Effect of beta-adrenergic blockade on hormonal responses during continuous and intermittent exercise

Summary The modifying effect on exercise performance and neuroendocrine response of the nonselective beta blocker timolol (10 mg b.i.d. for 5 days) and the beta₁-selective beta blocker metoprolol (100 mg b.i.d. for 5 days) was studied. The hormones studied were growth hormone, prolactin, cortisol, renin, epinephrine, dopamine, and norepinephrine. The response was studied during short-term maximal dynamic exercise, using two different exercise protocols; continuous (n=11) and intermittent (n=9) bicycle ergometry, in normal healthy young men. Accumulated work on placebo was nearly identical in the two studies, but was significantly reduced by 10.4% and 6.6% with timolol and by 4.7% and 6.7% with metoprolol, during continuous and intermittent exercise, respectively. During continuous exercise, accumulated work was 5.8% lower (p<0.05) with timolol than with metoprolol. The hormonal plasma concentrations of all hormones except renin were higher during continuous exercise than during intermittent exercise. Beta blockade had no effect on baseline hormonal levels, but the response was markedly changed during exercise. Maximum epinephrine, cortisol, and prolactin responses increased after beta blockade; dopamine remained nearly unchanged; while the renin responses were attenuated. Norepinephrine concentrations were slightly increased during continuous exercise by beta blockade and rose in direct proportion to the increase in workload. During intermittent exercise, maximum norepinephrine levels were significantly reduced by beta blockade compared with placebo. Thus the effect of beta₁-selective and nonselective beta receptor blockade on circulating hormones does not seem to explain the reduced exercise capacity following beta blockade.     

Incorporation of N-acetyl-[14C]D-glucosamine and [3H]L-leucine by isolated pig gastric mucosal cells

Glycoprotein and protein production of isolated pig gastric mucosal cells were determined by the incorporation of N-acetyl-[14C]D-glucosamine ([14C]GlcNAc) and [3H]L-leucine ([3H]Leu) into acid-insoluble macromolecules (AIM). In four cell fractions (F1-F4), obtained by counterflow centrifugation, specific [14C]GlcNAc incorporation was greatest in the mucous cell-enriched F2. Tracer incorporation by F2 cells, proceeded linearly up to 20 h, was inhibited by cycloheximide or incubation at 0 degree C, and enhanced by PGE2 1 mumol/l. Gel chromatography of released AIM revealed that PGE2-stimulated [14C]GlcNAc incorporation was predominantly directed into high molecular weight (2 X 10(6) daltons) glycoproteins, whereas [3H]Leu incorporation was mainly related to proteins of albumin-like molecular weight. We conclude that incorporation of [14C]GlcNAc by enriched pig gastric mucous cells (F2), further analyzed by gel chromatography, is a suitable probe to study the production of high molecular weight gastric mucous glycoproteins in vitro.     

Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features

Autoimmune destruction of the adrenal cortex is the most common cause of primary adrenocortical insufficiency (Addison's disease) in industrialized countries. We have investigated a large Norwegian cohort of patients with Addison's disease in terms of clinical manifestations, autoantibodies, and human leukocyte antigen (HLA) class II haplotypes. The study comprised 94 patients (54 females) of ages 6-85 yr (mean 45 yr) with, either isolated Addison's disease or part of autoimmune polyendocrine syndrome type II. Among those diagnosed before the age of thirty, 53% were men, while among those diagnosed at 30 or above, 30% were men. Altogether 77 (82%) of the 94 patients had autoantibodies against 21-hydroxylase (21OH). Thirty-eight of the 40 patients with disease duration 5 yr or less had such autoantibodies. This frequency fell to 60% among patients with a disease duration greater than 35 yr. Five women had gonadal failure. This failure correlated with antibodies against side-chain cleavage enzyme (P = 0.03). Antibodies against glutamic acid decarboxylase and IA2 correlated with the presence of type 1 diabetes (P < 0.005 and P = 0.003, respectively). The frequency of the HLA DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2) and DRB1*04-DQA1*03-DQB1*0302 (DR4-DQ8) haplotypes were positively correlated to Addison's disease, whereas the DRB1*01-DQA1*0101-DQB1*0501 (DR1-DQ5) haplotype was negatively correlated. In addition, the DRB1*04 subtype DRB1*0404 was increased among Addison patients relative to controls. We verify that autoimmunity is the main cause of Addison's disease in our cohort. In younger patients, the disease is equally common in men and women. Measurement of autoantibodies against 21OH is a valuable tool in establishing the etiological diagnosis, especially in patients with a short disease duration. Addison's disease is associated with the DR3-DQ2 and DR4 (0404)-DQ8 haplotypes. A particularly high risk for disease development is observed when these occur in a heterozygous combination (DR3-DQ2/DR4-DQ8).     

