1 A family history of depressive illness is common in women with PMS/PMDD.5 Women who seek treatment for premenstrual symptoms frequently have other emotional disorders, most commonly depressive disoders, substance abuse, or anxiety. Conversely, women who have mood disorders frequently experience http://www.selleckchem.com/products/Imatinib-Mesylate.html worsening of symptoms premenstrually.14 In spite of these observable similarities, increasing evidence suggests that PMS/PMDD is not a simple variant Inhibitors,research,lifescience,medical of depression, but a distinct disorder. While depressive

symptoms characterize a substantial number of women with selleck chem Pacritinib severe perimenstrual distress, there is also a sizeable group of women who do not suffer from either depression or anxiety symptoms, but experience severe or moderate perimenstrual distress with symptoms of irritability, nervousness, and tension.9 On the basis of epidemiologic Inhibitors,research,lifescience,medical findings, the researchers posited that the features of irritability and tension irrespective of the presence of depressive symptoms may form the core symptoms of the disorder, a premise also advanced by Eriksson, on the basis of results of antidepressant treatment studies.15,16 Data from epidemiologically based twin studies indicated that the degree to which premenstrual symptoms shared Inhibitors,research,lifescience,medical generic and environmental risk factors with major depression was modest, a possible indication that there

is no close etiologic relationship

between the Inhibitors,research,lifescience,medical two disorders.17 The evidence that severe PMS/PMDD responds much more robustly to serotonergic antidepressants than to other antidepressants that are clearly effective for depressive disorders suggests differences in underlying mechanisms. There is also empirical evidence that a good response of PMS/PMDD patients to serotonergic antidepressants is not. explained by depressive symptoms or a history of depression.18,19 The rapid response of several days rather than several weeks of PMS patients Inhibitors,research,lifescience,medical to selective serotonin reuptake inhibitors (SSRIs), the efficacy of SSRIs at low doses, and the efficacy of other serotonin agonists, including fenfluramine20 and buspirone,21 which are not effective for depression, all suggest that the underlying mechanisms of severe PMS/PMDD differ from other depressive disorders. Evaluation The diagnosis of premenstrual dysphoria, PMS, or PMDD is made primarily on Brefeldin_A the basis of the symptom pattern and the exclusion of other possible diagnoses. The essential elements are confirmation of the expected relationship of the symptoms to the menstrual cycle, ie, that the symptoms occur premenstrually and remit with menses; that the symptoms are distressing and warrant treatment, ie, that the symptoms impair usual functioning; and that the symptoms are not due to another physical or mental disorder.

Figure 6: Schwannoma. Left: permanent pathologic slide (hematoxyllin eosin ×10); fusiform cells with long nuclei and eosinophilic cytoplasm arranged in hypercellular and hypocellular matrix. Right: touch Axitinib purchase preparation (papanicolau x40); a cluster of Schwann … The accuracy of the touch preparation technique for pituitary adenomas was 84%. The cellular monomorphism and the absence of a significant reticulin network distinguish pituitary adenomas from non-neoplastic Inhibitors,research,lifescience,medical anterior pituitary

parenchyma (figure 4).13 These characteristics made the diagnosis of this type of tumor easy. Eleven of 13 cases were diagnosed correctly, but two cases were not diagnosed correctly using touch preparation technique. Figure 4: Pitutary adenoma: diffuse sheet of uniform cells, fibrovascular stroma, and absence of pleomorphic cells. Left: permanent pathologic slide (hematoxyllin eosin x40). Right: touch preparation (papanicolau ×40). In haemangioblastomas, obtaining good quality smears was difficult. This made the identification of numerous blood vessels difficult. Inhibitors,research,lifescience,medical The smears showed thick and dense trabeculae of elongated cells, which led to misinterpretation. The clinical history of posterior fossa location is mandatory for correct diagnosis. Haemangioblastoma had numerous mast cells 10, which helped in its diagnosis. All such characteristics Inhibitors,research,lifescience,medical helped correct diagnosing

