Worse yet, Linus Pauling, one of the greatest chemists of the twentieth century and the only person to win two individual Nobel prizes, was adamantly Alvespimycin nmr against the notion

that quasi-periodical crystals exist. In the October 10, 1985 issue of Nature he published a rebuttal article claiming that these irregularly shaped crystals were formed by a natural process Inhibitors,research,lifescience,medical called icosahedral twinning, several intergrown crystals whose shared boundary gives rise to a composite diffraction pattern. In paper after paper published in prestigious journals such as the Proceedings of the National Academy of Sciences and Science News, Pauling continued his crusade to debunk the entire notion of quasi-periodical crystals. During an American Chemical Society conference at Stanford, in front of thousands of scientists, Pauling proclaimed Inhibitors,research,lifescience,medical “Danny Shechtman is talking nonsense. There is no such thing as quasi-crystals, only quasi-scientists.” It took three years for scientists to develop methods to grow these crystals to the size needed for X-ray diffraction. I received X-ray diffraction patterns from scientists Inhibitors,research,lifescience,medical in Japan and France who confirmed that these crystals were quasi-periodical and that their structure had icosahedral symmetry (Figure 8). When I presented these findings

at the International Union of Crystallographers meeting in Perth, Australia in 1987, they said, “OK, Danny, now you are talking.” Figure 8 X-ray transmission Laue photograph of the quasi-crystal i-ZnMgHo, courtesy of An-Pang Tsai, Japan. A committee was formed that redefined crystals. This represented a very significant Inhibitors,research,lifescience,medical paradigm shift. In 1992, the International Union of Crystallographers came out with a new definition of crystals which reads as follows: “… By crystal we mean any solid having an essentially discrete diffraction diagram, and by aperiodic crystal we mean any crystal in which three dimensional lattice periodicity can be considered to be absent.” This is Inhibitors,research,lifescience,medical a humble

definition, an open definition. Humble scientists much are good scientists. They are open to listen to new ideas. They ask questions and critique, but do not knock down and dismiss ideas just because they do not fit their preconceived notions. Supported by the American Chemical Society members, Linus Pauling refused to accept the growing evidence for quasi-periodic crystals until his death in 1994. By the late 1980s, the tide was already turning regarding the existence of quasi-periodical crystals. All of Pauling’s alternative models which purported to explain the quasi-periodical crystals were proven wrong, and after Pauling’s death opposition to my discovery ceased. Not long after publication of my first article on the subject, I was given a book called The Structure of Scientific Revolutions written by the philosopher of science Thomas Kuhn.

24 Tolerance was seen only in relation to effects like hypertherm

24 Tolerance was seen only in relation to effects like hyperthermia, hypertonia, and anorexia, but not psychomotor stimulation.31,34,35 It should be stressed that the aforementioned side effects are observed not only

in depressed patients, but also in patients treated with psychostimulants for other indications. Development of dependency or tendency to abuse? The possible development of dependency and a withdrawal syndrome Inhibitors,research,lifescience,medical after withdrawing amphetamines has been a controversial issue. Addiction was reported by Kramer et al3 and Edison,36 and a withdrawal syndrome characterized by apathy, decreased activity, and sleep disturbances with an increase in rapid eye movement (REM) sleep Inhibitors,research,lifescience,medical by Oswald and Thacore37 and Watson et al.38 Most studies, however,

report, little or no dependence in depressed patients treated with amphetamines (see overview in refs 2 and 23). Psychostimulants may be withdrawn after several weeks of treatment without any danger of recurrence of depression.21 No tolerance or addiction has been reported to develop in geriatric patients. However, recurrence of mild depression, tiredness, and anxiety have been reported on stopping treatment with psychostimulants.39 Inhibitors,research,lifescience,medical Development of tolerance or abuse after patients are discharged from hospital is practically never reported.22,24,40 Dosage The dosage of the psychostimulants must imperatively be individually adjusted. The daily doses usually recommended in treatment-resistant depressed patients range between 2.5 mg41 and 15 mg20 for amphetamine and between 10 and 60 mg for methylphenidate.42 Indications in depressive disorders Inhibitors,research,lifescience,medical Some depressive disorders remain refractory to treatment despite intensive antidepressant therapy with adequate dosages and even combinations of antidepressants.43,44 These cases may benefit from adjuvant treatment with Inhibitors,research,lifescience,medical psychostimulants. The mood-elevating effects of the tricyclics, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAOIs) usually only manifest, after 10 to 12