Hypersensitivity pneumonitis in a cluster of sawmill workers: a 10-year follow-up of exposure,symptoms, and lung function

Background:

The long-term prognosis of repeated acute episodes of hypersensitivity pneumonitis (HP) is not well described. We report on a 10-year follow-up of a 10-person cluster from a Norwegian sawmill who had all experienced relapsing episodes of HP.

Objectives:

To evaluate the health symptoms, work-related sick-leave, and lung function of 10 workers exposed to mold in a Norwegian sawmill.

Methods:

Participants were evaluated at baseline and 10 years later at follow-up. A structured interview, measurement of serum IgG antibodies to Rhizopus microsporus (R. microsporus) antigens, lung function tests, high resolution computed tomography (HRCT) of the chest, and personal measurements of exposure to mold spores and dust were completed for each participant.

Results:

At baseline, nearly all workers reported acute episodes of HP more than twice a month. At follow-up, both the frequency and intensity of symptoms had declined. Sick-leave was reduced and gas diffusing capacity improved – paralleling the gradually reduced air levels of mold spores.

Conclusions:

In spite of an initially high occurrence of symptoms, long-term clinical and physiological outcome was good. With reduced exposure to mold spores, symptoms declined and lung function was restored.     

Activated platelets promote increased monocyte expression of CXCR5 through prostaglandin E2-related mechanisms and enhance the anti-inflammatory effects of CXCL13

Background

We have previously shown that the homeostatic chemokine CXCL13 is up-regulated in monocytes in atherosclerosis, mediating anti-apoptotic and anti-inflammatory effects.

Objective

To investigate the regulation of CXCL13s receptor, CXCR5.

Methods/patients

In vitro studies in THP-1 and primary monocytes and studies of CXCR5 expression in thrombus material obtained at the site of plaque rupture during myocardial infarction (MI).

Results

Our major findings were: (i) toll-like receptor agonists and particularly β-adrenergic receptor activation and releasate from thrombin-activated platelets increased CXCR5 mRNA levels in monocytes. (ii) The platelet-mediated induction of CXCR5 involved prostaglandin E₂/cAMP/protein kinase A-dependent as well as RANTES-dependent pathways with NFκB activation as a potential common down-stream mediator. (iii) Releasate from thrombin-activated platelets augmented the anti-inflammatory effects of CXCL13 in monocytes at least partly by enhancing the effects of CXCL13 on CXCR5 expression. (iv) We found strong immunostaining of CXCR5 in thrombus material obtained at the site of plaque rupture in patients with ST elevation MI (STEMI) and in unstable carotid lesions, co-localized with platelets.

Conclusion

Our findings suggest that platelet-mediated signaling through CXCR5 may be active in vivo during plaque destabilization, potentially representing a counteracting mechanism to inflammation.     

Cognitive subtypes of dyslexia are characterized by distinct patterns of grey matter volume

The variety of different causal theories together with inconsistencies about the anatomical brain markers emphasize the heterogeneity of developmental dyslexia. Attempts were made to test on a behavioral level the existence of subtypes of dyslexia showing distinguishable cognitive deficits. Importantly, no research was directly devoted to the investigation of structural brain correlates of these subtypes. Here, for the first time, we applied voxel-based morphometry (VBM) to study grey matter volume (GMV) differences in a relatively large sample (n = 46) of dyslexic children split into three subtypes based on the cognitive deficits: phonological, rapid naming, magnocellular/dorsal, and auditory attention shifting. VBM revealed GMV clusters specific for each studied group including areas of left inferior frontal gyrus, cerebellum, right putamen, and bilateral parietal cortex. In addition, using discriminant analysis on these clusters 79 % of cross-validated cases were correctly re-classified into four groups (controls vs. three subtypes). Current results indicate that dyslexia may result from distinct cognitive impairments characterized by distinguishable anatomical markers.     

