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A genetic analysis of a female with a 46,XY genotype and typical symptoms of the complete androgen insensitivity syndrome (CAIS) was conducted. The patient was diagnosed with an abdominal tumor due to the presence of a Sertoli cell adenoma in both gonads. Multiple temperature single-stranded conformational polymorphism (MSSCP) and sequence analyses of the androgen receptor gene revealed a c.C2754 > T mutation in exon 6. This mutation, which has not been previously reported, alters a Gln codon to a termination codon (Q798X). This results in the interruption of the amino acid sequence of the androgen receptor within the ligand-binding domain between helices VII and VIII. The truncated form of the receptor is devoid of 123 amino acids at the carboxyl end, a major part of the ligand-binding domain, and the AT2 sequence responsible for the activation of the transcription. It was concluded that the novel c.C2754 > T transition rendered the androgen receptor incapable of both ligand binding and activating the transcription, and was the cause of CAIS in the patient. [ABSTRACT FROM AUTHOR]

Background: A special regulatory role for prostaglandin E 2 (PGE 2 ) has been postulated in nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD)., Objective: To investigate the effect of systemic aspirin (acetylsalicylic acid) administration on airway PGE 2 biosynthesis in induced sputum supernatant (ISS) among subjects with NERD or aspirin-tolerant asthma with chronic rhinosinusitis with nasal polyposis (ATA-CRSwNP), as well as healthy controls (HC)., Methods: Induced sputum (IS) was collected from patients with NERD (n = 26), ATA-CRSwNP (n = 17), and HC (n = 21) at baseline and after aspirin challenge. Sputum differential cell count and IS supernatant (ISS) levels of prostanoids, PGE 2 , 8-iso-PGE 2 , tetranor-PGE-M, 8-iso-PGF 2 α, and leukotriene C 4 , D 4 , and E 4 , were determined using mass spectrometry. Urinary excretion of LTE 4 was measured by ELISA., Results: NERD subjects had elevated sputum eosinophilic count as compared to ATA-CRSwNP and HC (median NERD 9.1%, ATA-CRSwNP 2.1%, and HC 0.4%; P < 0.01). Baseline ISS levels of PGE 2 were higher in asthmatics as compared to HC at baseline (NERD vs HC P = 0.04, ATA-CRSwNP vs HC P < 0.05). Post-challenge ISS levels of PGE 2 compared to baseline significantly decreased in NERD and HC (P < 0.01 and P = 0.01), but not in ATA-CRSwNP. In NERD, a similar decrease in PGE 2 as in HC resulted from 2.8 times lower dose of aspirin., Conclusion: Aspirin-precipitated bronchoconstriction is associated with a decrease in airway PGE 2 biosynthesis. These results support the mechanism of PGE 2 biosynthesis inhibition as a trigger for bronchoconstriction in NERD., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The aim of this pilot study was to evaluate changes in the concentration of prostaglandin E2 (PGE2) in induced sputum supernatant in 3 groups: sub- jects with NSAID-exacerbated respira- tory disease (NERD), aspirin tolerant asthma (ATA) and healthy controls (HC), before and after oral aspirin chal- lenge test. The study was conducted in the years 2014-2015 at the Clinical Department of the Pulmonology Clinic at the University Hospital in Cracow. 43 patients were enrolled in the study (NERD - n = 15, ATA - n = 15 and HC - n = 13). All of them underwent a placebo-controlled oral aspirin challenge. Sputum was induced 24 hours before the challenge and immediately after the test. Induced sputum was processed in order to obtain cystospin slides to depict inflammatory cell patterns and supernatants, in which PGE2 was measured. The concentration of PGE2 was determined using mass spectrometry coupled with gas chromatography (gas chromatography/mass spectrometry - GC/MS). After aspirin challenge, the concentration of PGE2 in induced sputum supernatant decreased in both asthmatics hypersensitive to aspirin (p = 0.01) and those who tolerated aspirin well (p = 0.17). The change in the healthy control group was not statistically significant. These results support the cyclooxygenase theory of PGE2 inhibition by aspirin. However, the mechanism of bronchoconstriction after aspirin administration alone in patients with NSAID-exacerbated respiratory disease remains unclear.

