Sex-dependent influence of endogenous estrogen in pulmonary hypertension

Rationale: The incidence of pulmonary arterial hypertension (PAH) is greater in women suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males exogenously administered estrogen can protect against PH; however in models that display female susceptibility estrogens may play a causative role. Objectives: To clarify the influence of endogenous estrogen and gender in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. Methods: We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH; the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of gender on pulmonary expression of aromatase in these models and in lungs from PAH patients. Results: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was due to reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor alpha also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased BMPR2 and Id1 expression compared to male. Anastrozole treatment reversed the impaired BMPR2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared to male. Conclusions: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential

Phylogenomics of non-model ciliates based on transcriptomic analyses

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The All-Data-Based Evolutionary Hypothesis of Ciliated Protists with a Revised Classification of the Phylum Ciliophora (Eukaryota, Alveolata)

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ The file attached is the published version of the article

Systemic Treatment with CpG-B after Sublethal Rickettsial Infection Induces Mouse Death through Indoleamine 2,3-Dioxygenase (IDO)

Due to its strong immune stimulatory effects through TLR9, CpG-containing oligodeoxynucleotides (CpG ODN) have been tested in multiple clinical trials as vaccine adjuvant for infectious diseases and cancer. However, immune suppression induced by systemic administration of CpGs has been reported recently. In this study, we evaluated the impact of CpGs in an acute rickettsiosis model. We found that systemic treatment with type B CpG (CpG-B), but not type A CpG (CpG-A), at 2 days after sublethal R. australis infection induced mouse death. Although wild-type (WT) B6 and IDO−/− mice showed similar survival rates with three different doses of R. australis infection, treatment with CpG-B after sublethal infection consistently induced higher mortality with greater tissue bacterial loads in WT but not IDO−/− mice. Also, CpG-B treatment promoted the development of higher serum concentrations of proinflammatory cytokines/chemokines through IDO. Furthermore, while T cell-mediated immune responses enhanced by CpG-B were independent of IDO, treatment with CpG-B promoted T cell activation, PD-1 expression and cell apoptosis partially through IDO. A depletion study using anti-mPDCA-1 mAb indicated that plasmacytoid dendritic cells (pDC) were not required for CpG-B-induced death of R. australis-infected mice. Additionally, the results in iNOS−/− mice suggested that nitric oxide (NO) was partially involved in CpG-B-induced death of R. australis-infected mice. Surprisingly, pre-treatment with CpG-B before administration of a lethal dose of R. australis provided effective immunity in WT, IDO−/− and iNOS−/− mice. Taken together, our study provides evidence that CpGs exert complex immunological effects by both IDO-dependent and -independent mechanisms, and that systemic treatment with CpGs before or after infection has a significant and distinct impact on disease outcomes

Epiploic appendagitis – clinical characteristics of an uncommon surgical diagnosis

<p>Abstract</p> <p>Background</p> <p>Epiploic appendagitis (EA) is a rare cause of focal abdominal pain in otherwise healthy patients with mild or absent secondary signs of abdominal pathology. It can mimick diverticulitis or appendicitis on clinical exam. The diagnosis of EA is very infrequent, due in part to low or absent awareness among general surgeons. The objective of this work was to review the authors' experience and describe the clinical presentation of EA.</p> <p>Methods</p> <p>All patients diagnosed with EA between January 2004 and December 2006 at an urban surgical emergency room were retrospectively reviewed by two authors in order to share the authors' experience with this rare diagnosis. The operations were performed by two surgeons. Pathological examinations of specimens were performed by a single pathologist. A review of clinical presentation is additionally undertaken.</p> <p>Results</p> <p>Ten patients (3 females and 7 males, average age: 44.6 years, range: 27–76 years) were diagnosed with symptomatic EA. Abdominal pain was the leading symptom, the pain being localized in the left (8 patients, 80 %) and right (2 patients, 20%) lower quadrant. All patients were afebrile, and with the exception of one patient, nausea, vomiting, and diarrhea were not present. CRP was slightly increased (mean: 1.2 mg/DL) in three patients (33%). Computed tomography findings specific for EA were present in five patients. Treatment was laparoscopic excision (n = 8), excision via conventional laparotomy (n = 1) and conservative therapy (n = 1).</p> <p>Conclusion</p> <p>In patients with localized, sharp, acute abdominal pain not associated with other symptoms such as nausea, vomiting, fever or atypical laboratory values, the diagnosis of EA should be considered. Although infrequent up to date, with the increase of primary abdominal CT scans and ultrasound EA may well be diagnosed more frequently in the future.</p

