Colorectal cancer is a common and fatal disease. Approximately 148,810 new cases are detected each year. In the USA, and 108,070 of those have colon cancer and the others have rectal cancer (1). In terms of frequency it is the third disease in both females and males and it is the third leading cause of death. Colorectal cancers constitute 10% of all cancer cases and it is responsible for 10% of all cancer related deaths (2). Main selleck inhibitor treatment Inhibitors,research,lifescience,medical option for colorectal cancer

is the surgery. Adjuvant chemotherapy (CT) is recommended for patients with stage II disease keeping certain risk factors and for all stage III patients. Some of the patients with stage IV disease are treated following patient-based evaluations (2-4). Surgery Inhibitors,research,lifescience,medical is the main treatment option in rectal cancer. Afterwards, adjuvant treatment methods were investigated to increase the efficacy, and the initial researches were focused on adjuvant radiotherapy (RT), which demonstrated to decrease the recurrence rates (5). The following studies has shown that adjuvant chemoradiotherapy (CRT) is more efficient compared to adjuvant RT and this approach decreased

both local recurrences (6) and cancer related deaths (7,8). The ongoing studies revealed that neoadjuvant RT had better control on local recurrences compared with adjuvant Inhibitors,research,lifescience,medical RT (9), and the neoadjuvant CRT is superior to neoadjuvant RT in prevention of local recurrences and upward trend Inhibitors,research,lifescience,medical in survival, therefore neoadjuvant CRT was considered as the most appropriate approach (10-13). CT, another treatment option in rectal cancer, was also showed to be effective and it significantly increased the survival (5,14-16). Thus, the multimodal approach in which the surgery, neoadjuvant CRT and adjuvant CT are administered in combination generated the most optimal approach in the treatment of locally advanced stage rectal cancer (17,18). Particularly, the neoadjuvant administration of CRT provided benefits in terms of sphincter Inhibitors,research,lifescience,medical prevention and quality of life (11-13,18-20). Also, patients with locally advanced stage rectal cancer are treated by this approach in our department. In the literature,

it has been agreed that surgery is the main treatment method for rectal cancer. However, surgery cannot be administered in some patients due to various Casein kinase 1 reasons. Treatment with CRT and CT, which are the significant components of multimodal treatment, might be discussed for such patients. The data of the patients who could not undergo surgery due to any reason and who were followed up after receiving only CRT or CT following CRT, have not been completely presented yet. We have planned this study to evaluate the characteristics of the patients who had been diagnosed with locally advanced stage non-metastatic rectal cancer in their initial evaluations and who had not undergone surgery due to any reason but only received CRT or CT following CRT.

Results: The study included 9 female and 14 male patients with an age range of 5-23 years (mean: 13.42 years). Bronchiectasis (100%) and peribronchial wall thickening (100%) were the most frequent CT abnormalities. Mucus plugging, air trapping and parenchymal involvements were respectively seen in 95.7%, 91.3% and 47.8% of patients. The overall CT score for all patients was 57.6±24.2 (means±SD). The results of pulmonary function test showed a restrictive pattern; however, in 5.3% of the patients PFT was normal. The overall Shwachman-Kulczycki score was 53.48±13.8. There was a significantly (P=0.015) negative correlation between the total CT score and Shwachman-Kulczycki score; however, there was no significant

correlation between total CT score Inhibitors,research,lifescience,medical and the results of PFT Inhibitors,research,lifescience,medical (P=0.481) Conclusion: The Brody’s scoring system for high resolution computed tomography seems to be a sensitive and efficient method to evaluate the progression of CF, and can be more reliable when we combine the CT scores with Vadimezan chemical structure clinical parameters. Key Words: Clinical status, pulmonary function test, cystic fibrosis Introduction Cystic fibrosis (CF) is the most common fatal genetic disorder in white population.1,2 Due to new and restrict Inhibitors,research,lifescience,medical modalities in the treatment of CF patients, their survival has increased. However, CF is still responsible for major complications, which increase the mortality and morbidity rates in such

patients.3 The most common cause of mortality in CF patients is chronic pulmonary disease, which is the consequence of persistent Inhibitors,research,lifescience,medical infections and inflammations.1,2,4 To evaluate the pulmonary status in CF, a number of diagnostic procedures including chest radiography, high resolution computed tomography (HRCT), sputum culture