days. Side effects and drug interactions are quite common with these drugs. Although psychostimulants themselves are not as effective as conventional antidepressants,45,46 they have the dual advantage of a more rapid onset of action and of inducing a lower rate of adverse events. Because their acute effects develop within less crotamiton than a few hours,20 they may be used in combination with traditional antidepressants in order to cover the lattcr’s BAY 73-4506 cell line therapeutic latency period and potentiate their effect.13,35 In a review of the literature, Chiarello and Cole2 showed that the majority of studies – even though some were methodologically unsatisfactory – reported beneficial effects following administration of psychostimulants in treatment-resistant depression.

T2-weighted imaging can also provide assessment of the area at ri

T2-weighted imaging can also provide assessment of the area at risk. LV systolic dysfunction usually recovers rapidly with glucocorticoid therapy. Acromegaly due to pituitary adenoma There is a case report with severe dilated LV systolic dysfunction associated with acromegaly.57) In this case, LV systolic function improved with the removal of the pituitary adenoma. It has also shown to be associated with increased T2 values on CMR, which may represent myocardial edema. In

addition, patients with acromegaly have significantly Inhibitors,research,lifescience,medical increased LV mass on CMR.58) Acute growth hormone deficiency Reversible LV systolic dysfunction has been reported in acute growth Inhibitors,research,lifescience,medical hormone deficiency due to Sheehan’s syndrome.59) Tachycardia-induced cardiomyopathy Prolonged tachycardia can cause reversible cardiomyopathy.60) Sustained rapid atrial or ventricular pacing for about 24 hours can cause severe biventricular systolic and diastolic dysfunction in animal models.61) In a human series, various arrhythmias caused tachycardia-induced cardiomyopathy including atrial fibrillation, atrial tachycardia, accessory pathway associated tachycardias, atrioventricular node reentry tachycardia and ventricular tachycardia associated with LV systolic Inhibitors,research,lifescience,medical dysfunction. Frequent ventricular premature complexes can be associated

with transient LV systolic dysfunction.62) The precise mechanisms responsible

for developing Inhibitors,research,lifescience,medical cardiomyopathy are unknown. The proposed mechanisms include myocardial energy depletion and impaired utilization of energy, myocardial ischemia, abnormal regulation of cardiac calcium metabolism, and remodeling of cardiomyocytes and extracellular matrix.60) Tachycardia-induced cardiomyopathy can occur in any age group. Although the ventricular rate that causes tachycardia-induced cardiomyopathy has not been determined in this website humans, clinicians should suspect Inhibitors,research,lifescience,medical it when LV systolic dysfunction accompanies persistent tachycardia (> 100 beats/minute).63) The main differential diagnosis Oxalosuccinic acid is increased sympathetic activity and tachycardia due to reduced stroke volume. Echocardiography usually shows left and right ventricular dilatation and decreased systolic function, but this can occur in association with other forms of heart disease.64) CMR can provide precise assessment of LV and RV function and volumes. Tachycardia-induced cardiomyopathy should not result in DHE. The presence of DHE and the pattern of this finding should raise the suspicion of an alternative etiology for LV dysfunction, based on the pattern of fibrosis. This type of LV systolic dysfunction can improve rapidly (often within 4 weeks) with intervention or correction of the underlying cause of their tachycardia,65) but complete reverse remodeling may be slow (6 months or more).

(Figure ​services(Figure2)2) Patients who develop no venom effe

(Figure services.(Figure2)2) Patients who develop no venom effects during the observation period should be discharged with instructions to return promptly if signs of envenomation develop or progress. Figure 2 Factors Influencing Observation Time for Patients with Apparent Dry Bites and Initially Minor Envenomations Managed Without Antivenom. Discharge criteria and post-discharge management (boxes 7, 8, and 14) Patients who have had no further progression of venom effects during an appropriate period of observation may be discharged when certain criteria are met. As with

any patient going home from the hospital, the patient must be able to perform activities of Inhibitors,research,lifescience,medical daily living unassisted or with the assistance available in the home, have adequate pain control on oral medications, and have no other outstanding medical issues requiring hospital care. In addition, the Inhibitors,research,lifescience,medical patient should not have any unfavorable trends in protime, fibrinogen levels, or platelet counts, since deterioration

