Selective β-adrenergic Receptor Expression on Human Memory CD8+ T Lymphocyte Subsets Regulates Mobilization and INF-y Production

Introduction: CD8⁺ T lymphocytes (CD8TLs) express β-adrenergic receptors (βAR), which bind the neurotransmitter norepinephrine and stress hormone epinephrine released during inflammation, trauma, and psychological stress. Little is known about the functions of this βAR expression on CD8TLs. Methods: Volunteers were exposed to a psychological stressor (N=24). Flow cytometry identified CD8TL subsets by CCR7, CD27, CD28 and CD45RA expression. Adrenergic receptor subtype expression was determined by micro-array. The effects of βPAR stimulation on IFN-γ production in activated CD8TLs was tested in vitro using PMA/Ionomycin. Results: Stress caused selective migration of effector-memory (CCR7⁻CD27⁻CD28⁻) CD8TLs into the blood (+148%, p<.001). An 8-fold up-regulation of the β₂AR was demonstrated in effector-memory cells as compared to naïve CD8TLs. Stimulation of the β₂AR subtype completely inhibited IFN-γ production. Conclusion: These results show that β₂AR stimulation enhances peripheral immune surveillance in a highly selective manner, and might protect against excessive cytokine release during inflammation and stress.

     

The feasibility of quantitative MRI of extra‐ocular muscles in myasthenia gravis and Graves' orbitopathy

Although quantitative MRI can be instrumental in the diagnosis and assessment of disease progression in orbital diseases involving the extra‐ocular muscles (EOM), acquisition can be challenging as EOM are small and prone to eye‐motion artefacts. We explored the feasibility of assessing fat fractions (FF), muscle volumes and water T2 (T2_water) of EOM in healthy controls (HC), myasthenia gravis (MG) and Graves' orbitopathy (GO) patients. FF, EOM volumes and T2_water values were determined in 12 HC (aged 22‐65 years), 11 MG (aged 28‐71 years) and six GO (aged 28‐64 years) patients at 7 T using Dixon and multi‐echo spin‐echo sequences. The EOM were semi‐automatically 3D‐segmented by two independent observers. MANOVA and t‐tests were used to assess differences in FF, T2_water and volume of EOM between groups (P < .05). Bland–Altman limits of agreement (LoA) were used to assess the reproducibility of segmentations and Dixon scans. The scans were well tolerated by all subjects. The bias in FF between the repeated Dixon scans was ?0.7% (LoA: ±2.1%) for the different observers; the bias in FF was ?0.3% (LoA: ±2.8%) and 0.03 cm³ (LoA: ± 0.36 cm³) for volume. Mean FF of EOM in MG (14.1% ± 1.6%) was higher than in HC (10.4% ± 2.5%). Mean muscle volume was higher in both GO (1.2 ± 0.4 cm³) and MG (0.8 ± 0.2 cm³) compared with HC (0.6 ± 0.2 cm³). The average T2_water for all EOM was 24.6 ± 4.0 ms for HC, 24.0 ± 4.7 ms for MG patients and 27.4 ± 4.2 ms for the GO patient. Quantitative MRI at 7 T is feasible for measuring FF and muscle volumes of EOM in HC, MG and GO patients. The measured T2_water was on average comparable with skeletal muscle, although with higher variation between subjects. The increased FF in the EOM in MG patients suggests that EOM involvement in MG is accompanied by fat replacement. The unexpected EOM volume increase in MG may provide novel insights into underlying pathophysiological processes.     

Video capsule endoscopy for previous overt obscure gastrointestinal bleeding in patients using anti‐thrombotic drugs

Background and Aim: Little is known about the causes of overt obscure gastrointestinal bleeding (OGIB) in patients using anti‐thrombotic therapy. We aimed to describe video capsule endoscopy (VCE) findings and to identify factors associated with positive findings in these patients. Methods: We carried out a retrospective study of 56 patients who underwent VCE for evaluation of previous overt OGIB during anti‐thrombotic therapy. VCE studies were re‐evaluated by a gastroenterologist blinded to clinical details. Clinical data included in the multivariate analysis were sex, age, indication for and type of anti‐thrombotic therapy, hemodynamic instability on admission, type of blood loss, hemoglobin on admission, use of a proton pump inhibitor, NSAID use, time between bleeding episodes and VCE, and whether or not anti‐thrombotic therapy was resumed before the VCE study. Results: A probable cause for gastrointestinal bleeding was identified in 28 (50%) of the 56 studies. Angiodysplasia was found in 19 patients. Twenty‐two studies showed a possible cause in the small bowel. Multivariate logistic regression analysis showed that reinstitution of anti‐thrombotic therapy before VCE was carried out was the only independent predictor of positive VCE findings (OR: 8.61, 95% CI: 1.20–60.42, P = 0.032). Conclusions: Small intestinal angiodysplasia was the most common cause for overt OGIB. Reinstitution of withdrawn anti‐thrombotic drugs before the VCE examination was carried out was associated with positive VCE findings in multivariate analysis.     

Effects of chlorhexidine gluconate oral care on hospital mortality: a hospital-wide,observational cohort study

Purpose

Chlorhexidine oral care is widely used in critically and non-critically ill hospitalized patients to maintain oral health. We investigated the effect of chlorhexidine oral care on mortality in a general hospitalized population.

