This is reflected in the important role now attributed to the PFC in controlling emotional behavior in humans and animals. Molecular biology techniques, such as those used to create transgenic

and #this website randurls[1|1|,|CHEM1|]# knockout mice, have been successful in exploring the role of various neurotransmitters, peptides, hormones, and their receptors in mediating the appraisal of stressful stimuli, information processing through the Inhibitors,research,lifescience,medical various neuronal circuits, and the physiological responses and behaviors associated with fear and anxiety. It is now clear that individual differences in affective or coping styles, which are also observed in nonhuman species, are directly associated with vulnerability to psychopathology. Studying these individual differences, including sex-related differences, Inhibitors,research,lifescience,medical in humans and in animal models will give interesting clues about the brain mechanisms of emotional behavior. Finally, the study of genetic predisposition and environmental influences, particularly during early Inhibitors,research,lifescience,medical development, in determining vulnerability

traits and anxietyprone endophenotypes is certainly becoming one of the major, and perhaps most promising, domains of contemporary research with respect to our understanding of the etiology of anxiety and mood disorders. Selected abbreviations and acronyms ACTH adenocorticotropic hormone BIS behavioral inhibition system BNST bed nucleus of the stria terminalis CeA central nucleus of the amygdala CRF corticotropin-releasing

factor GABA γ-aminobutyric acid HPA hypothalamo-pituitary-adrenocortical (axis) 5-HT 5-hydroxytryptamine Inhibitors,research,lifescience,medical (serotonin) 5-HTT serotonin transporter LC locus ceruleus NA noradrenaline NTS nucleus tractus solitarius PAG periaqueductal gray PBR peripheral benzodiazepine Inhibitors,research,lifescience,medical receptor PFC prefrontal cortex PVN paraventricular nucleus Notes The author would like to express his gratitude to the Swiss National Science Foundation for supporting work on the Roman rat lines in his laboratory (grant 32-51187-97).
This issue of Dialogues in Clinical unless Neuroscience focuses on depression and senescence in women for several reasons. First, mood disorders linked to reproductive endocrine change in women (eg, premenstrual syndrome [PMS], postpartum depression [PPD], and perimenopausal depression [PMD]) are clinically significant: they are prevalent and attended to by considerable morbidity. Second, it is now clear that reproductive steroids are important regulators of virtually ever}’ aspect of brain organization and function, from neural differentiation and migration to intracellular and intercellular signaling to neuronal (and glial) survival and death. Simply put, these steroids create a context such that the brain functions differently in their presence and absence.

Patients on etanercept had greater improvements on measures of depression (as measured by Beck Depression Inventory) than those on placebo. Notably, these improvements were not associated with reduction in psoriatic plaques or joint pain, which indicates a primary effect of TNF antagonism on depression, not simply a cosmetic or analgesic effect.108 These LGK-974 concentration effects were confirmed in subsequent longer term studies in psoriasis patients109,110 and in patients with Inhibitors,research,lifescience,medical rheumatoid arthritis.111 A similar effect has been shown with the TNF-α

monoclonal antibody infliximab.112,113 Adiposity as a possible causal pathway to depression In considering possible sources of inflammation leading to depression, there has been increasing interest in the role of obesity. Rates of overweight and obesity have increased tremendously in recent years in both adults and children.114-119 Along with this has been an epidemic of related metabolic conditions Inhibitors,research,lifescience,medical like type 2 diabetes, dyslipidemias, cardiovascular and fatty liver disease, and certain forms of cancer.120-122 The bulk of evidence links obesity and its attendant complications to inflammation.123-125 Inhibitors,research,lifescience,medical The possible relationship between depression and obesity appears to be bidirectional, as evidence indicates that being depressed also increases the risk for the subsequent development of obesity, probably mediated, in part, by inactivity.126 Obesity

as an Inhibitors,research,lifescience,medical inflammatory state Adipose tissue is now understood as being a very complex organ system.127 White adipose tissue (WAT) is the main location for long-term fat storage in the body. WAT, particularly in the abdomen, is the main contributor to metabolic diseases.122,128,129 Adipocytes in WAT secrete a variety of hormones, inflammatory factors including cytokines (referred to Inhibitors,research,lifescience,medical as adipocytokines or adipokines).130,131 These factors include hormones traditionally associated with adipose tissue such as leptin, adiponectin, resistin, and visfatin; however, adipocytes can also secrete