Aspirin desensitization is considered to be an effective and well-tolerated therapy for patients with Non-steroidal anti-inflammatory(NSAIDs)-Exacerbated Respiratory Disease (NERD). The aim of the present study was to investigate the influence of aspirin desensitization on inflammatory cell count in induced sputum and nasal lavage in fifteen NERD individuals subjected to one-year aspirin therapy. The decrease in induced sputum count of eosinophils and macrophages was observed. Clinical efficacy of aspirin therapy in improving nasal symptoms and quality of life in NERD patients was also confirmed.

The article below shows different forms, patomechanisms and diagnostics criteria of hypersensitivity to NSAIDs based on available literature as well as up to date outlook on implementing low salicylate diet as a treatment.

Background: The purpose of this study was to describe clinical manifestations, laboratory findings and outcome of granulomatosis with polyangiitis (GPA) in pediatric patients living in two regions (Southern and Central) of Poland., Methods: Retrospective analysis of patient hospital records from four large hospitals during a period from 1995 to 2013. Patients with confirmed diagnosis of GPA according to American College of Rheumatology (ACR) and EULAR/PRINTO/PRES criteria for GPA were analyzed. All patients were subjected to clinical, laboratory, radiological and immunological assessment., Results: During this 18-year period only 9 children with confirmed diagnosis of GPA (6 girls, 3 boys) were identified. The average age of the disease onset was 12 years (range: 8-16 years). Average delay between first symptoms and diagnosis was approx. 20 months (range: 0-84 months). Organ system involvement at presentation included: kidneys 88.8% (8/9), lungs 77.7% (7/9), ear/nose/ throat 55.5% (5/9), gastrointestinal tract 55.5% (5/9), skin 44.4% (4/9), joints 22.2% (2/9), eyes 11.1% (1/9) and nervous system 11.1% (1/9). In 5 children disease course was progressive (constant progression of sinusitis in one case, end-stage renal disease in two, chronic kidney disease stage IV in one and one child died due to alveolar hemorrhage)., Conclusion: The majority of our patients were females. Clinical features of pediatric GPA were similar to those described in adults. None of our patients developed subglottic stenosis and in only 2 children saddle-nose deformity was observed. Although GPA was treated according to contemporary standards care, disease progression was observed in more than a half of children.

We present a case of a 57-year-old woman suffering from granulomatosis with polyangiitis (GPA), who in the seventh months of immunosuppressive treatment (cyclophosphamide) progressed with new pulmonary changes and perforations of the hard palate and bronchi. Rituximab was introduced resulting in B-cell depletion and disappearance of anti-PR3 antibody. Palatal holes have substantially diminished and all bronchial perforations disappeared, covered by fibrous tissue. In the fourth month after rituximab administration, large scarring obstruction of the right main bronchus with upper and middle lobes atelectasis emerged. Because of increasing dyspnoea, stenotic bronchus was re-opened by bronchoscopy. Intervention was complicated by bilateral pneumothorax and later, on the seventh day, by fatal pulmonary bleeding. To our knowledge, this is the first report of GPA refractory to cyclophosphamide complicated by palatal and bronchial perforations.

