Antiviral Defence Mechanisms during Early Mammalian Development.

The type-I interferon (IFN) response constitutes the major innate immune pathway against viruses in mammals. Despite its critical importance for antiviral defence, this pathway is inactive during early embryonic development. There seems to be an incompatibility between the IFN response and pluripotency, the ability of embryonic cells to develop into any cell type of an adult organism. Instead, pluripotent cells employ alternative ways to defend against viruses that are typically associated with safeguard mechanisms against transposable elements. The absence of an inducible IFN response in pluripotent cells and the constitutive activation of the alternative antiviral pathways have led to the hypothesis that embryonic cells are highly resistant to viruses. However, some findings challenge this interpretation. We have performed a meta-analysis that suggests that the susceptibility of pluripotent cells to viruses is directly correlated with the presence of receptors or co-receptors for viral adhesion and entry. These results challenge the current view of pluripotent cells as intrinsically resistant to infections and raise the fundamental question of why these cells have sacrificed the major antiviral defence pathway if this renders them susceptible to viruses.

Risk factors for stroke after total aortic arch replacement using the frozen elephant trunk technique.

OBJECTIVES: This study aimed to analyse risk factors for postoperative stroke, evaluate the underlying mechanisms and report on outcomes of patients suffering a postoperative stroke after total aortic arch replacement using the frozen elephant trunk technique. METHODS: Two-hundred and fifty patients underwent total aortic arch replacement via the frozen elephant trunk technique between March 2013 and November 2020 for acute and chronic aortic pathologies. Postoperative strokes were evaluated interdisciplinarily by a cardiac surgeon, neurologist and radiologist, and subclassified to each's cerebral territory. We conducted a logistic regression analysis to identify any predictors for postoperative stroke. RESULTS: Overall in-hospital was mortality 10% (25 patients, 11 with a stroke). A symptomatic postoperative stroke occurred in 42 (16.8%) of our cohort. Eight thereof were non-disabling (3.3%), whereas 34 (13.6%) were disabling strokes. The most frequently affected region was the arteria cerebri media. Embolism was the primary underlying mechanism (n = 31; 73.8%). Mortality in patients with postoperative stroke was 26.2%. Logistic regression analysis revealed age over 75 (odds ratio = 3.25; 95% confidence interval 1.20-8.82; P = 0.021), a bovine arch (odds ratio = 4.96; 95% confidence interval 1.28-19.28; P = 0.021) and an acute preoperative neurological deficit (odds ratio = 19.82; 95% confidence interval 1.09-360.84; P = 0.044) as predictors for postoperative stroke. CONCLUSIONS: Stroke after total aortic arch replacement using the frozen elephant trunk technique remains problematic, and most lesions are of embolic origin. Refined organ protection strategies, and sophisticated monitoring are mandatory to reduce the incidence of postoperative stroke, particularly in older patients presenting an acute preoperative neurological deficit or bovine arch.

The frozen elephant trunk technique for aortic dissection is safe after previous aortic repair.

OBJECTIVES: The goal of this study was to evaluate outcomes of aortic arch replacement using the frozen elephant trunk (FET) technique after previous proximal and/or distal open or endovascular thoracic aortic repair. METHODS: Sixty-three patients [median age: 63 (55-74) years; 65% men] were operated on for acute or chronic aortic dissection after previous proximal and/or distal open or endovascular thoracic aortic repair. Intraoperative details, clinical outcome and follow-up results were evaluated. RESULTS: The median time between the index and the FET procedure was 81 (40-113) months. Fifty-eight (92%) patients had already undergone proximal aortic surgery; supracoronary ascending aortic replacement was the most frequent index procedure [n = 25 (40%)]. Distal aortic interventions had been done in 8 (13%) patients including endovascular thoracic aortic repair in 6 patients (10%). In-hospital mortality was 3% (n = 2). Postoperative strokes occurred in 5 patients (8%); of those, 1 stroke was dissection-related (2%). Subsequent aortic reinterventions after the FET procedure had to be done in 33% (n = 21). CONCLUSIONS: Outcomes of aortic arch replacement using the FET technique after previous proximal and/or distal open or endovascular thoracic aortic repair are associated with low mortality and morbidity. Still, postoperative stroke remains an issue. After the successful accomplishments, the approach serves as an ideal platform for the secondary surgical or endovascular downstream aortic procedures, which are frequently needed.

Assessment of the impact of sex in intensity, skin flares and central processing of histaminergic itch-A pilot study.

