The rockefeller university

Objective. Rates of total knee arthroplasty (TKA) and total hip arthroplasty (THA) remain high for patients with rheumatoid arthritis (RA), who are at risk of flaring after surgery. We aimed to describe rates, characteristics, and risk factors of RA flare within 6 weeks of THA and TKA. Methods. Patients with RA were recruited prior to elective THA and TKA surgery and prospectively followed. Clinicians evaluated RA clinical characteristics 0-2 weeks before and 6 weeks after surgery. Patients answered questions regarding disease activity including self-reported joint counts and flare status weekly for 6 weeks. Per standard of care, biologics were stopped before surgery, while glucocorticoids and methotrexate (MTX) were typically continued. Multivariable logistic regression was used to identify baseline characteristics associated with postsurgical RA flares. Results. Of 120 patients, the mean age was 62 years and the median RA duration 14.8 years. Ninety-eight (82%) met 2010/1987 American College of Rheumatology/European League Against Rheumatism criteria, 53 (44%) underwent THA (and the rest TKA), and 61 (51%) were taking biologics. By 6 weeks, 75 (63%) had flared. At baseline, flarers had significantly higher disease activity (as measured by the 28-joint Disease Activity Score), erythrocyte sedimentation rate, C-reactive protein, and pain. Numerically more flarers used biologics, but stopping biologics did not predict flares, and continuing MTX was not protective. A higher baseline disease activity predicted flaring by 6 weeks (OR 2.12, p = 0.02). Conclusion. Flares are frequent in patients with RA undergoing arthroplasty. Higher baseline disease activity significantly increases the risk. Although more patients stopping biologics flared, this did not independently predict flaring. The effect of early postsurgery flares requires further study.

Human immunodeficiency virus (HIV) infection is currently incurable, due to the persistence of latently infected cells. The 'shock and kill' approach to a cure proposes to eliminate this reservoir via transcriptional activation of latent proviruses, enabling direct or indirect killing of infected cells. Currently available latency-reversing agents (LRAs) have however proven ineffective. To understand why, we used a novel HIV reporter strain in primary CD4 T cells and determined which latently infected cells are reactivatable by current candidate LRAs. Remarkably, none of these agents reactivated more than 5% of cells carrying a latent provirus. Sequencing analysis of reactivatable vs. non-reactivatable populations revealed that the integration sites were distinguishable in terms of chromatin functional states. Our findings challenge the feasibility of 'shock and kill', and suggest the need to explore other strategies to control the latent HIV reservoir.

Testosterone (T) can act directly through neural androgen receptors (AR) to facilitate male sexual behavior; however, T's metabolites also can play complicated and interesting roles in the control of mating. One metabolite, dihydrotestosterone (DHT) binds to AR with significantly greater affinity than that of T. Is that important behaviorally? Another metabolite, estradiol (E), offers a potential alternative route of facilitating male mating behavior by acting through estradiol receptors (ER). In this review we explore the roles and relative importance of T as well as E and DHT at various levels of the neuroaxis for the activation of male sex behavior in common laboratory animals and, when relevant research findings are available, in man. (C) 2017 Elsevier B.V. All rights reserved.

Behavioral flexibility and impulse control are necessary for successful execution of adaptive behavior. They are impaired in patients with damage to the prefrontal cortex (PFC) and in some clinically important conditions, such as obsessive-compulsive disorder. Although the medial prefrontal cortex (mPFC) has been investigated as a critical structure for behavioral flexibility and impulse control, the contribution of the underlying pyramidal neuron cell types in the mPFC remained to be understood. Here we show that interneuron-mediated local inactivation of pyramidal neurons in the mPFC of male and female mice induces both premature responses and choice bias, and establish that these impulsive and compulsive responses are modulated independently. Cell-type-specific photoinhibition of pyramidal deep layer corticostriatal or corticothalamic neurons reduces behavioral flexibility without inducing premature responses. Together, our data confirm the role of corticostriatal neurons in behavioral flexibility and demonstrate that flexible behaviors are also modulated by direct projections from deep layer corticothalamic neurons in the mPFC to midline thalamic nuclei.