and pulmonary function test are considered.1,2,4-7 Since CT Scan was found to be one of the best evaluation tools for cystic fibrosis progression, CT scoring system was proposed to make the evaluation more effective.8-11 A computed tomography scoring system is a tool to describe the abnormalities found by CT scan.12 The scoring system was introduced by Bhalla and colleagues 12. Since then, a number of other scoring systems Inhibitors,research,lifescience,medical have been proposed by Helbich,13,14 Santamaria,15 and no Brody,16 and their colleagues. Brody’s scoring system is a lobar scoring system, which assigns a score to each lobe separately. This scoring system describes the following morphologic changes: bronchiectasis, peri-bronchial wall thickening, mucus plugging, air trapping and parenchymal involvement.16 Although different studies were conducted to show the usefulness of Brody CT scoring system in the assessment of the progression of the disease,16-19 possible correlation between the Brody scoring system and clinical status in patients with CF has not been examined. Therefore, the present study was designed to examine the correlation of the Brody scoring system with clinical parameters and pulmonary function test (PFT) in pediatric patients with CF.

Polyps with a negative polypectomy margin, low grade histology, and no lymphovascular invasion can be

safely treated with endoscopic polypectomy. An increased risk of adverse outcomes has been shown to be associated with positive margin (defined as <2 mm from deep cauterized margin) (Figure 17), high grade (poorly differentiated) histology, and lymphovascular invasion. If any of these features is present, surgical resection is indicated (91-93). Therefore, it is important that polypectomy specimens be received in one intact piece in order for margins to be accurately evaluated by pathologists. Inability to assess margin status because of piecemeal Inhibitors,research,lifescience,medical resection should also be considered as a risk factor (91,93), and surgical resection may be recommended in clinically Inhibitors,research,lifescience,medical fit patients. Figure 17 A malignant polyp showing adenocarcinomatous glands present within 1 mm of polypectomy margin (original learn more magnification ×100) A pitfall in the assessment of

an adenomatous polyp is pseudoinvasion where adenomatous elements are misplaced or herniated into the submucosa, usually secondary to traumatization Inhibitors,research,lifescience,medical such as twisting and torsion of the stalk (Figure 18). Histologic features that help distinguish from true invasion include a lobular configuration of herniated elements, lack of overt high grade architectural and cytologic atypia, presence of a rim of lamina propria inflammatory cells around entrapped elements, lack of desmoplastic reaction, lack of direct contact with submucosal muscular vessels, and presence of hemosiderin or hemorrhage. Occasionally, herniated

adenomatous glands exhibit high grade histology, which can be even more difficult Inhibitors,research,lifescience,medical to distinguish from invasive adenocarcinoma. However, other histologic features that favor pseudoinvasion may still be present. For rare cases in which a definitive Inhibitors,research,lifescience,medical distinction cannot be made, complete polypectomy or surgical resection may be considered based on the clinical and endoscopic circumstances of the patient. Figure 18 Low power (A. original and magnification ×40) and high power (B. original magnification ×200) views of pseudoinvasion in a tubular adenoma. Note the presence of hemorrhage and hemosiderin Pathogenesis and molecular classification Colorectal cancer is a heterogeneous group of diseases with distinctive genetic and epigenetic background (94). In order to improve clinical management and better predict patient outcome, attempts have been made to classify colorectal cancers based on location, histology, etiologic factors, and molecular mechanisms of tumorigenesis. As early as in the 1980’s, it has been recognized that cancers arising in the proximal colon and distal colon involve different genetic mechanisms (95,96). For instance, Lynch syndrome preferentially involves the proximal colon whereas FAP tends to show more polyps in the left colon.

