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The clinical prognostic value of the Spinal Instability Neoplastic Score (SINS), in the context of vertebrectomy for neoplasia, has not yet been established. This retrospective study of 134 patients aims to evaluate the efficacy of the SINS to predict outcomes and survival after vertebrectomy for malignancy. The patients were classified into 2 groups: indeterminate stability (SINS 7–12) and unstable (SINS 13–18). Outcomes assessed included survival days after procedure, neurological function (modified Frankel grade), operative time, blood loss, complications, construct failure, and length of inpatient stay. The indeterminate group included 68 patients, whereas the unstable group included 66 patients. No patients were classified as stable (SINS 0–6). The median survival was 225 days (interquartile range, 81–522 days). There was a statistically significant difference (P < 0.001) in survival days after vertebrectomy between the indeterminate group (435 days) and the unstable group (126 days). The majority of patients (119) had a favourable Frankel grade after procedure with no significant difference between SINS groups (P = 0.534). There were no differences in the operative time (234 vs. 210; P = 0.130), inpatient hospital length of stay (10 days vs. 11 days; P = 0.152), complications, or need for intensive care admission (intensive care unit) between the 2 cohorts. There was a statistically significant difference (P = 0.006) for intraoperative blood loss between the indeterminate group (1400 mL) and the unstable group (850 mL). This study demonstrates a statistically significant increased survival in the indeterminate cohort. These results demonstrate the potential ability of the SINS to act as a clinical prognostic tool with regard to survival time. [ABSTRACT FROM AUTHOR]

Objective: To present our data evaluating the feasibility of simultaneous cochlear implantation with resection of acoustic neuroma. Methods: This paper describes a case series of eight adult patients with a radiologically suspected acoustic neuroma, treated at a tertiary referral centre in Newcastle, Australia, between 2012 and 2015. Patients underwent cochlear implantation concurrently with removal of an acoustic neuroma. The approach was translabyrinthine, with facial nerve monitoring and electrically evoked auditory brainstem response testing. Standard post-implant rehabilitation was employed, with three and six months' follow-up data collected. The main outcome measures were: hearing, subjective benefit of implant, operative complications and tumour recurrence. Results: Eight patients underwent simultaneous cochlear implantation with resection of acoustic neuroma over a 3-year period, and had 25–63 months' follow up. There were no major complications. All patients except one gained usable hearing and were daily implant users. Conclusion: Simultaneous cochlear implantation with resection of acoustic neuroma has been shown to be a safe treatment option, which will be applicable in a wide range of clinical scenarios as the indications for cochlear implantation continue to expand. [ABSTRACT FROM AUTHOR]

In this study, we describe a cluster of tyraminergic/octopaminergic neurons in the lateral dorsal deutocerebrum of desert locusts (Schistocerca gregaria) with descending axons to the abdominal ganglia. In the locust, these neurons synthesize octopamine from tyramine stress‐dependently. Electrophysiological recordings in locusts reveal that they respond to mechanosensory touch stimuli delivered to various parts of the body including the antennae. A similar cluster of tyraminergic/octopaminergic neurons was also identified in the American cockroach (Periplaneta americana) and the pink winged stick insect (Sipyloidea sipylus). It is suggested that these neurons release octopamine in the ventral nerve cord ganglia and, most likely, convey information on arousal and/or stressful stimuli to neuronal circuits thus contributing to the many actions of octopamine in the central nervous system. Schematic drawing of a locust brain and ventral nerve cord ganglia shows the descending octopaminergic/tyraminergic deutocerebral projection neurons (OA3/TA‐cluster) and other known types of octopaminergic/tyraminergic dorsal unpaired median neurons (DUM) of the ventral nerve cord ganglia: ascending, desceding, and efferent DUM‐neurons and paired intersegmental PV‐cells. [ABSTRACT FROM AUTHOR]