IL-6 and TNF-α.130,130 Nevertheless, one of the primary mechanisms for the induction of inflammation in adipose tissue is the secretion of chemokines, particularly MCP-1. MCP-1 attracts leukocytes such as macrophages, T lymphocytes, and dendritic cells to adipose tissue, which in turn secrete cytokines including IL1, IL6, and TNF-α.132,133 Thus, chemokines and cytokines produced by WAT may contribute to widespread the immune activation, potentially causing or exacerbating diseases associated with inflammation such as type 2 diabetes, cardiovascular disease, cancer, and depression.130 Leptin is another important peptide produced by adipocytes that regulates dietary intake. It regulates appetite by acting on leptin receptors in brain, particularly the hypothalamus.134 In the case of obesity, a state of leptin resistance develops in which circulating levels are actually increased but responsiveness is reduced.

63 Basic work on the psychobiology of OCD has suggested that neurotransmitters other than serotonin may be important in its pathogenesis. Indeed, the best studied SSRI-augmenting agents in OCD are low-dose atypical antipsychotics. Early work suggested that these were particularly useful in patients with comorbid tics,64 but subsequent work has indicated that they may be useful in both patients with and without tic disorders.65,66 More recently, evidence for the role of the glutamatergic system in mediating OCD has emerged, and

there has been interest in using Inhibitors,research,lifescience,medical glutamate-modulating drugs in the augmentation of treatment-resistant OCD. The anticonvulsant agent topiramate, which inhibits glutamatergic neurotransmission, may be useful in treatment-refractory OCD.67 Riluzole, which inhibits the release of glutamic acid, thus also blocking Inhibitors,research,lifescience,medical glutamatergic neurotransmission, has been found effective in proof of principle trials. 68,69 Memantine, another glutamatergic agent, may also be useful in treatment-refractory OCD.70 There has also been interest in using the NMDA partial agonist, cycloserine, in combination with CBT in OCD.71 Several other somatic treatment options in OCD are also being explored. First, a range of other mechanisms have been targeted by SSRI-augmentation strategies, including

use of Inhibitors,research,lifescience,medical the 5-HT3 receptor antagonist, STA-9090 order ondansetron.72 Second, given the abundance of literature on autoimmunity in OCD, one strand of work has focused on the use of immunoglobulins and plasmapheresis in patients with pediatric autoimmune neuropsychiatrie disorders associated with streptococcal

infection (PANDAS).73-75 Third, given the work on the neural circuitry of OCD, neurosurgery to remove specific lesions76 or deep brain Inhibitors,research,lifescience,medical stimulation after implantation of electrodes has been investigated.77,78 Such approaches provide promise for the future Inhibitors,research,lifescience,medical management of refractory OCD. Panic disorder Research on the pharmacotherapy of panic disorder (PD) was given significant impetus by the early serendipitous finding that tricyclic antidepressants are effective, and the hypothesis that different pharmacological agents are effective many for different anxiety disorders.79 Subsequent research done in order to register alprazolam and other benzodiazepines for the treatment of panic disorder did not provide a great deal of support for this hypothesis, but was important in contributing to the development of clinical trial methods in this condition. Subsequent rigorous randomized controlled trials of the SSRIs in PD were again an important advance insofar as they provided an effective and relatively well-tolerated treatment option.80-82 As in the case of GAD and OCD, however, much further work is required to optimize the treatment of refractory cases. Fortunately, ongoing studies of the psychobiology of PD have provided several leads which may be helpful in developing more targeted therapies in the future.

57 Schizophrenia spectrum disorders There is an emerging formulation from several laboratories that schizophrenia is part of a larger set of disorders called schizophrenia spectrum disorders or schizotaxia; these disorders are related to each other in terms of genetics, symptom expression, cognitive characteristics, and, potentially, pathophysiology. Schizophrenia itself may be the most severe manifestation of the class and #www.selleckchem.com/products/baricitinib-ly3009104.html keyword# characterized by the most flagrant psychosis and the worst psychosocial