Indeed, mood stabilizers may achieve their therapeutic effects by working through these diverse targets to restore cellular resilience; notably, however, chronic treatment is necessary for their neurotrophic and neuroprotective

actions to improve functional plasticity in cortical and limbic circuits and synapses. Below we focus on several intracellular signaling pathways targeted by Inhibitors,research,lifescience,medical mood stabilizers that may underlie these therapeutic mechanisms: i) the mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathway, ii) the phosphatidylinositol 3 kinase (PI3K) pathway, and ii) the wingless/glycogen synthase kinase 3 (Wnt/GSK3) pathway. Mood stabilizers activate neurotrophic signaling pathways Mood stabilizers have been reported to activate the intracellular Inhibitors,research,lifescience,medical MAPK/ERK signaling pathway (Figure 1). 1-3 This pathway is used by neurotrophins, neurotransmitters, and neuropeptides to exert their neurotrophic

and neuroprotective effects by specifically enhancing Inhibitors,research,lifescience,medical progenitor cell proliferation and differentiation, neuronal process growth and regeneration, neuronal survival, and long-term synaptic remodeling and plasticity.4-7 The key components of the pathway are three serine/threonine-selective kinases: RAP, MEK, and MAPK/ERK. GTP bond RAS, a small G protein, Ku-0059436 mw induces RAF activity. RAF then phosphorylates and activates MEK, which in turn phosphorylates and activates MAPK/ERK. The targets of ERK include protein kinases such as RSK and MNK, ion channel, neurotransmitter receptors, and transcription factors. RSK and MNK are thought to phosphoryiale Inhibitors,research,lifescience,medical and activate

transcription factor cAMP response element binding (CREB). CREB regulates the expression of Inhibitors,research,lifescience,medical many different genes, including B-cell lymphoma 2 (Bcl-2)1,8 and brain-derived neurotrophic factor (BDNF)9 to enhance neuroprotection and neuronal survival mechanisms. Figure 1. Intracellular signaling pathways targeted by psychotropic agents. The MAPK/ERK, PI3K, and Wnt/GSK3 signaling cascades. Psychotropic agents such as mood stabilizers, antidepressants, and antipsychotics target these signaling cascades. Targets reported … In SH-SY5Y human neuroblastoma almost cells, the mood stabilizers lithium and valproate activated AP-1 transcription factors, and that activation was blocked by a MEK inhibitor.10 That study also demonstrated that valproate increased levels of activated phospho-ERK and reporter gene expression driven by ELK, an ERK-regulated transcription factor; that activation was further blocked by RAS and RAF functional null mutant.10 Valproate also promoted neurite outgrowth and expression of GAP-43 in these cells, which could be blocked by an ERK pathway inhibitor.10 Taken together, these data indicate that valproate activates the ERK pathway and produces neurotrophic-like cellular effects through this activation.

In SULT1E1 knock-out mice, loss of SULT1E1 causing an excess of estrogens leads to the formation of smaller patches from white fat and insulin resistance [97]. In type 2 diabetes, induction of hepatic SULT1E1 is most

frequently observed. Loss of SULT1E1 improves the metabolic function in a female mouse model of type 2 diabetes, restores insulin sensitivity, and blocks hepatic gluconeogenesis and lipogenesis [98]. Since in diabetes, upregulation of SULT1E1 decreases E2 levels, inactivation of the enzyme will prevent loss of estrogens and normalize estrogenic activity in the liver. Inhibitors,research,lifescience,medical This beneficial effects of SULT1E1 inactivation were absent in ovariectomized mice. These effects were also sex specific, as SULT1E1 loss in males worsened the diabetic phenotype and led to a decreased islet beta-cell mass, failure Inhibitors,research,lifescience,medical of glucose-stimulated insulin secretion, increased macrophage infiltration, and inflammation in white adipose tissue. The authors suggest that inhibition of SULT1E1 at least in females may represent a novel approach in the therapy of type 2 diabetes [98, 99]. However, it has to be considered that type 2 diabetes mostly occurs in women after the learn more menopause when local formation of steroid hormones from adrenal precursors becomes important. Since extragonadal Inhibitors,research,lifescience,medical estrogen production is typical for primates [2], the benefit of increasing levels of active estrogens

by reducing SULT1E1 may have to be studied in a proper model for type 2 diabetes in this group. In any case, higher estrogen levels are thought to have beneficial effects on type 2 diabetes, but the risk of the induction of hormone-sensitive cancers may be considered as well. 5. Steroid Sulfatase Inhibitors as Agents for a Therapy of Hormone-Sensitive Tumors Inhibitors,research,lifescience,medical Hormone therapy is used to treat both early and advanced breast Inhibitors,research,lifescience,medical cancer and to prevent breast cancer in women who are at high-risk of developing the

