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Macrophages (mφ) are essential for intestinal homeostasis and the pathology of inflammatory bowel disease (IBD), but it is unclear whether discrete mφ populations carry out these distinct functions or if resident mφ change during inflammation. We show here that most resident mφ in resting mouse colon express very high levels of CX3CR1, are avidly phagocytic and MHCII(hi), but are resistant to Toll-like receptor (TLR) stimulation, produce interleukin 10 constitutively, and express CD163 and CD206. A smaller population of CX3CR1(int) cells is present in resting colon and it expands during experimental colitis. Ly6C(hi)CCR2(+) monocytes can give rise to all mφ subsets in both healthy and inflamed colon and we show that the CX3CR1(int) pool represents a continuum in which newly arrived, recently divided monocytes develop into resident CX3CR1(hi) mφ. This process is arrested during experimental colitis, resulting in the accumulation of TLR-responsive pro-inflammatory mφ. Phenotypic analysis of human intestinal mφ indicates that analogous processes occur in the normal and Crohn's disease ileum. These studies show for the first time that resident and inflammatory mφ in the intestine represent alternative differentiation outcomes of the same precursor and targeting these events could offer routes for therapeutic intervention in IBD.

Incentives to malinger vary greatly dependent on the context, as does the prevalence. Malingering in the medico-legal context of the criminal courts is generally for one of two purposes: to present as incompetent to stand trial or to successfully plead not guilty by reason of insanity. Estimates of the prevalence of malingering in these contexts vary between 8 and 21%. The prevalence of malingering increases dramatically in a general offender sample, where the external incentive is likely to be substantially different. Malingering in this context can be as high as 56% and generally occurs to obtain a more desirable housing situation or desired medications. Our study examined data from two distinct samples to evaluate incentives to malinger: patients found incompetent to stand trial (IST) and sent to a state hospital for restoration and jail inmates seeking psychiatric services (JPS). Our results indicate that the rate of malingering in the IST sample was consistent with rates published in comparable samples (17.5%) and the rate for the JPS sample was substantially higher (64.5%). Only in the IST sample was rate of malingering associated with offense severity: patients found IST for murder and robbery evidenced malingering rates more than double the sample as a whole. Offense severity bore no relationship to malingering in the JPS sample., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The American Academy of Psychiatry and the Law (AAPL) was organized in 1969, in large part through the efforts of Dr. Jonas Rappeport. The founders of AAPL emphasized that an important purpose of the organization was to advance knowledge in the area of psychiatry and the law. The science of forensic psychiatry has since been vigorously debated. In 2005, Congress enacted a statute authorizing the National Academy of Sciences (NAS) to conduct a study on the state of the forensic sciences in the United States. As a result of this legislation, a forensic science committee was formed, and the report, "Strengthening Forensic Science in the United States: A Path Forward," was produced, emphasizing the need for research in the forensic disciplines, particularly those that rely on more subjective assessments. The committee also identified two important factors relevant to standards of evidence admissibility: the scientific methodology used and the impact of bias on the interpretation of data. In this article, I apply the NAS committee's findings to the field of forensic psychiatry, with specific recommendations to assist educators in achieving more objective assessment methodologies, critical in forensic education and the search for truth.

Two major processes govern T cell proliferation and survival: interleukin-7-mediated homeostasis and antigen-induced selection. How cells transit between the two states is unknown. Here we show that T cell receptor ligation actively inhibits homeostatic survival signals while initiating a new, dominant survival programme. This switch is mediated by a change in the expression of pro- and anti-apoptosis proteins through the downregulation of Bcl-2 and the induction of Bim, A1 and Bcl-xL. Calcineurin inhibitors prevent the initiation of the new survival programme, while permitting the dominant repression of Bcl-2. Thus, in the presence of these drugs the response to antigen receptor ligation is cell death. Our results identify a molecular switch that can serve as an attractive target for inducing antigen-specific tolerance in treating autoimmune disease patients and transplant recipients.

Intestinal dendritic cells (DCs) continuously migrate through lymphatics to mesenteric lymph nodes where they initiate immunity or tolerance. Recent research has focused on populations of intestinal DCs expressing CD103. Here we demonstrate, for the first time, the presence of two distinct CD103(-) DC subsets in intestinal lymph. Similar to CD103(+) DCs, these intestine-derived CD103(-) DCs are responsive to Flt3 and they efficiently prime and confer a gut-homing phenotype to naive T cells. However, uniquely among intestinal DCs, CD103(-) CD11b(+) CX(3)CR1(int) lymph DCs induce the differentiation of both interferon-γ and interleukin-17-producing effector T cells, even in the absence of overt stimulation. Priming by CD103(-) CD11b(+) DCs represents a novel mechanism for the rapid generation of effector T-cell responses in the gut. Therefore, these cells may prove to be valuable targets for the treatment of intestinal inflammation or in the development of effective oral vaccines.

Until recently, there has been little information regarding female offenders who commit homicides that are motivated by psychosis. We investigated gender differences in the characteristics of psychosis and crime variables in psychotically motivated homicide. In the study, conducted at a large U.S. forensic facility, we reviewed the records of women (n = 47) found not guilty by reason of insanity (NGRI) who were hospitalized between January 1991 and August 2005 for a homicide offense. A random sample of 47 men who were committed during the same period for the same offenses was selected for comparison. Religious delusions were found more often in women who killed infants (0-1 year of age) and children between the ages of 2 and 18. Women were more likely to have a diagnosis of an affective problem and borderline personality disorder. The results indicate gender-specific areas to focus on during clinical and forensic assessments of the risk of violence in women with psychosis.