Itch is the commonest skin-related symptom, and sex differences are increasingly recognised as important determinants in stratified medicine, but only little is known about sex differences in itch. Questionnaire-based studies indicated that women perceive itch as more intensive and bothersome in comparison with men. However, data of studies using standardised itch models to objectify sex differences are scarce and inconsistent. To determine sex differences in intensity, skin flares and central processing of histaminergic itch, we compared 15 female and 15 male healthy subjects in a double-blinded, within-subject, placebo-controlled study using a histamine skin prick itch model (histamine 1% applied onto the volar forearm) and functional MRI. We found trends in higher mean itch intensity (0.58 VAS, CI 95% 0.004-1.19, P = .056) and maximum itch intensity (men 3.93 VAS ± 0.39 SD at 3 minutes, women 4.73 VAS ± 0.31 SD at 4 minutes, P = .073) in women paralleled by a trend in a stronger positive correlation between itch intensity and blood oxygen level-dependent (BOLD) activity in brain structures identified during itch in comparison with men (rs in women: .46, P = .08, rs in men: .07, P = .79). The erythema and wheal following histamine skin pricking were (non-significantly) larger in men, indicating that higher mean itch intensities on the right volar forearm in women may not be explained by more intense flares. The comparison of the activation patterns between the sexes revealed increased activity in men compared to women in the left middle temporal gyrus (temporooccipital part)/lateral occipital cortex. Thus, our findings indicate that histaminergic itch perception and central itch processing differ between the sexes under standardised conditions.

Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network.

Background: Subanesthetic dosages of the NMDAR antagonist, S-Ketamine, can cause changes in behavior in healthy subjects, which are similar to the state acute psychosis and are relevant in translational schizophrenia research. Functional magnetic resonance imaging (fMRI) can be used for non-hypothesis-driven analysis of brain connectivity. The correlation between clinical behavioral scores and neuroimaging can help to characterize ketamine effects on healthy brains in resting state. Method: seventeen healthy, male subjects (mean: 27.42 years, SD: 4.42) were administered an infusion with S-Ketamine (initial bolus 1 mg/kg and continuous infusion of 0.015625 mg/kg/min with dosage reduction -10%/10 min) or saline in a randomized, double-blind, cross-over study. During infusion, resting state connectivity was measured and analyzed with a seed-to-voxel fMRI analysis approach. The seed regions were located in the posterior cingulate cortex, intraparietal sulcus, dorsolateral prefrontal cortex and fronto-insular cortex. Receiver operating characteristics (ROC) were calculated to assess the accuracy of the ketamine-induced functional connectivity changes. Bivariate Pearson correlation was used for correlation testing of functional connectivity changes with changes of clinical scores (PANSS, 5D-ASC). Results: In the executive network (ECN), ketamine significantly increases the functional connectivity with parts of the anterior cingulum and superior frontal gyrus, but no significant correlations with clinical symptoms were found. Decreased connectivity between the salience network (SN) and the calcarine fissure was found, which is significantly correlated with negative symptoms (PANSS) (R2 > 0.4). Conclusion: Decreased ketamine-induced functional connectivity in the salience network may qualify as accurate and highly predictive biomarkers for ketamine induced negative symptoms.

The influence of long distance running on sonographic joint and tendon pathology: results from a prospective study with marathon runners.

BACKGROUND: The impact of physical exercise on joints and tendons is still a matter of debate. The aim of this study was to investigate with ultrasound the acute effects of extreme physical exercise on knee and ankle joints and their surrounding structures in trained athletes. METHODS: Participants of the Munich marathon were examined by arthrosonography before and after long distance running. Ultrasound assessment included grey scale and power Doppler examination of the knee and talocrural joints with surrounding tendons. Findings consistent with joint effusion, tendon and/or entheseal pathologies were documented. In addition to the ultrasound evaluation, information on training habits and past or present arthralgia or joint swelling was gathered. RESULTS: One Hundred Five runners completed both the pre- and post-excercise ultrasound assessments (baseline and follow-up), resulting in the sonographic evaluation of 420 knee and talocrural joints. At baseline, 105 knee (50) and 38 talocrural joints (18.1) showed effusions, compared to 100 knee (47.6) and 33 talocrural joints (15.7 %) at follow-up. The differences were not significant (p > 0.05 each). Effusion size did not correlate with the timepoint of ultrasound assessment and was independent of covariates such as gender, age or running distance. Hypervascularity of the patellar tendon was detected in 21 cases (10.0 %) at follow-up in contrast to one at baseline (p < 0.001). This observation was more frequent in male than in female participants (p < 0.05). CONCLUSIONS: Acute physical stress is significantly associated with hypervascularity of the patellar tendon. No significant changes of synovial effusion were detected in knee and talocrural joints.

Ultrasound of synovitis in rheumatoid arthritis: advantages of the dorsal over the palmar approach to finger joints.