disease. Currently, the most widely used therapies for the treatment of hormone-dependent cancer is to block the action of steroid hormones. Adjuvant endocrine therapy with the selective estrogen receptor modulator (SERM) tamoxifen is recommended for premenopausal women with a history of atypical hyperplasia to reduce breast cancer risk. Raloxifene, another selective Parvulin estrogen receptor modulator, was found to be equivalent to tamoxifen in reducing the risk of developing invasive breast cancer in postmenopausal women. However, it did not provide the same level of risk reduction for developing noninvasive breast cancer. Aromatase inhibitors, which block the conversion of androstenedione to estrone, are applied in postmenopausal women. Currently, third-generation aromatase inhibitors, which comprise the nonsteroidal compounds anastrozole and letrozole, and the steroidal exemestane are finding widespread application in the clinic (for reviews see [100, 101]).

In addition, high risk alcohol and drug use is positively correlated with PTSD symptomatology [12]. Several mitigating factors for PTSD in emergency workers and trainees have been identified. For example, social support following a traumatic incident has been found to be protective against PTSD [8,13,14]. In one study, ECW who reported strong peer support also reported lower levels of perceived stress [15]. Similarly, a Dutch study found that lack of social support from supervisors greatly compounded symptoms of burnout in ambulance

personnel [16]. Resilience, the ability to cope with adversity without being harmed by it, can also buffer against the onset of PTSD symptoms, Inhibitors,research,lifescience,medical and resilience-recovery Inhibitors,research,lifescience,medical variables (personality, coping strategies and social support) can aid in trauma adjustment [17,18]. ECW are AS703026 exposed to living individuals who are seriously injured or dying and, as such, are exposed to human pain and suffering [2]. They have to make quick appraisals and administer aid in an attempt to save lives, often Inhibitors,research,lifescience,medical without support or reassurance [4]. ECW workers are frequently unaware of the specifics of the emergency situation as they are often the first personnel on site and consequently do not have adequate time

or information to mentally prepare themselves. Due to the nature of their work, ECW face an increased risk of developing PTSD symptoms. The purpose of this study was firstly to assess and Inhibitors,research,lifescience,medical determine the frequency, nature and severity of direct trauma

exposure, posttraumatic stress symptoms and other psychopathology amongst paramedic trainees. Secondly, the study aimed to identify risk factors (e.g. trauma exposure) and resilience factors (e.g. social support) that contribute to the presence and severity of posttraumatic symptomatology amongst paramedic trainees. Thirdly, the study aimed to create a risk profile for paramedic trainees who Inhibitors,research,lifescience,medical are at higher occupational risk of developing PTSD. Methods Participants and procedure A hundred and thirty one paramedic trainees participated in the study. Data were collected between 2008 and 2011. Participants were recruited from Endonuclease a university in the Western Cape with the aid and permission of their supervisors. All the participants were first year paramedic trainees. During their first year of study, trainees gain practical experience in the field and are exposed to accident scenes and critical incidents. The study was approved by the Health Research Ethics Committee at Stellenbosch University, Cape Town, South Africa (N06/02/037). Informed consent was obtained from participants before assessment commenced. Two researchers (a psychiatry resident and research psychologist) conducted the assessments. Participants were assessed with a battery of questionnaires including a demographic questionnaire as well as several measures of psychiatric and psychological status.

At times, names and/or addresses

were reported to be incorrect or misspelled. Of the incorrect addresses, some were returned but others were potentially lost if the bereaved family member was no longer at that address and the invitation disposed of. A small number of bereaved family members found an incorrect name to be distressing, particularly during this time of bereavement. In some situations, where family members or someone close to the decedent were not available, a funeral director, nursing home or healthcare provider was recorded as the death certificate informant, people who were ineligible to participate. Because we have no knowledge about these issues unless directly Inhibitors,research,lifescience,medical told by the person receiving the mailed invitation, the full extent and COX signaling pathway inhibitor effect is unknown. Unfortunately, errors in the name and address of the informant occur at the time of death certificate completion. Once informed of this problem, apologies Inhibitors,research,lifescience,medical were made and the correct information relayed to the third party for correction in the Vital Statistics database which appeased distressed family members. Mail service delivery method Study invitations were mailed using a recorded delivery priority mail service. Although very costly compared to regular