Neuroanatomy of dyslexia: An allometric approach

Despite evidence for a difference in total brain volume between dyslexic and good readers, no previous neuroimaging study examined differences in allometric scaling (i.e. differences in the relationship between regional and total brain volumes) between dyslexic and good readers. The present study aims to fill this gap by testing differences in allometric scaling and regional brain volume differences in dyslexic and good readers. Object‐based morphometry analysis was used to determine grey and white matter volumes of the four lobes, the cerebellum and limbic structures in 130 dyslexic and 106 good readers aged 8–14 years. Data were collected across three countries (France, Poland and Germany). Three methodological approaches were used as follows: principal component analysis (PCA), linear regression and multiple‐group confirmatory factor analysis (MGCFA). Difference in total brain volume between good and dyslexic readers was Cohen's d = 0.39. We found no difference in allometric scaling, nor in regional brain volume between dyslexic and good readers. Results of our three methodological approaches (PCA, linear regression and MGCFA) were consistent. This study provides evidence for total brain volume differences between dyslexic and control children, but no evidence for differences in the volumes of the four lobes, the cerebellum or limbic structures, once allometry is taken into account. It also finds no evidence for a difference in allometric relationships between the groups. We highlight the methodological interest of the MGCFA approach to investigate such research issues.     

Left cytoarchitectonic area 44 supports selection in the mental lexicon during language production

This functional magnetic resonance imaging (fMRI) study investigated the role of Broca’s region for selecting semantic, syntactic, and phonological information during picture naming. According to psycholinguistic theory, selection is reflected in speech latency differences, e.g. during priming. Here, homogenous (priming) blocks in which German picture names had the same semantic category, syntactic gender, or initial phoneme alternated with heterogeneous (non-priming) blocks. Speech latencies revealed a negative priming effect. Speech latencies were used as regressors for the fMRI data in order to tap selection processes. In Broca’s region (BA 44), among others, fMRI data showed repetition priming, which was positive for semantic and syntactic but negative for phonological selection. The different effects in area 44 are discussed in terms of psycholinguistic theory. Overall, the activation pattern is in line with the hypothesis that area 44 generally supports selection processes during noun production at several levels of the mental lexicon.     

Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

Adenovirus (HAdV) infections confer a high risk of morbidity and mortality for immunocompromised patients after stem cell transplantation (SCT). Treatment with standard antiviral drugs is of limited efficacy and associated with a high rate of adverse effects. HAdV‐specific T cells are crucial for sustained viral elimination and the efficacy of adoptive T‐cell therapy with donor‐derived HAdV‐specific T cells has been reported by several investigators. Here, we report our experience with the transfer of HAdV‐specific T cells specific for penton, which was recently identified as an immunodominant target of T cells, and hexon in a 14‐year‐old boy after T‐cell‐depleted haploidentical SCT for myelodysplastic syndrome (MDS). He developed severe HAdV‐associated enteritis complicated by acute graft‐versus‐host disease (GvHD). The patient received ten infusions of allogeneic HAdV‐specific T cells manufactured from the haploidentical stem cell donor using the CliniMacs Interferon‐γ (IFN‐γ) cytokine capture and immunomagnetic selection. Initially, T cells were generated against the immunodominant target hexon and in subsequent transfers dual antigen‐specific T cells against hexon and penton were applied. T‐cell transfers were scheduled individually tailored to current immunosuppressive treatment. Each transfer was followed by reduction of HAdV load in peripheral blood and clinical improvement. Importantly, T‐cell responses to both penton and hexon pools emerged in patient blood after repetitive transfers. Unfortunately, the patient experienced bacterial sepsis, and in this context, severe GvHD requiring intensive immunosuppression followed by secondary progression of HAdV infection. The patient succumbed to multiorgan failure 283 days after SCT. This case demonstrates the feasibility of HAdV‐specific T‐cell transfer even in the presence of immunosuppressive treatment. Targeting of multiple immunodominant viral proteins may prove valuable in patients with complicated HAdV infections.