that leads to improved axon remyelination and neuroprotection observed. In summary, LQ treatment asserts a significant positive effect on axon myelination during EAE. LQ treatment caused a significant improvement in clinical scores even after peak EAE disease, when significant axon demyelination, Inhibitors,research,lifescience,medical axon damage, and OL

apoptosis have already been established (Tiwari-Woodruff et al. 2007; Mangiardi et al. 2011). Rotorod motor performance by EAE mice can Cilengitide be correlated to the motor aspect of EDSS scores in MS patients, and it can be an essential biomarker for therapeutic MS drugs. At peak disease, EAE animals are unable to remain on the rotorod due to significant motor deficits. Upon treatment with LQ (before onset of or after peak disease), EAE animals exhibited significant motor improvement. Motor performance improvement correlated with improved callosal conduction and cell survival in the CNS. These findings strongly suggest that LQ treatment has significant and functional beneficial effects on neuron survival, decreasing axon damage, improving survival and proliferation of OLs, and increasing myelination/remyelination.

2,4 What is the best strategy to improve phenotype identification? The genetic validity of the current customary criteria for standardized diagnosis has not been demonstrated. We have suggested two complementary strategies for finding genetically valid traits: one involves a description of the affected subjects; and the other involves the identification of vulnerability traits in nonaffected relatives of affected individuals, ie, the Inhibitors,research,lifescience,medical endophenotypic approach. The first strategy utilizes affected individuals and is called the candidate symptom approach. It is analogous

to the candidate gene approach as applied in molecular biology. The candidate symptom approach would identify several stringent clinical characteristics hypothetically associated with a disease genotype and show a pattern of inheritance related Inhibitors,research,lifescience,medical more robustly

to the narrow characteristics than to the diagnosis. Identification of specific subforms of the disorder would lead to identification of homogeneous families, which are more appropriate for linkage studies. The second strategy emphasizes the need to use broader approaches, such as related biochemical, neurophysiological, neuroanatomical, Inhibitors,research,lifescience,medical cognitive, and/or truly neuropsy chological markers, to identify pertinent phenotypes in nonaffected relatives carrying vulnerability genes. These subclinical associated traits, endophenotypes, might be valuable for identifying common alleles with nonspecific and moderate effects on disease risk. Thus, endophenotypes serve to better define the trait or its underlying genetic mechanism.47 To meet criteria for a marker trait, an endophenotype should Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical be measured

in an objective and cost-effective fashion among clinically unaffected relatives of patients, should occur before the onset of illness, should run in families, and should be associated with increased risk of clinical illness. This strategy is recommended for psychiatric disorders in which symptoms occur as the consequence of an interaction between several vulnerability factors, each having good genetic validity but not thorough necessarily disease-specificity. The candidate symptom strategy Target symptoms that Carfilzomib could allow the identification of a homogeneous form of the illness (ie, candidate symptoms) should fulfill the following criteria: they should show good concordance rates among affected monozygotic twins and should be correlated in pairs of affected siblings.48 This strategy has already proven helpful in the identification of subgroups in complex disorders other than psychiatric disorders. For example, subdivision according to age at onset has been particularly efficient in clarifying genetic heterogeneity in dementias of the Alzheimer’s type.