Paradoxical to its importance for generating a diverse T cell repertoire, thymic function progressively declines throughout life. This process has been at least partially attributed to the effects of ...sex steroids, and their removal promotes enhanced thymopoiesis and recovery from immune injury. We show that one mechanism by which sex steroids influence thymopoiesis is through direct inhibition in cortical thymic epithelial cells (cTECs) of Delta-like 4 (Dll4), a Notch ligand crucial for the commitment and differentiation of T cell progenitors in a dose-dependent manner. Consistent with this, sex steroid ablation (SSA) led to increased expression of Dll4 and its downstream targets. Importantly, SSA induced by luteinizing hormone-releasing hormone (LHRH) receptor antagonism bypassed the surge in sex steroids caused by LHRH agonists, the gold standard for clinical ablation of sex steroids, thereby facilitating increased Dll4 expression and more rapid promotion of thymopoiesis. Collectively, these findings not only reveal a novel mechanism underlying improved thymic regeneration upon SSA but also offer an improved clinical strategy for successfully boosting immune function.
Background Newborns have frequent infections and manifest impaired vaccine responses, motivating a search for neonatal vaccine adjuvants. Alum is a neonatal adjuvant but might confer a TH 2 bias. ...Toll-like receptor (TLR) agonists are candidate adjuvants, but human neonatal cord blood monocytes demonstrate impaired TH 1-polarizing responses to many TLR agonists caused by plasma adenosine acting through cyclic AMP. TLR8 agonists, including imidazoquinolines (IMQs), such as the small synthetic 3M-002, induce adult-level TNF from neonatal monocytes, but the scope and mechanisms of IMQ-induced activation of neonatal monocytes and monocyte-derived dendritic cells (MoDCs) have not been reported. Objective We sought to characterize IMQ-induced activation of neonatal monocytes and MoDCs. Methods Neonatal cord and adult peripheral blood monocytes and MoDCs were cultured in autologous plasma; levels of alum- and TLR agonist–induced cytokines and costimulatory molecules were measured. TLR8 and inflammasome function were assayed by using small interfering RNA and Western blotting/caspase-1 inhibitory peptide, respectively. The ontogeny of TLR8 agonist–induced cytokine responses was defined in rhesus macaque whole blood ex vivo. Results IMQs were more potent and effective than alum at inducing TNF and IL-1β from monocytes. 3M-002 induced robust TLR pathway transcriptome activation and TH 1-polarizing cytokine production in neonatal and adult monocytes and MoDCs, signaling through TLR8 in an adenosine/cyclic AMP–refractory manner. Newborn MoDCs displayed impaired LPS/ATP-induced caspase-1–mediated IL-1β production but robust 3M-002–induced caspase-1–mediated inflammasome activation independent of exogenous ATP. TLR8 IMQs induced robust TNF and IL-1β in whole blood of rhesus macaques at birth and infancy. Conclusions IMQ TLR8 agonists engage adenosine-refractory TLR8 and inflammasome pathways to induce robust monocyte and MoDC activation and represent promising neonatal adjuvants.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder. Objective To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL ...Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema. Methods This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours. Results Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. Conclusion C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We report the case of a 73-year-old woman diagnosed with heavy eye syndrome who underwent loop myopexy of the superior rectus and lateral rectus muscles after suffering pulled-in-two syndrome caused ...by exploration of the medial rectus muscle, which could not be recovered. Given that intraoperative forced ductions remained positive after loss of the muscle, a loop myopexy of the superior rectus muscle and lateral rectus muscles was performed. Postoperatively the patient regained full adduction, and her esotropia improved notably.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: trans Fatty acid (TFA) intake increases systemic inflammation in healthy persons. However, the effect in patients with established heart disease is unknown. Objective: Our aim was to ...determine whether TFAs are associated with systemic inflammation in patients with established heart disease. Design: Red blood cell membrane TFAs, a biomarker of dietary intake, and inflammatory marker concentrations were ascertained in 86 ambulatory patients with established heart failure. Associations between TFA levels and inflammatory markers were evaluated by linear regression. Results: Mean (+/-SD) TFA levels were 1.8 +/- 0.4% of membrane fatty acids (range: 0.7-2.9%). For each inflammatory marker, associations are presented as the absolute difference and percentage difference from the mean for each 1% higher membrane TFA level. After adjustment for age, sex, body mass index, diabetes, smoking, ejection fraction, New York Heart Association class, ischemic etiology, statin use, and serum glucose, TFA levels were positively associated with interleukin (IL) 1beta (difference from mean: 0.38 pg/mL; percentage difference from mean: 66%; P = 0.04), IL-1 receptor antagonist (4033 pg/mL; 297%; P = 0.006), IL-6 (9.5 pg/mL; 123%; P = 0.006), IL-10 (241 pg/mL; 183%; P = 0.02), tumor necrosis factor (TNF) alpha (256 pg/mL; 249%; P = 0.02), TNF receptor 1 (537 pg/mL; 41%; P = 0.03), TNF receptor 2 (39 242 pg/mL; 247%; P = 0.001), monocyte chemoattractant protein 1 (117 pg/mL; 119%; P = 0.004), and brain natriuretic peptide (40 pg/mL; 57%; P = 0.04). Further adjustments for other patient characteristics did not significantly alter the results. Conclusion: TFAs are strongly associated with systemic inflammation in patients with heart disease, which suggests that attention to TFA intake may be important for secondary prevention efforts.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is ...substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O).