Inhibitors,research,lifescience,medical mail, this service was selected in an effort to increase people’s attention to the receipt of the invitation package and to their perception of Inhibitors,research,lifescience,medical the study’s importance [24]. As well, all undelivered

mail was assured to be returned to the sender which alerted the research team to a potential problem. However, priority mail service required someone to be at home at time of delivery. If not, a notice was left for the recipient to pick it up at the local post office which created an unanticipated burden for some, particularly the elderly who had difficulty travelling outside the home. Due to the cost associated with the use of priority mail and the inconvenience it presented for some, a small nested Inhibitors,research,lifescience,medical study was initiated during the final wave of invitation package mailings. For the last wave, approximately half of the identified bereaved family members were contacted using the priority mail next service whereas the second half received invitations through regular mail. As anticipated, the number of invitation packages using the regular service known not to be delivered was lower than those reported using priority mail. However, although the proportion of bereaved family members consenting to take part was somewhat (2.5%) higher among those who received their invitations by priority mail, the cost savings associated with delivery by regular mail was substantial (75% less). Response rate and sample size Our original intent was to send study invitations to a sample of family members or informants recorded on potentially eligible death certificates.

Because the E2 region of the viral DNA normally represses the transcription of the E6 and E7 early viral genes, its interruption causes over expression of the E6 and E7 proteins of the HPV-16 and HPV-18.6 Oncogenic potential

of these HPVs may be related to these two early viral gene products.7,8 The E7 protein binds to the underphosphorylated Inhibitors,research,lifescience,medical form of the tumor-suppressor protein pRb and displaces the E2F transcription factors that are normally bound by pRb. The E6 protein binds to and facilitates the degradation of p53 gene product. The E6 and E7 proteins derived from high-risk HPVs (types 16, 18 and 31) bind to pRb and p53 with high affinity, whereas those Inhibitors,research,lifescience,medical of low-risk viruses (types 6 and 11) bind with low affinity. Thus, it seems that the E6 and E7 proteins of the high-risk HPVs disable two important tumor suppressor proteins that regulate

the cell cycle. It has been reported that one particular allele of p53 with an arginine rather than a proline at a certain position is much more susceptible to degradation by E6. Correspondingly, individuals with the “arginine form” of p53 have a seven fold higher risk of developing cervical cancer than those who do not posses this allele of p53.8,9 Although, these observations implicate certain HPV types in the pathogenesis of human cancer, it seems most likely that infection with HPV acts as an initiating event Inhibitors,research,lifescience,medical and that additional somatic mutations are essential for full malignant transformation. There are conflicting reports Inhibitors,research,lifescience,medical on the effects of formalin fixation on DNA quality. While a

number of reports indicate that the use of formalin for tissue fixation causes DNA degradation and reduces DNA solubility, a number of others suggest that formalin fixation does not have significant effect on the successful amplification of DNA.10-12 de Villiers and colleagues Inhibitors,research,lifescience,medical studied 117 Selleckchem Dapagliflozin samples of esophageal carcinoma originating from the high incidence areas of china, and showed that HPV DNA was present in 20 out of 117 samples (17.1%). Only three of Mucosotropic HPVs were of the high risk Resminostat types (HPV-16, 18 and 33).13 Li and colleagues evaluated specimens of balloon cytology examination from volunteers in two regions with significantly different incidence of esophageal carcinoma. Specimens were evaluated using both PCR and in situ hybridization (ISH) protocols. The results of PCR showed that the prevalence of HPV-16 E6 gene in the high incidence area was 1.9 fold higher than that of low incidence area (72% and 37% respectively, P<0.01). Similar results were obtained with HPV-16 E7 gene using ISH. They suggested that HPV-16 plays a causative role in the pathogenesis of esophageal cancer, especially in the high incidence area of China.14 Si and colleagues evaluated some HPV-16 positive cases of ESCC in order to determine physical status of HPV-16 in these cases.

