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Δευτέρα 29 Ιανουαρίου 2018
The Evolving Dilemma of Factor XI in Pregnancy: Suggestions for Management
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Sex Difference of Angiotensin IV–, LVV-Hemorphin 7–, and Oxytocin-Induced Antiallodynia at the Spinal Level in Mice With Neuropathic Pain
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A Systematic Review of Outcomes Associated With Withholding or Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Before Noncardiac Surgery
BACKGROUND: The global rate of major noncardiac surgical procedures is increasing annually, and of those patients presenting for surgery, increasing numbers are taking either an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). The current recommendations of whether to continue or withhold ACE-I and ARB in the perioperative period are conflicting. Previous meta-analyses have linked preoperative ACE-I/ARB therapy to the increased incidence of postinduction hypotension; however, they have failed to correlate this with adverse patient outcomes. The aim of this meta-analysis was to determine whether continuation or withholding ACE-I or ARB therapy in the perioperative period is associated with mortality and major morbidity. METHODS: This meta-analysis was prospectively registered on PROSPERO (CRD42017055291). A comprehensive search of MEDLINE (PubMed), CINAHL (EBSCO host), ProQuest, Cochrane database, Scopus, and Web of Science was conducted on December 6, 2016. We included adult patients >18 years of age on chronic ACE-I or ARB therapy who underwent noncardiac surgery in which ACE-I or ARB was either withheld or continued on the morning of surgery. Primary outcomes included all-cause mortality and major cardiac events (MACE). Secondary outcomes included the risk of congestive heart failure, acute kidney injury, stroke, intraoperative/postoperative hypotension, and the length of hospital stay. RESULTS: After abstract review, the full text of 25 studies was retrieved, of which 9 fulfilled the inclusion criteria: 5 were randomized control trials, and 4 were cohort studies. These studies included a total of 6022 patients on chronic ACE-I/ARB therapy before noncardiac surgery. A total of 1816 patients withheld treatment the morning of surgery and 4206 continued their ACE-I/ARB. Preoperative demographics were similar between the 2 groups. Withholding ACE-I/ARB therapy was not associated with a difference in mortality (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.62–1.52; I2 = 0%) or MACE (OR, 1.12; 95% CI, 0.82–1.52; I2 = 0%). However, withholding therapy was associated with significantly less intraoperative hypotension (OR, 0.63; 95% CI, 0.47–0.85; I2 = 71%). No effect estimate could be pooled concerning length of hospital stay and congestive heart failure. CONCLUSIONS: This meta-analysis did not demonstrate an association between perioperative administration of ACE-I/ARB and mortality or MACE. It did, however, confirm the current observation that perioperative continuation of ACE-I/ARBs is associated with an increased incidence of intraoperative hypotension. A large randomized control trial is necessary to determine the appropriate perioperative management of ACE-I and ARBs. Accepted for publication December 19, 2017. Funding: No outside funding was utilized in the search and retrieval of all articles. All funding was from departmental resources. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). PROSPERO registry: CRD42017055291. Reprints will not be available from the authors. Address correspondence to Caryl Hollmann, MBChB, DA (SA), Department of Anaesthesia and Perioperative Medicine, D23, Groote Schuur Hospital, University of Cape Town, Observatory, Cape Town 7925, South Africa. Address e-mail to carylhollmann@gmail.com. © 2018 International Anesthesia Research Society
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http://ift.tt/2FuY8Z5
Activation of Melatonin Receptors by Ramelteon Induces Cardioprotection by Postconditioning in the Rat Heart
Activation of melatonin receptors protects the heart against ischemia-reperfusion injury. Ramelteon, a clinically used drug for insomnia, acts via activation of melatonin receptors. We investigated whether ramelteon induces acute infarct size reduction by postconditioning. Male Wistar rats were randomized to 6 groups. Hearts were treated with melatonin and ramelteon at the beginning of reperfusion. The melatonin receptor inhibitor luzindole was administered with and without melatonin and ramelteon, respectively. Ramelteon reduced infarct size to the same extent as melatonin. Both effects were completely abolished by luzindole. The results show for the first time that ramelteon induces cardioprotection by postconditioning. Accepted for publication September 27, 2017. Funding: This work was supported by departmental funding only. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Ragnar Huhn, MD, PhD, Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. Address e-mail to Ragnar.Huhn@med.uni-duesseldorf.de. © 2018 International Anesthesia Research Society
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Summative Objective Structured Clinical Examination Assessment at the End of Anesthesia Residency for Perioperative Ultrasound
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Gender, Race and Disease Etiology Predict De Novo Malignancy Risk following Liver Transplantation: Insights for Future Individualized Cancer Screening Guidance
AbstractBackgroundMalignancy after liver transplant (LT) is a leading cause of mortality, but data is limited. The aim of this study was to identify patients at higher risk for de novo malignancies after LT in a large multicenter database.MethodsThe Scientific Registry of Transplant Recipients database comprising all 108,412 liver transplant recipients across the U.S. between 1987 and March 2015 was analyzed with a median follow-up of 6.95 years. Potential risk factors for malignancies after LT were assessed using Cox regression analysis for the outcome of time to first malignancy.ResultsMean age 51.9 ± 10.8 years, 64.6% male, 74.5% Caucasian, and 15.8% with previous malignancy. Malignancies during follow-up were 4,483 (41.3%) skin, 1,519 (14.0%) hematologic, and 4,842 (44.7%) solid organ. The 10-year probability of de novo malignancy was 11.5% (11.3-11.8%). On multivariable analysis, age by decade (HR 1.52; p
http://ift.tt/2DMKRuy
http://ift.tt/2DMKRuy
Incidence of Cytomegalovirus DNAemia in Pediatric Kidney Transplant Recipients after Cessation of Antiviral Prophylaxis
AbstractBackgroundLate cytomegalovirus (CMV) infection can occur after cessation of viral prophylaxis in kidney transplant recipients, yet, timing of infection is unclear and longer duration of prophylaxis may be warranted.MethodsWe conducted a retrospective cohort study of 86 children (35 CMV donor seropositive, recipient seronegative [D+R-] and 51 CMV recipient seropositive [R+])
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Successful sequential liver and haematopoietic stem cell transplantation in a child with CD40 ligand deficiency and Cryptosporidium-induced liver cirrhosis
ABSTRACTBACKGROUNDHematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a seven-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in one young adult to date.METHODSa closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft.RESULTScombined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur.CONCLUSIONShopefully this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child, will encourage others to adopt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies. BACKGROUND Hematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a seven-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in one young adult to date. METHODS a closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft. RESULTS combined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur. CONCLUSIONS hopefully this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child, will encourage others to adopt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies. Corresponding Author: Pier Luigi Calvo, MD, Paediatrician, Gastroenterologist & Hepatologist, Regina Margherita Children's Hospital, AOU Città della Salute e della Scienza, Piazza Polonia, 94, 10126 Turin, ITALY. pcalvo@cittadellasalute.to.it AUTHORSHIP PAGE QP, DOD and CPL had the patient under their care and conceived, designed and wrote the article. TF, RR, SM planned and performed liver transplant and critically reviewed the paper. DE performed liver histological analysis. CF, VE, FF performed haematopoietic stem cell transplantation and critically reviewed the paper. PM followed the patient after liver transplant and critically reviewed the paper. All authors listed contributed to writing the manuscript and are responsible for the content of the paper. The authors declare no conflicts of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2DMKRe2
Simultaneous detection of barrier- and immune-related gene variations in patients with atopic dermatitis by reverse blot hybridization assay
Summary
Background
Hereditary factors are involved in the pathogenesis of atopic dermatitis (AD). However, AD-related gene variations are significantly different across ethnicities.
Aim
To identify mutations and single-nucleotide polymorphisms (SNPs) in barrier- or immune-related genes from Korean patients with AD and compare the variations with those observed in nonatopic healthy controls (HCs), and to use novel reverse blot hybridization assay (REBA) for AD-related gene variants.
Methods
We carried out REBA to simultaneously detect variations in genes related to barrier or immune function, namely, FLG, SPINK5, KLK7, DEFB1, TNFα, KDR, FCER1A, IL4, IL5,IL5RA, IL9, IL10, IL12, IL12R, IL13 and IL18, from Korean patients with AD, and compared the variation to that in nonatopic healthy controls.
Results
The homozygous mutants of KLK7 and SPINK5-2475, and the heterozygous mutants of FLG 3321delA, SPINK5-1156, DEFB1, KDR, IL5RA, IL9 and IL12RB1 were significantly more frequent in AD. It has been predicted that the larger the number of gene variants, the higher the odds ratio of AD prevalence; however, we did not find any significant correlation between the number of gene variants and AD severity.
Conclusion
Using REBA, we identified more genetic variants that can predict AD occurrence. We also verified that REBA can be used to easily and accurately detect multiple AD-related gene variants simultaneously. In addition, we identified a correlation between KLK7 mutation and AD in Koreans, which is the first such report, to our knowledge.
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Simultaneous detection of barrier- and immune-related gene variations in patients with atopic dermatitis by reverse blot hybridization assay
Summary
Background
Hereditary factors are involved in the pathogenesis of atopic dermatitis (AD). However, AD-related gene variations are significantly different across ethnicities.
Aim
To identify mutations and single-nucleotide polymorphisms (SNPs) in barrier- or immune-related genes from Korean patients with AD and compare the variations with those observed in nonatopic healthy controls (HCs), and to use novel reverse blot hybridization assay (REBA) for AD-related gene variants.