of all three cases of haemangioblastomas in our study. Ivacaftor cystic fibrosis Hydatid cysts are endemic in Kashan, Iran. Two cases of hydatid cysts were among the cases in the present study. Hydatid cysts Inhibitors,research,lifescience,medical are diagnosed by the presence of scolex and a cyst with a laminated layer (figure 5). Touch preparation technique could not the two cases of hydatid cyst in our study. Figure 5: Hydatid cyst: cyst wall shows laminated layers and many scolexes. Left: permanent pathologic slide (hematoxyllin eosin x4), the structures are visible. Right: touch preparation (papanicolau ×100), the structures are not visible thus the diagnosis … Conclusion Touch preparation technique is a rapid diagnostic method and a good complimentary

technique for frozen section. Inhibitors,research,lifescience,medical Inadequate clinical and imaging data can contribute to wrong diagnosis. The experience of a pathologist is very important as diagnosis is made on cytology alone without any special stains and in a short time. Awareness of the cytomorphological Carfilzomib features on smears of various lesions is important. In 64% of cases correct diagnosis could be made on smears alone, and in another 20% after clinical and radiological correlation. Touch preparation technique is a very accurate and rapid method of intraoperative diagnosis, especially when combined with frozen section. However, adequate clinical history, neuroimaging details, and the intraoperative impression of the neurosurgeon, if provided, helps the neuropathologists to improve the diagnostic accuracy. Conflict of Interest: None declared.

This method may thus be used for individual risk prediction.29 It has yet to be applied more extensively to a larger number of MRI scans. Analysis of cortical thickness Another interesting automated method involves determining the cortical thickness of the neocortical association areas and the entorhinal cortex.30 Group separation

showed an accuracy of more than 90% in distinguishing between AD patients and healthy controls.31 However, this method has yet to be evaluated in an independent group, and the accuracy of this method in predicting conversion to AD in MCI subjects has not yet been studied. Imaging the cholinergic nuclei in the basal forebrain The imaging of structural changes in Inhibitors,research,lifescience,medical the region of the cholinergic nuclei of Inhibitors,research,lifescience,medical the basal forebrain was recentlyestablished using a combination of automated methods with regional information. The cholinergic projections from the basal forebrain to the cortex are affected early on in AD. An MRI-based method showed a signal reduction in the region of the Inhibitors,research,lifescience,medical lateral and medial nuclei of the basal nucleus of Meynert for the first time in vivo.32-34 overnight delivery functional magnetic resonance imaging (fMRI) The utilization of functional magnetic resonance imaging (fMRI) allows for the measurement of brain activation during cognitive

tasks at a high level of resolution without any radiation exposure to the patient. There have been many studies that have examined brain activation changes in MCI subjects compared with AD, for the development of a marker of early AD.35-37 One new approach has been to investigate changes in the functional connectivity between regions of an activated network.38 Functional Inhibitors,research,lifescience,medical connectivity gives a measure of the linear association between two regions and is a function of the phase relationship between the regions’ signals.39 An investigation of functional connectivity in MCI subjects

have shown that there are widespread changes in functional Inhibitors,research,lifescience,medical connectivity of the fusiform gyrus to other visual processing areas, and areas within the ventral and dorsal Entinostat visual pathways.38 The changes in functional connectivity http://www.selleckchem.com/products/Y-27632.html preceded differences in brain activation between the MCI and healthy control group. Given that cognitive function requires a high level of integration across the network subserving cognitive function, it suggests that the first factor that may be altered in the brain by the putative AD neuropathology is the integration across a neural network. In addition, it has been found that the activation level within the fusiform gyrus was more strongly correlated to the gray matter density in the ventral and dorsal visual pathways compared with the healthy controls, further suggesting that changes in the entire network affect activation within a network region.

Following this line, image-and coordinate-based

meta-analyses as well as data-sharing approaches are currently becoming increasingly important in imaging neuroscience. We would argue that this approach may provide a better capture of true effects in the underlying population as more conservative thresholding in an individual study. Nevertheless, we acknowledge that a formal correction for type II error within each individual Inhibitors,research,lifescience,medical study is highly advantageous if the effects are robust enough. Although our sample consisted of populations that could potentially differ in the frequency of the risk allele due to a different ethnical background, we did not Inhibitors,research,lifescience,medical genotype the sample for ancestry informative markers. Consequently, effects of ancestry could have led to

additional variance in our data. We included both male and female subjects in this study. Although gender was used as a covariate, a direct comparison between male and female T allele carriers would be interesting. However, the number of subjects included does not allow such a comparison. Future studies enrolling larger populations Inhibitors,research,lifescience,medical should also focus on gender-specific effects. In summary, we found both clusters of elevated and reduced FA in NRG1 rs35753505 C allele risk type carriers. Changes were most pronounced in the right perihippocampal region, where risk type carriers showed elevated FA values. The structural alterations described might in part be responsible for

