Nucleic acid-based approaches offer several advantages when compared to treatment with small molecules or proteins. They can be seen as mostly inactive prodrugs, which are activated at the tumor site producing a therapeutically active protein or knocking down a specific target gene. Importantly, nucleic acid targeted delivery systems, preferably also relying in transcriptional targeting, decreasing off-target effects and Inhibitors,research,lifescience,medical toxicity, and permitting a systemic administration otherwise not feasible with a

therapeutic agent with toxic properties. In parallel with new therapeutic nucleic acid tools, the last two decades brought insight into mTOR inhibitor tumorgenesis in general and unveiled a plethora of therapeutic concepts against cancer (Figure Inhibitors,research,lifescience,medical 3). The following paragraphs will deal with different antimelanoma approaches based on nucleic acids. Figure 3 Different strategies used in antitumor nucleic acid approaches. RNA-based strategies are commonly used to downregulate agents that are upregulated to favor cell proliferation or migration, such as Bcl-2. Alternatively, double stranded RNA (dsRNA) mimic … Despite the apparent tumor tolerance, humoral and cellular immune responses are naturally generated against tumor antigens. Hence, whether the tumor grows as a result of stealth and nonrecognition or as the result of escape and immunological shaping [128],

Inhibitors,research,lifescience,medical its recognition by the immune system can still be prompted. Indeed, at a later stage, during the progressive Inhibitors,research,lifescience,medical growth phase, tumors may become more immune-activating for varies reasons: damage or disruption of surrounding tissue, generation of reactive oxygen species, upregulation of stress protective factors, or death by necrosis or apoptosis. However, at this stage, it is not known whether the tumor still needs to escape immune recognition, as it is unclear that these immune responses

can cause tumor destruction [128]. Therefore, a number of studies have focused in eliciting earlier and suitable tumor recognition by the immune system. In a nucleic acid therapy context, this transliterates into genetic immunization Inhibitors,research,lifescience,medical or DNA vaccination: the delivery and transcription of a gene encoding antigens or immunestimulatory molecules that elicit PAK6 an immune response. As an example, interleukine-12 (IL-12) has been used and studied in different animal models [104, 105]. IL-12 is originally produced by mononuclear phagocytes and dendritic cells and is responsible for activating NK and CD4+ T cells and inducing the production of high levels of interferon gamma (INF-γ). Interestingly, IL-12 has been described to increase antitumor immune responses [129, 130], and later studies investigated its suitability for a DNA vaccine approach against melanoma [106]. IL-12 effects appeared to be long lasting and efficient against tumor metastases, although not mainly mediated by INF-γ [106].

However, some reports are worth considering, including those of Norwood et al.16,17 Altogether 177 patients were included in this study of whom 150 received enoxaparin at 24 hours after admission for intracerebral hemorrhage or after craniotomy for the injury. CT screening was performed at various intervals including admission, 24 hours after hospitalization, and then after receiving the LMWH. After administration of chemoprophylaxis, 4% of patients developed further hemorrhage as evidenced on CT head scans. The study raised the question whether

hemorrhagic changes on CT scan are a consequence of the prophylaxis or a natural progression of the TBI. The analysis did not have Inhibitors,research,lifescience,medical a control group.16,17 CONCLUSION Although trauma is a well-established etiology for thromboembolic events, only in the past decade have TBI patients been recognized with an increased risk for VTE. This is most likely due to lengthy hospital immobilization combined with delays in VTE drug regimen prophylaxis. Additionally, the native levels of TF already residing in the brain Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical increase during injury, along with circulating inflammatory cytokines which favor systemic hypercoagulation. Unfortunately, no significant randomized control trials exist with large patient populations, leaving clinicians with expert consensus and a series of retrospective or prospective studies. At

issue is the balance between hemorrhagic extension and VTE risk. These important studies yield information about the highest-risk individuals with inference toward practice parameters. Following these, clinical assessment might appear as follows: Establish degree of TBI severity and carry out a survey of additional Inhibitors,research,lifescience,medical injuries, especially of the lower extremities. Start patient on mechanical compression prophylaxis within 24 hours of admission unless contraindicated. As mechanical intervention is insufficient alone, LMWH or unfractionated heparin should