Methods
We carried out REBA to simultaneously detect variations in genes related to barrier or immune function, namely, FLG, SPINK5, KLK7, DEFB1, TNFα, KDR, FCER1A, IL4, IL5,IL5RA, IL9, IL10, IL12, IL12R, IL13 and IL18, from Korean patients with AD, and compared the variation to that in nonatopic healthy controls.
Results
The homozygous mutants of KLK7 and SPINK5-2475, and the heterozygous mutants of FLG 3321delA, SPINK5-1156, DEFB1, KDR, IL5RA, IL9 and IL12RB1 were significantly more frequent in AD. It has been predicted that the larger the number of gene variants, the higher the odds ratio of AD prevalence; however, we did not find any significant correlation between the number of gene variants and AD severity.
Conclusion
Using REBA, we identified more genetic variants that can predict AD occurrence. We also verified that REBA can be used to easily and accurately detect multiple AD-related gene variants simultaneously. In addition, we identified a correlation between KLK7 mutation and AD in Koreans, which is the first such report, to our knowledge.
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The Lateral Femoral Cutaneous Nerve: Description of the Sensory Territory and a Novel Ultrasound-Guided Nerve Block Technique
Background and Objectives Nerve blockade of the lateral femoral cutaneous (LFC) nerve provides some analgesia after hip surgery. However, knowledge is lacking about the extent of the cutaneous area anesthetized by established LFC nerve block techniques, as well as the success rate of anesthetic coverage of various surgical incisions. Nerve block techniques that rely on ultrasonographic identification of the LFC nerve distal to the inguinal ligament can be technically challenging. Furthermore, the branching of the LFC nerve is variable, and it is unknown if proximal LFC nerve branches are anesthetized using the current techniques. The primary aim of this study was to investigate a novel ultrasound-guided LFC nerve block technique based on injection into the fat-filled flat tunnel (FFFT), which is a duplicature of the fascia lata between the sartorius and the tensor fasciae latae muscle, in order to assess the success rate of anesthetizing the proximal LFC nerve branches and covering of the different surgical incisions used for hip surgery. Methods First, a cadaveric study was conducted in order to identify an FFFT injection technique that would provide adequate injectate spread to the proximal LFC nerve branches. Second, a clinical study was conducted in a group of 20 healthy volunteers over 2 consecutive days. On trial day 1, successful complete anesthesia of the LFC nerve was defined by performing a suprainguinal fascia iliaca block bilaterally in each subject. On trial day 2, a triple-blind randomized controlled trial compared the effect of the novel ultrasound-guided LFC nerve block technique for bupivacaine versus placebo. The primary end point was the success rate of anesthesia of the proximal cutaneous area innervated by the LFC nerve for the FFFT injection with bupivacaine versus placebo. Results Adequate spread of injectate to the proximal LFC nerve branches in cadavers was obtained by injecting 10 mL with dynamic needle-tip tracking in the FFFT. Application of this technique in the randomized controlled trial provided anesthesia of the lateral thigh with a success rate of 95% (95% confidence interval, 73.9%–99.8%) for the active side and 0% for placebo (P
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Efficacy and Safety of Lidocaine Infusion Treatment for Neuropathic Pain: A Randomized, Double-Blind, and Placebo-Controlled Study
Background and Objectives Lidocaine infusion therapy (LIT) is an effective treatment for relieving neuropathic pain (NeP). However, it remains unclear whether pain relief can be sustained through repeated lidocaine infusions. This study aimed to determine whether repeated intravenous administration of low-dose lidocaine could provide prolonged pain relief in patients with specific NeP conditions. Methods This is a prospective, randomized, double-blind, placebo-controlled, parallel study. We compared the efficacy and safety of lidocaine infusions (3 mg/kg) in the LIT group and normal saline infusions in the control group once a week for 4 consecutive weeks in patients with postherpetic neuralgia or complex regional pain syndrome type II. The primary outcome was the difference in the percentage change in the 11-point numerical rating scale (NRS) pain score from baseline to after the final infusion. Secondary outcomes included pain scores during 4 weeks of follow-up and any complications. Results Forty-two patients completed this study protocol. The percentage reduction in NRS pain scores after the final infusion was significantly greater in the LIT group compared with the control group (P = 0.011). However, this pain reduction was not detectable at the 4-week follow-up. The difference in the percentage change in NRS pain scores was especially prominent in the LIT group after the third and fourth infusions. None of the study participants experienced serious complications from the treatment. Conclusions Lidocaine infusion therapy (3 mg/kg of lidocaine administered over 1 hour) provided effective short-term pain relief, which was substantially prominent after repeated infusions were administered to patients with refractory NeP. Clinical Trial Registration This study was registered at ClinicalTrials.gov, identifier NCT02597257. Accepted for publication September 2, 2017. Address correspondence to: Jee Youn Moon, MD, PhD, FIPP, CIPS, Department of Anesthesiology and Pain Medicine, Seoul National University Hospital College of Medicine, 110 Daehang-ro, Jongno-gu, Seoul 110-744, Korea (e-mail: jymoon0901@gmail.com). This research was supported by a grant (14172MFDS178) from Korean Ministry of Food and Drug Safety in 2014. The agency was not involved in conduct of this study or its submission. The authors declare no conflict of interest. Y.-C.K., A.M.C., and C.-S.L. contributed equally to this study. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.
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http://ift.tt/2BD5UOq
Dexamethasone as an Adjuvant to Femoral Nerve Block in Children and Adolescents Undergoing Knee Arthroscopy: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial
Background and Objectives Perineural dexamethasone has been demonstrated to extend postsurgical analgesia after peripheral nerve blockade in adults. The mechanism of action of dexamethasone as a regional anesthetic adjuvant is unclear as intravenous dexamethasone has been shown to have similar analgesic efficacy as perineural dexamethasone. The efficacy of perineural dexamethasone has not been previously explored in the pediatric population. Methods After obtaining informed consent, children (aged 10–18 years) presenting for arthroscopic knee surgery with a femoral nerve block were randomized to 1 of 3 groups: ropivacaine 0.5% and intramuscular saline (group R), ropivacaine 0.5% plus perineural dexamethasone 0.1 mg/kg (maximum 4 mg) and intramuscular saline (group D), and ropivacaine 0.5% and intramuscular dexamethasone 0.1 mg/kg (maximum 4 mg) (group M). The primary outcome was the number of doses of analgesic agents in the first 48 hours after hospital discharge. The number of doses was compared across study groups using Wilcoxon rank sum tests. Results Seventy-seven patients were enrolled in the study, of whom 4 were withdrawn because of additional surgical repair being performed, emergence delirium requiring unblinding, or loss to follow-up. The remaining 36 boys and 37 girls (aged 15 ± 2 years) included 23 patients randomized to group D, 23 patients randomized to group M, and 27 patients randomized to group R. The median number of pain medication doses within 48 hours of discharge was 2, 3, and 2 in groups D, M, and R, respectively. There were no significant differences in this outcome between groups D and M (difference in medians, 1; 95% confidence interval [CI] of difference in medians, −1 to 2; P = 0.475), groups D and R (difference in medians, 0; 95% CI of difference, −2 to 1; P = 0.821), or groups M and R (difference in medians, −1; 95% CI of difference, −2 to 1; P = 0.594). Other secondary outcomes, including time to first analgesic consumption after discharge, visual analog scale pain score, and subjective intensity of motor block, did not evince statistically significant differences among the study groups. Conclusions In the pediatric population, perineural or intramuscular dexamethasone did not improve analgesia after femoral nerve blockade for knee arthroscopy. Whether the observed lack of benefit reflects a true adult-pediatric difference or a limitation of the study could not be determined. Future pediatric studies are needed to evaluate dexamethasone for other block types and other types of surgery. Clinical Trial Registration This study was registered at ClinicalTrials.gov, identifier NCT01971645. Accepted for publication October 4, 2017. Address correspondence to: Giorgio Veneziano, MD, Department of Anesthesiology & Pain Medicine, Nationwide Children's Hospital, 700 Children's Dr, Columbus, OH 43205 (e-mail: Giorgio.Veneziano@Nationwidechildrens.org). This project was supported by The Clinical and Translational Intramural Funding Program (award grant number UL1TR001070), through the Research Institute at Nationwide Children's Hospital (Columbus, OH). The content is solely the responsibility of the authors and does not necessarily represent the official views of Nationwide Children's Hospital. This work was presented in part at moderated abstract presentations at the Society of Pediatric Pain Medicine's CCAS 2017 Annual Meeting on March 2 and the SPA-AAP Pediatric Anesthesiology 2017, on March 3, 2017, both in Austin, TX. The authors declare no conflict of interest. This study was registered with the Food and Drug Administration as an investigational new drug (IND 120188). Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.
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http://ift.tt/2nlDwMp
A topical treatment containing heat-treated Lactobacillus johnsonii NCC 533 reduces Staphylococcus aureus adhesion and induces antimicrobial peptide expression in an in vitro reconstructed human epidermis model
Abstract
Staphylococcus aureus colonization is thought to contribute to the pathophysiology of atopic dermatitis (AD). AD patients exhibit reduced levels of cutaneous antimicrobial peptides (AMPs), which may explain their increased susceptibility to infections. Using an in vitro reconstructed human epidermis (RHE) model, we sought to determine whether topical application of a non-replicating probiotic, heat-treated Lactobacillus johnsonii NCC 533 (HT La1), could inhibit S. aureus adhesion to skin and boost cutaneous innate immunity. We found that application of HT La1 suspension to RHE samples reduced the binding of radiolabeled S. aureus by up to 74%. To investigate a potential effect of HT La1 on innate immunity, we analyzed the expression of nine AMP genes, including those encoding beta defensins and S100 proteins, following topical application of HT La1 in suspension or in a daily moisturizer lotion. Analyzed genes were induced by up to four-fold in a dose-dependent manner by HT La1 in suspension, and by up to 2.4-fold by HT La1 in the moisturizer lotion. Finally, using ELISA and immunohistochemical detection, we evaluated the expression and secretion of the AMPs hBD-2 and psoriasin, and determined that both proteins were induced by topical HT La1, particularly in the stratum corneum of the RHE. These findings demonstrate that a topically applied, non-replicating probiotic can modulate endogenous AMP expression and inhibit binding of S. aureus to an RHE model in vitro. Moreover, they suggest that a topical formulation containing HT La1 could benefit atopic skin by enhancing cutaneous innate immunity and reducing S. aureus colonization.
