Dissociable Contributions of Basolateral Amygdala and Ventrolateral Orbitofrontal Cortex to Flexible Learning Under Uncertainty.

Reversal learning measures the ability to form flexible associations between choice outcomes with stimuli and actions that precede them. This type of learning is thought to rely on several cortical and subcortical areas, including the highly interconnected orbitofrontal cortex (OFC) and basolateral amygdala (BLA), and is often impaired in various neuropsychiatric and substance use disorders. However, the unique contributions of these regions to stimulus- and action-based reversal learning have not been systematically compared using a chemogenetic approach particularly before and after the first reversal that introduces new uncertainty. Here, we examined the roles of ventrolateral OFC (vlOFC) and BLA during reversal learning. Male and female rats were prepared with inhibitory designer receptors exclusively activated by designer drugs targeting projection neurons in these regions and tested on a series of deterministic and probabilistic reversals during which they learned about stimulus identity or side (left or right) associated with different reward probabilities. Using a counterbalanced within-subject design, we inhibited these regions prior to reversal sessions. We assessed initial and pre-/post-reversal changes in performance to measure learning and adjustments to reversals, respectively. We found that inhibition of the ventrolateral orbitofrontal cortex (vlOFC), but not BLA, eliminated adjustments to stimulus-based reversals. Inhibition of BLA, but not vlOFC, selectively impaired action-based probabilistic reversal learning, leaving deterministic reversal learning intact. vlOFC exhibited a sex-dependent role in early adjustment to action-based reversals, but not in overall learning. These results reveal dissociable roles for BLA and vlOFC in flexible learning and highlight a more crucial role for BLA in learning meaningful changes in the reward environment.

Design of a Semi-Powered Stance-Control Swing-Assist Transfemoral Prosthesis.

This paper describes the design of a new type of knee prosthesis called a stance-control, swing-assist (SCSA) knee prosthesis. The device is motivated by the recognition that energetically-passive stance-controlled microprocessor-controlled knees (SCMPKs) offer many desirable characteristics, such as quiet operation, low weight, high-impedance stance support, and an inertially-driven swing-phase motion. Due to the latter, however, SCMPKs are also highly susceptible to swing-phase perturbations, which can increase the likelihood of falling. The SCSA prosthesis supplements the behavior of an SCMPK with a small motor that maintains the low output impedance of the SCMPK swing state, while adding a supplemental closed-loop controller around it. This paper elaborates upon the motivation for the SCSA prosthesis, describes the design of a prosthesis prototype, and provides human-subject testing data that demonstrates potential device benefits relative to an SCMPK during both non-perturbed and perturbed walking.

Impact of Regional Lymph Node Dissection on Disease Specific Survival in Adrenal Cortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. The purpose of this study is to evaluate the impact of a more extensive regional lymph node dissection (LND) has on survival in ACC patients in the United States. Patients ≥ 15 years of age without distant metastases who underwent surgical intervention for primary ACC were identified from the SEER18 registry from 1988-2009. Patients were divided into 2 groups: having a regional LND (≥ 5 LNs removed) vs. no-LND (0-4 LNs removed). Overall survival (OS) and disease specific survival (DSS) were compared between groups. Of 259 patients with complete data on nodal resection, 243 (93.8%) underwent no-LND and 16 (6.2%) LND. There was no difference in age, sex, metastases, or ENSAT stage between groups. However, LND patients had larger tumors (p=0.004), and more frequently underwent en-bloc surgery (p=0.002). One- and 3-year OS and DSS did not differ between groups. In a cox regression model, performance of a regional LND did not significantly influence DSS. However, female gender (HR: 1.67, CI: 1.04-2.69, p=0.033) and later stage (stage III-HR: 4.78, CI: 1.14-20.00, p=0.032) or positive LNs (HR: 5.92, CI: 2.05-17.08, p=0.001) were risk factors for worse DSS. Regional LND may not improve DSS or OS in nonmetastatic ACC patients undergoing adrenalectomy. It remains controversial as an essential part of the surgical management for ACC and deserves further investigation in a larger, prospective study. However, regional LND should still be considered for staging and prognostic purposes and to standardize surgical care.

Toward the Development of User-Centered Neurointegrated Lower Limb Prostheses.

The last few years witnessed radical improvements in lower-limb prostheses. Researchers have presented innovative solutions to overcome the limits of the first generation of prostheses, refining specific aspects which could be implemented in future prostheses designs. Each aspect of lower-limb prostheses has been upgraded, but despite these advances, a number of deficiencies remain and the most capable limb prostheses fall far short of the capabilities of the healthy limb. This article describes the current state of prosthesis technology; identifies a number of deficiencies across the spectrum of lower limb prosthetic components with respect to users' needs; and discusses research opportunities in design and control that would substantially improve functionality concerning each deficiency. In doing so, the authors present a roadmap of patients related issues that should be addressed in order to fulfill the vision of a next-generation, neurally-integrated, highly-functional lower limb prosthesis.