This study investigated differences in usage of inpatient and outpatient mental health services over a 2-year period following the index hospitalization between 50 decertified and 48 certified subjects with bipolar manic or mixed episode from an inpatient mental health treatment center. The decertified group had higher number of rehospitalization over the 2-year period compared to certified group (mean = 2.26, SE = 0.41 vs. mean = 1.19, SE = 0.24; Wald χ (2) = 5.50, p = 0.02). Median time to first rehospitalization was 40 weeks in the certified and 17 weeks in the decertified group, but the difference in time to rehospitalization failed to achieve statistical significance (p = 0.18). History of prior hospitalization was associated with higher numbers of rehospitalizations and crisis room visits (both p < 0.01) and with shorter time before first rehospitalization (p < 0.001).

This article provides a guide that is important to remember in evaluating a criminal defendant's amnesia claim. Important concepts to understand regarding memory formation, memory systems, proposed causes of amnesia, reasons why amnesia claims may be true or false, and important strategies to implement as part of the evaluation process are reviewed. Structured assessment approaches are critical components of amnesia evaluations and generally require detailed questioning, review of collateral records, medical and neurologic workups, psychological testing, neuropsychological testing, and specific malingering assessments., (Published by Elsevier Inc.)

Trp63, a transcription factor related to the tumor suppressor p53, is activated by diverse stimuli and can initiate a range of cellular responses. TAp63 is the predominant Trp53 family member in primordial follicle oocyte nuclei and is essential for their apoptosis triggered by DNA damage in vivo. After γ-irradiation, induction of the proapoptotic BH3-only members Puma and Noxa was observed in primordial follicle oocytes from WT and Trp53(-/-) mice but not in those from TAp63-deficient mice. Primordial follicle oocytes from mice lacking Puma or both Puma and Noxa were protected from γ-irradiation-induced apoptosis and, remarkably, could produce healthy offspring. Hence, PUMA and NOXA are critical for DNA damage-induced, TAp63-mediated primordial follicle oocyte apoptosis. Thus, blockade of PUMA may protect fertility during cancer therapy and prevent premature menopause, improving women's health., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Hospital-acquired infection costs money and lives. Improving compliance with hand hygiene is proving an intractable problem as initial gains often lack sustainability. A growing field of research suggests that health service managers may have a critical role in dealing with this issue, which crosses all professional boundaries.

Neoplastic transformation requires the elimination of key tumor suppressors, which may result from E3 ligase-mediated proteasomal degradation. We previously demonstrated a key role for the E3 ubiquitin ligase E6AP in the regulation of promyelocytic leukemia protein (PML) stability and formation of PML nuclear bodies. Here, we report the involvement of the E6AP-PML axis in B-cell lymphoma development. A partial loss of E6AP attenuated Myc-induced B-cell lymphomagenesis. This tumor suppressive action was achieved by the induction of cellular senescence. B-cell lymphomas deficient for E6AP expressed elevated levels of PML and PML-nuclear bodies with a concomitant increase in markers of cellular senescence, including p21, H3K9me3, and p16. Consistently, PML deficiency accelerated the rate of Myc-induced B-cell lymphomagenesis. Importantly, E6AP expression was elevated in ∼ 60% of human Burkitt lymphomas, and down-regulation of E6AP in B-lymphoma cells restored PML expression with a concurrent induction of cellular senescence in these cells. Our findings demonstrate that E6AP-mediated down-regulation of PML-induced senescence is essential for B-cell lymphoma progression. This provides a molecular explanation for the down-regulation of PML observed in non-Hodgkin lymphomas, thereby suggesting a novel therapeutic approach for restoration of tumor suppression in B-cell lymphoma.

The pro-apoptotic BH3-only protein, BIK, is widely expressed and although many critical functions in developmental or stress-induced death have been ascribed to this protein, mice lacking Bik display no overt abnormalities. It has been postulated that Bik can serve as a tumour suppressor, on the basis that its deficiency and loss of apoptotic function have been reported in many human cancers, including lymphoid malignancies. Evasion of apoptosis is a major factor contributing to c-Myc-induced tumour development, but despite this, we found that Bik deficiency did not accelerate Eμ-Myc-induced lymphomagenesis. Co-operation between BIK and NOXA, another BH3-only protein, has been previously described, and was attributed to their complementary binding specificities to distinct subsets of pro-survival BCL-2 family proteins. Nevertheless, combined deficiency of Bik and Noxa did not alter the onset of Eμ-Myc transgene induced lymphoma development. Moreover, although p53-mediated induction of Bik has been reported, neither Eμ-Myc/Bik(-/-) nor Eμ-Myc/Bik(-/-)Noxa(-/-) lymphomas were more resistant than control Eμ-Myc lymphomas to killing by DNA damaging drugs, either in vitro or in vivo. These results suggest that Bik, even in combination with Noxa, is not a potent suppressor of c-Myc-driven tumourigenesis or critical for chemotherapeutic drug-induced killing of Myc-driven tumours.

Reports indicate that germ-line stem cells present in adult mice can rapidly generate new oocytes and contribute to the primordial follicle reserve following conditions of ovotoxic stress. We further investigated the hypothesis that adult mice have the capacity to generate new oocytes by monitoring primordial follicle numbers throughout postnatal life and following depletion of the primordial follicle reserve by exposure to doxorubicin (DXR), trichostatin A (TSA), or whole-body γ-irradiation. We show that primordial follicle number remains stable in adult C57BL/6 mice between the ages of 25 and 100 days. However, within 2 days of treatment with DXR or TSA, primordial follicle numbers had declined to 65 and 51% respectively (P<0.05-0.01 when compared to untreated controls), with no restoration of follicle numbers evident after 7 days for either treatment. Furthermore, ovaries from mice subjected to sterilizing doses of γ-irradiation (0.45 or 4.5 Gy) revealed complete ablation of all primordial follicles 5 days after treatment, with no indication of follicular renewal. We conclude that neo-folliculogenesis does not occur following chemical or γ-irradiation mediated depletion of the primordial follicle reserve.

