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OBJECTIVE: To evaluate the published clinical literature on the role of pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF). DATA SOURCES: A systematic literature search was performed using the key words pirfenidone or Esbriet, alone and in combination, with IPF or idiopathic pulmonary fibrosis (expanded using MESH terminology). MEDLINE (1948-September 2012) was the primary database used for search purposes. In addition, all available articles and abstracts referenced by the articles identified via literature search were included. STUDY SELECTION AND DATA EXTRACTION: The search was limited to English-language publications. All available clinical trials of pirfenidone pertinent to its pharmacology, pharmacokinetics, efficacy, and safety were included. DATA SYNTHESIS: Pirfenidone is the first agent specifically developed for the treatment of IPF. It has been approved for use in Europe and Japan, but not in the US. Although Phase 3 trials have shown pirfenidone to improve certain clinical (6-minute walk test) and functional (change in forced vital capacity) outcomes in patients with IPF, an independent benefit on either mortality or acute exacerbation rates has yet to be demonstrated. Until more definitive supportive data are available, international guidelines have recommended against using pirfenidone to treat most patients with IPF. CONCLUSIONS: Although pirfenidone appears to be an effective treatment for IPF, additional clinical trials are needed to better delineate its risk-benefit profile.

Each fall, eastern North American monarch butterflies (Danaus plexippus) migrate from their northern range to their overwintering grounds in central Mexico [1-3]. Fall migrants are in reproductive diapause, and they use a time-compensated sun compass to navigate during the long journey south [4-6]. Eye-sensed directional cues from the daylight sky (e.g., the horizontal or azimuthal position of the sun) are integrated in the sun compass in the midbrain central complex region [7, 8]. Sun compass output is time compensated by circadian clocks in the antennae so that fall migrants can maintain a fixed flight direction south [9, 10]. In the spring, the same migrants remigrate northward to the southern United States to initiate the northern leg of the migration cycle. Here we show that spring remigrants also use an antenna-dependent time-compensated sun compass to direct their northward flight. Remarkably, fall migrants prematurely exposed to overwintering-like coldness reverse their flight orientation to the north. The temperature microenvironment at the overwintering site is essential for successful completion of the migration cycle, because without cold exposure, aged migrants continue to orient south. Our discovery that coldness triggers the northward flight direction in spring remigrants solves one of the long-standing mysteries of the monarch migration.

In early Caenorhabditis elegans embryos, the Wingless/int (Wnt)- and Src-signaling pathways function in parallel to induce both the division orientation of the endomesoderm (EMS) blastomere and the endoderm fate of the posterior EMS daughter cell, called E. Here, we show that, in addition to its role in endoderm specification, the beta-catenin-related protein Worm armadillo 1 (WRM-1) also plays a role in controlling EMS division orientation. WRM-1 localizes to the cortex of cells in both embryos and larvae and is released from the cortex in a Wnt-responsive manner. We show that WRM-1 cortical release is disrupted in a hypomorphic cyclin-dependent protein kinase 1 (cdk-1) mutant and that WRM-1 lacking potential CDK-1 phosphoacceptor sites is retained at the cortex. In both cases, cortical WRM-1 interferes with EMS spindle rotation without affecting endoderm specification. Finally, we show that removal of WRM-1 from the cortex can restore WT division orientation, even when both Wnt- and Src-signaling pathways are compromised. Our findings are consistent with a model in which Wnt signaling and CDK-1 modify WRM-1 in a temporal and spatial manner to unmask an intrinsic polarity cue required for proper orientation of the EMS cell division axis.

BACKGROUND: Criminal justice problems among those with bipolar disorder lead to disruption in social functioning, treatment, and recovery. Understanding factors that contribute to arrest during episodes of illness can help inform approaches to risk management and improve clinical care.

METHODS: Data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a longitudinal, nationally representative survey conducted in two waves were used to identify factors that predicted inter-wave criminal justice involvement during bipolar I manic episodes.

