The rockefeller university

Objectives: To evaluate the surgical management of vitreoretinal pathology in patients with a permanent Boston Type 1 keratoprosthesis (hereafter referred to as a KPro) in the era of small-gauge vitrectomy techniques. Methods: Retrospective review of 23 small-gauge vitreoretinal surgical procedures during or after Dohlman-Doane KPro placement in 14 eyes. Results: Established and innovative techniques were used, including sutureless small-gauge vitrectomy, temporal positioning of surgeon, long-term tamponades, and exploratory endoscopy. Retro-KPro membranes formed less frequently when vitrectomy was performed during KPro placement. Anatomical goals were achieved, and no serious complications directly resulted from these techniques. Visual acuity, frequently limited by preexisting pathology, improved in most cases. Conclusions: Modern posterior segment surgical techniques, including small-gauge sutureless vitrectomy, can be effectively used for patients with a permanent KPro. Vitrectomy and glaucoma tube revision by a team of subspecialists at the time of KPro placement may reduce subsequent complications.

T helper 17 (Th17) cells are characterized by the secretion of IL-17, a proinflammatory cytokine. They represent a newly described T helper subpopulation that is distinct from Th1 and Th2 lineages. Because of their pleiotropic activity on fibroblasts, keratinocytes, endothelial cells, neutrophils and memory T cells, Th17 cells are thought to be crucial in mediating tissue inflammation and autoimmunity. Autoimmune diseases were classically considered as Th1-mediated disorders such as rheumatoid arthritis or 'mixed' Th1/Th2 diseases such as inflammatory bowel diseases, systemic lupus erythematosus, bullous diseases, but new evidence suggests the deep involvement of Th17 cells in their pathogenesis that, potentially, may address a selective therapeutic approach targeting the IL23/Th17 pathway. This review summarizes the current knowledge of the pathogenic contribution of Th17 cells in select cutaneous autoimmune disorders, including lupus erythematosus, scleroderma, dermatomyositis, bullous pemphigoid and pemphigus vulgaris.

Increased caloric intake has been associated with increased risk for cancer of the large intestine. We studied caloric intake effect on tumor formation in Apc1638(N/+) mice, a preclinical model for human familial adenomatous polyposis. Mice were fed a controlled AIN-76A diet or a new Western-style diet (NWD). Intestinal tumor development was evaluated after 6 mu of feeding 1) AIN-76A diet (fed ad libitum) vs. AIN-76A (caloric intake reduced 30%); 2) NWD (led ad libitum) vs. NWD (caloric intake reduced 30%); and 3) AIN-76A (fed ad libitum) vs. NWD (paired-fed with NWD providing equal caloric intakes to AIN-76A). Intestinal tumor incidences were 78-100% with intergroup variation P > 0.05; however, tumor multiplicity responded differently to dietary treatment: 1) Tumor multiplicity was unchanged after AIN-76A (caloric intake reduced 30% vs. mice fed AIN-76A ad libitum); 2) tumor multiplicity was unchanged after NWD (caloric intake reduced 30% vs. NWD ad libitum); and 3) tumor multiplicity increased 130% after NWD was paired-fed with the same caloric intake as mice fed AIN-76A ad libitum (P < 0.05). Body weights showed no association with tumor development. Findings indicated modified nutrients in NWD were mainly responsible for increased tumors in mice fed NWD vs. AIN-76A in this preclinical mouse model for human FAP.