Methods
Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence‐based review, or evidence‐based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus.
Results
The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies.
Conclusion
This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To identify a melanoma microRNA (miRNA) expression signature that is predictive of outcome and then evaluate its potential to improve risk stratification when added to the standard-of-care staging ...criteria.
Total RNA was extracted from 59 formalin-fixed paraffin-embedded melanoma metastases and hybridized to miRNA arrays containing 911 probes. We then correlated miRNA expression with post-recurrence survival and other clinicopathologic criteria.
We identified a signature of 18 miRNAs whose overexpression was significantly correlated with longer survival, defined as more than 18 months post-recurrence survival. Subsequent cross-validation showed that a small subset of these miRNAs can predict post-recurrence survival in metastatic melanoma with an estimated accuracy of 80.2% (95% confidence interval, 79.8-80.6%). In contrast to standard-of-care staging criteria, a six-miRNA signature significantly stratified stage III patients into "better" and "worse" prognostic categories, and a multivariate Cox regression analysis revealed the signature to be an independent predictor of survival. Furthermore, we showed that most miRNAs from the signature also showed differential expression between patients with better and worse prognoses in the corresponding paired primary melanoma.
MiRNA signatures have potential as clinically relevant biomarkers of prognosis in metastatic melanoma. Our data suggest that molecularly based models of risk assessment can improve the standard staging criteria and support the incorporation of miRNAs into such models.
Newborns are prone to microbial infection and have poor memory responses to multiple antigens. We have previously shown that human neonatal blood monocytes exhibit impaired TNF-α responses to most ...known TLR agonists, including the pure TLR7 agonist imiquimod. Surprisingly, however, neonatal TNF-α responses to the imiquimod congener R-848 (TLR 7/8) were fully intact. We now show that TLR8 agonists, including R-848 (TLR7/8), the imidazoquinoline congeners 3M-003 (TLR7/8) and 3M-002 (TLR8), as well as single-stranded viral RNAs (TLR8) induced robust production of the Th1-polarizing cytokines TNF-α and IL-12 from neonatal antigen-presenting cells (APCs) that substantially exceeds responses induced by TLR-2, -4, or -7 (alone) agonists. TLR8 agonists also effectively induced up-regulation of the costimulatory molecule CD40 on neonatal and adult myeloid dendritic cells (DCs). The strong activity of TLR8 agonists correlates with their induction of p38 MAP kinase phosphorylation and with degradation of IκB-α in both neonatal and adult monocytes. We conclude that TLR8 agonists are uniquely efficacious in activating costimulatory responses in neonatal APCs and suggest that these agents are promising candidate adjuvants for enhancing immune responses in human newborns.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Elevated levels of chemokine receptor CCR9 expression in solid tumors may contribute to poor patient prognosis. In this study, we characterized a novel CCR9-mediated pathway that promotes pancreatic ...cancer cell invasion and drug resistance, indicating that CCR9 may play a critical role in cancer progression through activation of β-catenin. We noted that the CCL25/CCR9 axis in pancreatic cancer cells induced the activation of β-catenin, which enhanced cell proliferation, invasion, and drug resistance. CCR9-mediated activation of β-catenin and the resulting downstream effects were effectively inhibited by blockade of the PI3K/AKT pathway, but not by antagonism of Wnt. Importantly, we discovered that CCR9/CCL25 increased the lethal dose of gemcitabine, suggesting decreased efficacy of anti-cancer drugs with CCR9 signaling. Through in silico computational modeling, we identified candidate CCR9 antagonists and tested their effects on CCR9/β-catenin regulation of cell signaling and drug sensitivity. When combined with gemcitabine, it resulted in synergistic cytotoxicity. Our results show that CCR9/β-catenin signaling enhances pancreatic cancer invasiveness and chemoresistance, and may be a highly novel therapeutic target.
•CCR9 receptor mediated signaling increases resistance to chemotherapy agents.•CCR9 receptor mediated signaling activates β-catenin.•CCR9-mediated activation of β-catenin is dependent on the PI3K/AKT pathway.•Novel CCR9 inhibitor was identified in silico study of the CCR9 protein structure.•Novel CCR9 inhibitor synergizes with standard chemotherapy in pancreatic cancer.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Gigantism results from the presence of a growth hormone–secreting pituitary adenoma before epiphyseal fusion. The authors identified a mutation in a gene extracted from the teeth of an 18th-century ...giant and from contemporary Northern Irish families with gigantism, acromegaly, or prolactinomas.
Pituitary adenomas are usually benign, slow-growing tumors that cause symptoms due to excess hormone release, local space-occupying effects, or both. Adenomas that secrete excess growth hormone cause acromegaly. Patients with acromegaly have numerous symptoms and signs, such as hyperhidrosis, prognathism, frontal skull bossing, thickened skin, diabetes mellitus, hypertension, sleep apnea, osteoarthritis, and headache, as well as enlargement of the hands, feet, heart, and other internal organs. Large adenomas expand the pituitary fossa and can lead to visual-field defects and interfere with the production of other pituitary hormones, such as gonadotropic hormones, thyroid-stimulating hormone, or adrenocorticotropin.
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Increased prolactin levels are often . . .
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