Methods

In this single-center, retrospective, hospital-wide, observational cohort study we included adult hospitalized patients (2012–2014). Mortality associated with chlorhexidine oral care was assessed by logistic regression analysis. A threshold cumulative dose of 300 mg served as a dichotomic proxy for chlorhexidine exposure. We adjusted for demographics, diagnostic category, and risk of mortality expressed in four categories (minor, moderate, major, and extreme).

Results

The study cohort included 82,274 patients of which 11,133 (14%) received chlorhexidine oral care. Low-level exposure to chlorhexidine oral care (≤?300 mg) was associated with increased risk of death [odds ratio (OR) 2.61; 95% confidence interval (CI) 2.32–2.92]. This association was stronger among patients with a lower risk of death: OR 5.50 (95% CI 4.51–6.71) with minor/moderate risk, OR 2.33 (95% CI 1.96–2.78) with a major risk, and a not significant OR 1.13 (95% CI 0.90–1.41) with an extreme risk of mortality. Similar observations were made for high-level exposure (>?300 mg). No harmful effect was observed in ventilated and non-ventilated ICU patients. Increased risk of death was observed in patients who did not receive mechanical ventilation and were not admitted to ICUs. The adjusted number of patients needed to be exposed to result in one additional fatality case was 47.1 (95% CI 45.2–49.1).

Conclusions

These data argue against the indiscriminate widespread use of chlorhexidine oral care in hospitalized patients, in the absence of proven benefit in specific populations.

     

Expression of CXCR3 and its ligands CXCL9, ‐10 and ‐11 in paediatric opsoclonus–myoclonus syndrome

Opsoclonus–myoclonus syndrome (OMS) is a neuroinflammatory disorder associated with remote cancer. To understand more clearly the role of inflammatory mediators, the concentration of CXCR3 ligands CXCL10, CXCL9 and CXCL11 was measured in 245 children with OMS and 81 paediatric controls using enzyme‐linked immunosorbent assay (ELISA), and CXCR3 expression on CD4⁺ T cells was measured by flow cytometry. Mean cerebrospinal fluid (CSF) CXCL10 was 2·7‐fold higher in untreated OMS than controls. Intrathecal production was demonstrated by significantly different CXCL10 CSF : serum ratios. The dichotomized ‘high’ CSF CXCL10 group had higher CSF leucocyte count (P = 0·0007) and B cell activating factor (BAFF) and CXCL13 concentrations (P < 0·0001). CSF CXCL10 did not correlate with clinical severity or relapse using grouped data, although it did in some patients. Among seven types of immunotherapy, including rituximab or chemotherapy, only adrenocorticotrophic hormone (ACTH) monotherapy showed reduced CSF CXCL10, but prospective longitudinal studies of ACTH combination therapies indicated no reduction in CXCL10 despite clinical improvement (P < 0·0001). CXCL10 concentrations were 11‐fold higher in CSF and twofold higher in serum by multiplexed fluorescent bead‐based immunoassay than enzyme‐linked immunosorbent assay, but the two correlated (r = 0·7 and 0·83). In serum, no group differences for CXCL9 or CXCL11 were found. CXCR3 expression on CD4⁺ T cells was fivefold higher in those from CSF than blood, but was not increased in OMS or altered by conventional immunotherapy. These data suggest alternative roles for CXCL10 in OMS. Over‐expression of CXCL10 was not reduced by clinical immunotherapies as a whole, indicating the need for better therapeutic approaches.     

Is there an athlete’s artery? A comparison of brachial and femoral artery structure and function in male strength,power and endurance athletes

ObjectivesExercise places physiological demands upon the cardiovascular system, subsequently leading to adaptations in structure and function. Different exercise modalities (endurance, strength and power) lead to distinct hemodynamic demands and, possibly, different patterns of adaptation. Our aim was to assess and compare brachial and femoral artery function and structure in elite level athletes engaged in endurance, strength and power sports.Designcross sectional comparison.Methods30 male elite athletes (runners n = 10, powerlifters n = 11, weightlifters n = 9) and 23 healthy controls were recruited. Brachial and femoral arterial diameters were assessed using ultrasound. Arterial function (brachial and femoral arteries) was determined using the flow mediated dilation (FMD) technique and body composition using body mass index (BMI) and body surface area (BSA).ResultsWeightlifters had significantly larger brachial arterial diameters compared to controls (4.39 ± 0.34 vs 3.86 ± 0.42 mm, p < 0.01). As weightlifter and power athletes had significantly higher body mass, BMI and BSA, we adjusted diameter for BSA. BSA-correction ameliorated differences in brachial artery resting diameters between athletes and controls. However, BSA-corrected femoral artery diameter was significantly larger in runners compared to controls (3.51 ± 0.28 vs 3.25 ± 0.34 mm, p < 0.05). There were no differences in brachial FMD between groups. Femoral artery FMD was significantly higher in runners and weightlifters compared to controls (p < 0.05 for both groups).ConclusionsHeterogeneous, limb-specific structural and functional vascular adaptation is evident in athletes, which may be influenced by exercise modality. Further, vascular remodelling relates to differences in body shape, specifically body composition, which should be accounted for when comparing athletes.