Brief Report: Using Individualized Orienting Cues to Facilitate First-Word Acquisition in Non-Responders with Autism

Though considerable progress has been made in developing techniques for improving the acquisition of expressive verbal communication in children with autism, research has documented that 10–25% still fail to develop speech. One possible technique that could be significant in facilitating responding for this nonverbal subgroup of children is the use of orienting cues. Using a multiple baseline design, this study examined whether individualized orienting cues could be identified, and whether their presentation would result in verbal expressive words. The results suggest that using individualized orienting cues can increase correct responding to verbal models as well as subsequent word use. Theoretical and applied implications of orienting cues as they relate to individualized programming for children with autism are discussed

Gray matter correlates of cognitive ability tests used for vocational guidance

<p>Abstract</p> <p>Background</p> <p>Individual differences in cognitive abilities provide information that is valuable for vocational guidance, but there is an ongoing debate about the role of ability factors, including general intelligence (<it>g</it>), compared to individual tests. Neuroimaging can help identify brain parameters that may account for individual differences in both factors and tests. Here we investigate how eight tests used in vocational guidance correlate to regional gray matter. We compare brain networks identified by using scores for ability factors (general and specific) to those identified by using individual tests to determine whether these relatively broad and narrow approaches yield similar results.</p> <p>Findings</p> <p>Using MRI and voxel-based morphometry (VBM), we correlated gray matter with independent ability factors (general intelligence, speed of reasoning, numerical, spatial, memory) and individual test scores from a battery of cognitive tests completed by 40 individuals seeking vocational guidance. Patterns of gray matter correlations differed between group ability factors and individual tests. Moreover, tests within the same factor showed qualitatively different brain correlates to some degree.</p> <p>Conclusions</p> <p>The psychometric factor structure of cognitive tests can help identify brain networks related to cognitive abilities beyond a general intelligence factor (<it>g</it>). Correlates of individual ability tests with gray matter, however, appear to have some differences from the correlates for group factors.</p

Lack of NF1 expression in a sporadic schwannoma from a patient without neurofibromatosis

The neurofibromatosis type 1 (NF1) gene encodes a tumor suppressor protein, neurofibromin, which is expressed at high levels in Schwann cells and other adult tissues. Loss of NF1 expression has been reported in Schwann cell tumors (neurofibrosarcomas) from patients with NF1 and its loss is associated with increased proliferation of these cells. In this report, we describe downregulation of NF1 expression in a single spinal schwannoma from an individual without clinical features of neurofibromatosis type 1 or 2. Barely detectable expression of NF1 RNA was found in this tumor by in situ hybridization using an NF1 -specific riboprobe as well as by Northern blot and reverse-transcribed (RT)-PCR analysis. In Schwann cells cultured from this schwannoma, abundant expression of NF1 RNA could be detected by Northern blot and RT-PCR analysis. These results suggest that, in some tumors, expression of NF1 may be downregulated by factors produced within the tumor and may represent a novel mechanism for inactivating these growth suppressing genes and allowing for increased cell proliferation in tumors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45383/1/11060_2005_Article_BF01057754.pd

Generalization Mediates Sensitivity to Complex Odor Features in the Honeybee

Animals use odors as signals for mate, kin, and food recognition, a strategy which appears ubiquitous and successful despite the high intrinsic variability of naturally-occurring odor quantities. Stimulus generalization, or the ability to decide that two objects, though readily distinguishable, are similar enough to afford the same consequence [1], could help animals adjust to variation in odor signals without losing sensitivity to key inter-stimulus differences. The present study was designed to investigate whether an animal's ability to generalize learned associations to novel odors can be influenced by the nature of the associated outcome. We use a classical conditioning paradigm for studying olfactory learning in honeybees [2] to show that honeybees conditioned on either a fixed- or variable-proportion binary odor mixture generalize learned responses to novel proportions of the same mixture even when inter-odor differences are substantial. We also show that the resulting olfactory generalization gradients depend critically on both the nature of the stimulus-reward paradigm and the intrinsic variability of the conditioned stimulus. The reward dependency we observe must be cognitive rather than perceptual in nature, and we argue that outcome-dependent generalization is necessary for maintaining sensitivity to inter-odor differences in complex olfactory scenes