in one or more of these parameters may be an early sign of recurrent or delayed-onset hematologic venom effects. Following discharge, patients should be instructed to maintain limb elevation as much as possible to speed NVP-AUY922 cell line resolution of swelling. Progressive swelling Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical that does not improve with elevation or signs of abnormal bleeding, such as gingival bleeding, easy bruising, or melena, may be the hallmark of recurrent hematologic venom effects, and should lead to prompt re-evaluation. Serum sickness, a

type III hypersensitivity reaction caused by administration of exogenous proteins, is a known complication of antivenom therapy. In prospective studies, approximately 5 – 10% of patients treated with ovine Fab antivenom develop signs of serum sickness, such as fever, rash, myalgias, and arthralgias [44]. Inhibitors,research,lifescience,medical Serum sickness following Fab antivenom administration is generally mild and responds well to treatment with oral antihistamines mafosfamide and corticosteroids. At the time of discharge, patients should be instructed about the symptoms of serum sickness and given directions regarding follow-up care should serum sickness develop. Few data exist to inform the number and timing of follow-up visits. In general, the panel felt that mandatory follow-up visits were not needed for patients who had minimal envenomation and did not require antivenom administration. Similarly, because the risk of late hematologic venom effects is small, routine follow-up of patients with uncomplicated copperhead snake envenomations who did not develop hematologic venom effects during hospitalization is unlikely to provide clinical benefit to a patient.

1) T cell proliferation was monitored by 3H-thymidine incorporat

1). T cell proliferation was monitored by 3H-thymidine incorporation from day 2 to 7. Peak proliferation on day 5 was compared. 2.7. In Vivo DC Maturation C57BL/6 mice were injected with LPS (2μg) or CpG intradermally into each footpad, with or without IFN-gamma (2ng). After 18h, popliteal lymph node cells were collected. All mice

were treated and handled as approved by the AMREP animal ethics committee, Melbourne Australia and in accordance to the ethics guidelines by NHMRC Australia. The maturation state of live CD11c+ DCs was determined by labelling with FITC-conjugated anti-CD80 and anti-CD86 and analyzed by flow cytometry. 2.8. Statistical Analysis All data are shown as the mean ± standard Inhibitors,research,lifescience,medical error of the mean (SEM). The data generated in this study were analyzed by student’s t-test. Significance of difference Inhibitors,research,lifescience,medical was determined by the P value (≤0.05). 3. Results 3.1. IFN-Gamma Enhances DC Maturation with or without TLR Ligands The ability of IFN-gamma

to promote DC maturation in vitro was assessed using day 5 bone marrow-derived DC in the presence or absence of TLR ligands, LPS (TLR4), and CpG (TLR9), by measuring cell surface expression of CD40, CD80, CD86, and MHC class II (Figure 1). IFN-gamma alone had a moderate effect on the upregulation of the activation markers, compared to untreated cells, most notably learn more causing Inhibitors,research,lifescience,medical an enhancement in the levels of CD86 and MHC II expression. Likewise, CpG alone induced low levels Inhibitors,research,lifescience,medical of expression of the four surface markers compared to untreated cells; however, this was augmented in the presence of IFN-gamma, most notably, C40 and CD86. LPS strongly induced DC maturation as measured by the expression of the activation Inhibitors,research,lifescience,medical markers, and in the presence of IFN-gamma, only CD40 expression was further upregulated, albeit weak. Figure 1 IFN-gamma enhances DC maturation with or without TLR ligands in vitro. C57BL/6 bone marrow cells

were cultured with GM-CSF to generate bone marrow derived DCs. At days 4-5, cells were preconditioned with IFN-gamma for 2h (solid line) or no IFN-gamma … The ability of IFN-gamma to promote DC maturation in vivo was similarly assessed, following hock injection of mice with tuclazepam IFN-gamma in the presence or absence of TLR ligands (Figure 2). CD11c+ DCs from the popliteal lymph nodes showed increased CD80 and CD86 expression following IFN-gamma injection, compared to PBS-injected mice. Again, LPS alone strongly induced the expression of both activation markers which was not further augmented in the presence of IFN-gamma. CpG alone had minimal effect on CD86 expression, but increased CD80 expression; however, the inclusion of IFN-gamma further upregulated the expression of both markers, indicating enhancement of bone marrow-derived DC maturation. Figure 2 IFN-gamma enhances DC maturation with or without TLR ligands in vivo.