Rationale and Design of the TARGET-EFT Trial: Multicomponent Intervention for Frail and Pre-frail Patients Hospitalized with Acute Cardiac Conditions.

BACKGROUND: With the aging population and rising rates of cardiovascular disease (CVD), cardiologists and cardiac surgeons are encountering a growing number of frail older patients that have complex cardiac and non-cardiac issues. Measuring frailty provides valuable prognostic information to help personalize treatment decisions. However, there is minimal evidence on multicomponent frailty interventions in this setting. The TARGET-EFT (The MulTicomponent Acute Intervention in FRail GEriatric PaTients with cardiovascular disease using the Essential Frailty Toolset) trial aims to target physical and non-physical frailty deficits to improve health-related quality of life and hospital-acquired disability in frail patients hospitalized with CVD. METHODS: The TARGET-EFT trial is a single-center parallel-group randomized clinical trial in frail and pre-frail older adults ≥65 years admitted to the cardiovascular unit (CVU) at the Jewish General Hospital, Montreal, Quebec. The trial will compare usual inpatient care to a multicomponent intervention targeting physical weakness, cognitive impairment, malnutrition, and anemia. Outcomes of interest in both groups will be assessed at three time points: (1) study enrollment, (2) discharge from the CVU, and (3) 30 days after hospital discharge. CONCLUSIONS: The overarching goal is to treat patients' frailty in parallel with their CVD, and in doing so, optimize patient functional losses while in-hospital and shortly thereafter. The results of this trial will inform best practices for patient-centered care in this vulnerable patient group.

Effect of a Swing-Assist Knee Prosthesis on Stair Ambulation.

This paper describes stair ambulation control and functionality of a semi-powered knee prosthesis that supplements nominally passive prosthesis behavior with swing-phase assistance. A set of stair ascent and descent controllers are described. The controllers were implemented in a semi-powered prosthesis prototype, and the prospective benefits of swing assist in stair ambulation were assessed on a group of three participants with unilateral, transfemoral amputation, relative to their respective daily-use prostheses. Results indicate that ambulation with the semi-powered knee resulted in improved stair ascent gait symmetry when compared to the participants' passive daily-use devices, and increased similitude to healthy stair ascent movement.

Initiation of mammalian liver development from endoderm by fibroblast growth factors.

The signaling molecules that elicit embryonic induction of the liver from the mammalian gut endoderm or induction of other gut-derived organs are unknown. Close proximity of cardiac mesoderm, which expresses fibroblast growth factors (FGFs) 1, 2, and 8, causes the foregut endoderm to develop into the liver. Treatment of isolated foregut endoderm from mouse embryos with FGF1 or FGF2, but not FGF8, was sufficient to replace cardiac mesoderm as an inducer of the liver gene expression program, the latter being the first step of hepatogenesis. The hepatogenic response was restricted to endoderm tissue, which selectively coexpresses FGF receptors 1 and 4. Further studies with FGFs and their specific inhibitors showed that FGF8 contributes to the morphogenetic outgrowth of the hepatic endoderm. Thus, different FGF signals appear to initiate distinct phases of liver development during mammalian organogenesis.

Requirement of FGF-4 for postimplantation mouse development.

Fibroblast growth factors (FGFs) are thought to influence many processes in vertebrate development because of their diverse sites of expression and wide range of biological activities in in vitro culture systems. As a means of elucidating embryonic functions of FGF-4, gene targeting was used to generate mice harboring a disrupted Fgf4 gene. Embryos homozygous for the null allele underwent uterine implantation and induced uterine decidualization but did not develop substantially thereafter. As was consistent with their behavior in vivo, Fgf4 null embryos cultured in vitro displayed severely impaired proliferation of the inner cell mass, whereas growth and differentiation of the inner cell mass were rescued when null embryos were cultured in the presence of FGF-4 protein.

Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity.

The EPH-related transmembrane tyrosine kinases constitute the largest known family of receptor-like tyrosine kinases, with many members displaying specific patterns of expression in the developing and adult nervous system. A family of cell surface-bound ligands exhibiting distinct, but overlapping, specificities for these EPH-related kinases was identified. These ligands were unable to act as conventional soluble factors. However, they did function when presented in membrane-bound form, suggesting that they require direct cell-to-cell contact to activate their receptors. Membrane attachment may serve to facilitate ligand dimerization or aggregation, because antibody-mediated clustering activated previously inactive soluble forms of these ligands.

Subjective response to antipsychotics in bipolar disorders: A review of a neglected area.

