Burden of Uncontrolled Severe Asthma With and Without Elevated Type-2 Inflammatory Biomarkers

Background: Many patients with asthma have type-2 airway inflammation, identified by the presence of biomarkers, including history of allergy, high blood eosinophil (EOS) count, and high fractional exhaled nitric oxide levels. Objective: To assess disease burden in relation to type-2 inflammatory biomarker status (history of allergy, blood EOS count, and fractional exhaled nitric oxide level) in patients with uncontrolled and controlled severe asthma in the NOVEL observational longiTudinal studY (NOVELTY) (NCT02760329). Methods: Asthma diagnosis and severity were physician-reported. Control was defined using Asthma Control Test score (uncontrolled = 20) and/or 1 or more severe physician-reported exacerbation in the previous year. Biomarker distribution (history of allergy, blood EOS count, and fractional exhaled nitric oxide level), symptom burden (Asthma Control Test score, modified Medical Research Council dyspnea scale), health status (St George's Respiratory Questionnaire score), exacerbations, and health care resource utilization were assessed. Results: Of 647 patients with severe asthma, 446 had uncontrolled and 123 had controlled asthma. Among those with uncontrolled asthma, 196 (44%) had 2 or more positive biomarkers, 187 (42%) had 1 positive biomarker, 325 (73%) had low blood EOS, and 63 (14%) were triple-negative. Disease burden was similarly high across uncontrolled subgroups, irrespective of biomarker status, with poor symptom control (Asthma Control Test score 14.9-16.6), impaired health status (St George's Respiratory Questionnaire total score 46.7-49.4), clinically important breathlessness (modified Medical Research Council grade >= 2 in 47.3%-57.1%), and 1 or more severe exacerbation (70.6%-76.2%). Conclusions: Type-2 inflammatory biomarkers did not differentiate disease burden in patients with severe asthma. Patients with low type-2 inflammatory biomarker levels have few biologic therapy options; their needs should be addressed

Nitric Oxide Synthase in Human Parathyroid Glands and Parathyroid Adenomas

Nitric oxide (NO) is a novel gaseous intercellular transmitter thought to play important physiological roles in the regulation of blood flow and hormone secretion in, for example, the pituitary, the thyroid, and the endocrine pancreas. Whether nitric oxide synthase (NOS) is present in the human parathyroid glands has not yet been demonstrated. In the present study, histologically normal, but functionally suppressed human parathyroid glands and parathyroid adenomas from patients with primary hyperparathyroidism were investigated by immunocytochemistry with antibodies against neuronal NOS and by reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry. We also used H&E to identify the NOS-immunoreactive cells. Immunocytochemistry demonstrated the presence of neuronal-type NOS in a subpopulation of glandular cells, identified as oxyphilic cells, in both normal parathyroid glands and adenomas. NADPH-diaphorase staining visualized NOS in the endothelium of blood vessels and in glandular cells, corresponding to those containing immunoreactive NOS. In addition, we found NADPIH-diaphorase staining in many chief cells. Our results indicate that both glandular cells and vascular endothelium in human parathyroid glands and adenomas express NOS. There is thus a morphological substrate for locally produced NO that may be involved in the regulation of parathyroid blood flow and hormone secretion

Subepithelial Hydrostatic Pressure May Regulate Plasma Exudation across the Mucosa

This study demonstrated in guinea pig tracheal tubes in vitro that small increases in serosal hydrostatic pressure caused significant mucosal crossing of serosal macromolecules. Reversibility and repeatabilityof this passage agree with inflammatory stimulus-induced appearance of exuded plasma in airway lumen invivo. Bradykinin, histamine, and terbutaline, which induce and inhibit, respectively, plasma exudation in vivo, were without effect on the present in vitro permeability. Carbachol, similar to histamine, contracted the trachea, and did not increase, but rather decreased the pressure-induced luminal entry of serosal macromolecules.It is proposed that a plasma-exudation-induced hydrostatic pressure load transiently separates epithelial cells, providing a direction-selective and non-injurious intercellular pathway for passage of bulk plasma exudateinto the airway lumen. This mechanism would allow potent plasma protein systems to operate on mucosal surfaces at sites of insults without compromising the mucosa as a barrier to luminal solutes.</jats:p

Comparison of methods for evaluation of the suppressive effects of prednisolone on the HPA axis and bone turnover: changes in s-DHEAS are as sensitive as the ACTH test