function (Figure 1). But impairment at multiple levels and schizophrenialike symptoms span the entire spectrum group. Approximately 20% of family members of an individual with schizophrenia have spectrum manifestations. Moreover, approximately 20% of persons with spectrum Inhibitors,research,lifescience,medical manifestations have symptoms that are severe enough to impair work function and may benefit from antipsychotic treatment (G. Thaker, personal communication). Figure 1. Schizophrenia spectrum disorders. The prevalences of schizophrenia and schizophrenia-related personality disorders in the general population are 1% and 5%, respectively; the prevalence of both together is 6%. First-degree relatives of schizophrenic probands may display many of the cognitive symptoms characteristic of schizophrenia, only without the florid psychosis. These include task-related impairments in attention,

language Inhibitors,research,lifescience,medical comprehension, verbal fluency, verbal memory, and spatial working memory. It is suspected that these cognitive disturbances in relatives Inhibitors,research,lifescience,medical occur predominantly in those with spectrum symptoms, however more study is required. Some adjustments in the criteria for spectrum disorder (ie, loosening) may be required for that diagnosis to capture all affected persons. Considering Inhibitors,research,lifescience,medical spectrum disorders as a relevant diagnostic category adds 5% to the prevalence of the schizophrenia diagnosis. Perhaps up to 20% of the spectrum group is impaired enough to require treatment. These observations may serve to broaden our concepts of schizophrenia, its manifestations, and beneficial treatment opportunities. Brain

structure and function in schizophrenia Brain structure One of the first discoveries in schizophrenia using modern imaging technologies why was structural, first with computerized axial tomography (CAT) scanning and later with magnetic resonance imaging (MRI). Johnstone and Crow58 then Weinberger59 described enlarged cerebral ventricles in persons with the illness. Over time, an overwhelming number of confirmations have accumulated.59,60 Ventricular size is a crude and nonspecific indication of cerebral dysfunction, and possibly only an epiphenomenon of this illness. However, this observation has served to redirect interest toward examining the brain for abnormal characteristics in persons with the illness.

It is often noted that cognitive decline is one of the primary elements concerning the aging population. In recent years, researchers have focused on nonpharmacological interventions as a

way to alleviate deficits associated with cognitive decline. One of the most recent nonpharmacological interventions applied to individuals experiencing cognitive decline or cognitive impairment is a program of cognitive training (CT) (Zanetti et al. 1995; Loewenstein et al. 2004; Sitzer et al. 2006; Acevedo and Loewenstein 2007). Today, this type of procedure is used with individuals from varying populations; however, more historically this type of procedure was used with individuals experiencing traumatic brain injuries (TBI) and since Inhibitors,research,lifescience,medical has evolved more recently to be applied to individual’s experiencing cognitive declines related

to illnesses such as mild cognitive impairment (MCI) as well as individuals with more serious neurodegenerative Inhibitors,research,lifescience,medical afflictions, such as Alzheimer’s disease (AD) (Loewenstein et al. 2004; Cicerone et al. 2005; Cipriani et al. 2006; Farina et al. 2006; Sitzer et al. 2006). CT programs vary in their approach of application; the first strategies utilized with individuals experiencing cognitive decline are often ones that are compensatory in nature. Compensatory strategies, for example, involve developing plans to help individuals meet everyday requirements, such as remembering appointments, individual’s names, Inhibitors,research,lifescience,medical or basic self-grooming skills. Thus, compensatory procedures focus on identifying Inhibitors,research,lifescience,medical key areas of deficit and developing strategies and utilizing tools to remediate these deficits. This is in contrast to the restorative approach, where the focus is on holistic remediation through generalized LDK378 mw stimulation of the brain (Sitzer et al. 2006). Inhibitors,research,lifescience,medical Restorative strategies, therefore, focus on creating a program of general cognitive stimulation (e.g., problem solving and creative activities) aimed at engaging the participant in various tasks that are designed to activate the “brain” generally, and as such, there are no particular tasks tailored to a participant’s specified deficit. Both CT approaches have been examined via meta-analytic review, which

those demonstrated that restorative strategies were noted to be more effective (Sitzer et al. 2006). Specifically, the suggestion is that restorative programs offer significant benefits resulting in the greatest amount of change at posttraining evaluations in both cognitive and functional tasks (Sitzer et al. 2006). Previously, it has been noted that a reduction in one’s visuospatial (VS)/visuomotor (VM) ability can be an early identifier for the onset of a cognitive impairment such as AD (Tales et al. 2002; Tippett and Sergio 2006). Additionally, it can be shown that the brain is highly interconnected with identified bundles of nerve fibers, such as the inferior longitudinal fasciculus, inferior occipitofrontal fasciculus, and posterior thalamic radiation (Voineskos et al.

