Gene profiling reveals increased expression of uteroglobin and other anti-inflammatory genes in glucocorticoid-treated nasal polyps

BACKGROUND: Treatment with local glucocorticoids (GCs) decreases symptoms and the size of nasal polyps. This might depend on the downregulation of proinflammatory genes, as well as the upregulation of anti-inflammatory genes. OBJECTIVE: We sought to identify GC-regulated anti-inflammatory genes in nasal polyps. METHODS: Affymetrix DNA microarrays were used to analyze the expression of 22,283 genes in 4 nasal polyps before and after local treatment with fluticasone (400 microg/d). Expression of uteroglobin and mammaglobin B was analyzed with real-time PCR in 6 nasal polyps and in nasal biopsy specimens from 6 healthy control subjects. RESULTS: Two hundred three genes had changed in expression in treated polyps, and 139 had known functions: 54 genes were downregulated, and 85 were upregulated. Genes associated with inflammation constituted the largest single functional group. These genes affected key steps in inflammation (eg, immunoglobulin production; antigen processing and presentation; and the chemoattraction and activation of granulocytes, T cells, and B cells). Several proinflammatory genes were downregulated. In contrast, some anti-inflammatory genes were upregulated. The gene that increased most in terms of expression was uteroglobin. This was confirmed with real-time PCR. By contrast, expression of uteroglobin was lower in untreated polyps than in healthy nasal mucosa. Immunohistochemical investigation showed staining of uteroglobin in the epithelium and in seromucous glands in control subjects and in nasal polyps. CONCLUSION: Upregulation of anti-inflammatory genes, such as uteroglobin, might contribute to the effects of local treatment with GCs in nasal polyps.     

Autoimmune diseases in myelodysplastic syndrome favors patients survival: A case control study and literature review

Background

We conducted a monocentric retrospective study of patients with myelodysplastic syndromes (MDS) and autoimmune or inflammatory disorders (AIMs) and a literature review. We analyzed the association with subgroups of the WHO 2016 MDS classification and patient's survival in a case control study. Risk factors associated with survival were analyzed by uni- and multivariate analysis.

Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly

In a double-blind, randomized, crossover study, the H1-receptor antagonists, terfenadine and chlorpheniramine, were investigated in eight healthy, fasting female subjects, aged 67.8 +/- SD 0.8 years, who ingested single doses of terfenadine, 1 mg/kg (mean dose, 69.6 +/- 11.2 mg), and chlorpheniramine, 0.12 mg/kg (mean dose, 8.4 +/- 1.3 mg). The mean serum-elimination half-life of terfenadine metabolite I was 8.7 +/- 3.7 hours. After terfenadine ingestion, significant wheal suppression occurred from 2 to 24 hours compared to predose wheal size, with maximum wheal suppression, 42 +/- 13% to 60 +/- 16% from 2 to 12 hours. Significant flare suppression occurred from 2 to 24 hours, with maximum flare suppression, 75 +/- 15% to 78 +/- 13% from 4 to 8 hours. The mean serum-elimination half-life of chlorpheniramine was 22.6 +/- 11.0 hours. After chlorpheniramine ingestion, significant wheal suppression occurred from 1 to 10 hours, inclusive, compared to predose wheal size, with maximum wheal suppression, 36 +/- 11% to 37 +/- 11% from 5 to 6 hours. Significant flare suppression occurred from 1 to 12 hours, with maximum flare suppression of 43 +/- 14% to 46 +/- 19% at 2, 5, and 6 hours (p less than 0.01). Adverse effects, chiefly sedation, occurred in five of eight patients after receiving terfenadine, and in all eight patients after receiving chlorpheniramine; but, since no placebo control was administered, these adverse effects could not be definitely attributed to H1-receptor-antagonist ingestion.     

Synectin/syndecan-4 regulate coronary arteriolar growth during development.

Syndecan-4 and its cytoplasmic binding partner, synectin, are known to play a role in FGF-2 signaling and vascular growth. To determine their roles in coronary artery/arteriolar formation and growth, we compared syndecan-4 and synectin null mice with their wild-type counterparts. Image analysis of arterioles visualized by smooth muscle alpha-actin immunostaining revealed that synectin (-/-) mice had lower arteriolar length and volume densities than wild-type mice. As shown by electron microscopic analysis, arterioles from the two did not differ in morphology, including their endothelial cell junctions, and the organization and distribution of smooth muscle. Using micro-computer tomography, we found that the size and branching patterns of coronary arteries (diameters > 50 microm) were similar for the two groups, a finding that indicates that the growth of arteries is not influenced by a loss of synectin. Syndecan-4 null male mice also had lower arteriolar length densities than their gender wild-type controls. However, female syndecan-4 null mice were characterized by higher arteriolar length and volume densities than their gender-matched wild-type controls. Thus, we conclude that both synectin and syndecan-4 play a role in arteriolar development, a finding that is consistent with previous evidence that FGF-2 plays a role in coronary arterial growth. Moreover, our data reveal that gender influences the arteriolar growth response to syndecan-4 but not to synectin.     