be started, if no confounding coagulopathy. Timing of this step is variable and controversial. However, a comfortable balance point between extension of the bleed and VTE risk Isotretinoin appears to be 48–72 hours. Inhibitors,research,lifescience,medical Again, this is inferred from leading studies and not level I evidence. This differs from the Brain Trauma Selleckchem NVP AEW541 Foundation which omits timing guidelines. Several studies utilized serial head CTs for bleeding progression both before and after anticoagulant administration. The choice of regimen, unfractionated heparin versus LMWH, appears only mildly significant in the brain trauma patient. A number of studies show a superiority of LMWH, but bleeding risks are still a concern < 24 hours of initiating therapy. Options within LMWH indicate no superiority between enoxaparin or dalteparin, though the q12 hour dosing of the former may prove of greater benefit than daily dosing of dalteparin. The predominance of institutions utilized ultrasound venous Doppler in addition to clinical acumen.

However, the mean changes from baseline on the pulse rate hardly changed in the IM haloperidol injection group (Table 2). The systolic blood pressure increased significantly from baseline in the IM olanzapine injection group, but the mean change from baseline on the systolic blood pressure hardly changed in the IM haloperidol injection group. Inhibitors,research,lifescience,medical The glucose level (mg/dl) decreased significantly from baseline in both the IM olanzapine injection group and the IM haloperidol injection group, but no significant

differences were seen between the two groups (Table 2). The incidence of adverse events associated with injection site RO4929097 nmr reactions in both groups were 16.7% (2/12) in the IM olanzapine injection group and 18.2% (2/11) in the IM haloperidol injection group. All these adverse events were injection site pain; no redness, swelling or induration were observed. The most frequent adverse events in both groups are shown in Table 3. Table 3. Adverse events. The injections were administered at the same time in each group. The average medication doses of both groups were 7.7 ± 2.5 (mg) with Inhibitors,research,lifescience,medical the IM olanzapine Inhibitors,research,lifescience,medical injection group and 4.6 ± 1.0 (mg) with the IM haloperidol injection group. Discussion In this study, we compared the efficacy and safety of IM olanzapine and IM haloperidol in agitated elderly patients with schizophrenia at 2 hours postdose. The results of this study not only show that olanzapine has a different pharmacological

profile to haloperidol, but also suggest that IM olanzapine can, thanks to its pharmacokinetics, afford patients a more rapid sedative effect and more rapid improvement in impulse control and excitement than IM haloperidol. However, since both drugs possess affinity for dopamine (D2) receptors, Inhibitors,research,lifescience,medical no significant difference was found between the two groups in improvement in positive symptoms. Inhibitors,research,lifescience,medical The results were therefore consistent with the results of our previous research and the results of other studies conducted in the past [Centorrino et al. 2007; MacDonald et al. 2012; San

et al. 2006; Wright et al. 2001]. The results suggested that IM olanzapine prevented the emergence of drug-induced extrapyramidal symptoms 4-Aminobutyrate aminotransferase in the elderly compared with IM haloperidol. The findings also are consistent with those of previously conducted research [Perrin et al. 2012; Satterthwaite et al. 2008]. In the elderly, arrhythmias result in symptoms including dizziness, palpitations and shortness of breath that are a contributing factor for a poor prognosis. Although the results of this study showed that IM olanzapine resulted in a decrease in pulse rate, it remained within the range of normal in all the subjects. The results of this study therefore show that IM olanzapine had a small effect on pulse rate. Hypertension is a risk factor for cardiovascular disease. Furthermore, in the elderly, hypotension is accompanied by lightheadedness, and therefore increases the risk of falls and bone fractures.

31 Patients with this disorder appear to have a particularly profound deficit in cholinergic function and the symptoms are characterized by significant, psychiatric symptoms and behavioral disturbances. One hundred and twenty (120) patients who satisfied standard criteria for Lewy body dementia (the vast majority having fluctuating cognitive function and recurrent Inhibitors,research,lifescience,medical visual hallucinations) were recruited in the UK, Spain, and Italy (92 completed the study). Treatment started

with 1.5 mg rivastigmine or placebo twice a day, increasing by 1.5 mg twice a day, for 2 weeks until 12 mg/day or a maximum well-tolerated maintenance dosage was reached. The primary efficacy measure was a reduction in scores on the NPI. Inhibitors,research,lifescience,medical Results showed significant improvement over the course of the study, with evidence of some benefit on the global functioning. Galantamine Galantamine has a somewhat novel, dual mode of action in that, in addition to its