California's prisons are currently designed to house approximately 85,000 inmates. At the time of the U.S. Supreme Court's 2011 decision in Brown v. Plata, the California prison system housed nearly twice that many (approximately 156,000 inmates). The Supreme Court held that California's prison system violated inmates' Eighth Amendment rights. The Court upheld a three-judge panel's order to decrease the population of California's prisons by an estimated 46,000 inmates. They determined that overcrowding was the primary cause of the inmates' inadequate medical and mental health care. As a result, the California Department of Corrections and Rehabilitation (CDCR) has been working to redistribute inmates and parolees safely and decrease the overall population to the mandated levels. These large-scale adjustments to California's penal system create potential opportunities to study the long-term effects on affected inmates.

Poly adenosine diphosphate ribose polymerase (PARP) inhibitors have demonstrated single agent activity in the treatment of patients with recurrent BRCA1-mutated and BRCA2-mutated breast and ovarian cancers. They also appear to have a potential role as maintenance therapy following chemotherapy in patients with platinum sensitive recurrent sporadic and BRCA1/2 related high-grade serous ovarian cancers. The concept of BRCAness raises the possibility that PARP inhibitors may be active in selected patients with homologous recombination (HR) DNA repair-deficient tumors, even if they do not harbor a BRCA1/2 germline mutation. Further research will be required to identify the subset of patients with sporadic cancers who may benefit from PARP inhibitor therapy. Precise details on the mechanisms of action, relative potency and anti-cancer effects of different PARP inhibitors remain to be clarified and are being investigated. PARP inhibitors are known to inhibit the base excision repair (BER) pathway but in addition, recent reports indicate that aberrant activation of the error-prone non-homologous end-joining (NHEJ) pathway occurs in HR-deficient cells and that cell death provoked by PARP inhibition is dependent on NHEJ-induced genomic instability. Characterization of the precise molecular mechanisms responsible for PARP inhibitor activity should lead to the identification of predictive biomarkers of response and help identify which patients should be treated with PARP inhibitors. This is a very active field of research and the current status and future directions are reviewed., (© 2011 Blackwell Publishing Asia Pty Ltd.)

CD103(+) dendritic cells (DCs) in the intestinal mucosa play a crucial role in tolerance to commensal bacteria and food antigens. These cells originate in the lamina propria (LP) and migrate to the mesenteric lymph nodes (MLNs), where they drive the differentiation of gut-homing FoxP3(+) regulatory T cells by producing retinoic acid from dietary vitamin A. Local 'conditioning' factors in the LP might also contribute to this tolerogenic profile of CD103(+) DCs. Considerably less is understood about the generation of active immunity or inflammation in the intestinal mucosa. This might require alterations in pre-existing CD103(+) DCs, arrival of new DCs, or the action of a distinct DC population. Here, we discuss our current knowledge of this as yet incompletely understood population., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Avoidance of dental care and neglect of oral health may occur in patients with inherited bleeding disorders because of concerns about perioperative and postoperative bleeding, but this is likely to result in the need for crisis care, and more complex and high-risk procedures. Most routine dental care in this special needs group can be safely managed in the general dental setting following consultation with the patient's haematologist and adherence to simple protocols. Many of the current protocols for dental treatment of patients with inherited bleeding disorders were devised many years ago and now need revision. There is increasing evidence that the amount of factor cover previously recommended for dental procedures can now be safely reduced or may no longer be required in many cases. There is still a need for close cooperation and discussion between the patient's haematologist and dental surgeon before any invasive treatment is performed. A group of hospital based dentists from centres where patients with inherited bleeding disorders are treated met and, after discussions, a management protocol for dental treatment was formulated., (© 2011 Australian Dental Association.)

The concept of personalized anticancer therapy is based on the use of targeted therapeutics through in-depth knowledge of the molecular mechanisms of action of these agents when used alone and in combination. We have identified the apoptotic proteins and pathways necessary for synergistic tumor cell apoptosis and in vivo antitumor responses seen when the HDAC inhibitor vorinostat is combined with the BH3-mimetic ABT-737 in lymphomas overexpressing Bcl-2. Vorinostat "primes" tumors overexpressing Bcl-2 for rapid ABT-737-mediated apoptosis by inducing expression of the BH3-only gene bmf. Moreover, these synergistic effects of vorinostat/ABT-737 were blunted in cells with an inactive p53 pathway or in cells lacking expression of the p53 target gene, noxa. These studies show the important and complex functional interaction between specific proapoptotic BH3-only proteins and the BH3-mimetic compound ABT-737 and provide the most comprehensive functional link between tumor genotype and the apoptotic and therapeutic effects of HDACi combined with ABT-737., (©2011 AACR)

This randomized controlled trial evaluated the therapeutic benefit of mental practice with motor imagery in stroke patients with persistent upper limb motor weakness. There is evidence to suggest that mental rehearsal of movement can produce effects normally attributed to practising the actual movements. Imagining hand movements could stimulate restitution and redistribution of brain activity, which accompanies recovery of hand function, thus resulting in a reduced motor deficit. Current efficacy evidence for mental practice with motor imagery in stroke is insufficient due to methodological limitations. This randomized controlled sequential cohort study included 121 stroke patients with a residual upper limb weakness within 6 months following stroke (on average <3 months post-stroke). Randomization was performed using an automated statistical minimizing procedure. The primary outcome measure was a blinded rating on the Action Research Arm test. The study analysed the outcome of 39 patients involved in 4 weeks of mental rehearsal of upper limb movements during 45-min supervised sessions three times a week and structured independent sessions twice a week, compared to 31 patients who performed equally intensive non-motor mental rehearsal, and 32 patients receiving normal care without additional training. No differences between the treatment groups were found at baseline or outcome on the Action Research Arm Test (ANCOVA statistical P=0.77, and effect size partial η2=0.005) or any of the secondary outcome measures. Results suggest that mental practice with motor imagery does not enhance motor recovery in patients early post-stroke. In light of the evidence, it remains to be seen whether mental practice with motor imagery is a valid rehabilitation technique in its own right.