Egg-sharing in assisted conception: ethical and practical considerations

The present acute shortage of eggs for donation cannot be overcomeunless adequate guidelines are set to alleviate the anxietiesregarding payments, in cash or kind, to donors. The currentHuman Fertilisation and Embryology Authority (HFEA) guidelinesdo not allow direct payment to donors but accept the provisionof lower cost or free in-vitro fertilization (IVF) treatmentto women in recognition of oocyte donation to anonymous recipients.Egg-sharing achieved in this way enables two infertile couplesto benefit from a single surgical procedure. However, the practicalguidelines related to this approach are ill-defined at the presenttime leading to some justifiable uncertainty. A pilot studywas therefore undertaken in order to establish the place ofegg-sharing in an assisted conception programme. The currentHFEA guidelines on medical screening of patients, counselling,age and rigid anonymity between the donor and recipient werefollowed. The study involved 55 women (25 donors and 30 recipients)in 73 treatment cycles involving fresh and frozen-thawed embryos.Donors were previous IVF patients who, regardless of their abilityto pay, shared their eggs equally with matched anonymous recipients.They paid only for their consultations and tests right up tothe point of being matched with a recipient The sole recipientpaid the cost applicable in egg donation of a single egg collection,although both received embryo transfers. The results indicatethat although the recipients were older than the donors (41.4± 0.9 versus 31.6 ± 0.5 years), and there wasno difference in the mean number of eggs allocated, the percentagefertilization rates, or the mean number of embryos transferred,there were more births per patient amongst recipients than amongstdonors (30 versus 20%). We conclude that providing the donorsare selected carefully, this scheme whereby a sub-fertile donorhelps a sub-fertile recipient is a very constructive way ofsolving the problem of the shortage of eggs for donation. Thereare also the advantages of including a group of women who wouldotherwise be denied treatment Problems related to ‘patientcoercion’ can, in our view, be fully overcome by the applicationof strict common-sense safeguards. The ideal of pure altruismis not without its medical and moral risk. The success of egg-sharingdepends on shared interests and a degree of altruism betweenthe donor, the recipient and the centre. The current HFEA guidelinesshould be applauded for enabling a highly effective conceptof mutual help to develop.     

Allergen-stimulated interleukin-4 and interferon-gamma production in primary culture: responses of subjects with allergic rhinitis and normal controls.

The balance of interleukin-4 (IL-4) to interferon-gamma (IFN-gamma) production that is induced following exposure to common environmental antigens is believed to be instrumental in determining whether hypersensitivity or clinical unresponsiveness results to that antigen. To date, evaluation of cytokine (protein) production has been based predominantly on allergen-reactive CD4 T-cell clones or activation of fresh unselected peripheral blood mononuclear cell (PBMC) populations with non-physiological stimuli such as phorbal myristate acetate (PMA) and calcium ionophore, phytohaemagglutinin (PHA), anti-CD3 or anti-CD2/anti-CD28 monoclonal antibodies (mAb). Here, ultrasensitive IL-4 and IFN-gamma assays were optimized to allow direct analysis of antigen-stimulated cytokine production by fresh human PBMC. Primary cultures of cells from grass pollen-sensitive allergic rhinitis subjects and non-atopic controls were stimulated using a range of grass pollen allergen concentrations in the absence of exogenous cytokines or polyclonal activators. The majority of subjects (45 of 52) exhibited chloroquine-sensitive, CD4-dependent cytokine production in allergen-stimulated, short-term primary culture. Median IL-4 production was substantially greater among atopics (13.0 pg/ml versus < 1 pg/ml, Mann-Whitney U test, P < 0.0000001) and IFN-gamma was lower (P = 0.008), providing direct evidence for an imbalance in both IL-4 and IFN-gamma production among circulating, pollen-reactive cells in individuals with seasonal allergic rhinitis. The distinction in the allergen-driven cytokine responses elicited from normal and atopic donors was underscored by examination of the ratios of IFN-gamma:IL-4 synthesis. Non-atopic individuals exhibited intense IFN-gamma dominance of the T-cell response, in marked contrast to that observed among grass pollen-sensitive individuals (median IFN-gamma:IL-4 ratios of 14.0 versus 0.096, P = 0.000002). The observation that essentially all individuals produced IFN-gamma (+/- IL-4) following antigen stimulation in vitro argues that the most relevant consideration in determining susceptibility to immediate hypersensitivity versus clinical tolerance to environmental allergens is not a genetically defined capacity to recognize the antigen (i.e. if allergen-reactive T cells are present in that individual) but the nature of the cytokine response.     