46,47 CRF neurons in the amygdala project directly to the locus ceruleus and increase the firing rate of locus ceruleus neurons, resulting in increased noradrenaline release in the vast terminal fields of this ascending noradrenergic system. Thus, intracerebroventricular (ICV) infusion of CRF increases extracellular noradrenaline levels.48-52 The amygdaloid CRF projection to the locus ceruleus52-56 is also critical Inhibitors,research,lifescience,medical for the expression of behavioral responses to stress.57-64 Hence, the CRF neurons in the PVNh and amygdala serve as important mediators of both behavioral and endocrine responses to stress. We examine the relation between maternal care

and the development of stress responses Inhibitors,research,lifescience,medical using a rather simple model of naturally occurring variations in maternal behavior over the first 8 days after birth.65 We characterize individual differences in maternal

behavior through direct observation of mother-pup interactions in normally reared animals. These observations reveal considerable variation in maternal LG of pups Inhibitors,research,lifescience,medical (Figure 1). LG includes both body as well as anogenital licking.66 We then simply define mothers according to the frequency of pup LG, ie, high- or low-LG mothers. For the sake of most of the studies described here, high- and low-LG mothers are females whose scores on pup LG are ±1 SD above (high) or below (low) the mean for their cohort. Importantly, high- and low-LG mothers do not differ in the amount of contact time with pups; differences in the frequency of Inhibitors,research,lifescience,medical LG do not occur simply as a function of time in contact with pups. High- and low-LG mothers raise a comparable number of pups to weaning, and there are no differences in the weaning weights

of the pups, suggesting an adequate level of maternal care across the groups. Inhibitors,research,lifescience,medical These findings also suggest that we are examining the consequences of variations in maternal care that occur within a normal range. Indeed, the frequency of both pup LG is normally distributed across large populations of lactating female rats.65 Figure 1. Lactating female Long-Evans rat nursing litter in arched-back posture while licking/grooming an individual pup. The critical question concerns the potential consequences of these differences in maternal behavior for the development of behavioral and neuroendocrine responses secondly to stress. As Wnt cancer adults, the offspring of high-LG mothers show reduced plasma ACTH and corticosterone responses to acute stress by comparison to the adult offspring of lowLG mothers.39,67 Circulating glucocorticoids act at GR sites in corticolimbic structures, such as the hippocampus, to regulate HPA activity. Such negative-feedback effects commonly target CRF synthesis and release at the level of the PVNh.

The incidence of DFSP is thought to be 4.2 per million people annually in North America, with the vast majority of cases (42%) occurring in the truncal area and the remainder in the upper extremity, lower extremity, head and neck (83). DFSP appears as a solid, Cyclosporin A molecular weight nodular polypoid tumor almost always arising from the dermis, with invasion into the subcutaneous tissue. Microscopically, it is characterized by a whorl-like spindle cell pattern of monomorphic fibroblast growth, accompanied usually by a low mitotic activity. In

cases where Inhibitors,research,lifescience,medical the subcutaneous layer is invaded there is often evidence of entrapment of adipose tissue between extending “limbs” of fibroblast growth. Immunohistochemically, DFSP lesions often exhibit vimentin and CD34 reactivity with occasional focal actin staining and are often negative for factor XIIIa, keratin and S-100 proteins (86). The treatment of DFSP is surgical and the standard is wide local excision with at least 2 cm margins (87). Given the Inhibitors,research,lifescience,medical high recurrence rate, a negative margin is of outmost importance but is hard to achieve in areas close to critical perineal structures such as the anal sphincters and therefore MMS should be considered, especially for small, distal and superficial

lesions (88). There have been numerous analyses comparing Inhibitors,research,lifescience,medical wide excision to MMS for other disease sites, most with small patient numbers and varying outcomes. A retrospective review comparing the two in 48 patients concluded that although MMS provided fewer incidences of positive margins, it also required longer operative time, higher cost and a higher incidence of complex closure requiring graft or flap (89). Given that 90% of DFSP cases have a t[17;22] chromosomal translocation Inhibitors,research,lifescience,medical and over expression of the (PDGF) gene explained previously, clinical Inhibitors,research,lifescience,medical trials with imatinib mesylate have recently been conducted. In a pool of