Child sex tourism, the act of traveling to engage in sexual acts with minors, plagues developing nations worldwide. Several laws have been passed internationally in recent years designed to curtail this practice. Government entities and human rights organizations have driven these efforts. United States citizens represent a significant proportion of participants in child sex tourism. The PROTECT Act of 2003 prohibits United States citizens from participating in sexual acts with minors while traveling, and establishes extraterritorial jurisdiction. The case of Michael Lewis Clark, the first United States citizen convicted under this legislation, is highlighted. Child sex tourism poses unique issues to courts that will require ongoing clarification as challenges arise. This article discusses potential future challenges, describes strategies to address this problem, and relates this issue to psychiatry. Mental health providers may have the role of evaluating both the victims and perpetrators of child sex tourism. The authors propose a classification system for offenses and an initial list of topics to discuss with victims. The authors also describe the proper mechanism for reporting United States citizens suspected of participating in child sex tourism., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: DC are activated by pathogen-associated molecular patterns (PAMPs), and this is pivotal for the induction of adaptive immune responses. Thereafter, the clearance of activated DC is crucial to prevent immune pathology. While PAMPs are of major interest for vaccine science due to their adjuvant potential, it is unclear whether and how PAMPs may affect DC viability. We aimed to elucidate the possible apoptotic mechanisms that control activated DC lifespan in response to PAMPs, particularly in vivo., Methodology/principal Findings: We report that polyinosinic:polycytidylic acid (PolyIC, synthetic analogue of dsRNA) induces dramatic apoptosis of mouse splenic conventional DC (cDC) in vivo, predominantly affecting the CD8α subset, as shown by flow cytometry-based analysis of splenic DC subsets. Importantly, while Bim deficiency conferred only minor protection, cDC depletion was prevented in mice lacking Bim plus one of three other BH3-only proteins, either Puma, Noxa or Bid. Furthermore, we show that Type I Interferon (IFN) is necessary and sufficient for DC death both in vitro and in vivo, and that TLR3 and MAVS co-operate in IFNß production in vivo to induce DC death in response to PolyIC., Conclusions/significance: These results demonstrate for the first time in vivo that apoptosis restricts DC lifespan following activation by PolyIC, particularly affecting the CD8α cDC subset. Such DC apoptosis is mediated by the overlapping action of pro-apoptotic BH3-only proteins, including but not solely involving Bim, and is driven by Type I IFN. While Type I IFNs are important anti-viral factors, CD8α cDC are major cross-presenting cells and critical inducers of CTL. We discuss such paradoxical finding on DC death with PolyIC/Type I IFN. These results could contribute to understand immunosuppression associated with chronic infection, and to the optimization of DC-based therapies and the clinical use of PAMPs and Type I IFNs.

DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In Eμ-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in Eμ-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of Eμ-Myc/Puma(-/-)Noxa(-/-) lymphomas both in vitro and in vivo. Remarkably, c-MYC-driven lymphoma cell lines from Noxa(-/-)Puma(-/-)Bim(-/-) mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.

Nineteenth-century American reformers were concerned about the influence of immaturity and development in juvenile offenses. They responded to their delinquent youths through the creation of juvenile courts. This early American juvenile justice system sought to treat children as different from adults and to rehabilitate wayward youths through the state's assumption of a parental role. Although these rehabilitative goals were never fully realized, the field of American child psychiatry was spawned from these efforts on behalf of delinquent youths. Early child psychiatrists began by caring for juvenile offenders. The function of a child psychiatrist with juvenile delinquents expanded beyond strictly rehabilitation, however, as juvenile courts evolved to resemble criminal adult courts-due to landmark Supreme Court decisions and also juvenile legislation between 1966 and 1975. In response to dramatically increased juvenile violence and delinquency rates in the 1980s, juvenile justice became more retributional, and society was forced to confront issues such as capital punishment for juveniles, their transfer to adult courts, and their competency to stand trial. In the modern juvenile court, child psychiatrists are often asked to participate in the consideration of such issues because of their expertise in development. In that context we review the role of psychiatrists in assisting juvenile courts.

Diverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular lymphomas typical of vavP-BCL-2 mice, aging vavP-Mcl-1 mice were primarily susceptible to lymphomas having the phenotype of a stem/progenitor cell (11 of 30 tumors) or pre-B cell (12 of 30 tumors). Mcl-1 overexpression dramatically accelerated Myc-driven lymphomagenesis. Most vavP-Mcl-1/ Eμ-Myc mice died around birth, and transplantation of blood from bitransgenic E18 embryos into unirradiated mice resulted in stem/progenitor cell tumors. Furthermore, lethally irradiated mice transplanted with E13 fetal liver cells from Mcl-1/Myc bitransgenic mice uniformly died of stem/progenitor cell tumors. When treated in vivo with cyclophosphamide, tumors coexpressing Mcl-1 and Myc transgenes were significantly more resistant than conventional Eμ-Myc lymphomas. Collectively, these results demonstrate that Mcl-1 overexpression renders hematopoietic cells refractory to many cytotoxic insults, perturbs lymphopoiesis and promotes malignant transformation of hematopoietic stem and progenitor cells.

Background: During the United States Medical Licensing Examination Step 2 Clinical Skills examination, examinees rotate through 12 standardized patient (SP) encounters. Examinees have 25 minutes per encounter to interact with SPs and complete postencounter patient notes (PNs), and they may end the SP interaction early to spend extra time on the PN. The current work assesses the time examinees are spending on PNs and whether this is related to performance on the PN., Method: Encounters from 2,479 examinees' videos were time-stamped to indicate total encounter time and PN time. Hierarchical linear modeling was employed to assess how well total and PN time, along with other examinee and case-rater variables, predicted PN scores., Results: Examinee variables explained a significant portion of within-case-rater variability, but while PN time was significantly related to PN ratings, the effect was small., Conclusions: The results suggest that spending additional time on the PN does not translate to a meaningful score increase.