Objective: Different hypothalamic-pituitary-adrenal (HPA) axis function tests are used for diagnosing disease and evaluating suppressive effects of corticosteroid treatment. Our objectives were to evaluate sensitivity and precision of different HPA axis tests to be able to select one that combines good performance with good practicability, suitable for investigation of new corticosteroids in clinical trials. Methods: In this descriptive, double-blind, parallel-group study, 60 healthy male volunteers were treated with once-daily morning doses of prednisolone for 2 weeks. The volunteers were randomized to 1 of 5 treatment groups (prednisolone 2.5, 5, 7.5, 10, or 15 mg). We compared the plasma-cortisol (p-cortisol) 24-hour average concentration (C,) with morning (08:00 hours) p-cortisol, daytime p-cortisol C,, and 24-hour urinary cortisol excretion. Adrenocorticotrophic hormone (ACTH) stimulation tests and the metyrapone test were also performed. Furthermore, we analyzed levels of serum dehydroepiandrosterone sulfate (s-DHEAS), insulin, and markers of bone turnover. Results: Dose-related effects were shown, but the magnitude of effects and sensitivities varied greatly between the tests. P-cortisol measurements over the course of 24 hours were used as the reference method. Low- and standard-dose ACTH tests and morning s-DHEAS levels had similar sensitivity. Urinary cortisol excretion and the metyrapone stimulation test had low sensitivity. The effects of prednisolone on markers of bone turnover were, in general, less than those on the HPA axis. Only osteocalcin, procollagen type 1 C-peptide and procollagen type 3 N-peptide were significantly affected. Treatment with prednisolone was well tolerated. Conclusion: Changes in s-DHEAS and the low-dose ACTH test combine good sensitivity and precision for evaluation of the suppressive effect of exogenous corticosteroids on the HPA axis, and they are easy to perform

Supplementary Materials 3 from Identification of New MicroRNAs in Paired Normal and Tumor Breast Tissue Suggests a Dual Role for the &lt;i&gt;ERBB2/Her2&lt;/i&gt; Gene

Supplementary Materials 3 from Identification of New MicroRNAs in Paired Normal and Tumor Breast Tissue Suggests a Dual Role for the &lt;i&gt;ERBB2/Her2&lt;/i&gt; Gene</jats:p

Long lasting smooth muscle relaxation by a novel PACAP analogue in guinea-pig and primate airways in vitro

1. We compared the relaxant effect of pituitary adenylate cyclase activating peptide (PACAP) 1–27 with that of a newly developed PACAP 1–27 analogue, [Arg(15,20,21)Leu(17)]-PACAP-Gly-Lys-Arg-NH(2), in the guinea-pig trachea and primate bronchi in vitro (n=4–5). 2. In the guinea-pig trachea precontracted by a submaximally effective carbachol concentration (0.1 μM), cumulative administration of PACAP 1–27 and the β(2)-adrenoceptor agonist salbutamol (3 nM–3 μM) caused significant and concentration-dependent smooth muscle relaxation, with salbutamol being approximately one log-step more potent in this model. However, in primate bronchi precontracted by carbachol (0.1 μM), cumulative administration of PACAP 1–27 and salbutamol caused concentration-dependent smooth muscle relaxation with very similar potencies and maximum relaxant effects. 3. In the guinea-pig trachea, non-cumulative administration of the PACAP 1–27 analogue and the original PACAP 1–27 (0.3–3 μM) caused concentration-dependent relaxation with a very similar maximum relaxant effect and potency. However, the onset and offset of action was markedly slower for the PACAP 1–27 analogue than for the original PACAP 1–27 (>90% versus <10% of peak relaxation remaining 6 h after administration). Separate experiments confirmed that the PACAP 1–27 analogue also caused significant relaxation with slower onset and offset of action than did the original PACAP 1–27 in primate bronchi. 4. Peptidase inhibition by captopril (10 μM) and phosphoramidon (1 μM) significantly increased the maximum relaxant effect and duration of action of PACAP 1–27 but not of the PACAP 1–27 analogue, during the 3 h of observation in the guinea-pig trachea. 5. We conclude that [Arg(15,20,21)Leu(17)]-PACAP-Gly-Lys-Arg-NH(2) produces significant, concentration-dependent and sustained airway smooth muscle relaxation in vitro. The sustained relaxant effect is due, at least in part, to the PACAP 1–27 analogue being less susceptible to cleavage by peptidases than the original peptide PACAP 1–27

Identification of new microRNAs in paired normal and tumor breast tissue suggests a dual role for the ERBB2/Her2 gene.

To comprehensively characterize microRNA (miRNA) expression in breast cancer, we performed the first extensive next-generation sequencing expression analysis of this disease. We sequenced small RNA from tumors with paired samples of normal and tumor-adjacent breast tissue. Our results indicate that tumor identity is achieved mainly by variation in the expression levels of a common set of miRNAs rather than by tissue-specific expression. We also report 361 new, well-supported miRNA precursors. Nearly two-thirds of these new genes were detected in other human tissues and 49% of the miRNAs were found associated with Ago2 in MCF7 cells. Ten percent of the new miRNAs are located in regions with high-level genomic amplifications in breast cancer. A new miRNA is encoded within the ERBB2/Her2 gene and amplification of this gene leads to overexpression of the new miRNA, indicating that this potent oncogene and important clinical marker may have two different biological functions. In summary, our work substantially expands the number of known miRNAs and highlights the complexity of small RNA expression in breast cancer