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Staphylococcal scalded skin syndrome in a 4-year-old child: a case report
Staphylococcal scalded skin syndrome is an exfoliating skin disease which primarily affects children. Differential diagnosis includes toxic epidermal necrolysis, staphylococcal scalded skin syndrome, epidermol...
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Homeobox transcription factor DLX4 is not necessary for skin development and homeostasis
Abstract
Dlx4 is a member of a family of homeobox genes with homology to Drosophila distal-less (dll) gene. We show that Dlx4 expression pattern partially overlaps with its cis-linked gene Dlx3 during mouse development as well as in neonatal and adult skin. In mice, Dlx4 is expressed in the branchial arches, embryonic limbs, digits, nose, hair follicle and in the basal and suprabasal layers of mouse interfollicular epidermis in neonatal and adult skin. We show that inactivation of Dlx4 in mice did not result in any overtly gross pathology. Skin development, homeostasis and response to TPA treatment was similar in mice with loss of Dlx4 compared to wild type counterparts.
This article is protected by copyright. All rights reserved.
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The prevalence of human papillomavirus in pediatric tonsils: a systematic review of the literature
Abstract
Background
HPV-related head and neck cancer rates have been increasing in recent years, with the tonsils being the most commonly affected site. However, the current rate of HPV infection in the pediatric population remains poorly defined. The objective of this study was to systematically review and evaluate the prevalence and distribution of HPV in the tonsils of pediatric patients undergoing routine tonsillectomy.
Methods and Results
The literature was searched using PubMed, EMBASE, Scopus, CINAHL, Cochrane Library, and ProQuest Dissertations & Theses Global databases (inception to December 2017) by two independent review authors. Inclusion criteria included articles which evaluated the prevalence of HPV in a pediatric cohort without known warts or recurrent respiratory papillomatosis, those which used tonsil biopsy specimens for analysis, and those with six or more subjects and clear outcomes reported. Eleven studies met the inclusion criteria. Using the Oxford Clinical Evidence-based Medicine (OCEBM) guidelines, two reviewers appraised the level of evidence of each study, extracted data, and resolved discrepancies by consensus. The systematic review identified 11 articles (n = 2520). Seven studies detected HPV in the subject population, with prevalence values ranging from 0 to 21%. The level of evidence for all included studies was OCEBM Level 3.
Conclusions
HPV may be present in pediatric tonsillectomy specimens; however, the largest included study demonstrated a prevalence of 0%. Future testing should be performed using methods with high sensitivities and specificities, such as reverse transcript real-time PCR or digital droplet PCR.
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Cd and Cu accumulation, translocation and tolerance in Populus alba clone (Villafranca) in autotrophic in vitro screening
Abstract
The present study investigated accumulation, translocation and tolerance of autotrophic Populus alba clone "Villafranca" in response to excess concentrations of cadmium (Cd) and copper (Cu) provided to the plants. For this purpose, increasing concentrations of Cd (0, 5, 50 and 250 μM) and Cu (0, 5, 50, 250 and 500 μM) were administered to the growth medium in which micropropagated poplar plantlets were exposed to metal treatments for 15 days. Filter bags, instead of the conventional in vitro screening, were applied to improve the experimental design. Results showed that Cd and Cu increased in shoots and roots at increasing metal concentration in the medium. The highest Cd content was found in leaves, while the highest Cu content was found in roots. In "Villafranca", Cu showed toxic effects on the development of the seedlings, especially at the highest concentrations, reducing plant dry mass. However, the tolerance index (Ti) indicated good tolerance in this clone under exposure to excess metal concentrations, whereas plants had higher translocation factor (Tf). We recommend in vitro selection of tolerant genotypes, aimed at providing early indication on accumulation potentiality and tolerance capability in research on plant sensitivity to excess heavy metal concentrations.
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Nickel hypersensitivity following closure of atrial septal defect: A case report and review of the literature
Abstract
We present an unusual case where symptoms of headache and chest pain persisted for 3 years following the implantation of a septal occluder device for an atrial septal defect despite endothelialisation of the device. The patient was found to have nickel hypersensitivity on patch testing. Following the removal of the device the patient had complete resolution of headaches and chest pain up to 10 months post-explantation.
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Exercise and Hypertrophic Cardiomyopathy: Time for a Change of Heart.
Author: Saberi, Sara MD, MS; Day, Sharlene M. MD
Page: 419-421
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High-Sensitivity Cardiac Troponin and the Risk Stratification of Patients With Renal Impairment Presenting With Suspected Acute Coronary Syndrome.
Author: Miller-Hodges, Eve MBChB, PhD *,,; Anand, Atul MBChB *,; Shah, Anoop S.V. MBChB, PhD; Chapman, Andrew R. MBChB; Gallacher, Peter MBChB; Lee, Kuan Ken MBChB; Farrah, Tariq MBChB; Halbesma, Nynke MBChB; Blackmur, James P. MBChB; Newby, David E. MBChB, PhD; Mills, Nicholas L. MBChB, PhD; Dhaun, Neeraj MBChB, PhD
Page: 425-435
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The Cardiac Troponin Renal Disease Diagnostic Conundrum: Past, Present, and Future.
Author: deFilippi, Christopher MD; Seliger, Stephen MD, MS
Page: 452-454
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Chronic Rejection of Cardiac Allografts Is Associated With Increased Lymphatic Flow and Cellular Trafficking.
Author: Edwards, Lindsey A. PhD; Nowocin, Anna K. PhD; Jafari, Nazila V. PhD; Meader, Lucy L. MRes; Brown, Kathryn PhD; Sarde, Aurelien MSc; Lam, Carolyn BSc; Murray, Alex BSc; Wong, Wilson DPhil, MRCP
Page: 488-503
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Lymphangiogenesis in Chronic Rejection and Coronary Allograft Vasculopathy: An Emerging Diagnostic and Therapeutic Target?.
Author: Baldwin, H. Scott MD; Drakos, Stavros G. MD, PhD
Page: 504-507
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Sham-Controlled Trial Questions Benefit of Stents for Stable Angina.
Author: Kuehn, Bridget M.
Page: 519-520
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Unique ECG During Sinus Rhythm in a Patient With a Postmyocardial Infarction-Sustained Ventricular Tachycardia.
Author: Farre, Jeronimo MD, PhD; Wellens, Hein J. MD, PhD
Page: 527-530
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Does Sport Participation Worsen the Clinical Course of Hypertrophic Cardiomyopathy?: Clinical Outcome of Hypertrophic Cardiomyopathy in Athletes.
Author: Pelliccia, Antonio MD; Lemme, Erika MD; Maestrini, Viviana MD; Di Paolo, Fernando M. MD; Pisicchio, Cataldo MD; Di Gioia, Giuseppe MD; Caselli, Stefano MD
Page: 531-533
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High Prevalence of Occult Heart Failure With Preserved Ejection Fraction Among Patients With Atrial Fibrillation and Dyspnea.
Author: Reddy, Yogesh N.V. MBBS; Obokata, Masaru MD, PhD; Gersh, Bernard J. MB ChB, DPhil; Borlaug, Barry A. MD
Page: 534-535
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Letter by Jin-shan and Xue-bin Regarding Article, "Prevalence of Subclinical Coronary Artery Disease in Masters Endurance Athletes With a Low Atherosclerotic Risk Profile".
Author: Jin-shan, He MD; Xue-bin, Li MD
Page: 536
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Letter by Harrell et al Regarding Article, "Prevalence of Subclinical Coronary Artery Disease in Masters Endurance Athletes With a Low Atherosclerotic Risk Profile".
Author: Harrell, Travis E. MD; Stoebner, Richard A. MD; Boswell, Gilbert E. MD
Page: 537-538
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Letter by Schmermund Regarding Article, "Prevalence of Subclinical Coronary Artery Disease in Masters Endurance Athletes With a Low Atherosclerotic Risk Profile".
Author: Schmermund, Axel MD
Page: 539-540
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Response by Merghani et al to Letters Regarding Article, "Prevalence of Subclinical Coronary Artery Disease in Masters Endurance Athletes With a Low Atherosclerotic Risk Profile".
Author: Merghani, Ahmed MRCP; Maestrini, Viviana PhD; Rosmini, Stefania MRCP; Cox, Andrew T. MRCP; Dhutia, Harshil MRCP; Bastiaenan, Rachel PhD; David, Sarojini MRCR; Yeo, Tee Joo MD; Narain, Rajay MRCP; Malhotra, Aneil MRCP; Papadakis, Michael MD; Wilson, Mathew G. PhD; Tome, Maite MD; AlFakih, Khaled MD; Moon, James C. MD; Sharma, Sanjay MD
Page: 541-542
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Intra-Arterial Thrombolytic Therapy Is Not a Therapeutic Option for Filler-Related Central Retinal Artery Occlusion
Facial plast Surg
DOI: 10.1055/s-0037-1621730
Cosmetic facial filler-related central retinal artery occlusion (CRAO) is a devastating complication of facial hyaluronic acid (HA) injection and can be managed by intra-arterial thrombolytic therapy (IATT). The authors report on a 20-year-old woman who developed unilateral CRAO due to facial HA injection and who, despite prompt IATT, lost vision. A review of the related literature found 14 other female patients who developed cosmetic facial filler-related CRAO and accepted IATT management. In no case was vision loss clinically improved. IATT is not an effective preventive treatment of dermal filler-associated CRAO. The authors suggest careful preprocedural patient selection to prevent this complication.