Lung development requires coordinated signaling between airway and vascular growth, but the link between these processes remains unclear. Mammalian target of rapamycin complex-1 (mTORC1) can amplify hypoxia-inducible factor-1α (HIF-1α) vasculogenic activity through an NH(2)-terminal mTOR binding (TOS) motif. We hypothesized that this mechanism coordinates vasculogenesis with the fibroblast growth factor (FGF)-10/FGF-receptor2b/Spry2 regulator of airway branching. First, we tested if the HIF-1α TOS motif participated in epithelial-mesenchymal vascular signaling. mTORC1 activation by insulin significantly amplified HIF-1α activity at fetal Po(2) (23 mmHg) in human bronchial epithelium (16HBE14o-) and induced vascular traits (Flk1, sprouting) in cocultured human embryonic lung mesenchyme (HEL-12469). This enhanced activation of HIF-1α by mTORC1 was abolished on expression of a HIF-1α (F99A) TOS-mutant and also suppressed vascular differentiation of HEL-12469 cocultures. Next, we determined if vasculogenesis in fetal lung involved regulation of mTORC1 by the FGF-10/FGFR2b/Spry2 pathway. Fetal airway epithelium displayed distinct mTORC1 activity in situ, and its hyperactivation by TSC1(-/-) knockout induced widespread VEGF expression and disaggregation of Tie2-positive vascular bundles. FGF-10-coated beads grafted into fetal lung explants from Tie2-LacZ transgenic mice induced localized vascular differentiation in the peripheral mesenchyme. In rat fetal distal lung epithelial (FDLE) cells cultured at fetal Po(2), FGF-10 induced mTORC1 and amplified HIF-1α activity and VEGF secretion without induction of ERK1/2. This was accompanied by the formation of a complex between Spry2, the cCBL ubiquitin ligase, and the mTOR repressor, TSC2, which abolished GTPase activity directed against Rheb, the G protein inducer of mTORC1. Thus, mTORC1 links HIF-1α-driven vasculogenesis with the FGF-10/FGFR2b/Spry2 airway branching periodicity regulator.

Although tumor development requires impaired apoptosis, we describe a novel paradigm of apoptosis-dependent tumorigenesis. Because DNA damage triggers apoptosis through p53-mediated induction of BH3-only proteins Puma and Noxa, we explored their roles in gamma-radiation-induced thymic lymphomagenesis. Surprisingly, whereas Noxa loss accelerated it, Puma loss ablated tumorigenesis. Tumor suppression by Puma deficiency reflected its protection of leukocytes from gamma-irradiation-induced death, because their glucocorticoid-mediated decimation in Puma-deficient mice activated cycling of stem/progenitor cells and restored thymic lymphomagenesis. Our demonstration that cycles of cell attrition and repopulation by stem/progenitor cells can drive tumorigenesis has parallels in human cancers, such as therapy-induced malignancies.

The ability of thymocytes to assess T cell receptor (TCR) signaling strength and initiate the appropriate downstream response is crucial for determining their fate. We have previously shown that a c-Cbl RING finger mutant knock-in mouse, in which the E3 ubiquitin ligase activity of c-Cbl is inactivated, is highly sensitive to TCR-induced death signals that cause thymic deletion. This high intensity signal involves the enhanced tyrosine phosphorylation of the mutant c-Cbl protein promoting a marked increase in the activation of Akt. Here we show that this high intensity signal in c-Cbl RING finger mutant thymocytes also promotes the enhanced induction of two mediators of TCR-directed thymocyte apoptosis, Nur77 and the pro-apoptotic Bcl-2 family member, Bim. In contrast, a knock-in mouse harboring a mutation at Tyr-737, the site in c-Cbl that activates phosphatidylinositol 3-kinase, shows reduced TCR-mediated responses including suppression of Akt activation, a reduced induction of Nur77 and Bim, and greater resistance to thymocyte death. These findings identify tyrosine-phosphorylated c-Cbl as a critical sensor of TCR signal strength that regulates the engagement of death-promoting signals.

Objective: High concentrations of circulating glucose are believed to contribute to defective insulin secretion and beta-cell function in diabetes and at least some of this effect appears to be caused by glucose-induced beta-cell apoptosis. In mammalian cells, apoptotic cell death is controlled by the interplay of proapoptotic and antiapoptotic members of the Bcl-2 family. We investigated the apoptotic pathway induced in mouse pancreatic islet cells after exposure to high concentrations of the reducing sugars ribose and glucose as a model of beta-cell death due to long-term metabolic stress., Research Design and Methods: Islets isolated from mice lacking molecules implicated in cell death pathways were exposed to high concentrations of glucose or ribose. Apoptosis was measured by analysis of DNA fragmentation and release of mitochondrial cytochrome c., Results: Deficiency of interleukin-1 receptors or Fas did not diminish apoptosis, making involvement of inflammatory cytokine receptor or death receptor signaling in glucose-induced apoptosis unlikely. In contrast, overexpression of the prosurvival protein Bcl-2 or deficiency of the apoptosis initiating BH3-only proteins Bim or Puma, or the downstream apoptosis effector Bax, markedly reduced glucose- or ribose-induced killing of islets. Loss of other BH3-only proteins Bid or Noxa, or the Bax-related effector Bak, had no impact on glucose-induced apoptosis., Conclusions: These results implicate the Bcl-2 regulated apoptotic pathway in glucose-induced islet cell killing and indicate points in the pathway at which interventional strategies can be designed.

The Americans With Disabilities Act Amendments Act of 2008 (ADAAA) significantly modifies the 1990 Americans With Disabilities Act. As a result of this legislation, more Americans are likely to qualify as disabled and to be further protected from discrimination under the ADA. The ADAAA also effectively overturns key rulings in the U.S. Supreme Court cases of Sutton v. United Air Lines, Inc. and Toyota Motor Manufacturing v. Williams. This article summarizes important changes resulting from the ADAAA legislation that psychiatrists and psychologists must understand when evaluating ADA disability claims.