RESULTS: Over 10% of respondents experienced legal involvement during their most severe manic episode. Risk was found in a range of historical, clinical, and contextual factors. Multivariate analyses suggest risk is particularly high for those who are unemployed, non-white, have past juvenile detention, have a prior arrest (while using substances or when manic), used an illicit drug in the past year, and whose mania is characterized by both social and occupational impairment. Legal problems were particularly elevated among those who lacked health insurance while experiencing both social and occupational impairment.

LIMITATIONS: Respondents did not include prisoners and hospital inpatients; criminal justice problems were only assessed with regard to the most severe manic episode.

CONCLUSIONS: The particular array of factors that elevate the risk of legal involvement during manic episodes offers guidance when identifying prevention strategies and evaluating patients in clinical and forensic settings. Reducing such involvement will require that these issues be dealt with in the broader context of mental health and other services, which in turn necessitates providing adequate access to healthcare.

Abstract Intraperitoneal (IP) injection is frequently reported to be as effective as intravenous (IV) injection. Because it allows administering a larger volume with more radioactivity, we have investigated this route and the possibility of using it to circumvent the volume constraint we earlier experienced with pretargeting radiotherapy. Using 99mTc as the label, the pharmacokinetics (PK) of the cMORF effector (a DNA analogue) was evaluated after IP or IV injection in normal mice by necropsy and SPECT/CT imaging. In another experiment, nude mice bearing tumors were used and they received MORF-CC49 pretargeting antibody IV 2 days earlier than labeled cMORF IV or IP. Tumor accumulations of cMORF were measured at 6 hours after its injections. The absorbed radiation doses for 188Re or 90Y pretargeting were estimated using the 99mTc data and a self-absorbed model. Although the absorbed radiation doses to other organs were comparable, the dose to intestines after IP injection was 30-fold higher than IV injection due to the slow entry into the circulation. It had reached such a level as high as the dose to the kidneys that cleared the radioactivity and usually were at the highest level. Nevertheless, the slow entry did not reduce the tumor accumulation. In conclusion, using IP in place of IV led to an unacceptably high absorbed radiation dose to the intestines although the tumor accumulation was not compromised. This effect may be applicable to other radiotherapeutic agents as well.

Mesenchymal stem cells (MSCs), due to their paracrine, transdifferentiation, and immunosuppressive effects, hold great promise as a therapy for peripheral arterial disease. Diabetes is an important risk factor for peripheral arterial disease; however, little is known of how type II diabetes affects the therapeutic function of MSCs. This review summarizes the current status of preclinical and clinical studies that have been performed to determine the efficacy of MSCs in the treatment of peripheral arterial disease. We also present findings from our laboratory regarding the impact of type II diabetes on the therapeutic efficacy of MSCs neovascularization after the induction of hindlimb ischemia. In our studies, we documented that experimental type II diabetes in db/db mice impaired MSCs' therapeutic function by favoring their differentiation towards adipocytes, while limiting their differentiation towards endothelial cells. Moreover, type II diabetes impaired the capacity of MSCs to promote neovascularization in the ischemic hindlimb. We further showed that these impairments of MSC function and multipotency were secondary to hyperinsulinemia-induced, Nox4-dependent oxidant stress in db/db MSCs. Should human MSCs display similar oxidant stress-induced impairment of function, these findings might permit greater leverage of the potential of MSC transplantation, particularly in the setting of diabetes or other cardiovascular risk factors, as well as provide a therapeutic approach by reversing the oxidant stress of MSCs prior to transplantation.