BACKGROUND: The term "subjective response to antipsychotic" (SRA) refers to changes in the subjective state experienced due to antipsychotic (AP) exposition that is independent of the therapeutic or physical side effects of these drugs. This dimension of analysis has been extensively explored in schizophrenic disorders, finding that negative SRA is an early and independent predictor of compliance as well as a successful pathway to construct current theoretical frameworks of these disorders. There is an increasing use of AP in bipolar disorders' treatment (BD) but no reviews on the topic have been published to date in this population. The aim of this work is to review published data of SRA in BD patients and to discuss their clinical and theoretical implications. METHODS: An extensive search in online databases was performed. Reports were reviewed and included if they described SRA in BD or included instruments aimed to assess it. Reports of cognitive, sexual, motor autonomic side effects were excluded. Findings were summarized in a narrative fashion. RESULTS: Nine reports fulfilled the inclusion criteria and were included in the revision, reporting data from 1282 BD patients. Among these, three were prospective studies and three explored relations between SRA and treatment compliance. CONCLUSIONS: There is an asymmetry between the increase in the use of antipsychotics in BD and the lack of data regarding the SRA. Phenomenologically, SRA in BD is similar to that found in schizophrenic subjects. Some of these symptoms may be misdiagnosed as depressive symptoms. The existing data show that SRA has a strong correlation with treatment compliance as well as a promising way to develop theoretical paradigms for these disorders.

The low affinity NGF receptor, p75, can collaborate with each of the Trks to potentiate functional responses to the neurotrophins.

NGF and the other neurotrophins all bind to the low affinity NGF receptor (LNGFR). Although early studies suggested that the LNGFR was absolutely required for the formation of a functional neurotrophin receptor, current evidence indicates that the Trk family of receptor tyrosine kinases, in the absence of the LNGFR, can directly bind to and mediate responses to the neurotrophins. Here we describe a functional approach, in fibroblasts, designed to assay for the ability of the LNGFR to potentiate Trk-mediated responses to the neurotrophins. We report that although collaboration between the LNGFR and the Trks could be detected in this system, a truncated form of the LNGFR displayed a much more dramatic ability to interact functionally with each of the Trks, potentiating masked autocrine loops as well as responses to limiting amounts of exogenously provided neurotrophins.

Evidence that fibroblast growth factor 5 is a major muscle-derived survival factor for cultured spinal motoneurons.

We examined the potential role of fibroblast growth factor 5 (FGF-5) as a target-derived trophic factor for spinal motoneurons. Northern analysis of total RNA from rat skeletal muscle revealed an FGF-5 mRNA transcript both during the period of embryonic motoneuron death and in the adult. Recombinant human FGF-5 supported the survival of highly enriched cultures of embryonic chick motoneurons. Significant proportions of the motoneuron survival activity of rat skeletal muscle extracts could be immunoprecipitated using an antiserum to FGF-5. The immunoprecipitable activity was present in soluble and matrix-bound forms in embryonic muscle, but bound exclusively to the extracellular matrix in adult muscle. These results, along with the secretory nature of FGF-5, suggest that FGF-5 may act as a target-derived trophic factor for motoneurons.

Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Fibroblast growth factor homologous factors are intracellular signaling proteins.

Fibroblast growth factors (FGFs) mediate cell growth, differentiation, migration, and morphogenesis by binding to the extracellular domain of cell surface receptors, triggering receptor tyrosine phosphorylation and signal transduction [1-5]. FGF homologous factors (FHFs) were discovered within vertebrate DNA sequence databases by virtue of their sequence similarity to FGFs [3, 6, 7], but the mechanism of FHF action has not been reported. We show here that FHF-1 is associated with the MAP kinase (MAPK) scaffold protein Islet-Brain-2 (IB2) [8] in the brain and in specific cell lines. FHF/IB2 interaction is highly specific, as FHFs do not bind to the related scaffold protein IB1(JIP-1b) [9, 10], nor can FGF-1 bind to IB2. We further show that FHFs enable IB2 to recruit a specific MAPK in transfected cells, and our data suggest that the scaffolds IB1 and IB2 have different MAPK specificities. Hence, FHFs are intracellular components of a tissue-specific protein kinase signaling module.

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.

Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

Growth factor requirements of oncogene-transformed NIH 3T3 and BALB/c 3T3 cells cultured in defined media.

We report conditions for the efficient growth of NIH 3T3 and BALB/c 3T3 cells cultured in a defined medium supplemented with either platelet-derived growth factor (PDGF) or pituitary-derived fibroblast growth factor (FGF). The oncogenes v-mos, v-src, v-sis, and c-H-ras Val 12 can induce morphological transformation of these cells and can release them from the mitogen requirement for growth, while the oncogene v-fos cannot abrogate the PDGF-FGF requirement. The radically different behavior of normal and transformed NIH 3T3 cells in PDGF-FGF-free defined medium can form the basis of a sensitive new fibroblast transformation assay.