Introduction and Purpose: Little information exists on surgical characteristics, complications and outcomes with corrective surgery for rigid cervical kyphosis (CK). To collate the experience of international experts, the CSRS-Europe initiated an international multi-centre retrospective study.Methods: Included were patients at all ages with rigid CK. Surgical and patient specific characteristics, complications and outcomes were studied. Radiographic assessment included global and regional sagittal parameters. Cervical sagittal balance was stratified according to the CSRS-Europe classification of sagittal cervical balance (types A-D).Results: Eighty-eight patients with average age of 58 years were included. CK etiology was ankylosing spondlitis (n = 34), iatrogenic (n = 25), degenerative (n = 9), syndromatic (n = 6), neuromuscular (n = 4), traumatic (n = 5), and RA (n = 5). Blood loss averaged 957 ml and the osteotomy grade 4.CK-correction and blood loss increased with osteotomy grade (r = 0.4/0.6, p < .01). Patients with different preop sagittal balance types had different approaches, preop deformity parameters and postop alignment changes (e.g. C7-slope, C2-7 SVA, translation). Correction of the regional kyphosis angle (RKA) was average 34° (p < .01). CK-correction was increased in patients with osteoporosis and osteoporotic vertebrae (POV, p = .006). 22% of patients experienced a major long-term complication and 14% needed revision surgery. Patients with complications had larger preop RKA (p = .01), RKA-change (p = .005), and postop increase in distal junctional kyphosis angle (p = .02). The POV-Group more often experienced postop complications (p < .0001) and revision surgery (p = .02). Patients with revision surgery had a larger RKA-change (p = .003) and postop translation (p = .04). 21% of patients had a postop segmental motor deficit and the risk was elevated in the POV-Group (p = .001).Conclusions: Preop patient specific, radiographic and surgical variables had a significant bearing on alignment changes, outcomes and complication occurrence in the treatment of rigid CK. [ABSTRACT FROM AUTHOR]

The etiology of depression is unknown but has been associated with dysregulation of neuronal activity at numerous loci on the limbic-cortical circuitry. The Flinders Sensitive Line (FSL) is a validated rodent model of human depression with spontaneously emerging behavioral and physiological phenotype, however, the durability and robustness of the phenotypes have not been described. The objective of the current study was to evaluate longitudinal dynamics of the depressive-like symptoms in this animal model. FSL and control rats of both genders were assessed over 8 months, characterizing their performance at different time points on motor, sensorimotor and complex learning/memory based tasks. Changes over time in physiological parameters, such as corticosterone and blood glucose levels, were monitored. Regional glucose metabolism, used as a marker of neuronal activity, was assessed at different time points using F18-FDG Positron Emission Tomography (PET). Results show that certain deficits at 2–3 months – on tests such as the Elevated Plus Maze, Object Recognition, and the Forced Swim Test – were transitory and the phenotype was no longer present when re-testing at 6–7 months of age. However, a stable impairment was detected on a learning and memory task, particularly indicating dysfunction in retention of spatial information. Furthermore, at multiple time points, the PET scan indicated a significate bilateral, hypo-metabolism in the temporal lobes in the FSL rats compared to healthy controls. The data suggests possible alterations of entorhinal cortex metabolism concomitant with specific behavioral changes and supports the importance of understanding the dynamics and the time and gender dependence of the phenotypes present. [ABSTRACT FROM AUTHOR]

Emerging resistively switching devices are thought to enable ultradense passive nanocrossbar arrays for use as random access memories (ReRAM) by the end of the decade, both for embedded and mass storage applications. Moreover, ReRAMs offer inherent logic-in-memory (LIM) capabilities due to the nonvolatility of the devices and therefore great potential to reduce the communication between memory and calculation unit by alleviating the so-called von Neumann bottleneck. A single bipolar resistive switching device is capable of performing 14 of 16 two input logic functions in the logic concept presented by Linn et al. ('CRS-logic'). In this paper, five types of selectorless devices are considered to validate this CRS-logic concept is experimentally by means of the IMP and AND logic operations. As reference device a TaO x -based ReRAM cell is considered, which is compared to three more advanced device configurations consisting either of a threshold supported resistive switch (TS-ReRAM), a complementary switching device (CS), or a complementary resistive switch (CRS). It is shown that all of these devices offer the desired LIM behavior. Moreover, the feasibility of XOR and XNOR operations using a modified logic concept is applied for both CS and CRS devices and the pros and cons are discussed. [ABSTRACT FROM AUTHOR]

Members of the PRDM protein family have been shown to play important roles during embryonic development. Previous in vitro and in situ analyses indicated a function of Prdm6 in cells of the vascular system. To reveal physiological functions of Prdm6, we generated conditional Prdm6-deficient mice. Complete deletion of Prdm6 results in embryonic lethality due to cardiovascular defects associated with aberrations in vascular patterning. However, smooth muscle cells could be regularly differentiated from Prdm6-deficient embryonic stem cells and vascular smooth muscle cells were present and proliferated normally in Prdm6-deficient embryos. Conditional deletion of Prdm6 in the smooth muscle cell lineage using a SM22-Cre driver line resulted in perinatal lethality due to hemorrhage in the lungs. We thus identified Prdm6 as a factor that is essential for the physiological control of cardiovascular development. [ABSTRACT FROM AUTHOR]