24 cases from two phase II trials in which daily imatinib was given to patients with locally advanced or metastatic DFSP, 45.9% of the patients showed at least partial response (90). These trials and other reports set the ground for the use of imatinib in the neoadjuvant setting and a phase II trial of 21 patients with positive fusion gene “COL1A1 & PDGF” (91). Eight patients (31%) had complete or partial response with a median 20% decrease Endonuclease in size. This limited data opens the possibility of considering imatinib mesylate preoperatively for anorectal DFSP, in cases where the extent of excision is an issue. There are only two reported cases of DFSP involving the anorectal region (92,93). One was a four year old child with no co-morbidities and a background history of trauma to the region. The tumor initially involved the right scrotum and then extended onto the anal margin. The lesion was excised using Mohs micrographic surgery (MMS) (92).

4, 4.5 and 7.4. The microparticles were retrieved from the dissolution vessel after the endpoint at pH 7.4 and dried selleck before SEM analysis. SEM Images 7(a), and 7(b) represent dried SF samples that remained as a compact porous matrix. Figure 7 SEM images obtained from different spray-dried microparticles extracted with different dissolution media after in vitro release study. SF:NS (2:1) porous matrix remaining from macroparticles

Inhibitors,research,lifescience,medical after dissolution ((a) and … 4. Discussion 4.1. Silk Fibroin Processing Natural silk fibers dissolve only in a limited number of solvents, compared to globular proteins, because of the presence in fibroin of a large amount of Inhibitors,research,lifescience,medical intra- and intermolecular hydrogen bonds and its high

crystallinity and specific physicochemical properties. The isoelectric point of fibroin varies in the range pH 3.6–5.2, depending on the conditions of solution preparation [22]. Fibroin dissolves in concentrated aqueous solutions of acids (phosphoric, formic, sulfuric, and hydrochloric) and in concentrated aqueous, organic, and aqueous-organic solutions of salts [LiCNS, LiBr, CaCl2, Ca(CNS)2, ZnCl2, NH4CNS, CuSO4 + NH4OH, Ca(NO3)2]. The main disadvantages of salt-containing aqueous, aqueous-organic, and organic solutions of fibroin are the long preparation time (aqueous solutions Inhibitors,research,lifescience,medical of fibroin should be dialyzed for several days). It should be noted that the concentrations of salts in such solutions reach the saturation limit. It was reported [23] that the efficiency of aqueous salt systems depends on the salt Inhibitors,research,lifescience,medical concentration and

increases in the following order: for anions, sulfate < citrate < tartrate < acetate < chloride < nitrite < bromide < iodide < thiocyanate < dichloroacetate; for cations, Ca2+ < Sr2+ < Ba2+ < Li+ < Zn2+. A 75:25 (weight ratio) mixture of Ca(NO)2·4H2O and absolute methanol was used earlier for dissolving Bombyx mori silk Inhibitors,research,lifescience,medical [24, 25] as it has the strongest dissolving capacity for the SF. Some solvent systems containing LiBr, LiCNS, and Ca(CNS)2 are unfavorable because Unoprostone LiBr, LiCNS, and Ca(CNS)2 are classified as toxic chemicals. Hence, in this study two solvent systems CaCl2:EtOH:H2O (1:2:8 mole ratio) and Ca(NO)2·4H2O were utilized for SF processing. Since purification of SF by dialysis usually takes 3-4 days and is applicable only for small batches of SF solution, we attempted to develop a scalable process using Sephadex G-25 media as described in the literature [19]. Effective chromatographic separation of SF from salt in solution was demonstrated by the data shown in Figure 1. Both UV absorbance and conductivity measurements for detecting SF and CaCl2, respectively, were quick and effective techniques for differentiating between the two solution components.

In the first instance, proteins such as enzymes, transporters, and receptors more specifically devoted to the serotonergic functions will be described. Methodological limits of the classical postmortem approaches in the human and new 5-HT in vivo imaging modalities will also be considered. At the present time, more than 100 000 scientific publications concern 5-HT (PubMed). Wherever

possible, we have tried Inhibitors,research,lifescience,medical to include up-to-date references dealing with the human brain. The main molecular protagonists in 5-HT neurotransmission From tryptophan to serotonin In the brain, neuron subpopulations have a set of enzymes permitting the two-step synthesis of 5-HT from its precursor tryptophan, an essential aminoacid provided