Background: During the United States Medical Licensing Examination Step 2 Clinical Skills exam, examinees rotate through 12 standardized patient (SP) encounters. SPs rate examinees on Communication and Interpersonal Skills (CIS). Examinees have at most 15 minutes to interact with each SP, but can end the encounter sooner. The current work assesses the relationship between CIS ratings and time examinees spend interacting with the SP., Method: A total of 5,955 encounters from a fall 2007 sample of examinees were time-stamped to indicate total encounter time and closure time. Hierarchical linear modeling was employed to assess how well total and closure time, in conjunction with other examinee- and SP-case-related variables, predicted CIS scores., Results: Time spent on closure had a larger impact on CIS scores than overall time used. Other variables, such as examinee gender, Spoken English Proficiency, and SP stringency, were also significantly related to CIS scores., Conclusions: Both time measures were significantly positively related to the CIS outcome variable, indicating a link between time used and SP satisfaction with communication, with closure time having the larger coefficient. This finding suggests that a good closure may be a lengthy one.

LAQ824 and LBH589 (panobinostat) are histone deacetylase inhibitors (HDACi) developed as cancer therapeutics and we have used the Emu-myc lymphoma model to identify the molecular events required for their antitumor effects. Induction of tumor cell death was necessary for these agents to mediate therapeutic responses in vivo and both HDACi engaged the intrinsic apoptotic cascade that did not require p53. Death receptor pathway blockade had no effect on the therapeutic activities of LAQ824 and LBH589; however, overexpression of Bcl-2 or Bcl-X(L) protected lymphoma cells from HDACi-induced killing and suppressed their therapeutic activities. Deletion of Apaf-1 or Caspase-9 delayed HDACi-induced lymphoma killing in vitro and in vivo, associated with suppression of many biochemical indicators of apoptosis, but did not provide long-term resistance to these agents and failed to inhibit their therapeutic activities. Emu-myc lymphomas lacking a functional apoptosome displayed morphologic and biochemical features of autophagy after treatment with LAQ824 and LBH589, indicating that, in the absence of a complete intrinsic apoptosis pathway involving apoptosome formation, these HDACi can still mediate a therapeutic response. Our data indicate that damage to the mitochondria is the key event necessary for LAQ824 and LBH589 to mediate tumor cell death and a robust therapeutic response.

Therapeutic targeting of tumours on the basis of molecular analysis is a new paradigm for cancer treatment but has yet to fulfil expectations. For many solid tumours, targeted therapeutics, such as inhibitors of oncogenic kinase pathways, elicit predominantly disease-stabilizing, cytostatic responses, rather than tumour regression. Combining oncogenic kinase inhibitors with direct activators of the apoptosis machinery, such as the BH3 mimetic ABT-737, may unlock potent anti-tumour potential to produce durable clinical responses with less collateral damage.

Evasion of apoptosis contributes importantly to c-Myc-induced tumorigenesis. The BH3-only Bcl-2 family members Puma and Noxa are critical pro-apoptotic transcriptional targets of p53, a major mediator of Myc-induced apoptosis and suppressor of Myc-induced tumorigenesis. Hence, we have explored the impact of their individual or combined loss on myc-driven lymphomagenesis. Notably, Puma deficiency both increased B-lineage cells and accelerated the development of B lymphoma, accompanied by leukaemia, but not of pre-B lymphoma. Noxa deficiency alone also increased B-lineage cells but did not accelerate lymphomagenesis. However, its deficiency combined with loss of one puma allele produced more rapid onset of both pre-B and B lymphomas than did loss of a single puma allele alone. Nevertheless, the acceleration evoked by loss of both genes was not as marked as that caused by p53 heterozygosity. These results show that Puma imposes a significant, and Noxa a minor barrier to c-Myc-driven lymphomagenesis. They also indicate that additional BH3-only proteins probably also drive Myc-induced apoptosis and that non-apoptotic functions of p53 may contribute substantially to its tumour suppressor role.

The liver is responsible for key metabolic functions, including control of normal homoeostasis in response to diet and xenobiotic metabolism/detoxification. We have shown previously that inactivation of the hepatic cytochrome P450 system through conditional deletion of POR (P450 oxidoreductase) induces hepatic steatosis, liver growth and P450 expression. We have exploited a new conditional model of POR deletion to investigate the mechanism underlying these changes. We demonstrate that P450 induction, liver growth and hepatic triacylglycerol (triglyceride) homoeostasis are intimately linked and provide evidence that the observed phenotypes result from hepatic accumulation of unsaturated fatty acids, which mediate these phenotypes by activation of the nuclear receptor CAR (constitutive androstane receptor) and, to a lesser degree, PXR (pregnane X receptor). To our knowledge this is the first direct evidence that P450s play a major role in controlling unsaturated fatty acid homoeostasis via CAR. The regulation of P450s involved in xenobiotic metabolism by this mechanism has potentially significant implications for individual responses to drugs and environmental chemicals.

Deregulated Myc expression drives many human cancers, including Burkitt's lymphoma and a highly aggressive subset of diffuse large cell lymphomas. Myc-driven tumors often display resistance to chemotherapeutics because of acquisition of mutations that impair the apoptosis pathway regulated by the Bcl-2 protein family. Given the need to identify new therapies for such lymphomas, we have evaluated the efficacy of ABT-737, a small molecule that mimics the action of the BH3-only proteins, natural antagonists of the prosurvival Bcl-2 proteins. ABT-737 selectively targets certain prosurvival proteins (Bcl-2, Bcl-x(L), and Bcl-w) but not others (Mcl-1 and A1). We treated mice transplanted with lymphomas derived either from Emu-myc transgenic mice or Emu-myc mice that also expressed an Emu-bcl-2 transgene. As a single agent, ABT-737 significantly prolonged the survival of mice transplanted with the myc/bcl-2 lymphomas but was ineffective for the myc lymphomas, probably because of the relatively higher Mcl-1 levels found in the latter. Strikingly, when combined with low-dose cyclophosphamide, ABT-737 produced sustained disease-free survival of all animals transplanted with two of three myc/bcl-2 lymphomas tested. The combination therapy was also more effective against some myc lymphomas than treatment with either agent alone. Our data suggest that antagonism of Bcl-2 with small organic compounds is an attractive approach to enhance the efficacy of conventional therapy for the treatment of Myc-driven lymphomas that over-express this prosurvival molecule.