CD40, a member of the TNF receptor family, is expressed on all mature B cells and on most B-cell lymphomas. Recently, we have shown that constitutive activation of CD40 signaling in B cells induced by a fusion protein consisting of the transmembrane part of the Epstein-Barr viral latent membrane protein 1 (LMP1) and the cytoplasmic part of CD40 (LMP1/CD40) drives B-cell lymphoma development in transgenic mice. Because LMP1/ CD40-expressing B cells showed an upregulation of CD19, we investigated CD19's function in CD40-driven B-cell expansion and lymphomagenesis. Here, we demonstrate that ablation of CD19 in LMP1/CD40 transgenic mice resulted in a severe loss and reduced lifespan of mature B cells and completely abrogated development of B-cell lymphoma. CD19 is localized to lipid rafts and constitutively activated by the LMP1/CD40 fusion protein in B cells. We provide evidence that the improved survival and malignant transformation of LMP1/CD40-expressing B cells are dependent on activation of the MAPK Erk that is mediated through CD19 in a PI3K-dependent manner. Our data suggest that constitutively active CD40 is dependent on CD19 to transmit survival and proliferation signals. Moreover, we detected a similarly functioning prosurvival pathway involving phosphorylated CD19 and PI3Kdependent Erk phosphorylation in human diffuse large B-cell lymphoma cell lines. Our data provide evidence that CD19 plays an important role in transmitting survival and proliferation signals downstream of CD40 and therefore might be an interesting therapeutic target for the treatment of lymphoma undergoing chronic CD40 signaling. [ABSTRACT FROM AUTHOR]

Triggering of antigen receptors on lymphocytes is critical for initiating adaptive immune response against pathogens. T-cell receptor (TCR) engagement induces the formation of the Carma1–Bcl10–Malt1 (CBM) complex that is essential for activation of the IκB kinase (IKK)/NF-κB pathway. However, the molecular mechanisms that link CBM complex formation to IKK activation remain unclear. Here we report that Malt1 is polyubiquitinated upon T-cell activation. Ubiquitin chains on Malt1 provide a docking surface for the recruitment of the IKK regulatory subunit NEMO/IKKγ. TRAF6 associates with Malt1 in response to T-cell activation and can function as an E3 ligase for Malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of Malt1. Multiple lysine residues in the C-terminus of Malt1 serve as acceptor sites for the assembly of polyubiquitin chains. Malt1 mutants that lack C-terminal ubiquitin acceptor lysines are impaired in rescuing NF-κB signaling and IL-2 production in Malt1−/− T cells. Thus, our data demonstrate that induced Malt1 ubiquitination is critical for the engagement of CBM and IKK complexes, thereby directing TCR signals to the canonical NF-κB pathway. [ABSTRACT FROM AUTHOR]

Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-κB signaling and proliferation. It is unknown how caspase-8 is activated following T cell stimulation, and what is the caspase-8 substrate(s) that is necessary to initiate T cell cycling. We observe that following TCR ligation, a small portion of total cellular caspase-8 and c-FLIPL rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIPL at a known caspase-8 cleavage site. The active caspasec-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-κB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-κB regulators PKCθ, CARMA1, Bcl-10, and MALT1, which connect to the ICR. The lack of caspase-8 results in the absence of MALT1 and Bcl-10 in the active caspase complex. Consistent with this observation, inhibition of caspase activity attenuates NF-κB activation. The current findings define a link among TCR, caspases, and the NF-κB pathway that occurs in a sequestered lipid raft environment in T cells. [ABSTRACT FROM AUTHOR]

Summary: T cell receptor (TCR) signaling to IκB kinase (IKK)/NF-κB is controlled by PKCθ-dependent activation of the Carma1, Bcl10, and Malt1 (CBM) complex. Antigen-induced phosphorylation of Bcl10 has been reported, but its physiological function is unknown. Here we show that the putative downstream kinase IKKβ is required for initial CBM complex formation. Further, upon engagement of IKKβ/Malt1/Bcl10 with Carma1, IKKβ phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKγ ubiquitination. Mutation of the IKKβ phosphorylation sites on Bcl10 enhances expression of NF-κB target genes IL-2 and TNFα after activation of primary T cells. Thus, our data provide evidence that IKKβ serves a dual role upstream of its classical substrates, the IκB proteins. While being essential for triggering initial CBM complex formation, IKKβ-dependent phosphorylation of Bcl10 exhibits a negative regulatory role in T cell activation. [Copyright &y& Elsevier]

The foundation has determined that the adjusted gross billing methodology is a viable method to be considered for a nonprofit medical foundation in compensating physicians. The foundation continues to experiment with the margin formula and is exploring other potential formulas, but believes with certain modifications the percentage of adjusted gross billing methodology can be effective and useful because of its simplicity, ease of administration, and motivational effect on the physicians. The primary improvement to the model needed would be the ability to adjust the formula on a frequent basis for individual practice variations. Modifications will continue to be made as circumstances change, but the basic principles will remain constant.