This observation laid the foundation for extensive research efforts on the experimental psychopathology of panic, which offers a unique opportunity in the field of psychiatry. The scientific and clinical promises of such symptom provocation studies for

the pathophysiology and psychopharmacology of psychiatric disorders have been drafted as follows3: In this paradigm investigators administer a psychopharmacologic agent or psychological challenge procedure to patients under controlled conditions to probe psychiatric symptoms and other neurobiological Proteasomal inhibitor responses. The principal scientific rationale behind this approach is to learn more about the underlying pathophysiological Inhibitors,research,lifescience,medical mechanisms responsible for the symptomatic expression of psychiatric illnesses. In addition, the knowledge gained from this type of study might lead to better predictors of treatment response or identification of novel therapeutic interventions. A quintessential ethical framework of challenge studies

includes preserved decision-making capacity, informed consent, potential Inhibitors,research,lifescience,medical scientific and future clinical benefits, consent of an ethical committee, a favorable or acceptable Inhibitors,research,lifescience,medical risk:benefit ratio, absence of severe or long-lasting effects of the challenge agent, and follow-up studies on the effects of participation in symptom-provoking studies. In addition to lactate infusion, several further methods to provoke experimental panic attacks in patients with panic disorder by pharmacological means have been developed during the past decades (overview in ref 4). These display many different modes of action and have different targets. They include other agents that influence respiration, such as carbon dioxide inhalation or doxapram infusion. Further established panicogens Inhibitors,research,lifescience,medical act specifically on neurotransmission, such as the noradrenergic substances yohimbine and isoprenaline, Inhibitors,research,lifescience,medical the serotonergic agents metachlorophenylpiperazine (mCPP) and fenfluramine, benzodiazepine-receptor agents, such as the inverse agonist FG 7142 and the antagonist flumazenil, agonists at the CCK-2 (formerly type B) receptor, such as cholecystokinin

tetrapeptide (CKK-4) and pentagastrin, and the adenosine receptor antagonist caffeine. The following criteria for an ideal panicogen for human use have been proposed (compiled according to Gutmacher et al5 and Gorman et al6): It should be safe It should mimic naturally occurring panic attacks It should foster both central and peripheral Oxymatrine manifestations of panic It should be replicable The phenomena should be either short-lived or readily reversible It should differentiate between healthy subjects and those with pathology It should reflect the potential for a state response; those who have been successfully treated clinically should not respond or respond far less than those who have had no treatment The effects should not be blocked by drugs, which do not work against spontaneous panic.

53 While

these are therefore not monocausally related to schizophrenia, they are one of the best genetic clues yet for a genetical high-risk state that deserves intensive further study. This applies both to chartacterizing brain phenotypes in subjects carrying or not carrying the disorder, and to trying to further dissect why these, and not any of the many other microdeletions present in the human Inhibitors,research,lifescience,medical population, increase risk for psychosis. For the former approach, the main problem is that due to the relative rarity of these variants even in clinical populations, large numbers will have to be screened and characterized. Nevertheless, this work is ongoing and promises insights not only in studying the phenotypes of each of these variants by itself, but also in examining whether there are overlaps in structural or neurofunctional impairments across these microdeletions that would identify core systems related to a high-risk state. For the latter Inhibitors,research,lifescience,medical attempt of trying to understand why these specific

microdeletions are highrisk, complex cis- and trans-acting genetic effects (ie, those that concern the genes affected by the microdeletion itself, or outside of it) will have to be considered. However, a simple AMD3100 hypothesis that can be tested is Inhibitors,research,lifescience,medical whether there could be, by chance, several common risk variants for schizophrenia located in spatial proximity that are jointly affected by a microdeletion, causing a superadditive effect. Some preliminary evidence for this idea comes from 22q11DS, which includes the muchstudied risk gene COMT, discussed above, but also several other genes where schizophrenia Inhibitors,research,lifescience,medical risk variants have been studied. One of these, PRODH, encoding proline oxidase (POX), has been associated with schizophrenia Inhibitors,research,lifescience,medical through linkage and association. A recent study showed that functional

polymorphisms had opposite effects on schizophrenia risk depending on whether they increased or decreased POX activity54 In multimodal genetic imaging, both functional (working memory and emotional recognition) and structural (VBM) datasets showed dissociable genetic effects: risk haplotype carriers had decreased striatal volume and not increased striatal-frontal functional connectivity, while the protective haplotype was associated with decreased striatal-frontal functional connectivity, mirroring findings in patients and suggesting that functional genetic variation in POX impacts on neostriatal-frontal circuits mediating risk and protection for schizophrenia. Since, as reviewed above, the biochemically unrelated COMT gene on overlapping circuitry in human brain, this suggests a neural mechanism whereby deletion of both genes in 22q11 syndrome could have a superadditive impact on schizophrenia risk.