anticholinesterase activity, it has a modulating effect, Inhibitors,research,lifescience,medical on nicotinic acetylcholine receptors in the brain, which seem to have a role in potentiating the response to acetylcholine. In Europe and Canada, Wilcock32 PKC activity inhibition reported a 6-month study of 653 patients with mild-to-moderate Alzheimer’s disease, who were randomly assigned to either placebo or a maintenance dosage of galantamine of 24 or 32 mg/day. At. 6 months, improvements in ADL and on the CIBTC+ were recorded. Raskind et al33 reported on a 6-month, randomized, placebo-controlled trial followed by a 6-month extension. Patients with mild-to-moderate Alzheimer’s Inhibitors,research,lifescience,medical disease (n=636) were assigned to either placebo or an escalating dosage of 24 or 32 mg/day galantamine, followed by a 6-month, open-label study with 24 mg/day. The conclusion was that at 24 mg/day, the drug is effective and safe in improving cognitive function and global function (Figure 3) over 6 months, and maintaining Inhibitors,research,lifescience,medical that improvement at 12 months. A total of

978 patients were enrolled in a relatively slow escalation study described by Tariot et al.34 A 4-week, placebo run-in was concluded with patients being randomized to receive placebo or 8, 16, or 24 mg/day galantamine. After 5 months, Unoprostone those on galantamine showed improvement on the ADAS-Cog, the CIBIC+, a number of psychiatric symptoms, and ADL. Adverse events resulting in discontinuation from the trial were found in 10% of the galantamine group and 7% of the placebo group. Coylc and Kershaw35 carried out. an analysis of the extension studies of galantamine and found that patients who had been treated with 24 mg/day throughout the trials had better cognitive function compared with those on placebo. The suggestion that stabilization occurs would be in keeping with the additional nicotinic receptor modulation activity of the drug. Figure 3.

Depressed patients … The finding of a negative correlation between AATSH and post-APO ACTH and Cortisol values in patients without a history of suicidal behavior is rather paradoxical. Owing to the regulations between HPT and DA systems, one could have expected a positive correlation and not a negative

one (ie, an increase in TRH secretion should have led to a decrease in D2 function). Whether hypofunctionality of D2 receptors exists on both hypothalamic and pituitary levels, the absence of GH, ACTH, and Cortisol response to APO in depression would suggest, an upregulation of other DA receptor subtypes (such as D1) in the hypothalamus. Indeed, Inhibitors,research,lifescience,medical GH, ACTH, and Cortisol response to Inhibitors,research,lifescience,medical APO reflects primarily stimulation of the hypothalamic releasing inhibitors hormones (GHreleasing hormone and CRH, respectively) rather than a direct, effect on the

pituitary Moreover, Cortisol response to APO, which is correlated to ACTH (p=0.74; n=98; P<0.00001), can be considered as an index of central DA function connected with the regulation of the HPA axis. Thus, the negative correlation between ΔΔSH and post-APO ACTH and Cortisol Inhibitors,research,lifescience,medical values in patients without a history of suicidal behavior suggests that the efficacy of compensatory mechanisms requires a new functional balance between HPT and DA systems. In the depressed group with a history of suicidal behavior, the absence of a functional link between HPT and DA activity in the hypothalamus may play a role in the pathophysiology of suicidal behavior. However, one may note that half of the patients of this Inhibitors,research,lifescience,medical group showed HPT and DA functional adjustment (Figure 4; ie, those exhibiting blunted ΔΔTSH values), suggesting that this requirement

is not sufficient Inhibitors,research,lifescience,medical in the efficacy of compensatory mechanisms. In other words, other processes – so far unknown – are also involved in the efficacy of compensatory mechanisms. Conclusions Taken together our findings in depressed inpatients suggest, that: HPA axis hyperactivity is not responsible for the reduced 5-HT activity found in patients with a history of suicidal behavior. HPT dysregulation may be regarded as a compensatory mechanism for diminished central 5-HT Farnesyltransferase activity. Cooccurrence of HPT axis and tuberoinfundibular DA dysregulation is compatible with a decreased TRH and D2 receptor function (possibly secondary to increased TRH tone). The absence of a functional link between HPT and DA activity in the hypothalamus may be implicated in the pathogenesis of suicidal behavior. A better knowledge of processes involved in the efficacy of compensatory mechanisms could lead to new therapeutic strategies in patients with recurrent major depressive disorder, especially those with a history of suicidal behavior.