The mammalian homolog B1 of Unc-93 Caenorhabditis elegans known as UNC93B1 is a chaperone protein that mediates translocation of the nucleic acid-sensing Toll-like receptors (TLRs) from the endoplasmic reticulum to the endolysosomes. The triple deficient (UNC93B1 mutant) mice have a functional single point mutation in the UNC93B1 that results in non-functional TLR3, TLR7, and TLR9. Herein, we demonstrate that UNC93B1 mutant mice, in the C57BL/6 (resistant) genetic background, are highly susceptible to Leishmania major infection. Enhanced swelling of the footpad was associated with high levels of interleukin 10, decreased levels of interferon gamma, and increased parasitism. None of the single TLR3, TLR7, and TLR9 knock-out (KO) mice resemble the UNC93B1 mutant phenotype upon infection with L. major. Whereas the double TLR7/TLR9 KO showed a partial phenotype, the triple TLR3/TLR7/TLR9 KO mice were as susceptible as the UNC93B1 mutant mice, when infected with Leishmania parasites. Finally, we demonstrate that treatment with either anti-interleukin 10 receptor monoclonal antibody or recombinant interleukin 12 restored a robust anti-parasite TH1 response and reverted the susceptible phenotype of UNC93B1 mutant mice. Altogether, our results indicate the redundant and essential role of nucleic acid-sensing TLR3, TLR7 and TLR9 in inducing interleukin 12, development of a TH1 response, and resistance to L. major infection in resistant C57BL/6 mice.

OBJECTIVE: The impact of hot flashes on sleep is of great clinical interest, but results are inconsistent, especially when both hot flashes and sleep are measured objectively. Using objective and subjective measurements, we examined the impact of hot flashes on sleep by inducing hot flashes with a gonadotropin-releasing hormone agonist.

METHODS: The gonadotropin-releasing hormone agonist leuprolide was administered to 20 healthy premenopausal volunteers without hot flashes or sleep disturbances. Induced hot flashes were assessed objectively (skin conductance monitor) and subjectively (daily diary) during 1-month follow-up. Changes from baseline in objective sleep quality (actigraphy) and subjective sleep quality (Pittsburgh Sleep Quality Index) were compared between women who developed and women who did not develop objective hot flashes and, in parallel analyses, subjective hot flashes.

RESULTS: New-onset hot flashes were recorded in 14 (70%) women and reported by 14 (70%) women (80% concordance). Estradiol was universally suppressed. Objective sleep efficiency worsened in women with objective hot flashes and improved in women without objective hot flashes (median decrease, 2.6%; median increase, 4.2%; P = 0.005). Subjective sleep quality worsened more in those with subjective hot flashes than in those without subjective hot flashes (median increase in Pittsburgh Sleep Quality Index, 2.5 vs 1.0; P = 0.03). Objective hot flashes were not associated with subjective sleep quality, nor were subjective symptoms linked to objective sleep measures.

CONCLUSIONS: This experimental model of induced hot flashes demonstrates a causal relationship between hot flashes and poor sleep quality. Objective hot flashes result in worse objective sleep efficiency, whereas subjective hot flashes worsen perceived sleep quality.

The Tec family tyrosine kinase, Itk, regulates signaling downstream of the TCR. The absence of Itk in CD4(+) T cells results in impaired Th2 responses along with defects in maturation, cytokine production, and survival of iNKT cells. Paradoxically, Itk(-/-) mice have spontaneously elevated serum IgE levels, resulting from an expansion of the Vgamma1.1(+)Vdelta6.3(+) subset of gammadelta T cells, known as gammadelta NKT cells. Comparisons between gammadelta NKT cells and alphabeta iNKT cells showed convergence in the pattern of cell surface marker expression, cytokine profiles, and gene expression, suggesting that these two subsets of NKT cells undergo similar differentiation programs. Hepatic gammadelta NKT cells have an invariant TCR and are derived predominantly from fetal progenitors that expand in the thymus during the first weeks of life. The adult thymus contains these invariant gammadelta NKT cells plus a heterogeneous population of Vgamma1.1(+)Vdelta6.3(+) T cells with diverse CDR3 sequences. This latter population, normally excluded from the liver, escapes the thymus and homes to the liver when Itk is absent. In addition, Itk(-/-) gammadelta NKT cells persistently express high levels of Zbtb16 (PLZF) and Il4, genes that are normally downregulated in the most mature subsets of NKT cells. These data indicate that Itk signaling is required to prevent the expansion of gammadelta NKT cells in the adult thymus, to block their emigration, and to promote terminal NKT cell maturation.