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Unerwartete Folgen einer HNO-Standardtherapie
Laryngo-Rhino-Otol
DOI: 10.1055/s-0044-100257
© Georg Thieme Verlag KG Stuttgart · New York
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A study through batch tests on the analytical determination and the fate and removal of methamphetamine in the biological treatment of domestic wastewater
Abstract
Methamphetamine (MET) is one of the most used illicit drugs in Europe and is recognized as one of the Emerging Organic Micropollutants. It is discharged into the sewerage system from different sources and then enters the wastewater treatment plants. The present study aimed at providing a better knowledge of the fate of MET through the wastewater treatment plants. The study addressed two different issues: (1) optimization of the analytical methods for MET determination in both liquid and sludge phases, focusing on the effects of potentially interfering substances and (2) investigation on the behaviour of MET in the biological treatment process, with specific concern for the biomass activity at different drug concentrations. Results of the study on issue 1 highlighted that the applied analytical method for MET determination (UPLC–MS/MS) is affected by the main components of wastewater for about 9–23%, which is comparable with the uncertainties of the method (about ± 28%). The method showed also to be repeatable and reliable (recovery > 75%; repeatability < 10–15%; bias uncertainty < 30%), and relatively easy-to-use. Therefore, it can be considered suitable for measurements on routine base in the WWTPs. Batch tests conducted to address issue 2 showed total removal of 84, 90, and 96% at 50, 100, and 200 ng/L initial MET concentration, respectively, for a contact time of 6 h. The removal process was mainly ascribed to the biological activity of both heterotrophic and autotrophic bacteria. The pseudo first-order kinetic model provided the best fitting of the experimental data of the overall biological processes at all the tested concentrations. Furthermore, the respirometric tests showed that MET does not induce any inhibition. Adsorption of MET on activated sludge was always very low.
http://ift.tt/2EmRuoM
Effects of air pollution on hospital visits for pneumonia in children: a two-year analysis from China
Abstract
Although the effect of air pollution on respiratory health has been identified, few studies can be available to evaluate the association of air pollution with hospital visits for children's pneumonia in China. To explore whether high concentrations of air pollutants (including PM2.5, PM10, NO2, and SO2) are related to hospital visits for pneumonia in children, we conducted a population-based time-series study in Ningbo, China, from January 1st, 2014 to November 1st, 2015. We used a generalized additive Poisson regression model to calculate risk ratios and 95% confidence intervals for the associations of air pollutants and hospital visits for pneumonia in children and found that these four pollutants were associated with the increased hospital visits for pneumonia in children (1.3% for PM2.5, 1.0% for PM10, 2.9% for NO2, 5.0% for SO2 per 10-μg/m3 increase in PM2.5, PM10, NO2, and SO2, respectively). Stronger associations were observed in the cold seasons and among children under 5 years.
http://ift.tt/2DLcF2t
Anti-Mullerian Hormone and Inhibin B Levels in Obese Boys; Relations with Cardiovascular Risk Factors
Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0044-101141
Objective Obesity may reduce sertoli cell functions in men. The aim of the study was to investigate antimullerian hormone (AMH) and inhibin B levels (sertoli cell markers) in obese boys and their relations to cardiovascular risk factors such as insulin sensitivity index, aortic intima media thickness (aIMT) and high sensitive c-reactive protein (hsCRP). Patients, methods 121 obese and 38 healthy lean adolescents were included in the study. Serum AMH, inhibin B, gonadotropins, total testosterone, lipids, hsCRP, glucose and insulin levels were detected and analyzed. Insulin resistance was analyzed using the homeostasis model assessment (HOMA-IR). aIMT was measured by high-resolution B-mode ultrasonography. Results Serum AMH, inhibin B and total testosterone levels were lower in the obese adolescents (p=0.01, p=0.009 and p=0.002, respectively). aIMT measurements (p<0.001, 0.63±0.09 and 0.47±0.06 mm, respectively) and hsCRP levels (p<0.001, 2.5±0.4 and 0.66±0.69 mg/L, respectively) were significantly increased in the obese group. Obese with IR group had decreased AMH levels (p=0.02, 53.0±20.5 and 66.7±19.5 ng/mL, respectively) and increased triglycerides, HOMA-IR, aIMT measurements than non-IR obese group. AMH levels were correlated negatively with body mass index (r:−0.108, p=0.03), HOMA-IR (r:−0.358, p=0.003) and fasting insulin levels (r:−0.389, p=0.001) in obese group with IR. Conclusion We found that concentrations of both sertoli cell markers (AMH and inhibin B) were significantly lower in obese pubertal boys especially in obese with IR. Obesity and IR might be important factors for the sertoli cell impairment in pubertal boys.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
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The Variation of Disulfides in the Progression of Type 2 Diabetes Mellitus
Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0044-100376
Aim The purpose of this study was to examine thiol-disulfide balance in patients with type 2 diabetes mellitus. Methods This study included 32 subjects with known type 2 diabetes mellitus without complications, 30 patients with type 2 diabetes mellitus with complications, 28 newly diagnosed patients with type 2 diabetes mellitus, and 45 healthy individuals. Thiol-disulfide profile tests were quantified in all groups. Results Compared to the control group, patients in each of the diabetic groups had significantly lower native and total thiol levels, higher disulfide levels, and higher disulfide/native thiol and disulfide/total thiol ratios (p<0.05 for all). Disulfide levels were significantly lower in the newly diagnosed group than in other diabetic groups (p<0.05). There were significant associations between glycemic parameters and thiol-disulfide tests (p<0.05). Conclusions A disequilibrium between thiol-disulfide pairs occurs in patients with type 2 diabetes mellitus, and a gradual increase to disulfide levels may contribute to the disease's severity. Deteriorated thiol-disulfide homeostasis may be relevant to the pathophysiology of type 2 diabetes mellitus.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Immunohistochemical Analysis of Inflammatory Rheumatoid Synovial Tissues Using Anti-Human Podoplanin Monoclonal Antibody Panel
Monoclonal Antibodies in Immunodiagnosis and Immunotherapy , Vol. 0, No. 0.
http://ift.tt/2Furvel
Characterization and cancer risk assessment of VOCs in home and school environments in gran La Plata, Argentina
Abstract
Three areas are highlighted in Gran La Plata, Argentina: industrial, urban, and residential. In this work, the levels of volatile organic compounds (VOCs) in indoor air of homes and schools in those areas were analyzed, through the use of passive monitors. The study period is between 2007 and 2010. Higher levels of VOCs were found in homes and schools in the industrial zone, higher than the levels corresponding to urban and residential. Taking into account the relationship between indoor and outdoor levels of VOCs, they have ratios (I/O) between 1.5 and 10 are evidenced contributions of emission sources of VOCs both indoor and outdoor. Complementarily, we estimated the life time cancer risk (LCR) for benzene, styrene, trichloroethylene, and tetrachloroethylene in children who spend their time mostly in such indoor environments. The results show high LCR values for benzene, which exceed acceptable values for the US EPA.
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Dobutamine Stress Echocardiography for Management of Low-Flow, Low-Gradient Aortic Stenosis
AbstractBackground
In the American College of Cardiology/American Heart Association guidelines, patients are considered to have true-severe stenosis when the mean gradient (MG) is ≥40 mm Hg with an aortic valve area (AVA) ≤1 cm2 during dobutamine stress echocardiography (DSE). However, these criteria have not been previously validated.
ObjectivesThe aim of this study was to assess the value of these criteria to predict the presence of true-severe AS and the occurrence of death in patients with low-flow, low-gradient aortic stenosis (LF-LG AS).
MethodsOne hundred eighty-six patients with low left ventricular ejection fraction (LVEF) LF-LG AS were prospectively recruited and underwent DSE, with measurement of the MG, AVA, and the projected AVA (AVAProj), which is an estimate of the AVA at a standardized normal flow rate. Severity of AS was independently corroborated by macroscopic evaluation of the valve at the time of valve replacement in 54 patients, by measurement of the aortic valve calcium by computed tomography in 25 patients, and by both methods in 8 patients. According to these assessments, 50 of 87 (57%) patients in the study cohort had true-severe stenosis.
ResultsPeak stress MG ≥40 mm Hg, peak stress AVA ≤1 cm2, and the combination of peak stress MG ≥40 mm Hg and peak stress AVA ≤1 cm2 correctly classified AS severity in 48%, 60%, and 47% of patients, respectively, whereas AVAProj ≤1 cm2 was better than all the previous markers (p < 0.007), with 70% correct classification. Among the subset of 88 patients managed conservatively (47% of the cohort), 52 died during a follow-up of 2.8 ± 2.5 years. After adjustment for age, sex, functional capacity, chronic kidney failure, and peak stress LVEF, peak stress MG and AVA were not predictors of mortality in this subset. In contrast, AVAProj ≤1 cm2 was a strong predictor of mortality under medical management (hazard ratio: 3.65; p = 0.0003).