differences in BOLD response found by functional imaging studies in a largely overlapping population Inhibitors,research,lifescience,medical (Krug et Inhibitors,research,lifescience,medical al. 2008b, 2010; Cabozantinib cancer Kircher et al. 2009b). Acknowledgments We acknowledge funding by the DFG (IRTG 1328, T. N. J., F. S., U. H.). Conflict of Interest None declared. Funding Information We acknowledge funding by the DFG (IRTG 1328, T. N. J., F. S., U. H.).
Impaired self-awareness, that is, an inaccurate subjective evaluation of one’s trait or state relative to a more objective measurement, has been reported in various neuropsychiatric or disorders, including neurodegenerative diseases (Orfei et al. 2008). It can involve the inadequate awareness of one’s disease state (disease unawareness) or focally impaired self-reflective abilities in a specific modality, AV-951 such as body sensation, various domains of cognition, or one’s characteristic traits and attitudes (modality-specific unawareness) (Clare 2004b; Ecklund-Johnson and Torres 2005; David et al. 2012). These specific modes of self-awareness, and the objective evidence against which one’s subjective self-evaluation is compared, are on a continuum from simple and concrete to highly abstract.

These phenomena, which occur during well-defined sleep stages, constitute the microstructure

of sleep, and provide important additional data in the evaluation of both normal and pathological sleep processes. In fact, phasic events appear to regulate the alternation between stationary sleep stages. For instance, sleep is very rich in arousals Inhibitors,research,lifescience,medical of different degrees, and these arousals lead to sleep stage transitions, which, in turn, determine the organization of sleep cycles and the balance between the various stages of sleep. Thus, sleep microstructure provides evidence of some important dynamic characteristics of the sleep process, which are not Inhibitors,research,lifescience,medical reflected by macrostructural evaluation. Therefore, it clearly appears that both the macrostructure and the microstructure of sleep are valuable physiologically and clinically. Traditional stage scoring of polysomnographic records provides necessary descriptions of sleep macroarchitectural abnormalities in a variety of psychiatric disorders. However, the relationships between sleep, sleep disorders, and psychiatric disorders

are quite complex. Psychiatric patients often complain about their sleep, and they may show sleep abnormalities that increase with the severity of their selleck chemicals llc illness. Also, psychiatric disorders can be associated Inhibitors,research,lifescience,medical with sleep disorders, and most often with insomnia. Therefore, the purpose of this paper is to consider whether analysis of sleep microstructure can provide an additional significant contribution to the understanding of the relationships between sleep

and psychiatric disorders. Sleep and psychiatric disorders One of the most Inhibitors,research,lifescience,medical fundamental aspects of sleep research is to clarifying what normal sleep is and determining how to quantify sleep disturbance. Existing standards for macrostructure indices, such as amount of sleep, sleep efficiency, sleep latency, time spent in each sleep stage, and so on, must take into account large interindividual Inhibitors,research,lifescience,medical variability and large age differences. For GSK-3 microstructure descriptors, the uncertainty is even larger and normative data are still lacking, especially for the appreciation of normal interindividual variability. Changes in sleep and sleep patterns are often seen with any type of physical or mental impairment. However, classical quantitative measures of sleep, derived from polysomnographic recording, are sometimes insufficient to detect sleep abnormalities in patients suffering from psychiatric disorders. Between 50% and 80% of psychiatric patients complain of sleep disturbances during the acute phase of their illness.2 Even when macrostructure of sleep appears to be normal, there still can be significant modifications in sleep microstructure as expressed by the http://www.selleckchem.com/products/Lenalidomide.html arousal-related phasic events.