Viral infections have variable outcomes, with severe disease occurring in only few individuals. We hypothesized that this variable outcome could correlate with the nature of responses made to previous microbes. To test this, mice were infected initially with influenza A virus (IAV) and in memory phase challenged with lymphocytic choriomeningitis virus (LCMV), which we show in this study to have relatively minor cross-reactivity with IAV. The outcome in genetically identical mice varied from mild pneumonitis to severe acute lung injury with extensive pneumonia and bronchiolization, similar to that observed in patients who died of the 1918 H1N1 pandemic. Lesion expression did not correlate with virus titers. Instead, disease severity directly correlated with and was predicted by the frequency of IAV-PB1703- and IAV-PA224-specific responses, which cross-reacted with LCMV-GP34 and LCMV-GP276, respectively. Eradication or functional ablation of these pathogenic memory T cell populations, using mutant-viral strains, peptide-based tolerization strategies, or short-term anti-IFN-gamma treatment, inhibited severe lesions such as bronchiolization from occurring. Heterologous immunity can shape outcome of infections and likely individual responses to vaccination, and can be manipulated to treat or prevent severe pathology.

Surgery for elderly women is likely to increase steadily as the population of elderly people increases globally. Although increasing age increases perioperative morbidity and mortality, the functional age and physiologic reserve rather than chronological age is more important in preventing complications. Preparation for surgery, with special attention to functional capacity and activity, mental status, and existing comorbid conditions, can improve outcomes. Perioperative management must be tailored to physiologic changes of ageing, which affect respiratory, cardiac and renal function, as well as guidelines for preventing infection and thrombotic events. Of particular note is the enhanced effect of narcotic medications in elderly people, which affects intraoperative and postoperative management of pain. Prevention of postoperative delirium is accomplished through preoperative and postoperative planning. Discharge planning, particularly for frail elderly people, must start before surgery.

Estrogen receptor beta (ERbeta) promotes the degradation of hypoxia inducible factor 1alpha (HIF-1alpha), which contributes to the ability of this hormone receptor to sustain the differentiation of epithelial and carcinoma cells. Although the loss of ERbeta and consequent HIF-1 activation occur in prostate cancer with profound consequences, the mechanism by which ERbeta promotes the degradation of HIF-1alpha is unknown. We report that ERbeta regulates the ligand (3beta-adiol)-dependent transcription of prolyl hydroxylase 2 (PHD2) also known as Egl nine homolog 1 (EGLN1), a 2-oxoglutarate-dependent dioxygenase that hydroxylates HIF-1alpha and targets it for recognition by the von Hippel-Lindau tumor suppressor and consequent degradation. ERbeta promotes PHD2 transcription by interacting with a unique estrogen response element in the 5' UTR of the PHD2 gene that functions as an enhancer. PHD2 itself is critical for maintaining epithelial differentiation. Loss of PHD2 expression or inhibition of its function results in dedifferentiation with characteristics of an epithelial-mesenchymal transition, and exogenous PHD2 expression in dedifferentiated cells can restore an epithelial phenotype. Moreover, expression of HIF-1alpha in cells that express PHD2 does not induce dedifferentiation but expression of HIF-1alpha containing mutations in the proline residues that are hydroxylated by PHD2 induces dedifferentiation. These data describe a unique mechanism for the regulation of HIF-1alpha stability that involves ERbeta-mediated transcriptional regulation of PHD2 and they highlight an unexpected role for PHD2 in maintaining epithelial differentiation.

Understanding the interdependence of multiple mutations in conferring drug resistance is crucial to the development of novel and robust inhibitors. As HIV-1 protease continues to adapt and evade inhibitors while still maintaining the ability to specifically recognize and efficiently cleave its substrates, the problem of drug resistance has become more complicated. Under the selective pressure of therapy, correlated mutations accumulate throughout the enzyme to compromise inhibitor binding, but characterizing their energetic interdependency is not straightforward. A particular drug resistant variant (L10I/G48V/I54V/V82A) displays extreme entropy-enthalpy compensation relative to wild-type enzyme but a similar variant (L10I/G48V/I54A/V82A) does not. Individual mutations of sites in the flaps (residues 48 and 54) of the enzyme reveal that the thermodynamic effects are not additive. Rather, the thermodynamic profile of the variants is interdependent on the cooperative effects exerted by a particular combination of mutations simultaneously present.