26 He listed situations where, in contrast to the classical paradigm, incidents do not compensate for each other, but are additive, and where statistical predictions become invalid. He described his theory in a book,27 where he presented what is now known as the Mandelbrot set. This is a fractal defined as the set of points c from the complex Inhibitors,research,lifescience,medical plane for which the recurring

series defined by zn+1 = zn 2 + c, with the condition z0 = 0, remains bounded (SB525334 clinical trial Figure 3). Figure 3. The Mandelbrot set a point c is colored black if it belongs to the set and white if not. A characteristic of fractals is the repetition of similar forms at different levels of observation (theoretically at all levels of observation). Thus, a part of a cloud looks like the complete cloud, or a rock looks like Inhibitors,research,lifescience,medical a mountain. Fractal forms in living species are for example, a cauliflower or the bronchial tree, where the parts are the image of the whole. A simple mathematical example of a fractal is the so-called Koch curve, or Koch snowflake.28 Starting with a segment of a straight line, one substitutes the two sides of an equilateral triangle to the central third of the line. This is then repeated for each of the smaller segments obtained. At each substitution, the total length of the figure increased

Inhibitors,research,lifescience,medical by 4/3, and within 90 substitutions, from a 1 -meter segment, one obtains the distance from the earth to the sun (Figure 4). Figure 4. The first four interations of the Koch snowflake. Fractal objects have the following fundamental property: the finite (in the case of the Koch snowflake, a portion Inhibitors,research,lifescience,medical of the surface) can be associated with the infinite (the length of the line). A second fundamental property of fractal objects, clearly found in snowflakes, is that of self similarity, meaning that parts are identical to the whole, at each scaling step. A few years later, Mandelbrot discovered fractal geometry and found that Lorenz’s attractor was a fractal figure, as are the majority of strange attractors. He defined fractal dimension (Table I). Mandelbrot quotes, Inhibitors,research,lifescience,medical as illustration of this new sort of randomness, the French coast

of Brittany; its length depends on the scale at which it is measured, and has a fractal dimension between 1 and 2. This coast is neither heptaminol a one-dimensional nor a two-dimensional object. For comparison the dimension of Koch snowflake is 1.26, that of Lorenz’s attractor is around 2.06, and that of the bifurcations of Feigenbaum is around 0.45. Thorn, Prigogine, and determinism again René Thorn is the author of catastrophe theory.29 This theory is akin to chaos theory, but it was constructed from the study of singularities, ie, continuous actions that produce discontinuous results. Catastrophe theory is interesting in that it places much emphasis on explanation rather than measurement. Thom was at the origin of a renewed debate on the issue of determinism.

Hence, various scoring systems, which can evaluate the morphologic abnormalities found in HRCT, have been recommended.14,22-24 Although different studies have been performed to determine the importance of using CT scoring system to assess the progression of the disease,16-19 there are still some limitations such as the lack of a study evaluating the correlation of patients’ clinical status with CT scoring system results. Twenty

three children with CF were included in the present study. Inhibitors,research,lifescience,medical The mean age was 13.4 years indicating the age range of the participants was higher than those of similar studies.14 This might be due to delayed diagnosis. The lack of neonatal screening and high cost of evaluation for genetic mutation in Iran have led to the diagnosis of the disease on the basis of clinical manifestations and sweat test results in a higher range of age. The evaluation of HRCT findings showed the following defects Inhibitors,research,lifescience,medical in decreasing order of frequency: bronchiectasis (100%), peribronchial wall thickening (100%), mucus plugging (95.7%), air trapping (91.3%) and parenchymal Inhibitors,research,lifescience,medical involvement (47.8%). A similar study conducted by Helbich et al.14 showed that bronchiectasis and peribronchial wall thickening were the most common findings on HRCT (80.3% and 76.1%, respectively). The other common findings

were mucus plugging (63.9%) and mosaic perfusion (51.3%). Inhibitors,research,lifescience,medical The presence of all abnormalities in the majority of patients in the present study can be related to their high range of age. In other words, the higher the age of the