2006) Questionnaires

were completed within 3 months of m

2006). Questionnaires

were completed within 3 months of magnetic resonance imaging (MRI) scan in the patient sample (median time span = same day; range, 0–69 days). Socioemotional self-awareness To obtain an index of subjects’ socioemotional self-awareness, we generated discrepancy scores by subtracting the informant’s rating of the subject’s current empathic concern (considered the most accurate rating) from the subject’s self-rating of his/her current empathic concern. Thus, scores close to zero indicated that the subject’s Inhibitors,research,lifescience,medical self-awareness was accurate, while scores farther from zero suggested greater inaccuracy. The directionality of the discrepancy score indicated whether subjects overestimated (positive value) or underestimated (negative value) their level of empathic concern relative to the informants’ rating. To avoid spurious brain–behavior correlations due to extreme discrepancy scores, we converted discrepancy scores to z-scores based on subjects’ mean and standard Inhibitors,research,lifescience,medical deviation (SD) and checked for z-scores above +3 SDs and

below −3 SDs, though none were found and no subject was excluded on this basis. Change in empathic concern Inhibitors,research,lifescience,medical Some subjects in the study were expected to have undergone significant changes (typically decreases) in their level of empathic concern in the past 5–10 years due to neurologic disease. Such changes may have directly influenced the accuracy

of subjects’ self-description of the trait (Clare 2004a). To account for this potentially confounding effect, change in empathic concern score was generated by subtracting the informant’s rating of the subject’s current empathic concern from the informant’s rating of the subject’s Inhibitors,research,lifescience,medical premorbid empathic concern. This score was included as a covariate in the VBM analysis removing potential confounds. Separation into polisher/neutral Inhibitors,research,lifescience,medical and tarnisher/neutral subsamples The sample was separated into polisher/neutral and tarnisher/neutral subsamples based on value and directionality of the subjects’ discrepancy scores. Subjects with discrepancy scores above the mean − ½ SD were part of the polisher/neutral sample (n = 69). Subjects with discrepancy scores below the mean + ½ SD were part of the tarnisher/neutral GBA3 sample (n = 72). Consequently, subjects with discrepancy scores close to the mean (“neutrals”) were part of both groups. “Neutrals” were included in both groups to retain the naturally occurring variability in discrepancy scores and gray matter volumes in the statistical parametric mapping (SPM) group analyses, increasing power to detect neural substrates of over—and underestimation of one’s empathic concern across the whole brain. Notably, all seven diagnostic groups included “Dynasore in vivo Neutrals,” suggesting high variability in gray matter volumes within the “neutrals.

The dose and duration of endosulfan exposure were selected based

The dose and duration of endosulfan exposure were selected based on previous studies in rats.17,22 Sperm Parameter Analysis At the end of the treatment period, the animals were weighed and anesthetized with diethylether. Then, blood samples were collected via cardiac puncture, and their plasmas were separated and used to assay for testosterone and lactate dehydrogenase (LDH). The testes were removed, weighed, rinsed with in ice-cold saline. The relative GDC-0068 weight of the

testes was reported as a percentage of Inhibitors,research,lifescience,medical the body weight. A fraction of the testes of each animal was stored at -20°C for malondialdehyde (MDA) determination, while the remaining fraction was used to determine DSP. For determination of DSP, the testes were decapsulated and homogenized for 4 min in 50 mL of phosphate buffer saline (PBS) solution. The number of homogenization resistant sperm nuclei was counted using a hemocytometer. The numbers were then divided by 6.1 (the duration in days of spermatogenic cycle in rats) to determine Inhibitors,research,lifescience,medical DSP.23 To analyze

the sperm motility and viability, the left epididymis was excised and placed in pre-warmed Petri dish. Caudal epididymes was minced in 4 ml of pre-warmed PBS at 37˚C. The Inhibitors,research,lifescience,medical minced tissue was placed in a 37˚C incubator for 5 min and then filtered through Inhibitors,research,lifescience,medical nylon mesh. To evaluate the sperm viability, a drop of the Eosin stain was