Growth factor-deprived BALB/c 3T3 murine fibroblasts can enter the S phase after induction of c-myc gene expression.

Induction of quiescent BALB/c 3T3 murine fibroblasts by platelet-derived growth factor (PDGF) or fibroblast growth factor (FGFs) is accompanied by induction of c-myc gene expression. To study the role of c-myc in cell growth, we transfected BALB/c 3T3 cells with a plasmid construct containing a glucocorticoid-inducible c-myc gene. When these transfected cells were growth arrested in PDGF-FGF-freedefined medium, glucocorticoid treatment induced S-phase DNA synthesis. This induction of DNA synthesis was inefficient, and cell proliferation was not evident, suggesting that growth factors act through stimulation of c-myc expression together with other intracellular events.

Fibroblast growth factor receptors have different signaling and mitogenic potentials.

Fibroblast growth factor (FGF) receptors (FGFRs) are structurally related receptor protein tyrosine kinases encoded by four distinct genes. Activation of FGFR-1, -2, and -3 by FGFs induces mitogenic responses in various cell types, but the mitogenic potential of FGFR-4 has not been previously explored. We have compared the properties of BaF3 murine lymphoid cells and L6 rat myoblast cells engineered to express FGFR-1 or FGFR-4. Acidic FGF binds with high affinity to and elicits tyrosine phosphorylation of FGFR-1 or FGFR-4 receptors displayed on BaF3 cells, but only FGFR-1 activation leads to cell survival and growth. FGFR-4 activation also fails to elicit detectable signals characteristic of the FGFR-1 response: tyrosine phosphorylation of SHC and extracellular signal-related kinase (ERK) proteins and induction of fos and tis11 RNA expression. The only detected response to FGFR-4 activation was weak phosphorylation of phospholipase C gamma. A chimeric receptor containing the extracellular domain of FGFR-4 and the intracellular domain of FGFR-1 confers FGF-dependent growth upon transfected BaF3 cells, demonstrating that the intracellular domains of the receptors dictate their functional capacity. Activation of FGFR-1 in transfected L6 myoblasts induced far stronger phosphorylation of phospholipase C gamma, SHC, and ERK proteins than could activation of FGFR-4 in L6 cells, and only FGFR-1 activation induced tyrosine phosphorylation of a characteristic 80-kD protein. Hence, the signaling and biological responses elicited by different FGF receptors substantially differ.

The human FGF-5 oncogene encodes a novel protein related to fibroblast growth factors.

We previously described the isolation of a human oncogene which had acquired transforming potential by a DNA rearrangement accompanying transfection of NIH 3T3 cells with human tumor DNA (X. Zhan, A. Culpepper, M. Reddy, J. Loveless, and M. Goldfarb, Oncogene 1:369-376, 1987). We now term this oncogene the FGF-5 gene, since it specifies the fifth documented protein related to fibroblast growth factors (FGFs. Two regions of the FGF-5 sequence, containing 122 of its 267 amino acid residues, were 40 to 50% homologous to the sequences of acidic and basic FGFs as well as to the sequences of the FGF-related oncoproteins int-2 and hst/KS3. The FGF-5 gene bears the three exon structures typical for members of this family. FGF-5 was found to be expressed in the neonatal brain and in 3 of the 13 human tumor cell lines examined. Several experiments strongly suggested that FGF-5 is a growth factor with properties common to those of acidic and basic FGFs. The rearrangement which activated the FGF-5 gene during DNA transfection had juxtaposed a retrovirus transcriptional enhancer just upstream from the native promoter of the gene.

Abelson murine leukemia virus induces platelet-derived growth factor-independent fibroblast growth: correlation with kinase activity and dissociation from full morphologic transformation.

Abelson murine leukemia virus (A-MuLV) encodes a single protein product, a tyrosine-specific protein kinase, whose activity is necessary for cell transformation by this retrovirus. Using a defined medium culture system, we demonstrate that transformation of NIH 3T3 fibroblasts by A-MuLV abrogates their normal requirement for platelet-derived growth factor (PDGF) for cell growth. Analysis of constructed insertional mutant viruses revealed an absolute correlation between A-MuLV-encoded tyrosine kinase activity and PDGF-independent fibroblast growth. Sequences of the provirus not required for kinase activity appeared unnecessary for abrogating the fibroblast requirement for PDGF. Conversely, sequences required for kinase activity appeared necessary, suggesting that induction of PDGF-independent fibroblast growth, like cell transformation, is a function of this tyrosine kinase. Fibroblasts transformed by a partially transformation-defective mutant demonstrated incomplete morphological transformation but were still independent of PDGF for growth. Thus, the processes of full morphological transformation and growth factor independence can be partially dissociated.