B-RAF is frequently mutated in solid tumors, resulting in activation of the MEK/ERK signaling pathway and ultimately tumor cell growth and survival. MEK inhibition in these cells results in cell cycle arrest and cytostasis. Here, we have shown that MEK inhibition also triggers limited apoptosis of human tumor cell lines with B-RAF mutations and that this effect was dependent on upregulation and dephosphorylation of the proapoptotic, Bcl-2 homology 3-only (BH3-only) Bcl-2 family member Bim. However, upregulation of Bim was insufficient for extensive apoptosis and was countered by overexpression of Bcl-2. To overcome apoptotic resistance, we treated the B-RAF mutant cells both with MEK inhibitors and with the BH3 mimetic ABT-737, resulting in profound synergism and extensive tumor cell death. This treatment was successful because of both efficient antagonism of the prosurvival Bcl-2 family member Mcl-1 by Bim and inhibition of Bcl-2 and Bcl-x(L) by ABT-737. Critically, addition of ABT-737 converted the predominantly cytostatic effect of MEK inhibition to a cytotoxic effect, causing long-term tumor regression in mice xenografted with human tumor cell lines. Thus, the therapeutic efficacy of MEK inhibition requires concurrent unleashing of apoptosis by a BH3 mimetic and represents a potent combination treatment for tumors harboring B-RAF mutations.

Although the construct of psychopathy is related to community violence and recidivism in various populations, empirical evidence suggests that its association with institutional aggression is weak at best. The current study examined, via both variable-level and group-level analyses, the relationship between standard violence risk instruments, which included a measure of psychopathy, and institutional violence. Additionally, the incremental validity of dynamic risk factors also was examined. The results suggest that PCL-R was only weakly related to institutional aggression and only then when the behavioral (Factor 2) aspects of the construct were examined. The clinical and risk management scales on the HCR-20, impulsivity, anger, and psychiatric symptoms all were useful in identifying patients at risk for exhibiting institutional aggression. These data suggest that factors other than psychopathy, including dynamic risk factors, may be most useful in identifying forensic patients at higher risk for exhibiting aggression.

Changes in emotional and social behaviour are relatively common following traumatic brain injury (TBI). Impairments in recognising the emotional state of others may underlie some of the problems in social relationships that these patients experience. The few previous studies examining emotion recognition in TBI typically assessed patients once, long after the onset of brain injury, making it difficult to distinguish the direct effect of brain injury from the effects of environmental changes. This study examined 30 patients with TBI shortly after brain injury and 32 orthopaedic control patients on their recognition of emotions expressed in the face and the voice using discrimination and labelling tasks. These patients were followed up 1 year later to examine the longitudinal development of emotion recognition deficits. TBI patients were found to be impaired on emotion recognition compared to the control patients both early after injury and 1 year later. The fact that impairments in emotion recognition were evident early after TBI and no evidence of recovery over time was found, suggests a direct effect of brain injury.

The problem with the practical application of decision-making regarding release of mentally ill defenders lies in the inherently ambiguous definitions of mental illness and dangerousness, both of which are necessary for the continued commitment of insanity acquittees. In this study, we examined how clinicians make release decisions in a forensic facility, with particular attention paid to how such decision-making may have changed over time. Records were reviewed to determine documented criteria indicating readiness for release. The results indicated that compliance and treatment response were the primary reasons that the patients were judged ready for release. In addition, increasing attention to the use of substances as a risk factor was evident in the records, with substantially more documentation found in the most recent decade. Our data suggest that clinicians view three concerns to be of primary import when making release decisions: responsiveness to and compliance with the treatment, substance use, and risk of violence.

The pro-apoptotic BH3-only members of the Bcl2 family, crucial initiators of cell death, are activated by a diverse array of developmental cues or experimentally applied stress stimuli. We have investigated, through gene targeting in mice, the biological roles for the BH3-only family member HRK (also known as DP5) in apoptosis regulation. Hrk gene expression was found to be restricted to cells and tissues of the central and peripheral nervous systems. Sensory neurons from mice lacking Hrk were less sensitive to apoptosis induced by nerve growth factor (NGF) withdrawal, consistent with the induction of Hrk following NGF deprivation. By contrast, cerebellar granule neurons that upregulate Hrk upon transfer to low-K+ medium underwent apoptosis normally under these conditions in the absence of Hrk. Furthermore, loss of Hrk was not sufficient to rescue the neuronal degeneration in lurcher mutant mice. Despite previous reports, no evidence was found for Hrk expression or induction in growth-factor-dependent haematopoietic cell lines following withdrawal of their requisite cytokine, and haematopoietic progenitors lacking HRK died normally in response to cytokine deprivation. These results demonstrate that HRK contributes to apoptosis signalling elicited by trophic factor withdrawal in certain neuronal populations but is dispensable for apoptosis of haematopoietic cells.

Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that affect tumor growth and survival, including inhibition of cell cycle progression, induction of tumor cell-selective apoptosis, suppression of angiogenesis, and modulation of immune responses, and show promising activity against hematological malignancies in clinical trials. Using the Emu-myc model of B cell lymphoma, we screened tumors with defined genetic alterations in apoptotic pathways for therapeutic responsiveness to the HDACi vorinostat. We demonstrated a direct correlation between induction of tumor cell apoptosis in vivo and therapeutic efficacy. Vorinostat did not require p53 activity or a functional death receptor pathway to kill Emu-myc lymphomas and mediate a therapeutic response but depended on activation of the intrinsic apoptotic pathway with the proapoptotic BH3-only proteins Bid and Bim playing an important role. Our studies provide important information regarding the mechanisms of action of HDACi that have broad implications regarding stratification of patients receiving HDACi therapy alone or in combination with other anticancer agents.