ConclusionsIn patients with low LVEF LF-LG AS, the DSE criteria of a peak stress MG ≥40 mm Hg, or the composite of a peak stress MG ≥40 mm Hg and a peak stress AVA ≤1 cm2 proposed in the guidelines to identify true-severe AS and recommend valve replacement, have limited value to predict actual stenosis severity and outcomes. In contrast, AVAProj better distinguishes true-severe AS from pseudo-severe AS and is strongly associated with mortality in patients under conservative management. (Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis [TOPAS]; NCT01835028)
http://ift.tt/2DHQz0R
Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease
AbstractBackground
Patients with prior myocardial infarction (MI) and multivessel coronary disease (MVD) are at high risk for recurrent coronary events.
ObjectivesThe authors investigated the efficacy and safety of ticagrelor versus placebo in patients with MVD in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial.
MethodsPatients with a history of MI 1 to 3 years before inclusion in the PEGASUS-TIMI 54 trial were stratified in a pre-specified analysis based on the presence of MVD. The effect of ticagrelor (60 mg and 90 mg) on the composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events [MACE]), as well as the composite of coronary death, MI, or stent thrombosis (coronary events), and on TIMI major bleeding, intracranial hemorrhage (ICH), and fatal bleeding were evaluated over a median of 33 months.
ResultsA total of 12,558 patients (59.4%) had MVD. In the placebo arm, compared with patients without MVD, those with MVD were at higher risk for MACE (9.37% vs. 8.57%, adjusted hazard ratio [HRadj]: 1.24; p = 0.026) and for coronary events (7.67% vs. 5.34%, HRadj: 1.49; p = 0.0005). In patients with MVD, ticagrelor reduced the risk of MACE (7.94% vs. 9.37%, HR: 0.82; p = 0.004) and coronary events (6.02% vs. 7.67%, HR: 0.76; p < 0.0001), including a 36% reduction in coronary death (HR: 0.64; 95% confidence interval: 0.48 to 0.85; p = 0.002). In this subgroup, ticagrelor increased the risk of TIMI major bleeding (2.52% vs. 1.08%, HR: 2.67; p < 0.0001), but not ICH or fatal bleeds.
ConclusionsPatients with prior MI and MVD are at increased risk of MACE and coronary events, and experience substantial relative and absolute risk reductions in both outcomes with long-term ticagrelor treatment relative to those without MVD. Ticagrelor increases the risk of TIMI major bleeding, but not ICH or fatal bleeding. For patients with prior MI and MVD, ticagrelor is an effective option for long-term antiplatelet therapy. (Prevention of Cardiovascular Events [e.g., Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562)
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Effect of Plaque Burden and Morphology on Myocardial Blood Flow and Fractional Flow Reserve
AbstractBackground
Atherosclerotic plaque characteristics may affect downstream myocardial perfusion, as well as coronary lesion severity.
ObjectivesThis study sought to evaluate the association between quantitative plaque burden and plaque morphology obtained using coronary computed tomography angiography (CTA) and quantitative myocardial perfusion obtained using [15O]H2O positron emission tomography (PET), as well as fractional flow reserve (FFR) derived invasively.
MethodsTwo hundred eight patients (63% men; age 58 ± 8.7 years) with suspected coronary artery disease were prospectively included. All patients underwent 256-slice coronary CTA, [15O]H2O PET, and invasive FFR measurements. Coronary CTA-derived plaque burden and morphology were assessed using commercially available software and compared with PET perfusion and FFR.
ResultsAtherosclerotic plaques were present in 179 patients (86%) and 415 of 610 (68%) evaluable coronary arteries. On a per-vessel basis, traditional coronary plaque burden indexes, such as plaque length and volume, minimal lumen area, and stenosis percentage, were significantly associated with impaired hyperemic myocardial blood flow (MBF) and FFR. In addition, morphological features, such as partially calcified plaques, positive remodeling (PR), and low attenuation plaque, displayed a negative impact on hyperemic MBF and FFR. Multivariable analysis revealed that the morphological feature of PR was independently related to impaired hyperemic MBF as well as an unfavorable FFR (p = 0.004 and p = 0.007, respectively), next to stenosis percentage (p = 0.001 and p < 0.001, respectively) and noncalcified plaque volume (p < 0.001 and p = 0.010, respectively).
ConclusionsPR and noncalcified plaque volume are associated with detrimental downstream hyperemic myocardial perfusion and FFR, independent of lesion severity.
http://ift.tt/2DJl32l
18F-Sodium Fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA3 Study
AbstractBackground
Fluorine-18–sodium fluoride (18F-NaF) uptake is a marker of active vascular calcification associated with high-risk atherosclerotic plaque.
ObjectivesIn patients with abdominal aortic aneurysm (AAA), the authors assessed whether 18F-NaF positron emission tomography (PET) and computed tomography (CT) predicts AAA growth and clinical outcomes.
MethodsIn prospective case-control (n = 20 per group) and longitudinal cohort (n = 72) studies, patients with AAA (aortic diameter >40 mm) and control subjects (aortic diameter <30 mm) underwent abdominal ultrasound, 18F-NaF PET-CT, CT angiography, and calcium scoring. Clinical endpoints were aneurysm expansion and the composite of AAA repair or rupture.
ResultsFluorine-18-NaF uptake was increased in AAA compared with nonaneurysmal regions within the same aorta (p = 0.004) and aortas of control subjects (p = 0.023). Histology and micro-PET-CT demonstrated that 18F-NaF uptake localized to areas of aneurysm disease and active calcification. In 72 patients within the longitudinal cohort study (mean age 73 ± 7 years, 85% men, baseline aneurysm diameter 48.8 ± 7.7 mm), there were 19 aneurysm repairs (26.4%) and 3 ruptures (4.2%) after 510 ± 196 days. Aneurysms in the highest tertile of 18F-NaF uptake expanded 2.5x more rapidly than those in the lowest tertile (3.10 [interquartile range (IQR): 2.34 to 5.92 mm/year] vs. 1.24 [IQR: 0.52 to 2.92 mm/year]; p = 0.008) and were nearly 3x as likely to experience AAA repair or rupture (15.3% vs. 5.6%; log-rank p = 0.043).
ConclusionsFluorine-18-NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events. (Sodium Fluoride Imaging of Abdominal Aortic Aneurysms [SoFIA3]; NCT02229006; Magnetic Resonance Imaging [MRI] for Abdominal Aortic Aneurysms to Predict Rupture or Surgery: The MA3RS Trial; ISRCTN76413758)
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Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis
AbstractBackground
Disrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the interaction between CD40 and tumor necrosis factor receptor-associated factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity.
ObjectivesThis study evaluates the potential of TRAF-STOP treatment in atherosclerosis.
MethodsThe effects of TRAF-STOPs on atherosclerosis were investigated in apolipoprotein E deficient (Apoe–/–) mice. Recombinant high-density lipoprotein (rHDL) nanoparticles were used to target TRAF-STOPs to macrophages.
ResultsTRAF-STOP treatment of young Apoe–/– mice reduced atherosclerosis by reducing CD40 and integrin expression in classical monocytes, thereby hampering monocyte recruitment. When Apoe–/– mice with established atherosclerosis were treated with TRAF-STOPs, plaque progression was halted, and plaques contained an increase in collagen, developed small necrotic cores, and contained only a few immune cells. TRAF-STOP treatment did not impair "classical" immune pathways of CD40, including T-cell proliferation and costimulation, Ig isotype switching, or germinal center formation, but reduced CD40 and β2-integrin expression in inflammatory monocytes. In vitro testing and transcriptional profiling showed that TRAF-STOPs are effective in reducing macrophage migration and activation, which could be attributed to reduced phosphorylation of signaling intermediates of the canonical NF-B pathway. To target TRAF-STOPs specifically to macrophages, TRAF-STOP 6877002 was incorporated into rHDL nanoparticles. Six weeks of rHDL-6877002 treatment attenuated the initiation of atherosclerosis in Apoe–/– mice.
ConclusionsTRAF-STOPs can overcome the current limitations of long-term CD40 inhibition in atherosclerosis and have the potential to become a future therapeutic for atherosclerosis.
http://ift.tt/2DLnUrX
Thyroid Hormone Promotes β-Catenin Activation and Cell Proliferation in Colorectal Cancer
Abstract
Thyroid hormone status has long been implicated in cancer development. Here we investigated the role of thyroxine (T4) in colorectal cancer cell lines HCT 116 (APC wild type) and HT-29 (APC mutant), as well as the primary cultures of cancer cells derived from patients. Cell proliferation was evaluated with standard assay and proliferation marker expression. β-Catenin activation was examined according to nuclear β-catenin accumulation and β-catenin target gene expression. The results showed that T4 increased colorectal cancer cell proliferation while cell number and viability were elevated by T4 in both established cell lines and primary cells. Moreover, the transcriptions of proliferative genes PCNA, CCND1, and c-Myc were enhanced by T4 in the primary cells. T4 induced nuclear β-catenin accumulation, as well as high cyclin D1 and c-Myc levels compared to the untreated cells. In addition, the β-catenin-directed transactivation of CCND1 and c-Myc promoters was also upregulated by T4. CTNNB1 transcription was raised by T4 in HCT 116, but not in HT-29, while the boosted β-catenin levels were observed in both. Lastly, the T4-mediated gene expression could be averted by the knockdown of β-catenin. These results suggested that T4 promotes β-catenin activation and cell proliferation in colorectal cancer, indicating that an applicable therapeutic strategy should be considered.