added to the sperm suspension on the slide, kept for 5 min at 37˚C, and then observed under microscope. The head of the dead spermatozoa was stained with red color while the live spermatozoa unstained with Eosin stain. Sperm viability was expressed as the live sperm percentage of as the total sperm counted. For the analysis of sperm motility, one drop of sperm suspension was placed on a Inhibitors,research,lifescience,medical warmed microscope slide and a cover slip was placed over the droplet. At least 10 microscopic fields were observed at 400 X magnification under a microscope and the percentage of motile sperm was calculated. The degree of sperm maturation was assessed by Aniline Blue (AB) staining. The protamine-rich nuclei of mature spermatozoa which contain abundant arginine and cysteine and low level of lysine isothipendyl react negatively with aniline blue stain and remain unstained whereas the histone-rich nuclei of immature spermatozoa with abundant lysine were stained by AB.24 To perform this staining, 5 µl of the sperm collected from the epididymis was smeared onto the glass slide and allowed to dry. The smears were fixed in 3% buffered glutaraldehyde in 0.2 M phosphate buffer (pH 7.2) for 30 min. The slides were then stained with 5% aqueous AB mixed with 4% acetic acid (pH 3.5) for 5 min. On each slide 200 sperms were examined for the proportion of sperm with unstained head.

In the following sections, I shall endeavor to show to what exten

In the following sections, I shall endeavor to show to what extent the current diagnostic system has furthered or impeded progress. The group of mood disorders, in particular the construct of major depression, will be used as a paradigm, but the same reasoning can be applied to most of the diagnostic constructs selleck kinase inhibitor currently distinguished. Problems of validity Predictive validity

is the basic quality any diagnostic construct should possess. A diagnosis, once made, should allow reliable prognostication of symptoms, cause, course, outcome, and response Inhibitors,research,lifescience,medical to treatment. This is clearly not the case as far as the diagnostic construct of major depression is concerned: The diagnosis of major depression is based on evidencing Inhibitors,research,lifescience,medical X out of a scries of Y symptoms, irrespective of which ones. This construct therefore encompasses a wide range of syndromes without providing any information on the type of depressive syndrome thus observed. Major depression can be precipitated by a variety of etiological factors, psychological, biological, or related

to living conditions. In some instances, no precipitating factors are demonstrable. With regard to pathophysiology, current hypotheses postulate a causal role of serotonergic dysfunction and hypothalamo-pituitary-adrenocortical (HPA) axis disturbances. These Inhibitors,research,lifescience,medical have indeed been found to be associated with major depression in some patients, Inhibitors,research,lifescience,medical but not in others, without these patient subgroups coinciding with any of the currently distinguished depression subtypes. Furthermore, disturbances of these systems are not specific to depression, but occur in other diagnostic categories as well.3-4 Course and outcome also fail to show a characteristic pattern.5,6 Inhibitors,research,lifescience,medical Some patients only develop a single episode, whereas the majority of them experience several. One patient may recover completely, another will suffer

from residual symptoms, and in another still chronicity will set in.7,8 Treatment response, finally, is difficult to predict. Antidepressants may achieve complete recovery, partial response, or no response at all. Psychological interventions will be helpful in some patients, or totally useless in others. The construct of major depression therefore shows great Amisulpride variability at almost every diagnostic level. Hence there is no question of any predictability being associated with the diagnostic characteristics: no single characteristic is reliably predictive of any other. In other words, the predictive validity of this construct is all but null. Not only does the construct of major depression encompass a wide range of syndromes, but in the majority of cases it is also associated with other disorders, most notably personality and anxiety disorders.10-13 Thus it appears that major depression is not so much a diagnostic entity as a diagnostic multiplicity.

Most studies to date involved at least some contact to therapists

Most studies to date involved at least some contact to therapists.33 In a recent

study by Tolin and coworkers,34 patients performed an exposure and response prevention, either self- or therapist-directed. This study demonstrated that bibliotherapy is an effective method, although direct treatment led to more favorable results. In this study, therapist contact was minimal (first session). To reach patients outside the treatment system, for the present study, participants with OCD were recruited over the Internet for the present Inhibitors,research,lifescience,medical study. Assessments were also made online. Half of the patients were LY2157299 cell line allocated to a waitlist group and the other half received the myMCT immediately after participation in the initial assessment. The post assessment was performed