Background Psoriasiform and eczematous eruptions are the most common dermatological adverse reactions linked to anti-tumour necrosis factor (TNF)-alpha therapy. Yet, a detailed characterization of their immune phenotype is lacking. Objectives To characterize anti-TNF-alpha-induced inflammatory skin lesions at a histopathological, cellular and molecular level, compared with psoriasis, eczema (atopic dermatitis) and healthy control skin. Methods Histopathological evaluation, gene expression (quantitative real-time polymerase chain reaction) and computer-assisted immunohistological studies (TissueFAXS) were performed on 19 skin biopsies from patients with inflammatory bowel disease (n = 17) and rheumatoid arthritis (n = 2) with new-onset inflammatory skin lesions during anti-TNF-alpha-therapy. Results Although most biopsies showed a psoriasiform and/or spongiotic (eczematous) histopathological architecture, these lesions were inconsistent with either psoriasis or eczema on a molecular level using an established chemokine (C-C motif) ligand 27/inducible nitric oxide synthase classifier. Despite some differences in immune skewing depending on the specific histopathological reaction pattern, all anti-TNF-alpha-induced lesions showed strong interferon (IFN)-gamma activation, at higher levels than in psoriasis or eczema. IFN-gamma was most likely produced by CD3/CD4/Tbet-positive T helper 1 lymphocytes. Conclusions New-onset anti-TNF-alpha-induced eruptions previously classified as psoriasis or spongiotic dermatitis (eczema) exhibit a molecular profile that is different from either of these disorders.

Peripheral nerve lesions provoke apoptosis in the dorsal horn of the spinal cord. The cause of cell death, the involvement of neurons, and the relevance for the processing of somatosensory information are controversial. Here, we demonstrate in a mouse model of sciatic nerve injury that glutamate-induced neurodegeneration and loss of gamma-aminobutyric acid (GABA)ergic interneurons in the superficial dorsal horn promote the transition from acute to chronic neuropathic pain. Conditional deletion of Grin1, the essential subunit of N-methyl-D-aspartate-type glutamate receptors (NMDARs), protects dorsal horn neurons from excitotoxicity and preserves GABAergic inhibition. Mice deficient in functional NMDARs exhibit normal nociceptive responses and acute pain after nerve injury, but this initial increase in pain sensitivity is reversible. Eliminating NMDARs fully prevents persistent pain-like behavior. Reduced pain in mice lacking proapoptotic Bax confirmed the significance of neurodegeneration. We conclude that NMDAR-mediated neuron death contributes to the development of chronic neuropathic pain.

Simian-human immunodeficiency virus (SHIV) infection provides a relevant animal model to study HIV-1 neutralization breadth. With previously identified SHIVSF162P3N infected rhesus macaques that did or did not develop neutralization breadth, we characterized the transmitted/founder viruses and initial autologous/homologous neutralizing antibodies in these animals. The plasma viral load and blood CD4 count did not distinguish macaques with and without breadth, and only one tested homologous envelope clone revealed a trend for macaques with breadth to favor an early homologous response. In two macaques with breadth, GB40 and FF69, infected with uncloned SHIVSF162P3N, multiple viral variants were transmitted, and the transmitted variants were not equal in neutralization sensitivity. The targets of initial autologous neutralizing antibodies, arising between 10 and 20 weeks post infection, were mapped to N462 glycan and G460a in gp120 V5 in GB40 and FF69, respectively. Although it is unclear whether these targets are related to later neutralization breadth development, the G460a target but not N462 glycan appeared more common in macaques with breadth than those without. Longitudinal plasmas revealed 2-3 sequential waves of neutralizing antibodies in macaques with breadth, implicating that 3 sequential envelope variants, if not more, may be required for the broadening of HIV-1 neutralizing antibodies.

A search for a heavy neutral lepton N of Majorana nature decaying into a W boson and a charged lepton is performed using the CMS detector at the LHC. The targeted signature consists of three prompt charged leptons in any flavor combination of electrons and muons. The data were collected in proton-proton collisions at a center-of-mass energy of 13 TeV, with an integrated luminosity of 35.9 fb(-1). The search is performed in the N mass range between 1 GeV and 1.2 TeV. The data are found to be consistent with the expected standard model background. Upper limits are set on the values of vertical bar V-eN vertical bar(2) and vertical bar V-mu N vertical bar(2), where V-lN is the matrix element describing the mixing of N with the standard model neutrino of flavor l. These are the first direct limits for N masses above 500 GeV and the first limits obtained at a hadron collider for N masses below 40 GeV.