Structural MRI Structural MRI is increasingly accepted as a surrogate for anatomic phenotype in neuroscience research. In many areas, anatomic MRI has replaced the need for analysis of the postmortem brain in order to elucidate relationships between structure and function. It is not hard to find examples in which anatomic MRI has transformed the entire research landscape of a field: cerebrovascular disease, epilepsy, multiple sclerosis, and other inflammatory conditions, cerebral developmental disorders, to some extent psychiatric disorders, and neurodegenerative disorders. Animal model studies at high magnetic fields have made unique contributions to

this development. Morphological images of brain tissue rely largely on proton #phase 3 keyword# density, T1 and T2 differences between tissue types (eg, white matter vs. gray matter, cortex vs. subcortical nuclei etc.). Proton density is clearly a magnetic field independent parameter. However, relaxation times T1 and T2 are field dependent, Inhibitors,research,lifescience,medical generally increasing63,64 and decreasing1,9,65,66 respectively, with higher magnetic fields Inhibitors,research,lifescience,medical (see review in ref 67). It was recently shown that, contrary to expectations, the dispersion in T1 http://www.selleckchem.com/products/Trichostatin-A.html increases

with increasing magnetic fields in the brain, leading to superior T1-weighted structural Images at the higher magnetic fields.68 Lengthening of T1 with increasing magnetic field also holds true Inhibitors,research,lifescience,medical for blood. Blood T1 is virtually insensitive to its oxygenation state. Ex vivo measurements have shown that blood T1 varies linearly with field strength going from 1.5 T to 9.4 T according to T1= 1.226+ 0.134B0.69 This imparts a clear benefit in time-of-flight type vascular imaging, as well as perfusion imaging using spin labeling techniques. Mapping signals in all hemodynamic-based functional imaging

methods, such as fMRI and optical Inhibitors,research,lifescience,medical imaging with intrinsic signals, are mediated through the vasculature. Consequently, vascular components in these methods are of utmost significance in determining the ultimate spatial and temporal accuracy of the neural activity maps produced by these methods. Therefore, it is important to be able to image vasculature in great detail, and ideally together with functional data in order Batimastat to understand more precisely the source of the fMRI signals and their spatial correlation with the volume of altered neuronal activity. Vascular imaging with high resolution is also of paramount importance in other fields of biomedical research such as tumor biology, where angiogenesis is a necessary component of tumor growth. Taking advantage of the gains in SNR and longer T1 values, the feasibility of obtaining high-resolution MR images of intracortlcal vessels was demonstrated in the cat brain.70 This accomplishment relied on a combination of time-of -flight MR angiography and T2*-weighted contrast based on both endogenous BOLD effect and exogenous iron-oxide particles.

Finally, the present study found changes over time in brain activation, but these changes were not reflected in significant direct behavioral effects. An indirect effect of selleck inhibitor anxious apprehension on behavior through Broca’s area was observed, along with a nonsignificant effect through right SFG

that was in the expected direction for RT. Therefore, it is Inhibitors,research,lifescience,medical possible that more power is needed to detect the SFG indirect effect and/or there may be as yet unidentified selleck bio regions that mediate effects that are in the direction opposite to that of Broca’s area. Additionally, given that the hypothesized behavioral effect for anxious arousal was in the expected direction, although far from significant, lack of significance here may also be due to a lack of power rather than a true absence of behavioral findings. Furthermore, researchers

have begun to caution against discounting neural findings because behavioral effects are not evident, given that behavior is not necessarily the gold standard for the occurrence of relevant psychological processes (e.g., Wilkinson Inhibitors,research,lifescience,medical and Halligan 2004). However, caution should be maintained when making inferences about present findings given the lack of significant direct Inhibitors,research,lifescience,medical behavioral effects. Future research with either more potent threat stimuli (which may have a larger effect on behavior) or a sample size large enough to detect small overt behavioral effects is needed in order to determine whether the patterns of behavioral

habituation associated with anxious arousal and apprehension are consistent with the present neural findings. In summary, the present study provides evidence for differential time courses of neural habituation associated with Inhibitors,research,lifescience,medical anxious apprehension and anxious arousal in line with Corbetta et al.’s (2008) theory of brain mechanisms serving attention and Heller and colleagues (Heller et al. 1995, 1997; Nitschke et al. 1999, 2000; Engels et al. 2007, 2010) distinction between these two types of anxiety. Inhibitors,research,lifescience,medical Present findings suggest that anxious arousal is associated with immediate engagement with negative stimuli and a concurrent recruitment of an attentional surveillance Dacomitinib system, followed by habituation of this response. In contrast, anxious apprehension is associated with immediate engagement in worry and delayed engagement with negatively valenced stimuli that occurs only after worry decreases. Acknowledgments This work was supported by the National Institute of Mental Health (R01 MH61358, T32 MH19554, P50 MH079485). The authors wish to thank Katie Mimnaugh and Kyle Gerst for their assistance. Footnotes 1The present sample partially overlapped the samples used in Engels et al. (2010) and Spielberg et al. (2012) by 89% and 92%, respectively. However, these studies did not examine variance in activation across time or connectivity between brain regions. Therefore, the studies report independent findings.