Abscission is the last step of cytokinesis that leads to the physical separation of two daughter cells. An emerging picture is that abscission is a complex event that relies on changes in both lipid composition and cytoskeletal dynamics. These subcellular processes lead to the establishment of the abscission site and recruitment of the ESCRT-III protein complex to mediate the final separation event. It has become apparent that endocytic transport to the cleavage furrow during late cytokinesis mediates and coordinates lipid and cytoskeleton dynamics, thus playing a key role in abscission. Furthermore, new evidence suggests that endosomes may have additional roles in post-mitotic cellular events such as midbody inheritance and degradation. Here, we highlight recent findings regarding the function of these endosomes in the regulation of cell division.

We report on a polyethylenimine (PEI) covalently conjugated (alpha-NaYbF4:Tm3+)/CaF2 upconversion nanoparticle (PEI-UCNP) and its use for labeling rat mesenchymal stem cells (rMSCs). The PEI-UCNPs absorb and emit near-infrared light, allowing for improved in vivo imaging depth over conventional probes. We found that such covalent surface conjugation by PEI results in a much more stable PEI-UCNP suspension in PBS compared to conventional electrostatic layer by layer (LbL) self-assembling coating approach. We systematically examined the effects of nanoparticle dose and exposure time on rat mesenchymal stem cell (rMSC) cytotoxicity. The exocytosis of PEI-UCNPs from labeled rMSCs and the impact of PEI-UCNP uptake on rMSC differentiation was also investigated. Our data show that incubation of 100-microg/mL PEI-UCNPs with rMSCs for 4 h led to efficient labeling of the MSCs, and such a level of PEI-UCNP exposure imposed little cytotoxicity to rMSCs (95% viability). However, extended incubation of PEI-UCNPs at the 100 microg/mL dose for 24 hour resulted in some cytotoxicity to rMSCs (60% viability). PEI-UCNP labeled rMSCs also exhibited normal early proliferation, and the internalized PEI-UCNPs did not leak out to cause unintended labeling of adjacent cells during a 14-day transwell culture experiment. Finally, PEI-UCNP labeled rMSCs were able to undergo osteogenic and adipogenic differentiation upon in vitro induction, although the osteogenesis of labeled rMSCs appeared to be less potent than that of the unlabeled rMSCs. Taken together, PEI-UCNPs are promising agents for stem cell labeling and tracking.

Retrograde signals from postsynaptic targets are critical during development and plasticity of synaptic connections. These signals serve to adjust the activity of presynaptic cells according to postsynaptic cell outputs and to maintain synaptic function within a dynamic range. Despite their importance, the mechanisms that trigger the release of retrograde signals and the role of presynaptic cells in this signaling event are unknown. Here we show that a retrograde signal mediated by Synaptotagmin 4 (Syt4) is transmitted to the postsynaptic cell through anterograde delivery of Syt4 via exosomes. Thus, by transferring an essential component of retrograde signaling through exosomes, presynaptic cells enable retrograde signaling.

This article will focus on the less commonly injured nerves of the upper extremity. These nerves may be involved when trauma results in fractures, dislocations, or swelling with resultant nerve compression. Tumors and ganglions can also compress nerves, causing pain and, over time, demyelination or axon degeneration with weakness. Other mechanisms for upper limb nerve injury include participation in high-level sports, that is, those that generate torque about the arm and shoulder, abnormal stresses about the joints and muscles, or muscle hypertrophy, which may result in nerve injury. The goals of this review are to discuss the clinical presentation and possible causes of upper extremity nerve entrapments and to formulate an electrodiagnostic plan for evaluation. Descriptions of the appropriate nerve conduction studies or needle electromyographic protocols are included for specific nerves. The purpose of the electrodiagnostic examination is to evaluate the degree of nerve injury, axon loss over time, and later, evidence for reinnervation to assist with prognostication. The latter has implications for management of the neuropathy, including the type of exercises and therapy that may be indicated to help maintain the stability and motion of the involved joint(s) and promote strengthening over time as the nerve regenerates. Published by Elsevier Inc. All rights reserved.