Magnetic resonance imaging confirmation of resolution of periodontoid pannus formation following C1/C2 posterior transarticular screw fixation.

Chronic odontoid fractures are considered unstable spinal lesions. Chronic instability in this region leads to the development of an inflammatory pannus, which can progress resulting in spinal cord compression radiographically and a myelopathy syndrome clinically. In this report we document three cases of reversal of pannus after C1/C2 transarticular screw fixation of an unstable odontoid fracture. Three patients were identified with chronic odontoid fractures and spinal cord compression due to periodontoid pannus formation. All patients presented with a progressive myelopathy syndrome. All patients underwent preoperative and postoperative magnetic resonance imaging (MRI) of the craniovertebral junction. C1/C2 transarticular screw fixation was performed for stabilization of C1/C2. Postoperatively there were no complications. Postoperative MRI at 6 months demonstrated resolution of the ventral pannus. Moreover, all patients exhibited improvement of preoperative neurological deficits. MRI is the imaging technique of choice for diagnosis and follow-up of patients with chronic odontoid fractures and ventral pannus. C1/C2 transarticular screw fixation provides a viable method for spinal stabilization in this region. In addition, stabilization can result in resolution of inflammatory pannus formation secondary to instability of the C1/C2 articulation.     

Splenic Amyloidosis: A Case Report of Spontaneous Splenic Rupture with a Review of the Pertinent Literature

A case of spontaneous rupture of the spleen as a complication and presenting factors of systemic amyloidosis is reported with a review of the pertinent literature. the sequelae of amyloid involvement of the spleen is discussed with emphasis on possible mechanisms involved in the causation of spontaneous rupture of this organ.     

Activated T-Lymphocytes Express Occludin, a Component of Tight Junctions

T-lymphocytes routinely traffic from the lymphoid and vascular compartments to the tissues during immune surveillance and inflammatory responses. This egress occurs without compromising endothelial barrier, which is maintained by tight junctions (zonula occludens). We report that T-lymphocytes up-regulate the expression of occludin, a major component of the tight junction in response to stimulation with phorbol ester (PMA) + calcium ionophore, CD3 antibody or T-cell receptor (TCR) antibody. Only activated T-lymphocytes express occludin; this adhesion molecule is nearly absent in resting T-lymphocytes. By immunofluorescence, occludin is seen in lymphocyte aggregates, but does not appear to mediate aggregation since only 50% of the cells in these clusters express occludin. Occludin is expressed between 8 and 24 h following stimulation, and persists for at least 48 h. These data indicate that activated T cells produce occludin which may regulate lymphocyte adhesion and trafficking.     

Characterization of FcepsilonRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis

BACKGROUND: The high-affinity receptor for IgE (FcepsilonRI) on myeloid dendritic cells has been shown to play a major role in atopic dermatitis (AD). Plasmacytoid dendritic cells (pDCs), which are instrumental in the defense of viral infections, are present in reduced amounts in the skin of patients with AD, which is characterized by a high susceptibility to viral infections. OBJECTIVE: We explored phenotypical and functional characteristics of pDC in the peripheral blood of patients with AD and healthy individuals. METHODS: Blood dendritic cell antigen-2+CD123+ pDCs were enriched from the peripheral blood of patients with AD and studied in functional assays. RESULTS: Skin-homing molecules such as cutaneous lymphocyte antigen and L-selectin CD62L were expressed in lower levels on pDCs of patients with AD. pDCs expressed high amounts of IgE-occupied FcepsilonRI. Further, FcepsilonRI aggregation on pDCs impaired the surface expression of MHC I and II, induced the production of IL-10, and enhanced the apoptosis of pDCs. Importantly, FcepsilonRI preactivated pDC produced less IFN-alpha and IFN-beta after stimulation with CpG motifs and enhanced the outcome of immune responses of the TH2 type. CONCLUSION: From these data, we conclude that FcepsilonRI-bearing pDCs from patients with AD (1) are different from pDCs of healthy individuals, (2) might be important in the pathophysiology of AD, and (3) contribute to the enhanced susceptibility of patients with AD to viral infections.     

Genetic linkage maps of the West African clawed frog Xenopus tropicalis.

Amphibians, and particularly the African clawed frog Xenopus laevis, have been used for more than a century as models of vertebrate embryonic development. However, in many cases, elucidation of developmental functions of specific gene sequences could be severely impeded, because X. laevis is a tetraploid species, with multiple functional copies of many genes of interest. Recent studies have shifted focus to the West African or tropical clawed frog, X. tropicalis, the only known diploid species of the genus Xenopus. Here, we present two preliminary linkage maps, constructed by analysis of joint segregation of amplified fragment length polymorphism (AFLP) markers in a X. tropicalis interstrain hybrid. A total of 53 markers, including 51 AFLP markers and 2 isozyme markers, are presently assigned to 13 multipoint linkage groups on a map of the maternal strain, whereas 9 AFLP markers from the paternal strain are assigned to 3 linkage groups on a separate map. A dense genetic linkage map is essential in mapping new developmental mutants and determining their sequences by positional cloning.     