1 month later. We expected myMCT to be superior to the waitlist group, especially for the reduction of obsessions. As exposure and response prevention was not included in the manual at that time (this aspect was incorporated later), a negligible Inhibitors,research,lifescience,medical improvement on compulsions Inhibitors,research,lifescience,medical was expected. However, in view of poor attention, motivation, and slowness in many patients, we expected that not all patients in the experimental (myMCT) arm would read the manual and perform the exercises. Methods Recruitment The first author posted an invitation for an Internetbased self-help trial aimed at reducing OCD symptoms on three Internet forums for OCD. Two sites were hosted by the German and Swiss Societies for ObsessiveCompulsive Disorder which

provide help to OCD sufferers and disseminate information about OCD to the public. The third Web site was again Inhibitors,research,lifescience,medical solely devoted to OCD. This strategy ensured approaching persons with OCD only. If we had posted the announcement in forums with a broader scope, our invitation might have attracted patients with non-OCD diagnoses. Subjects were asked to refrain from participation if they did not experience obsessive thoughts, did not regard their obsessional worries as at least exaggerated (low illness insight), had no time to perform exercises Inhibitors,research,lifescience,medical in the course of the following four weeks, or did not agree to participate in an anonymous (Internet-based) survey before and after the intervention. Further, it was made mandatory that a diagnosis of OCD had to be determined by a health care professional beforehand. No compensation was offered for study participation except isothipendyl for the cost-free delivery of an electronic self-help manual (PDF-converted ebook). A Web link was then provided for those willing to participate. When accessing the Internet questionnaire, participants were welcomed and the study rationale was repeated. It was made clear that participation would not require personal or telephone contact and that it was strictly anonymous. MyMCT was not described beforehand to avoid recruitment biases.

2009), highlighting the need to confirm the link between early life stress and epigenetic alterations at this locus. Early life stress has been shown to bring about epigenetic changes at the arginine vasopressin gene (Avp), with a regulatory region in the gene being hypomethylated following MS

(Murgatroyd et al. 2009). Similar changes following an environmental stressor have been observed in several other Inhibitors,research,lifescience,medical genes including Bdnf (Fuchikami et al. 2009; Roth et al. 2009), Crh (Elliott et al. 2010), Dlgap2 (Chertkow-Deutsher et al. 2010), Mecp2, Cnr1, and Crhr2 (Franklin et al. 2010), suggesting that such changes may occur in multiple neurobiological pathways in response to stress. In this study, our aim was to explore physiological, behavioral, and epigenetic changes in response to early life stress in the mouse, and determine whether these differed as a function of genetic background. We used MS, a validated model of early postnatal life stress in rodents, that is known to induce long lasting effects on emotional Inhibitors,research,lifescience,medical behavior and stress-reactivity (Boccia and Pedersen Inhibitors,research,lifescience,medical 2001; Holmes et al. 2005), changes to the hypothalamic–pituitary–adrenocortical (HPA) axis (Schmidt et al. 2004), and result in a significant loss of neurons in the hippocampus of adult mice (Fabricius

et al. 2008). MS models vary in the literature both in the frequency and in the length of separation, which has led to a disparity in phenotypic changes seen. We chose to use the single 24 h separation model to avoid the phenotypic variability found in repeated separation models, as the length of the separation period seems to mediate whether a positive or negative behavioral change is seen (Holmes et al. 2005), possibly Inhibitors,research,lifescience,medical due

to the increase of maternal care after Inhibitors,research,lifescience,medical the separation (Millstein and Holmes 2007). Corticosterone levels in response to a stress challenge and a range of behavioral www.selleckchem.com/products/pf299804.html phenotypes were measured in adult mice following MS. DNA methylation levels in the promoter regions of three candidate genes in two strains of inbred mouse (C57BL/6J and DBA/2J) following MS were determined; based on previous studies we chose Nr3c1 and second Avp as likely targets of early life stress, and Nr4a1, encoding a brain-expressed nuclear hormone receptor, was selected given its involvement in disorders such as schizophrenia and depression. Methods Animals C57BL/6J and DBA/2J mice were bred in the Biological Services Unit at the Institute of Psychiatry, Kings College London using original stocks [respective stock numbers: 000664, 000671] purchased from The Jackson Laboratory (Bar Harbor, ME). DBA/2J and C57BL/6J strains were selected as these represent members of a priority list based on the most well-characterized, commonly used strains for gene manipulation and crosses (Mouse Phenome Project, http://aretha.jax.org/pub-cgi/phenome/mpdcgi?rtn=docs/home).