patients, the higher the rate of lung involvements found on HRCT. In this study, there was a significant (P=0.037) correlation between total CT scores and the patients’ age. This indicates that CT scoring seem to be sensitive in the assessment of the disease progression. Moreover, there was a significant relationship between the most common abnormalities found on CT and the aggravation of the clinical manifestations of patients in this study. The progression of Inhibitors,research,lifescience,medical these abnormalities during the disease course could be explained by recurrent pulmonary infections and chronic inflammation.9,22,23 Endonuclease Long-term mucus plugging is accompanied by BGB324 datasheet progressive bronchial destruction ending in bronchiectasis and bronchial wall thickening.9,22,23 In our study, a significant correlation was found between the advancement of age and the decrease of FEV1.This contradicts the results obtained from previous studies, which showed an increase in CT score in contrast to no change or improvement of respiratory test during the course of the disease.25,26 In this study there was no relationship between clinical score and the patients’ age, which can be due to imprecise reflection of lung status by Schwachman-Kulczycki score,24 and also the few number of patients recruited in this study.

75 However, the tools to assess the cost-effectiveness of pharmacogenetic tests are still insufficiently developed.76 Consensus TDM should be limited to situations where it may be expected that the result will help to solve a therapeutic problem. There are many indications for using TDM (Table II) in antidepressant pharmacotherapy, such as suspicion of noncompliance or

intoxication. In pharmacovigilance programs, TDM may be considered as a valid indication for all drugs and groups of patients. To recommend TDM as routine monitoring, it must be proven that TDM is of value. Five levels of recommendation for TDM were defined, which range from “strongly recommended” to “not recommended.” In a second step, Inhibitors,research,lifescience,medical a recommendation tailored to the individual drug was defined. Table II. General Inhibitors,research,lifescience,medical indications for therapeutic drug monitoring (TDM) of antidepressants.11 Levels of recommendations to use TDM as routine monitoring The therapeutic strategy will only be improved by the use of TDM, if the already mentioned

criteria are fulfilled.60 There is sufficient evidence that TDM can be useful Inhibitors,research,lifescience,medical for patients treated with antidepressants, as concluded by the authors of this consensus guideline, after a careful examination of the literature: (i) guidelines; (ii) meta-analyses; (iii) prospective studies on the clinical effectiveness of drugs in which drug http://www.selleckchem.com/products/bgj398-nvp-bgj398.html plasma concentrations were reported; and (iv) pharmacokinetic studies. However, the latter often do not allow

definition of a therapeutic plasma concentration range, in the absence of clinical data. Five levels of recommendation to use TDM as routine monitoring were defined as follows, Inhibitors,research,lifescience,medical as reported earlier.10 1. Strongly recommended Established therapeutic range Level of evidence: Controlled clinical trials have shown benefit Inhibitors,research,lifescience,medical of TDM; reports on toxic effects at “supratherapeutlc” plasma concentrations. Clinical consequences: At therapeutic plasma concentrations highest probability of response; at “subtherapeutic” plasma concentrations response rate similar to placebo; at plasma concentrations higher than therapeutlc concentrations increasing risk of adverse effects. 2. Recommended Suggested therapeutic ranges obtained from plasma concentrations at therapeutically effective doses (fixed dose studies). Level of evidence: At least Nature Methods one welldeslgned prospective study with well-defined outcome criteria reports intoxications at “suprather apeutlc” plasma concentrations. Clinical consequences: TDM most probably will optimize response in nonresponders: at “subtherapeutic” plasma concentrations risk of poor response; at “supratherapeutlc” plasma concentrations risk of adverse effects and/or decreased response. 3. Useful Suggested therapeutic ranges are plasma concentrations at effective doses obtained from steady-state pharmacokinetic studies.