Objective: This study examined factors motivating inpatient aggression in a sample of chronically assaultive state hospital patients., Methods: Inpatients who had committed three or more assaults over a one-year period were identified by using an incident report database. Aggressive episodes were categorized as impulsive, organized, or psychotic by using a procedure for classifying assaultive acts based on record review. Each assault type was further subcategorized. The relationship between assault type, victim (staff or patient), and legal status of the assaulter was also assessed., Results: A total of 839 assaults committed by 88 chronically aggressive patients were reviewed. Although most patients had a primary psychotic disorder, the most common type of assault was impulsive (54%), rather than psychotic or organized. Staff were most often victimized by impulsive assaults in situations involving attempts to change a patient's unwanted behavior and refusal of a patient request. Organized and psychotic assaults occurred less frequently (29% and 17%, respectively) and were more likely to target other patients. Organized assaults were most often motivated by a desire to seek revenge. Psychotic assaults were most often committed by an assailant acting under the influence of paranoid ideations. Civilly committed patients were overrepresented in the sample. Criminally committed patients committed more acts of organized aggression, although this finding did not reach significance., Conclusions: These findings indicate that assaultive behavior among state hospital inpatients is complex and heterogeneous. Because each type of assault requires a different management approach, characterizing aggressive behavior may be important in determining which institutional programs and treatment-plan interventions to implement when addressing inpatient aggression.

Chromobox 7 (CBX7) is a chromobox family protein and a component of the Polycomb repressive complex 1 (PRC1) that extends the lifespan of cultured epithelial cells and can act independently of BMI-1 to repress the INK4a/ARF tumor suppressor locus. To determine whether CBX7 might be oncogenic, we examined its expression pattern in a range of normal human tissues and tumor samples. CBX7 was expressed at high levels in germinal center lymphocytes and germinal center-derived follicular lymphomas, where elevated expression correlated with high c-Myc expression and a more advanced tumor grade. By targeting Cbx7 expression to the lymphoid compartment in mice, we showed that Cbx7 can initiate T cell lymphomagenesis and cooperate with c-Myc to produce highly aggressive B cell lymphomas. Furthermore, Cbx7 repressed transcription from the Ink4a/Arf locus and acted epistatically to the Arf-p53 pathway during tumorigenesis. These data identify CBX7 as a chromobox protein causally linked to cancer development and may help explain the low frequency of INK4a/ARF mutations observed in human follicular lymphoma.

Despite a growing body of research investigating the origins and effects of food aversions, few research instruments have been developed to measure aversions to specific types or categories of food. Undergraduates (N = 209) responded to a series of food aversion questionnaires. The results suggest that people tend to be averse to 2 types of foods (vegetables and meats or fats) and to the texture and taste of certain foods (e.g., oysters). Aversions were slightly more prevalent among women than among men and were correlated with lower educational levels. The authors provide a means of advancing future research on this problem by reliably identifying 3 categories of food aversions. Future researchers should evaluate additional food categories and expand the focus on food aversions beyond the current concern with learned avoidance of specific food items.

Competence to stand trial is a legal construct used to identify those criminal defendants who have the requisite mental capacity to understand the nature and objective of the proceedings against them and to participate rationally in preparing their defense. This Practice Guideline has described how psychiatrists should evaluate individuals concerning their competence to stand trial. The Guideline describes acceptable forensic psychiatric practice for such evaluations. Where possible, it specifies standards of practice and principles of ethics and also emphasizes the importance of analyzing an individual defendant's case in the context of statutes and case law applicable in the jurisdiction where the evaluation takes place. The recommendations in the Guideline both reflect and are limited by evolving case law, statutory requirements, legal publications, and the current state of psychiatric knowledge. The authors have taken note of nationally applicable case law, federal constitutional standards, statutory language, and federal and state interpretations of the rights or statutes, recognizing that jurisdictions may differ in their specific interpretation or application of statutes or general constitutional standards. The review of cases concerning specific psychiatric diagnoses illustrates general U.S. trends, and psychiatrists must remain cognizant of their jurisdictions' interpretations of statutes or constitutional requirements. By surveying a variety of practices and approaches to data gathering and case analysis, the authors believe that this Guideline will stimulate additional collegial discussion about what is necessary and sufficient for adequate evaluations of adjudicative competence. The notion that psychiatrists should apply expertise to competence assessments stems from the principal that, before allowing a defendant to face criminal prosecution and possible punishment, courts need reasonable assurance--based, if necessary, on a careful, individualized evaluation--that the defendant has adequate mental capacity to make a defense. At a minimum, a psychiatrist's opinion about adjudicative competence should reflect an understanding of the jurisdictional standard and of how the defendant's mental condition affects competence as defined with the jurisdiction. The psychiatrist's report should clearly describe the opinion and the reasoning that leads to it. Psychiatrists who provide mental health expertise concerning adjudicative competence give trial courts information needed to assure that defendants can appropriately protect themselves and that criminal proceedings will be accurate, dignified,and just.

Although currently there is a large body of research on the characteristics and treatment of sex offenders, very little research has been conducted to investigate the characteristics of sex offenders who have been adjudicated insane. This study included 42 patients at Napa State Hospital who were adjudicated not guilty by reason of insanity (NGRI) for a sex offense. The sample was further divided into offenders whose victims were children and those whose victims were adults. Data were collected with a structured chart review instrument. A large percentage of the sex offenders received a primary diagnosis of schizophrenia or schizoaffective disorder, and many had a comorbid substance use disorder. The high percentage of sex offenders in the current study with diagnosed schizophrenia or schizoaffective disorder may represent a previously unstudied subgroup of sex offenders. An alternative explanation is that the experts did not evaluate substance use and intoxication adequately, assess for malingering, or apply the proper legal standard for insanity.