Social Media Content of Idiopathic Pulmonary Fibrosis Groups and Pages on Facebook: Cross-sectional Analysis

BackgroundPatients use Facebook as a resource for medical information. We analyzed posts on idiopathic pulmonary fibrosis (IPF)-related Facebook groups and pages for the presence of guideline content, user engagement, and usefulness.ObjectiveThe objective of this study was to describe and analyze posts from Facebook groups and pages that primarily focus on IPF-related content.MethodsCross-sectional analysis was performed on a single date, identifying Facebook groups and pages resulting from separately searching “IPF” and “idiopathic pulmonary fibrosis.” For inclusion, groups and pages needed to meet either search term and be in English, publicly available, and relevant to IPF. Every 10th post was assessed for general characteristics, source, focus, and user engagement metrics. Posts were analyzed for presence of IPF guideline content, useful scientific information (eg, scientific publications), useful support information (eg, information about support groups), and potentially harmful information.ResultsEligibility criteria were met by 12 groups and 27 pages, leading to analysis of 523 posts. Of these, 42% contained guideline content, 24% provided useful support, 20% provided useful scientific information, and 5% contained potentially harmful information. The most common post source was nonmedical users (85%). Posts most frequently focused on IPF-related news (29%). Posts containing any guideline content had fewer likes or comments and a higher likelihood of containing potentially harmful content. Posts containing useful supportive information had more likes, shares, and comments.ConclusionsFacebook contains useful information about IPF, but posts with misinformation and less guideline content have higher user engagement, making them more visible. Identifying ways to help patients with IPF discriminate between useful and harmful information on Facebook and other social media platforms is an important task for health care professionals.     

Telomere Length and Preterm Birth in Pregnant Mexican-Origin Women

Objectives

Despite the obstacles of limited education and employment opportunities—and the stress associated with immigration and pregnancy—Mexican immigrant women have low rates of preterm birth (PTB) compared to the US national average for all races and ethnicities. Stressors during pregnancy, and stressors associated with acculturation, may accelerate cellular aging manifested by shortened telomere length (TL) in pregnant women. Our objectives were to: (1) determine whether women with PTBs had shorter telomere lengths compared to women who had full term births; (2) assess the association of acculturation with TL and PTB.

Methods

This prospective pilot study collected data from 100 self-identified Mexican-origin pregnant women. Survey data included self-administered sociodemographic and acculturation measures and was collected from participants via paper and pen, while biologic data was collected via a single blood draw during a regularly scheduled prenatal visit between 26 and 36 weeks gestation. PTB data was collected from the participant’s medical record after delivery.

Results

TL was significantly associated with PTB; the median TL of the women with PTB was less than the median TL for the full sample (p?=?0.02). Based on regression analysis for PTB vs acculturation, we found no significant associations between acculturation and PTB or TL.

Conclusions for Practice

This study provides important evidence of the association between shortened maternal TL and adverse birth outcomes. By linking social, clinical and biologic data, we can enhance our understanding of social determinants that may affect racial and ethnic disparities in preterm birth.

     

Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.

Mu-opioid receptor (MOR) agonists are the most effective treatments for moderate to severe acute and chronic pain, yet their use is limited by serious side effects, including constipation, respiratory depression, and physical and psychological dependence. These side effects are on-target effects (MOR-mediated) and result from the wide distribution of MORs across the central nervous system (CNS) (1, 2). Safer pain therapies are desperately needed. However, because of the efficacy of MOR agonists in blocking pain, this receptor continues to be a primary target for the discovery of novel pain therapies. Unfortunately, most drug discovery programs involve designing compounds that bind to the orthosteric site on MOR—the site that binds endogenous opioid peptides as well as exogenous opioids. Not surprisingly, these newer drugs tend to exhibit qualitatively similar side effect profiles to traditional opioid analgesics.As an alternative, we have discovered small molecule, positive allosteric modulators of MOR [mu-PAMs (3)], including BMS-986122 (SI Appendix, Fig. S1). Such compounds interact with a site on MOR that is spatially distinct from the orthosteric site (3–7). Across a variety of in vitro assays, mu-PAMs increase the affinity and/or potency of orthosteric agonists at MOR, including exogenous MOR agonists as well as the endogenous opioid peptides Leucine- and Methionine-enkephalin, endomorphin-1, and β-endorphin (3, 8).These in vitro studies have led to development of a so-far untested hypothesis that in vivo, mu-PAMs will promote the activity of endogenous opioid peptides released during pain (9–11). If this hypothesis is correct, mu-PAMs could replace traditional opioids by boosting the body’s own natural response to pain to provide clinically meaningful analgesia. In support of this concept, so called “enkephalinase inhibitors” that prolong the lifetime of endogenous opioid peptides are effective in the management of pain in preclinical and clinical studies (12–14), although such compounds are not selective for opioid peptides. Since mu-PAMs do not alter peptide release or metabolism, they should be more selective than enkephalinase inhibitors and also preserve the natural spatial and temporal release of the peptides in vivo following injury and/or during pain. To test this hypothesis, we examined the antinociceptive effects of BMS-986122 in mouse models of acute and inflammatory pain using measures of pain-evoked and pain-depressed behaviors as well as opioid side effects and the potential role of endogenous opioid peptides in these responses.     

Concurrent DNA Copy‐Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

Somatic mosaicism for DNA copy‐number alterations (SMC‐CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC‐CNAs can undergo clonal expansion, it has been proposed that SMC‐CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array‐based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC‐CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC‐CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC‐CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co‐occurrence of gross SMC‐CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.