OBJECTIVE: To compare the dorsal and palmar ultrasound (US) examination of finger joints in early rheumatoid arthritis (RA) with regard to the concurrence of greyscale (GSUS) and power Doppler (PDUS) positivity, and to correlate both approaches with clinical variables. METHODS: Patients with newly diagnosed RA were assessed by clinical examination and US. GSUS and PDUS of metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints were performed using the dorsal and palmar approach. Findings of synovitis in GSUS and PDUS were graded semiquantitatively from 0 to 3. Clinical and sonographic reevaluation was performed after 6 months. RESULTS: With 44.6% versus 32.2% positive findings, palmar GSUS identified significantly more joints with synovitis than did dorsal GSUS. With 22.1% versus 8.9%, PDUS abnormalities were detected significantly more often from the dorsal side. With 71.2% versus 21.8% for the MCP and 57.5% versus 17.4% for the PIP joints, significantly more GSUS and PDUS double-positive joints were found with the dorsal as opposed to the palmar approach. These differences remained significant at Month 6. Both palmar and dorsal GSUS and PDUS correlated with comparable strength with clinical variables such as the Disease Activity Score 28, Clinical Disease Activity Index, and Simple Disease Activity Index. CONCLUSION: Although the dorsal approach detected fewer GSUS findings than the palmar approach, PDUS signals were significantly more frequently detected by dorsal US. In addition, the prevalence of double-positive joints with concurrent GSUS and PDUS findings was significantly higher with the dorsal approach. These data argue in favor of the dorsal US approach to finger joints in RA.

Relevance of grade 1 gray-scale ultrasound findings in wrists and small joints to the assessment of subclinical synovitis in rheumatoid arthritis.

OBJECTIVE: To investigate the clinical relevance of grade 1 findings on gray-scale ultrasound (GSUS) of the joints in patients with rheumatoid arthritis (RA). METHODS: We examined the wrists and small joints of 100 patients with early or established RA and 30 healthy controls, using GSUS and power Doppler ultrasound (PDUS). Independent clinical assessment of all joints for tenderness and swelling according to the European League Against Rheumatism examination technique was performed. Joints with grade 1 findings on GSUS were identified, and associations with swelling, pain, and findings on PDUS were assessed. Grade 1 findings on GSUS in patients with early RA were reassessed after 6 months of antirheumatic treatment. RESULTS: Grade 1 results represented the majority of all GSUS findings in patients with RA and were also frequently recorded in healthy controls. Grade 1 GSUS findings were not associated with tenderness, swelling, or positive results on PDUS. In comparison to joints with grade 2 and grade 3 findings on GSUS, joints with grade 1 findings were less likely to respond to treatment. CONCLUSION: The present results indicate that grade 1 findings on GSUS have limited clinical relevance.

Intravenous thrombolysis in nonagenarians with ischemic stroke.

BACKGROUND AND PURPOSE: Demographic changes will result in a rapid increase of patients age ≥90 years (nonagenarians), but little is known about outcomes in these patients after intravenous thrombolysis (IVT) for acute ischemic stroke. We aimed to assess safety and functional outcome in nonagenarians treated with IVT and to compare the outcomes with those of patients age 80 to 89 years (octogenarians). METHODS: We analyzed prospectively collected data of 284 consecutive stroke patients age ≥80 years treated with IVT in 7 Swiss stroke units. Presenting characteristics, favorable outcome (modified Rankin scale [mRS] 0 or 1), mortality at 3 months, and symptomatic intracranial hemorrhage (SICH) using the National Institute of Neurological Disorders and Stroke (NINDS) and Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria were compared between nonagenarians and octogenarians. RESULTS: As compared with octogenarians (n=238; mean age, 83 years), nonagenarians (n=46; mean age, 92 years) were more often women (70% versus 54%; P=0.046) and had lower systolic blood pressure (161 mm Hg versus 172 mm Hg; P=0.035). Patients age ≥90 years less often had a favorable outcome and had a higher incidence of mortality than did patients age 80 to 89 years (14.3% versus 30.2%; P=0.034; and 45.2% versus 22.1%; P=0.002; respectively), while more nonagenarians than octogenarians experienced a SICH (SICH(NINDS), 13.3% versus 5.9%; P=0.106; SICH(SITS-MOST), 13.3% versus 4.7%; P=0.037). Multivariate adjustment identified age ≥90 years as an independent predictor of mortality (P=0.017). CONCLUSIONS: Our study suggests less favorable outcomes in nonagenarians as compared with octogenarians after IVT for ischemic stroke, and it demands a careful selection for treatment, unless randomized controlled trials yield more evidence for IVT in very old stroke patients.

Keratins and their associated skin disorders.

Keratins are the largest group of intermediate filament proteins that are expressed in the cytoplasm of epithelial cells. They form a cytoskeletal scaffold that maintains cell and tissue integrity and provides vital mechanical support to epithelia. Mutations in 19 different keratin genes have so far been identified as the cause of at least 15 different genetic diseases. Identification of the molecular basis of the keratin disorders has contributed to definite diagnoses and has facilitated genetic counselling. Better understanding of the structure, function and regulatory mechanisms of keratins will be the basis for the development of novel therapeutic approaches to overcome the current treatment limitations.