http://ift.tt/2DUOvpM
Deletion of the Duffy antigen receptor for chemokines (DARC) promotes insulin resistance and adipose tissue inflammation during high fat feeding
Publication date: Available online 16 January 2018
Source:Molecular and Cellular Endocrinology
Author(s): Tyler W. Benson, Daniel S. Weintraub, Matthew Crowe, Nicole K.H. Yiew, Orishebawo Popoola, Ajay Pillai, Joel Joseph, Krystal Archer, Charlotte Greenway, Tapan K. Chatterjee, James Mintz, David W. Stepp, Brian K. Stansfield, Weiqin Chen, Julia Brittain, Vladimir Y. Bogdanov, Yan Gao, James G. Wilson, Yaoliang Tang, Ha Won Kim, Neal L. Weintraub
ObjectiveInflammation in adipose tissues in obesity promotes insulin resistance and metabolic disease. The Duffy antigen receptor for chemokines (DARC) is a promiscuous non-signaling receptor expressed on erythrocytes and other cell types that modulates tissue inflammation by binding chemokines such as monocyte chemoattractant protein-1 (MCP-1) and by acting as a chemokine reservoir. DARC allelic variants are common in humans, but the role of DARC in modulating obesity-related metabolic disease is unknown.MethodsWe examined body weight gain, tissue adiposity, metabolic parameters and inflammatory marker expression in wild-type and DARC knockout mice fed a chow diet (CD) and high fat diet (HFD).ResultsCompared to wild-type mice, HFD-fed DARC knockout mice developed glucose intolerance and insulin resistance independent of increases in body weight or adiposity. Interestingly, insulin sensitivity was also diminished in lean male DARC knockout mice fed a chow diet. Insulin production was not reduced by DARC gene deletion, and plasma leptin levels were similar in HFD fed wild-type and DARC knockout mice. MCP-1 levels in plasma rose significantly in the HFD fed wild-type mice, but not in the DARC knockout mice. Conversely, adipose tissue MCP-1 levels were higher, and more macrophage crown-like structures were detected, in the HFD fed DARC knockout mice as compared with the wild-type mice, consistent with augmented adipose tissue inflammation that is not accurately reflected by plasma levels of DARC-bound MCP-1 in these mice.ConclusionsThese findings suggest that DARC regulates metabolic function and adipose tissue inflammation, which may impact obesity-related disease in ethnic populations with high frequencies of DARC allelic variants.
http://ift.tt/2nm0Klw
Prostaglandins in teleost ovulation: A review of the roles with a view to comparison with prostaglandins in mammalian ovulation
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Takayuki Takahashi, Akane Hagiwara, Katsueki Ogiwara
Prostaglandins are well known to be central regulators of vertebrate ovulation. Studies addressing the role of prostaglandins in mammalian ovulation have established that they are involved in the processes of oocyte maturation and cumulus oocyte complex expansion. In contrast, despite the first indication of the role of prostaglandins in teleost ovulation appearing 40 years ago, the mechanistic background of their role has long been unknown. However, studies conducted on medaka over the past decade have provided valuable information. Emerging evidence indicates an indispensable role of prostaglandin E2 and its receptor subtype Ptger4b in the process of follicle rupture. In this review, we summarize studies addressing the role of prostaglandins in teleost ovulation and describe recent advances. To help understand differences from and similarities to ovulation in mammalian species, the findings on the roles of prostaglandins in mammalian ovulation are discussed in parallel.
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Metformin improves obesity-associated inflammation by altering macrophages polarization
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Yuanyuan Jing, Fan Wu, Dai Li, Lei Yang, Qi Li, Rong Li
Obesity is reported to be a chronic low-grade inflammatory state. Adipose tissue macrophages play a key role in obesity-related inflammation. Metformin, the most widely used anti-diabetic drug, has recently been reported to have an effect on inflammation, but the mechanism is poorly understood. This study aims to investigate how metformin works on chronic low-grade inflammation in obesity and whether the mechanism underlying it is associated with macrophage polarization. Metformin was administered for 7 weeks to high fat-fed C57/6J male mice in vivo. Metformin, compound C (an AMPK inhibitor) and AICAR (an AMPK activator) were used for the in vitro intervention. The gene expression of macrophages markers was examined. Pro-inflammatory cytokines IL-6 and TNF-α were tested by ELISA. The macrophage subsets were analyzed by flow cytometry. In vivo, we discovered that metformin not only decreased the serum level of the pro-inflammatory cytokines IL-6 and TNF-α but also lowered the expression of the M1 macrophage markers CD11c and MCP-1 in adipose tissue. In vitro, metformin reduced the secretion of IL-6 and TNF-α in palmitate-stimulated RAW264.7 macrophages, while compound C treatment blocked the effect of metformin. Moreover, treatment with metformin and AICAR decreased the proportion of M1 macrophages and increased the proportion of M2 macrophages, as analyzed by flow cytometry, in palmitate-stimulated BMDMs. In addition, the effect of AICAR on macrophage polarization was stronger than that of metformin. These results suggest that metformin improves low-grade inflammation in obesity and modulates macrophage polarization to an anti-inflammatory, M2 phenotype partly via the activation of AMPK.
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Estrogen directly stimulates LHb expression at the pituitary level during puberty in female zebrafish
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Gaofei Li, Haipei Tang, Yu Chen, Yike Yin, Satoshi Ogawa, Meifeng Liu, Yin Guo, Xin Qi, Yun Liu, Ishwar S. Parhar, Xiaochun Liu, Haoran Lin
The LHb expression is up-regulated during puberty in female zebrafish. However, the molecular mechanism underlying how LHb expression is regulated during puberty remains largely unknown. In this study, we found that the mRNA expression levels of lhb, fshb and cyp19a1b were up-regulated along with the puberty onset in zebrafish. Among the three nuclear estrogen receptors (nERs), the esr2b is the only type whose expression is significantly up-regulated during puberty onset in the pituitary. However, in situ hybridization results revealed that lhb mRNA was colocalized with esr1 and esr2a but not esr2b. Exposure to estradiol (E2) significantly stimulates LHb expression in both wild-type and kiss1−/−;kiss2−/−;gnrh3−/− triple knockout pubertal zebrafish. Moreover, exposure of cultured pituitary cells to E2 increased the LHb expression, indicating that the estrogenic effect on LHb expression could be acted at the pituitary level. Finally, we cloned and analyzed the promoter of lhb by luciferase assay. Our results indicated that the E2 responsive regions of lhb promoter for ERα and ERβ2 are identical, suggesting that ERα and ERβ2 could bind to the same half ERE region of the promoter of lhb, exhibiting a classical ERE-dependent pathway. In summary, we demonstrate that E2 could directly act on the pituitary level to stimulate LHb transcription during puberty in zebrafish.
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Sex-dependent changes in lipid metabolism, PPAR pathways and microRNAs that target PPARs in the fetal liver of rats with gestational diabetes
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Daiana Fornes, Verónica White, Romina Higa, Florencia Heinecke, Evangelina Capobianco, Alicia Jawerbaum
Gestational diabetes mellitus (GDM) is a prevalent disease that impairs fetal metabolism and development. We have previously characterized a rat model of GDM induced by developmental programming. Here, we analyzed lipid content, the levels of the three PPAR isotypes and the expression of microRNAs that regulate PPARs expression in the liver of male and female fetuses of control and GDM rats on day 21 of pregnancy. We found increased levels of triglycerides and cholesterol in the livers of male fetuses of GDM rats compared to controls, and, oppositely, reduced levels of triglycerides, cholesterol, phospholipids and free fatty acids in the livers of female fetuses of GDM rats compared to controls. Although GDM did not change PPARα levels in male and female fetal livers, PPARγ was increased in the liver of male fetuses of GDM rats, a change that occurred in parallel to a reduction in the expression of miR-130, a microRNA that targets PPARγ. In livers of female fetuses of GDM rats, no changes in PPARγ and miR-130 were evidenced, but PPARδ was increased, a change that occurred in parallel to a reduction in the expression of miR-9, a microRNA that targets PPARδ, and was unchanged in the liver of male fetuses of GDM and control rats. These results show clear sex-dependent changes in microRNAs that target different PPAR isotypes in relation to changes in the levels of their targets and the differential regulation of lipid metabolism evidenced in fetal livers of GDM pregnancies.
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Deletion of protein kinase D1 in osteoprogenitor cells results in decreased osteogenesis in vitro and reduced bone mineral density in vivo
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Wendy B. Bollag, Vivek Choudhary, Qing Zhong, Ke-Hong Ding, Jianrui Xu, Ranya Elsayed, Kanglun Yu, Yun Su, Lakiea J. Bailey, Xing-Ming Shi, Mohammed Elsalanty, Maribeth H. Johnson, Meghan E. McGee-Lawrence, Carlos M. Isales
Protein kinase D1 (PRKD1) is thought to play a role in a number of cellular functions, including proliferation and differentiation. We hypothesized that PRKD1 in bone marrow-derived mesenchymal stem cells (BMMSC) could modulate osteogenesis. In BMMSCs from floxed PRKD1 mice, PRKD1 ablation with adenovirus-mediated Cre-recombinase expression inhibited BMMSC differentiation in vitro. In 3- and 6-month-old conditional knockout mice (cKO), in which PRKD1 was ablated in osteoprogenitor cells by osterix promoter-driven Cre-recombinase, bone mineral density (BMD) was significantly reduced compared with floxed control littermates. Microcomputed tomography analysis also demonstrated a decrease in trabecular thickness and bone volume fraction in cKO mice at these ages. Dynamic bone histomorphometry suggested a mineralization defect in the cKO mice. However, by 9 months of age, the bone appeared to compensate for the lack of PRKD1, and BMD was not different. Taken together, these results suggest a potentially important role for PRKD1 in bone formation.