Introduction: Smell identification deficits are associated with negative symptoms in schizophrenia, particularly in males. Far less information is known about the relationship of odor detection sensitivity (acuity) and negative symptoms in schizophrenia, and currently there is a dearth in sex-stratified research specifically examining odor sensitivity and smell identification. Methods: Fifty-eight individuals with schizophrenia and 42 healthy comparison subjects were assessed on tests of odor sensitivity, smell identification and cognition. Negative symptoms were assessed with the Positive and Negative Syndrome Scale and the Schedule for the Deficit Syndrome. Results: In healthy males, increased odor detection sensitivity predicted better smell identification scores. In contrast, male schizophrenia patients showed a significant inverse relationship, in which increased odor sensitivity predicted lower smell identification scores. Odor sensitivity and smell identification were unrelated in both schizophrenia and healthy females. Olfactory processing was strongly linked to negative symptoms, but the relationships differed by sex. Emotional expression deficits were related to odor detection hypersensitivity in female patients, whereas smell identification deficits predicted these emotional deficits in male cases. Conclusion: Sex differences in olfactory functioning were identified in healthy subjects and in schizophrenia patients. Smell identification was related to negative symptoms in males with schizophrenia, whereas odor detection sensitivity predicted these features in females. Sex differences should be considered in future analyses that employ odor stimuli for neuropsychiatric research. (C) 2011 Elsevier B.V. All rights reserved.

Combined results are reported from searches for the standard model Higgs boson in proton-proton collisions at root s = 7 TeV in five Higgs boson decay modes: gamma gamma, bb, tau tau, WW, and ZZ. The explored Higgs boson mass range is 110-600 GeV. The analysed data correspond to an integrated luminosity of 4.6-4.8 fb(-1). The expected excluded mass range in the absence of the standard model Higgs boson is 118-543 GeV at 95% CL. The observed results exclude the standard model Higgs boson in the mass range 127-600 GeV at 95% CL, and in the mass range 129-525 GeV at 99% CL. An excess of events above the expected standard model background is observed at the low end of the explored mass range making the observed limits weaker than expected in the absence of a signal. The largest excess, with a local significance of 3.1 sigma, is observed for a Higgs boson mass hypothesis of 124 GeV. The global significance of observing an excess with a local significance >= 3.1 sigma anywhere in the search range 110-600 (110-145) GeV is estimated to be 1.5 sigma (2.1 sigma). More data are required to ascertain the origin of the observed excess. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved.

A pathological increase in the late component of the cardiac Na+ current, I-NaL, has been linked to disease manifestation in inherited and acquired cardiac diseases including the long QT variant 3 (LQT3) syndrome and heart failure. Disruption in I-NaL leads to action potential prolongation, disruption of normal cellular repolarization, development of arrhythmia triggers, and propensity to ventricular arrhythmia. Attempts to treat arrhythmogenic sequelae from inherited and acquired syndromes pharmacologically with common Na+ channel blockers (e.g. flecainide, lidocaine, and amiodarone) have been largely unsuccessful. This is due to drug toxicity and the failure of most current drugs to discriminate between the peak current component, chiefly responsible for single cell excitability and propagation in coupled tissue, and the late component (I-NaL) of the Na+ current. Although small in magnitude as compared to the peak Na+ current (similar to 1-3%), I-NaL alters action potential properties and increases Na+ loading in cardiac cells. With the increasing recognition that multiple cardiac pathological conditions share phenotypic manifestations of I-NaL upregulation, there has been renewed interest in specific pharmacological inhibition of I-Na. The novel antianginal agent ranolazine, which shows a marked selectivity for late versus peak Na+ current, may represent a novel drug archetype for targeted reduction of I-NaL. This article aims to review common pathophysiological mechanisms leading to enhanced I-NaL in LQT3 and heart failure as prototypical disease conditions. Also reviewed are promising therapeutic strategies tailored to alter the molecular mechanisms underlying I-Na mediated arrhythmia triggers. (C) 2011 Elsevier Ltd. All rights reserved.