.. Cholinergic system There is selleck Vandetanib considerable evidence for a presynaptic

cholinergic deficit during aging in many brain regions based on reductions in the enzyme responsible for the synthesis of acetylcholine, choline acetyltransferase (ChAT), in cortex and striatum (as reviewed Palmer and DeKosky52) and in acetylcholine synthesis in temporal cortex.53 Furthermore, there arc decreases with age in both muscarinic and nicotinic cholinergic receptors.54 Using proton magnetic spectroscopy, Cohen et al55 demonstrated reductions in the uptake of circulating choline with advancing age. Selective imaging selleck Carfilzomib ligands Inhibitors,research,lifescience,medical for the cholinergic system have proved elusive. However, PET studies with the relatively nonselective cholinergic receptor ligands [11C]benztropine, [11C]tropanyl benzilatc, and [11C]-N-methylpiperidyl bcnzilate (NMPB) have supported in vivo losses in muscarinic receptor density with age, although they disagree on the magnitude of the reductions.56-58 Also, modest reductions in cholinergic terminal density Inhibitors,research,lifescience,medical with aging have been demonstrated by SPECT imaging of the vesicular acetylcholine transporter [123I]iodobenzovesamicol.59 Monoaminergic systems There is wide variation in the response of monoaminergic systems to aging. While postmortem studies

show considerable loss of markers of the 5-HT system (5-HT, 5-HT1A, Inhibitors,research,lifescience,medical and 5-HT2A receptors), particularly in the neocortex, and of dopaminergic markers (dopamine, major metabolites, transporter, and receptors) in the striatum, there is little evidence of change outside those regions or in markers of the noradrenergic system.52 The development, of selective imaging ligands for the 5-HT and dopamine binding sites has allowed Inhibitors,research,lifescience,medical these systems to be further studied in humans in vivo. PET studies confirm substantial aging reductions in specific

binding to dopamine D1 and D2 receptors.47,48,60 Further, alterations in cognition and coordination of motor activity that frequently accompany aging have been shown to correlate with PET measures of dopamine receptor function.61 Aging losses of presynaptic dopamine Inhibitors,research,lifescience,medical transporter sites have also been demonstrated with PET and SPECT, suggesting that age affects the integrity of dopaminergic neuronal pathways.62-65 Recently developed PET ligands for several 5-HT receptor subtypes and the 5-HT transporter GSK-3 have facilitated in vivo imaging of this important neurotransmitter system, which is central to mood and sleep regulation.66,67 Marked widespread aging reductions in binding of the pharmacologically well-characterized 5-HT2A receptor using [18F]altanserin and [18F]setoperone have been shown by several investigators.49,50,68 The magnitude of the inverse relationship between age and 5-HT2A receptor binding supports the hypothesis that loss of serotonergic function in aging may contribute to the susceptibility of the elderly to alterations in mood and 5-HT-mcdiated behaviors.

Deletion of galectin-3 was also associated with an increase in microglia, and elevated levels of TNF-α and protein carbonyls, a marker of oxidative injury. Microglial number and phenotype significantly influence the http://www.selleckchem.com/products/mek162.html progression of motor neuron disease. Increases in wild-type (non-SOD1G93A) selleck inhibitor microglia reduced neurodegeneration slowed disease progression and increased survival of SOD1G93A mice, supporting a generally protective role for healthy

microglia against the disease process Inhibitors,research,lifescience,medical (Beers et al. 2006). Alternatively, selective reduction of SOD1 overexpression within diseased microglia increased survival time, particularly at the end stage of disease (Boillee et al. 2006; Wang et al. 2010), suggesting that mSOD1 imparts neurotoxic properties to microglia that contribute to neurodegeneration.