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Editorial Board
Source:Molecular and Cellular Endocrinology, Volume 461
http://ift.tt/2BD8CmZ
Mifepristone enhances insulin-stimulated Akt phosphorylation and glucose uptake in skeletal muscle cells
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Izela Bernal-Sore, Mario Navarro-Marquez, César Osorio-Fuentealba, Francisco Díaz-Castro, Andrea del Campo, Camila Donoso-Barraza, Omar Porras, Sergio Lavandero, Rodrigo Troncoso
Mifepristone is the only FDA-approved drug for glycaemia control in patients with Cushing's syndrome and type 2 diabetes. Mifepristone also has beneficial effects in animal models of diabetes and patients with antipsychotic treatment-induced obesity. However, the mechanisms through which Mifepristone produces its beneficial effects are not completely elucidated.PurposeTo determine the effects of mifepristone on insulin-stimulated glucose uptake on a model of L6 rat-derived skeletal muscle cells.ResultsMifepristone enhanced insulin-dependent glucose uptake, GLUT4 translocation to the plasma membrane and Akt Ser473 phosphorylation in L6 myotubes. In addition, mifepristone reduced oxygen consumption and ATP levels and increased AMPK Thr172 phosphorylation. The knockdown of AMPK prevented the effects of mifepristone on insulin response.ConclusionsMifepristone enhanced insulin-stimulated glucose uptake through a mechanism that involves a decrease in mitochondrial function and AMPK activation in skeletal muscle cells.
http://ift.tt/2nki9Lj
MXRA5 is decreased in preeclampsia and affects trophoblast cell invasion through the MAPK pathway
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Lan Ding, Shaocong Li, Yanshang Zhang, Junfeng Gai, Jianfang Kou
Preeclampsia causes gestational failure in a significant number of women annually. Insufficient trophoblast cell invasion plays an essential role in preeclampsia pathogenesis. Matrix-remodeling associated 5 (MXRA5) is a proteoglycan involved in adhesion and matrix remodeling. This study sought to explore the role of MXRA5 in trophoblast cell invasion. Preeclamptic villi were obtained for the delineation of MXRA5 expression. Specific MXRA5 siRNA and pcDNA3.1/MXRA5 were used to manipulate MXRA5 expression in HTR-8/SVneo. Cell viability was determined by MTT and apoptosis by flow cytometry. Cell invasion was evaluated using Matrigel invasion assay. MXRA5 expression was lower in preeclamptic villi and cytotrophoblasts. Silencing MXRA5 expression in HTR-8/SVneo decreased cell viability and invasion, which were augmented by MXRA5 overexpression. Furthermore, MXRA5 modulated N-cadherin, E-cadherin, MMP-2, and MMP-9 expression through p38 MAPK and ERK1/2 signaling transduction. In addition, the expression of MXRA5 was influenced by exogenous TNF-α but not by IFN-γ. Overexpression of MXRA5 attenuated HTR-8/SVneo apoptosis induced by TNF-α. MXRA5 is downregulated in preeclamptic cytotrophoblasts and can regulate trophoblast cell invasion via the MAPK pathway.
http://ift.tt/2BBVDlH
Mutational analysis of rare subtypes of congenital adrenal hyperplasia in a highly inbred population
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Meshael M. Alswailem, Ohoud S. Alzahrani, Doha S. Alhomaidah, Rahma Alasmari, Ebtesam Qasem, Avaniyapuram Kannan Murugan, Afaf Alsagheir, Imad Brema, Bassam Ben Abbas, Mohammed Almehthel, Ali Almeqbali, Ali S. Alzahrani
ContextApart from 21 Hydroxylase deficiency, other subtypes of congenital adrenal hyperplasia (CAH) are rare. We studied the clinical features and molecular genetics of a relatively large series of patients with CYP17A1, HSD3β2 and StAR deficiencies.Patients and methodsWe studied 21 patients including 7 patients with CYP17A1, 10 patients with HSD3β2 and 4 patients with StAR deficiencies. For mutation detection, we isolated DNA from peripheral leucocytes, amplified genes of interest using polymerase chain reaction and directly sequenced the amplicons using Dideoxy Chain Termination method.ResultsRegardless of their karyotype, patients with CYP17A1 deficiency presented with normally looking external female genitalia and were raised as females. Hypertension and hypokalemia were prominent features in 4 of 7 patients. Two missense (p.R416H, p.R239Q) and 2 non-sense (p.Y329X, p.Y329X) mutations were found in these 7 cases. In 3 unrelated families with 10 affected siblings with HSD3β2 mutations, two non-sense mutations were found (p.Q334X, p.R335X). 46XY patients with HSD3β2 deficiency presented with ambiguous genitalia while 46XX patients presented with normal female external genitalia. Adrenal crisis was common in patients with both karyotypes. In the 4 patients with StAR deficiency, both genetic male and female patients presented with normally looking female external genitalia and adrenal crisis. One previously reported missense mutation (p.R182H) was found in 3 unrelated patients and a novel non-sense mutation (p.Q264X) in the fourth patient.ConclusionsThese cases of rare subtypes of CAH illustrate the heterogeneous phenotypic and genetic features of these subtypes and add unique novel mutations to the previously known ones.
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Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer
Publication date: 5 February 2018
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Therina du Toit, Amanda C. Swart
Although the adrenal C19 steroids, androstenedione and testosterone, contribute to prostate cancer (PCa) progression the full complement of adrenal androgens, including the C11-oxy C19 steroids, 11β-hydroxyandrostenedione (11OHA4) and 11β-hydroxytestosterone (11OHT) and their androgenic metabolites, 11keto-testosterone (11KT) and 11keto-dihydrotestosterone (11KDHT) have, to date, not been considered. This study investigated the contribution of 11OHA4 and 11OHT to the pool of active androgens in the prostate. Steroid profiles were determined in LNCaP, C4-2B and VCaP cell models, in PCa tissue, and in plasma focussing on the inactivation, reactivation and glucuronidation of 11OHA4, 11OHT and their downstream products using ultra-performance convergence chromatography tandem mass spectrometry (UPC2-MS/MS). The C11-oxy C19 steroids were the predominant steroids with the production of 11KT and 11KDHT in prostate cell models identifying 11β-hydroxysteroid dehydrogenase type 2 activity. Active:inactive steroid ratios indicated efficient inactivation of dihydrotestosterone (DHT) and 11KDHT by 3α-hydroxysteroid dehydrogenases, while the reactivation of DHT by retinol-like dehydrogenases was greater than the reactivation of 11KDHT. In PCa tissue, inactive C11-oxy C19 steroids ranged from 27 to 30 ng/g, whereas inactive C19 steroids were below 1 ng/g. Steroid glucuronidation was impeded: in VCaP cells, the C11-oxy C19 steroids were unconjugated and the C19 steroids fully conjugated; in C4-2B cells, all steroids were unconjugated, except for DHT of which 50% was conjugated; in LNCaP cells only androsterone, 11KT and 11β-hydroxyandrosterone were unconjugated. In PCa patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated (90–95%). Even though plasma and tissue sample numbers were limited, this study serves to demonstrate the abundance of C11-oxy C19 steroids, with notable differences in their metabolism, dictated by steroidogenic enzymes and hampered conjugation, affecting active androgen levels. Larger cohorts are required to analyse profiles in modulated metabolic pathways, in order to shed light on treatment outcomes. The C11-oxy C19 steroids are involved in PCa, with impeded glucuronidation in PCa ascribing a dominant role to these steroids in disease progression.
Graphical abstract
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The AGP-PPARγ axis promotes oxidative stress and diabetic endothelial cell dysfunction
Source:Molecular and Cellular Endocrinology
Author(s): Ryoko Tsukahara, Hisao Haniu, Yoshikazu Matsuda, Tamotsu Tsukahara
Alkyl-glycerophosphate (AGP) accumulates in atherogenic oxidized-LDL and human atherosclerotic plaques and is a potent agonist of peroxisome-proliferator-activated receptor-gamma (PPARγ). Recent studies suggest a potential regulatory role for PPARγ in endothelial nitric oxide synthase (eNOS) expression/activation and nitrogen oxide (NO) generation in the vascular endothelium. Importantly, eNOS-induced NO and advanced glycation end-products (AGEs) are involved in blood-vessel damage, and diabetic patients exhibit high serum NO and AGE levels; however, the effect of AGP on NO- and AGE-mediated endothelium dysfunction remains unknown. Investigation of the AGP-specific effects on NO- and AGE-mediated dysfunction and the underlying molecular mechanisms revealed that AGP upregulated eNOS expression and NO production, and that eNOS silencing and PPARγ antagonism inhibited AGP-mediated eNOS upregulation and NO production. Moreover, AGP-PPARγ-axis-mediated NO production promoted the generation of reactive oxygen species and AGE formation. These results suggested that AGP plays a significant role in the initiation/progression of diabetes-related atherosclerosis through PPARγ activation.