Web-based virtual microscopy in teaching and standardizing Gleason grading

Gleason grading forms the basis of prognostic and therapeutic assessment in prostatic carcinoma despite its subjective nature and substantial interobserver variation. The accuracy of Gleason grading can be improved by the use of educational tools such as reference images. However, conventional microscopy images are of limited educational value because it is neither possible to view the sample at different magnifications nor to navigate into different areas of the specimen. This limitation can be overcome by the use of virtual microscopy, which allows viewing entire digitized microscope slides. We created an interactive Web site ( www.webmicroscope.net/gleason ) featuring a comprehensive set of prostatic needle biopsies as virtual slides, which can be viewed with a standard Web browser (Internet Explorer or Netscape). To evaluate the validity of Web-based virtual microscopy for Gleason grading, an experienced uropathologist (TK) scored a series of 62 biopsies from the original glass slides and 6 weeks later from virtual slides on the Web site using an ordinary desktop computer. The intraobserver agreement was excellent, with identical Gleason scores found in 48 of the 62 cases ( kappa = 0.73). The 14 remaining scores differed only by 1 point on the Gleason scale (2-10). The virtual slides were viewed by 2 other uropathologists (PM and HH), with interobserver kappa coefficients ranging from 0.55 to 0.62, which is within the range of previously reported studies using glass slides. The 3 uropathologists' Gleason scores were included as reference scores on the Web site, which now serves as a publicly open platform for self-testing and learning of Gleason grading. We conclude that Web-based virtual microscopy is a promising new tool for teaching and standardizing Gleason grading.     

High-resolution computed tomography study of the cranium of a fossil anthropoid primate, Parapithecus grangeri: new insights into the evolutionary history of primate sensory systems

Extant anthropoids have large brains, small olfactory bulbs, and high-acuity vision compared with other primates. The relative timing of the evolution of these characteristics may have important implications for brain evolution. Here computed tomography is used to examine the cranium of a fossil anthropoid, Parapithecus grangeri. It is found that P. grangeri had a relatively small brain compared with living primates. In addition, it had an olfactory bulb in the middle of the range for living primates. Methods for relating optic foramen area and other cranial measurements to acuity are discussed. Multiple regression is used to estimate retinal ganglion cell number in P. grangeri. Given currently available comparative data, P. grangeri seems to have had retinal ganglion cell counts intermediate for living primates, overlapping with the upper end of the range for strepsirrhines and possibly with the lower end for anthropoids.     

Semantic knowledge and episodic memory for faces in semantic dementia

Previous studies have documented poor recognition memory for faces in patients with semantic dementia. Preserved face recognition memory was found in this study, however, so long as atrophy was confined predominantly to the left temporal lobe. Patients with structural damage to the right temporal lobe were typically impaired, with the status of the hippocampus and parahippocampal gyrus (including the perirhinal cortex) on the right being critical. Two single-case studies of patients with predominantly left temporal lobe pathology confirmed good recognition memory for famous faces, even if semantic knowledge about the celebrities depicted was severely degraded. An effect of semantic knowledge on recognition memory became apparent only when perceptually different photographs of the famous people were used at study and test. These results support the view that new episodic learning typically draws on information from both perceptual and semantic systems.     

On the ERN and the significance of errors

The error-related negativity (ERN) is an event-related brain potential observed when subjects commit errors. To examine whether the ERN is sensitive to the value of errors, the motivational significance of errors was manipulated in two experiments. In Experiment 1, low and high monetary value errors were compared to evaluate the effect of trial value on the ERN. In Experiment 2, subjects performed a flanker task both while their performance was being evaluated and during a control condition. Consistent with the notion that the error-detection system is sensitive to the significance of errors, the ERN was significantly larger on high-value trials in Experiment 1 and during evaluation in Experiment 2. There were no corresponding effects on the correct response negativity, and no behavioral differences between conditions were evident in either experiment. These results are discussed in terms of the functional role of the ERN in response monitoring.