Incorporation of Ags by dendritic cells (DCs) increases when Ags are targeted to endocytic receptors by mAbs. We have previously demonstrated in the mouse that mAbs against C-type lectins administered intradermally are taken up by epidermal Langerhans cells (LCs), dermal Langerin(neg) DCs, and dermal Langerin(+) DCs in situ. However, the relative contribution of these skin DC subsets to the induction of immune responses after Ag targeting has not been addressed in vivo. We show in this study that murine epidermal LCs and dermal DCs transport intradermally injected mAbs against the lectin receptor DEC-205/CD205 in vivo. Skin DCs targeted in situ with mAbs migrated through lymphatic vessels in steady state and inflammation. In the skin-draining lymph nodes, targeting mAbs were found in resident CD8 alpha(+) DCs and in migrating skin DCs. More than 70% of targeted DCs expressed Langerin, including dermal Langerin(+) DCs and LCs. Numbers of targeted skin DCs in the nodes increased 2-3-fold when skin was topically inflamed by the TLR7 agonist imiquimod. Complete removal of the site where OVA-coupled anti-DEC-205 had been injected decreased endogenous cytotoxic responses against OVA peptide-loaded target cells by 40-50%. Surprisingly, selective ablation of all Langerin(+) skin DCs in Langerin-DTR knock-in mice did not affect such responses independently of the adjuvant chosen. Thus, in cutaneous immunization strategies where Ag is targeted to DCs, Langerin(+) skin DCs play a major role in transport of anti-DEC-205 mAb, although Langerin(neg) dermal DCs and CD8 alpha(+) DCs are sufficient to subsequent CD8(+) T cell responses. The Journal of Immunology, 2012, 188: 2146-2155.

A unifying feature of eukaryotic nuclear organization is genome segregation into transcriptionally active euchromatin and transcriptionally repressed heterochromatin. In metazoa, lamin proteins preserve nuclear integrity and higher order heterochromatin organization at the nuclear periphery, but no non-metazoan lamin orthologues have been identified, despite the likely presence of nucleoskeletal elements in many lineages. This suggests a metazoan-specific origin for lamins, and therefore that distinct protein elements must compose the nucleoskeleton in other lineages. The trypanosomatids are highly divergent organisms and possess well-documented but remarkably distinct mechanisms for control of gene expression, including polycistronic transcription and trans-splicing. NUP-1 is a large protein localizing to the nuclear periphery of Trypanosoma brucei and a candidate nucleoskeletal component. We sought to determine if NUP-1 mediates heterochromatin organization and gene regulation at the nuclear periphery by examining the influence of NUP-1 knockdown on morphology, chromatin positioning, and transcription. We demonstrate that NUP-1 is essential and part of a stable network at the inner face of the trypanosome nuclear envelope, since knockdown cells have abnormally shaped nuclei with compromised structural integrity. NUP-1 knockdown also disrupts organization of nuclear pore complexes and chromosomes. Most significantly, we find that NUP-1 is required to maintain the silenced state of developmentally regulated genes at the nuclear periphery; NUP-1 knockdown results in highly specific mis-regulation of telomere-proximal silenced variant surface glycoprotein (VSG) expression sites and procyclin loci, indicating a disruption to normal chromatin organization essential to life-cycle progression. Further, NUP-1 depletion leads to increased VSG switching and therefore appears to have a role in control of antigenic variation. Thus, analogous to vertebrate lamins, NUP-1 is a major component of the nucleoskeleton with key roles in organization of the nuclear periphery, heterochromatin, and epigenetic control of developmentally regulated loci.

The family of Eph tyrosine kinase receptors is an important part of signaling pathways involved in development, tissue homeostasis and tumorigenesis. Binding and activation of the receptors by their ligands, the ephrins, result in bidirectional signaling into both receptor and ligand expressing cells. Adult stem cell niches and tumors frequently express receptors and ligands, although their function is only beginning to be understood. Thus, Eph receptors and ephrins have become important molecules for understanding basic biological processes as well as tumorigenesis, and are promising targets for potential therapeutic intervention in human disease.

How and why the brain reversibly switches from a waking to a sleep state remain among the most intriguing questions in biology. We show that cyclin A (CycA) and regulator of cyclin A1, essential cell cycle factors, function in postmitotic neurons to promote sleep in Drosophila melanogaster. Reducing the abundance of CycA in neurons delayed the wake-sleep transition, caused multiple arousals from sleep, and reduced the homeostatic response to sleep deprivation. CycA is expressed in similar to 40 to 50 neurons in the adult brain, most of which are intermingled with circadian clock neurons, suggesting functional interactions among neurons controlling sleep and circadian behavior.