With the principle of parsimony in mind, the model with the top 10 sMRI variables was selected for interpretation. Figure 3 also shows that as more sMRI variables were added to the model, there typically was a progressive reduction in the mean MSE until it was minimized. For the Negative Emotions task, however, the top two ranked variables almost minimized the mean Inhibitors,research,lifescience,medical MSE, although the addition of other sMRI variables did result in a slightly lower mean MSE. Figure 4 displays the spatial maps of the top-ranked sMRI correlates of performance for each cognitive measure according to their mean rank order of importance, with lighter colors corresponding to

more highly ranked sMRI variables. The exact rank order of sMRI variable importance is listed in Table 2. An inspection of the data showed that for all top-ranked sMRI correlates of each cognitive measure, greater cortical thinning and striatal atrophy were associated with worse performance. Table Inhibitors,research,lifescience,medical 2 Rank order of importance for the top sMRI correlates of performance in each cognitive domain Figure 3 Number of top structural MRI (sMRI) correlates of performance for each cognitive measure. Each circle in the plot represents a sMRI predictor variable. The x axis

shows the number of sMRI variables based on their mean squared error (MSE) ranking in the … Figure 4 Spatial maps of the top-ranked structural MRI Inhibitors,research,lifescience,medical (sMRI) correlates of performance in each cognitive domain. Cortical regions are displayed on the lateral (1st and 2nd rows) and medial (3rd and 4th rows) surfaces of the left (L) and right (R) hemispheres. … Figure 4 shows that the top-ranked correlates of SDMT performance included elements of the motor circuit (bilateral putamen, right precentral Inhibitors,research,lifescience,medical gyrus, bilateral

postcentral gyrus), right hemisphere cognitive-control centers in prefrontal cortex (PFC) (right superior frontal, caudal and rostral middle-frontal cortex), an auditory and semantic Inhibitors,research,lifescience,medical processing hub including Broca’s area (left pars opercularis, bilateral superior temporal cortex), and visual centers (left cuneus, right lingual gyrus). The highest ranked sMRI variables were the bilateral putamen, followed by the bilateral superior temporal cortices and then right hemisphere PFC regions (Table 2). Top-ranked correlates of letter-number sequencing performance included the striatal-frontoparietal working memory CP-673451 supplier network (left caudate, bilateral rostral middle frontal, right caudal Nature Reviews Cancer middle frontal, right pars triangularis, left inferior parietal), an auditory and semantic processing hub (left superior temporal), and elements of the right ventral attention network (right lateral occipital and middle-temporal cortices). The highest ranked sMRI variables were the right lateral occipital and right rostral middle-frontal cortices, followed by the left caudate and the right middle-temporal cortex (Table 2).

First, impairments in neurocognition are core features of schizophrenia. These impairments

are present during acute MAPK Inhibitor Library cost exacerbations of the illnesses and during periods of remission. In addition, first- and secondgeneration antipsychotics are relatively ineffective at treating these symptoms. Patients treated with these agents tend to have continuing deficits even when adequately treated with antipsychotics.5 Further, the neurocognitive deficits tend to be relatively severe. A metaanalysis by Heinrichs and Zakzanis6 demonstrates that the impairments in Inhibitors,research,lifescience,medical schizophrenia are particularly severe for memory, attention, and executive function. In these areas, individuals Inhibitors,research,lifescience,medical with schizophrenia – on average – performed 1.5 standard deviations below community norms. The most important, reason for the focus on neurocognition may be that these impairments appear to be related to the functional outcomes of patients. A Inhibitors,research,lifescience,medical review by Green7 found that the impairments in social and vocational functioning in schizophrenia were strongly related to the impairments in neurocognition. The magnitudes for the relationships between cognitive deficits and functional outcome are

medium Inhibitors,research,lifescience,medical for individual cognitive constructs

such as attention or working memory, but the relationships can be strong when summary scores (eg, composites of several cognitive functions) are used.8-10 This literature on cognitive linkages to functional outcome provides a compelling rationale for intervention development at the level of cognition. In contrast, to cognitive deficits, clinical symptoms are only weakly Inhibitors,research,lifescience,medical related to functional outcome in schizophrenia. Facilitating drug development Hyman and Fen ton2 have suggested a strategy for drug development that focuses on dissecting psychiatric disorders into component, dimensions of psychopathology that may be more closely related to pathophysiological processes. These components rather than the illnesses themselves may be more (-)-p-Bromotetramisole Oxalate amenable to novel pharmacological approaches to therapeutics. This strategy encourages the development, of new therapeutics for schizophrenia that move beyond positive symptoms as clinical targets to focus on dimensions of the illness most, associated with functional disability. The goal of the MATRICS initiative is to address important, obstacles that are likely to interfere with the development of new pharmacological approaches to improving neurocognition in schizophrenia.