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SIRT1 is a transcriptional enhancer of the glucocorticoid receptor acting independently to its deacetylase activity
Publication date: 5 February 2018
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Shigeru Suzuki, James R. Iben, Steven L. Coon, Tomoshige Kino
Glucocorticoids have strong effects on diverse human activities through the glucocorticoid receptor (GR). Sirtuin 1 (SIRT1) is a NAD+-dependent histone deacetylase and promotes longevity by influencing intermediary metabolism and other regulatory activities including mitochondrial function. In this study, we examined the effects of SIRT1 on GR-mediated transcriptional activity. We found that SIRT1 enhanced GR-induced transcriptional activity on endogenous and exogenous glucocorticoid-responsive genes, whereas knockdown of SIRT1 attenuated it. This effect of SIRT1 was independent to its deacetylase activity, as the SIRT1 mutant defective in this activity (H363Y) enhanced GR transcriptional activity, and the compounds inhibiting or activating the SIRT1 deacetylase activity did not influence it. RNA-seq analysis revealed that SIRT1 knockdown influenced ∼30% of the glucocorticoid-responsive transcriptome for most of which it acted as an enhancer for positive/negative effects of this hormone. SIRT1 physically interacted with GR, and was attracted to GR-bound glucocorticoid response elements in a glucocorticoid-dependent fashion. SIRT1 cooperatively activated GR transcriptional activity with the PPARγ coactivator-1α also in its deacetylase activity-independent fashion. Thus, SIRT1 is a novel transcriptional enhancer of GR-induced transcriptional activity possibly by functioning as a scaffold for the transcriptional complex formed on GR.
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The retrotransposon gag domain containing protein Rgag4 is an Ikaros target in the pituitary
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Zhongyi Shen, Sylvia L. Asa, Shereen Ezzat
Previous studies have established the common and critical involvement of the zinc finger protein Ikaros in lymphoid and pituitary cell development and expansion. Key to the assembly of several transcriptional networks, we have demonstrated up-regulation of Ikaros and its interacting partner the C-terminal Binding Protein (CtBP) in response to hypoxia. This prompted us to explore common transcriptional targets using a chromatin immunoprecipitate (ChIP) screen of DNA from pituitary corticotroph cells. This strategy yielded a finite list of targets common to both transcription factors that included the metalloprotease ADAMTS10. In this report, we focus on validation of a second candidate target, the retrotransposon gag domain containing protein Rgag4. We identified the ability of Ikaros to bind the Rgag4 promoter, influence its transcriptional activity, and induce endogenous gene expression. Robust expression of Rgag4 was noted in the anterior lobe of the pituitary gland which was diminished in Ikaros knockout mice. Down-regulation of Rgag4 resulted in profound reduction of hormone gene expression with diminished ACTH secretion, recapitulating the effect of Ikaros deficiency in knockout mice. The results introduce Rgag4 to the repertoire of effectors serving to couple the chromatin remodeler Ikaros with the hormonal stress response.
http://ift.tt/2nkjORb
Role of fibroblast growth factor receptors (FGFR) and FGFR like-1 (FGFRL1) in mesenchymal stromal cell differentiation to osteoblasts and adipocytes
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): T.E. Kähkönen, K.K. Ivaska, M. Jian, K.G. Büki, H.K. Väänänen, P.L. Härkönen
Fibroblast growth factors (FGF) and their receptors (FGFRs) regulate many developmental processes including differentiation of mesenchymal stromal cells (MSC). We developed two MSC lines capable of differentiating to osteoblasts and adipocytes and studied the role of FGFRs in this process. We identified FGFR2 and fibroblast growth factor receptor like-1 (FGFRL1) as possible actors in MSC differentiation with gene microarray and qRT-PCR. FGFR2 and FGFRL1 mRNA expression strongly increased during MSC differentiation to osteoblasts. FGF2 treatment, resulting in downregulation of FGFR2, or silencing FGFR2 expression with siRNAs inhibited osteoblast differentiation. During adipocyte differentiation expression of FGFR1 and FGFRL1 increased and was down-regulated by FGF2. FGFR1 knockdown inhibited adipocyte differentiation. Silencing FGFR2 and FGFR1 in MSCs was associated with decreased FGFRL1 expression in osteoblasts and adipocytes, respectively. Our results suggest that FGFR1 and FGFR2 regulate FGFRL1 expression. FGFRL1 may mediate or modulate FGFR regulation of MSC differentiation together with FGFR2 in osteoblastic and FGFR1 in adipocytic lineage.
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Sulforaphane improves disrupted ER-mitochondria interactions and suppresses exaggerated hepatic glucose production
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Emily Tubbs, Annika S. Axelsson, Guillaume Vial, Claes B. Wollheim, Jennifer Rieusset, Anders H. Rosengren
AimsExaggerated hepatic glucose production is one of the hallmarks of type 2 diabetes. Sulforaphane (SFN) has been suggested as a new potential anti-diabetic compound. However, the effects of SFN in hepatocytes are yet unclear. Accumulating evidence points to the close structural contacts between the ER and mitochondria, known as mitochondria-associated ER membranes (MAMs), as important hubs for hepatic metabolism. We wanted to investigate whether SFN could affect hepatic glucose production and MAMs.Materials and methodsWe used proximity ligation assays, analysis of ER stress markers and glucose production assays in hepatoma cell lines, primary mouse hepatocytes and diabetic animal models.ResultsSFN counteracted the increase of glucose production in palmitate-treated mouse hepatocytes. SFN also counteracted palmitate-induced MAM disruptions. Moreover, SFN decreased the ER stress markers CHOP and Grp78. In ob/ob mice, SFN improved glucose tolerance and reduced exaggerated glucose production. In livers of these mice, SFN increased MAM protein content, restored impaired VDAC1-IP3R1 interactions and reduced ER stress markers. In mice on HFHSD, SFN improved glucose tolerance, MAM protein content and ER-mitochondria interactions to a similar extent to that of metformin.ConclusionsThe present findings show that MAMs are severely reduced in animal models of glucose intolerance, which reinforces the role of MAMs as a hub for insulin signaling in the liver. We also show that SFN restores MAMs and improves glucose tolerance by a similar magnitude to that of metformin. These data highlight SFN as a new potential anti-diabetic compound.
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PDZ domain containing protein 1 (PDZK1), a modulator of membrane proteins, is regulated by the nuclear receptor THRβ
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): Celio Ferreira, Katharina Prestin, Janine Hussner, Uwe Zimmermann, Henriette E. Meyer zu Schwabedissen
Genome wide association studies revealed single nucleotide polymorphisms (SNP) located within the promoter of PDZ domain containing protein 1 (PDZK1) to be associated with serum uric acid levels. Since modulation of transporters and particularly of membrane proteins involved in uric acid handling by PDZK1 has previously been reported, the aim of this study was to analyze the impact of the polymorphisms rs1967017, rs1471633, and rs12129861 on promoter activity and thereby transcription of PDZK1. Cell-based reporter gene assays showed transactivation of the PDZK1-promoter by triiodothyronine mediated by thyroid hormone receptors (THR) α and β. In silico analysis verified localization of the polymorphism rs1967017 within the most likely THR binding site whose deletion reduced THR-mediated transactivation. Furthermore, our study shows regulation of PDZK1 by thyroid hormones, thereby providing a mechanistic basis for the previously reported associations between thyroid hormone status and uric acid homeostasis.
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SKOV3 cells containing a truncated ARID1a protein have a restricted genome-wide response to glucocorticoids
Source:Molecular and Cellular Endocrinology, Volume 461
Author(s): F.E. Stubbs, M.T. Birnie, S.C. Biddie, S.L. Lightman, B.L. Conway-Campbell
AT-rich interacting domain subunit 1a (ARID1a) is an essential SWI/SNF component frequently mutated in human cancers. ARID1a mutations have also been associated with glucocorticoid resistance, potentially related to the well-established role of the SWI/SNF complex in glucocorticoid target gene regulation. Glucocorticoids are steroid hormones important for regulating many physiological processes through the activation of the glucocorticoid receptor (GR). As GR interacts directly with ARID1a, we hypothesized that a truncating ARID mutation would interfere with GR-dependent gene regulation. Using high throughput RNA sequencing (RNA-SEQ) we show a restricted glucocorticoid response in SKOV3 cells, which contain an inactivating ARID1a mutation. We also show a lack of GR binding at the GR-dependent regulatory site in the Period 1 gene, which has previously been shown to require chromatin remodelling. Taken together, our data suggests that ARID1a may be required for regulation of a subset of glucocorticoid responsive genes. In the case of SKOV3 cells, in which ARID1a is mutated, glucocorticoid-dependent transcriptional regulation of these genes is significantly impaired.
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Riedel’s thyroiditis: clinical presentation, treatment and outcomes
Abstract
Background
Riedel´s thyroiditis (RT) is a rare inflammatory disease of the thyroid gland, causing compression and fibrosis of adjacent tissues. Typically the goiter is hard and firm. Hoarseness, dyspnea, and dysphagia may be present.
Methods
We retrospectively reviewed all patients known by us with RT in addition to all patients with appropriate ICD-10 codes evaluated at the Karolinska University Hospital 2003–2015. Clinical, biochemical, and histological data of patients with RT were recorded in detail. Histological preparations were re-examined when available.
Results
RT was diagnosed in six patients. Five were females and the median age at first presentation was 50 years (25–81 years). Median follow-up time was 3.75 years (1–22 years). At diagnosis five had hypothyroidism. Four had extrathyroidal manifestations, and one of these had also distant fibrosis. One patient had a clear IgG4/IgG ratio over 40%. One patient was treated with tracheostomy, one with isthmectomy and one with total thyroidectomy. Four had been treated with glucocorticoids, four with tamoxifen, and two with both drugs. One had also been treated with mycophenolate mofetil combined with Rituximab. At the end of follow-up four was doing fine, one had recurrent episodes of inflammation and one had died of possible complications to RT.
Conclusion
It is important to recognize RT and give adequate treatment. Steroids are still the mainstay of therapy but other medications against fibrosclerosis can be considered. Wakefulness of other fibrosing manifestations is essential. Immunohistochemistry can show whether IgG-4 plasma cells are increased which could lead to fibrosis in other organs.
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