Indeed, SOD1G03A microglia display an inflammatory phenotype characterized by elevations in TNF and other inflammatory molecules (Sargsyan Inhibitors,research,lifescience,medical et al. 2009). Thus, the presence of more SOD1G93A microglial cells in the SOD1G93A/Gal-3−/− cohort may have increased the neurotoxic/pro-inflammatory load on neurons, and accelerated disease progression. Also possible, is that deletion of galectin-3 further enhanced the already neurotoxic properties of the mSOD1G93A microglia. This is indirectly supported by data showing that a 50% reduction in the number of proliferating galectin-3/Mac-2+ mutant (mSOD1) Inhibitors,research,lifescience,medical microglia in CD11b-TKmut−30, SOD1G93A doubly transgenic mice had no effect on neurodegeneration Inhibitors,research,lifescience,medical (Gowing et al. 2008). Increased protein carbonyls correlate with an upregulation

of TNF-α transcripts at an early stage of disease in SOD1G93A mice (Hensley et al. 2006). TNF-α elevation also correlates Inhibitors,research,lifescience,medical with disease progression in the mouse, and TNF-α is increased in serum from ALS patients (Poloni et al. 2000; Hensley et al. 2003). Although the precise role of TNF in disease progression is unclear (Gowing et al. 2006), it has many pro-inflammatory effects, including activation and stimulation of free radical release from microglia, as well as potential synergisms with other pathogenic factors involved in the disease (McGeer and McGeer 2002; Mir et al. 2009). While the present studies do not address any direct Drug_discovery relationship between TNF-α and oxidative injury, the observation that both were increased in SOD1G93A/Gal-3−/− mice supports that neuroinflammation was exacerbated in the absence of galectin-3. Though not always consistent (Doverhag et al. 2010), some evidence suggests a protective role for galectin-3+/Mac-2 expressing microglia, at least in models of acute neurodegeneration (Lalancette-Hebert et al. 2007). Such protection is associated with transition of microglia to a galectin-3 positive alternative activation phenotype (M2) that expresses increased levels of IGF-1 and a type Th2 immune bias (Ohtaki et al. 2008).

A brief summary of the complexity of genetic causation of psychiatric inhibitor Nilotinib disorders will be detailed in this review. We also discuss the idea that studies of genetic susceptibility in selleck chem JQ1 complex polygenic disorders

such as schizophrenia might be enhanced by the identification of intermediate phenotypes,11-13 and we present evidence derived from more than Inhibitors,research,lifescience,medical a century-worth of clinical, epidemiological, molecular genetic, and clinical neuroscience investigations in support of the view of cognitive impairment as a core clinical feature of schizophrenia. Most importantly, evidence of heritability of specific impairments discussed here may serve to further empower the search for genes of risk. Necessarily, we shall not discuss Inhibitors,research,lifescience,medical all the potential intermediate phenotypes, such as eye-tracking for example, which have been recently reviewed in depth.14 Definitions An intermediate phenotype (often referred to as an endophenotype) is a quantitative biological trait that is reliable and reasonably heritable, ie, shows greater prevalence in unaffected relatives of patients than in the general population. A complex disorder arises from Inhibitors,research,lifescience,medical a polygenic matrix whose individual components each confer only a small portion of total risk,

in contrast to a monogenic or mendelian disorder. If a candidate intermediate phenotype is to provide Inhibitors,research,lifescience,medical meaningful information about a disorder, it should be associated with variant alleles that distinguish patients and their unaffected siblings from healthy controls on quantitative measures. The most useful intermediate phenotype candidates will also be functionally associated with aspects of

the core clinical deficits of the disorder. The intensive search for such candidates is based in part on a reasonable, but incompletely substantiated assumption that intermediate phenotypes in schizophrenia are more likely to be modeled by a less complex genetic architecture than the disorder as a whole. Figure 1 displays a simplified scheme of this concept. Figure 1. A schematic illustration of Inhibitors,research,lifescience,medical the assumption that individual traits are controlled by fewer risk alleles than the disorder taken as a whole. This scheme is the principal experimental design incorporated by the majority of studies discussed in this review. … The above statement Entinostat “less complex genetic architecture than the disorder as a whole,” does not imply “simple”; an intermediate phenotype could conceivably be more genetically complex than its parent disorder. However, in the context of this discussion, we will refer to intermediate phenotypes as having a less complex relationship to susceptibility genes than the diagnostic phenotype. The proof of this assumption rests on the demonstration that genetic association is statistically stronger for the intermediate phenotype than for the clinical phenotype.