The von Hippel-Lindau (VHL) gene is lost in ≈ 70% of all renal cell carcinomas (RCCs); however, increasing evidence supports the involvement of alternative mechanisms in the regulation of VHL expression, including suppression by microRNAs (miRNAs). miRNAs are small, noncoding RNA molecules that regulate gene expression through binding to target mRNAs. In this study, we found that miRNAs, which are dysregulated in cases of RCC, can target multiple members of RCC-related signaling pathways. Importantly, both VHL and the hypoxia-inducible factor 1-α gene are experimentally validated and are likely direct targets of miR-17-5p and miR-224, as shown by both luciferase assay and Western blot analysis. We found a negative correlation between miR-17-5p and its two predicted targets, VEGF-A and EGLN3, and between miR-224 and its targets SMAD4 and SMAD5 in RCC specimens, suggesting that downstream signaling pathways are also modulated by clear cell RCC-dysregulated miRs. Results from our bioinformatics analysis show that a single miRNA molecule can target multiple components of the same pathway and that multiple miRNAs can target the same molecule. Our results also indicate that miRNAs represent a mechanism for the inactivation of VHL in cases of RCC and can elucidate a new dimension in cancer pathogenesis. As such, miRNAs exemplify new potential therapeutic targets with a significant effect on both tumor growth and metastatic potential., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Intermittent hypoxia (IH) is a major pathological factor in the development of neural deficits associated with sleep-disordered breathing. Here we demonstrate that IH lasting 2 or 30 days, but not sustained hypoxia (SH) of the same duration, was accompanied by several posttranslational modifications of the large subunit of RNA polymerase II, Rpb1, including hydroxylation of proline 1465, phosphorylation of serine 5 residues within the C-terminal domain, and nondegradative ubiquitylation. These modifications were found to occur in two regions of the brain, hippocampal region CA1 and the prefrontal cortex, but not in neocortex, brainstem and CA3 region of hippocampus. We also found that mice exposed to 14 or 30 days of IH, but not SH, demonstrated cognitive deficits in behavioral assays. Furthermore, by using the pheochromocytoma-derived PC12 cell line, we showed that, under in vitro IH conditions, induction of Rpb1 hydroxylation, phosphorylation, and ubiquitylation required that the von Hippel-Lindau protein be present. We hypothesize that the observed modifications of Rpb1 participate in regulating the expression of genes involved in mediating cognitive deficits evoked by chronic IH.

The action of testosterone and 5 alpha-dihydrotestosterone are essential to the development of the male phenotype. Patients with karyotype 46,XY, resistant to these hormones, exhibit a wide spectrum of phenotypes: from phenotypic female, through a range of incomplete masculinization, to under-virilized, infertile man. These disturbances are caused by mutations in the androgen receptor gene (AR). We studied a 46,XY fenotypic female with typical symptoms of Complete Androgen Insensitivity Syndrome (CAIS). Multiple temperature single-stranded conformation polymorphism (MSSCP) and sequence analysis of exon 6 of the AR gene in a patient revealed a C2718T transition causing R786X mutation in the loop between helices VII and VIII of the LBD of the androgen receptor. The R786X mutation has been described in a patient with CAIS only once and no such mutations have been described in Eastern Europe.

Familial male-limited precocious puberty (MPP) is described in a 10 year old patient with typical symptoms of the disease. Sequence analysis of genomic DNA clearly demonstrated a heterozygous T1193C transition in exon 11 of the LH receptor (LHR) gene, which results in M398T substitution in the second transmembrane helix of the protein product of this gene. The same mutation was found in the patient's mother and in her brother. The grandmother and the relatives of the patient's father were free of the mutation. The boy was successfully treated with inhibitors of steroid biosynthesis and androgen antagonists. It is suggested that this mutation caused constitutive activation of the LHR, which results in excessive formation of androgens in Leydig cells and is responsible for the symptoms of precocious puberty in this patient. This is the second case of the familial form of MPP that was maternally inherited.

Familial male-limited precocious puberty (FMPP) is a genetically determined, gonadotropin-independent disorder manifested by the sexual maturation at an early childhood. Low levels of blood gonadotropins, accompanied by a high testosterone levels, may suggest stimulation of androgen synthesis. The reports on the association of a constitutive activation of protein G-coupled receptors and pathogenesis of some clinical conditions have prompted searches for an abnormal structure of the LH/hCG receptor in the affected individuals. Point mutations, located mainly in the sixth transmembrane loop have been demonstrated to be responsible for the constitutive activation of the receptor and the cAMP-mediated stimulation of androgen formation in the Leydig cells.

We have cloned and sequenced glutamate-tRNA synthetase (GluRS) and glutaminyl-tRNA synthetase (GlnRS) from Arabidopsis thaliana. They have conservative motifs found in all known GlxRS genes. For Lupinus luteus we found only one gene of GlxRS. At the moment we do not know exactly, whether it corresponds to GlnRS or GluRS.