by nutrients and Inhibitors,research,lifescience,medical check details actively cotransported with other neutral large amino acids from the blood to the brain.53 The consequences of tryptophan depletion or loading on physiological functions, including memory, cognition, mood, facial expression of emotion, and sleep, have been reported in detail Inhibitors,research,lifescience,medical elsewhere.53-56 Contrasting with the peripheral glandular serotonergic systems (eg, the enterochromafin cells or the pineal gland) that uses a first tryptophan hydroxylase form (TPOH1), 5-HT synthesizing neurons in the brain express another tryptophan hydroxylase (TPOH2) recently evidenced from knockout studies in mice.57 The respective sequences of these isoenzymes revealed 30% heterology, offering the perspective of a selective modulation Inhibitors,research,lifescience,medical by appropriate drugs in central or peripheral pathologies.57 Some 5-HT-related neuropsychiatric disorders are possibly correlated with genetic variants of TPOH2.57-61 Additionally, recent analyses indicate that TPOH1 polymorphisms could increase susceptibility to schizophrenia62 and suicidal behavior.63 5-hydroxytryptophan

formed during the first rate-limiting step by TPOH1 or TPOH2 is then transformed into 5-HT Inhibitors,research,lifescience,medical via an aromatic L-amino acid decarboxylase (AADC) also present in catecholaminergic neurons. Rare AADC point mutations reported in humans result in deficiency of catecholamines and serotonin with severe neuropsychiatric symptoms.64 In the nervous system, 5-HT is mainly metabolized by the monoamine oxidase A (MAOA) and Ribonucleotide reductase a 5-HT half-life of only a few minutes is reported.65 Thus, reciprocal 5-HT exchanges between the central nervous system (CNS) and other tissues appear to be limited, although a brain 5-HT efflux through the blood-brain barrier was observed in rat species.66 Abnormality in 5-HT metabolites, especially low 5-hydroxyindolacetic acid (5-HIAA) levels in the cerebrospinal fluid (CSF) was correlated with suicidality and severity of aggressive behaviour.67,68 Furthermore, an association between CSF 5-HIAA and cholesterolemia was described in certain suicidal patients.

An appropriate approach seems the classification of haplotypes Into functionally related (Ideally functionally equivalent) ones based on sequence-structure-function similarity Once a classification has been derived, the haplotype frequencies of cases and controls In the different classes can be compared. By this approach, the multiplicity of haplotypes could be condensed to two functionally related categories, one of which was more frequent In substance-dependent Individuals.9 Common to this category was a characteristic pattern of sequence variants located In the 5′ regulatory region, reflecting a specific constellation of putative transcription

regulatory Inhibitors,research,lifescience,medical motifs that may confer different regulatory properties.9,12 Taken together, this analysis at the gene level demonstrates a remarkable gene sequence and haplotype diversity, the rule rather than the exception for the majority of candidate genes. This work provides, moreover, an example of approaches that can be successfully applied to establish complex genotype-phenotype Inhibitors,research,lifescience,medical relationships against Inhibitors,research,lifescience,medical a background of high natural genome sequence diversity Perspectives Observed diversity presents challenges to the traditional views of the concept of “a” gene with far-reaching implications on the analysis of “gene” “function” relation-ships.13,14

Classical single mutation analysis no longer appears appropriate. The units of functional analysis must be the SB203580 research buy entire individual sequence of haplotypes, involving potentially abundant variation in all regulatory, coding, and intronic sequences. Analysis will include the spectrum of haplotypes existing in a population, and the pairs of haplotypes existing Inhibitors,research,lifescience,medical in each individual We have now determined in a first comprehensive study the molecular haplotypes of a key candidate gene in hundreds of individuals, confirming the existence

of multiple Inhibitors,research,lifescience,medical individually different forms of a gene at the molecular level (Hoehe et al, in preparation). This work provides at the same time knowledge of the concrete molecular templates to allow dissection of what may be an entire spectrum of functions underlying molecular gene diversity. At this stage, individual variation and its functional implications until have been addressed at the level of a single gene only However, this is integral part of an entire network of genes as a higher-level functional unit; multiple individual molecular haplotypes interact to produce a common output signal Thus, progress in the future is expected to come from whole systems analysis-based approaches,13 integrating individual variation in all genes involved in all pathways of relevance. This will prepare the basis for “personalized” medicine in its true sense. Notes MRH would like to acknowledge Dr Theodora Duka, School of Life Sciences, University of Sussex, a major collaborator in the psychoneuroendocrinological opiate studies.