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Objective: To evaluate the time-independent effect of the early administration of epinephrine (EPI) on favorable neurological outcome (as CPC [cerebral performance category] 1-2) at 1 month in patients with out-of-hospital cardiac arrest.Materials and Methods: A total of 119 639 witnessed cardiac arrest patients from 2008 to 2012 were eligible for this nationwide, prospective, population-based observational study. Patients were divided into EPI group (n = 20 420) and non-EPI group (n = 99 219). To determine the time-dependent effects of EPI, EPI-administered patients were divided into 4 groups as follows: early EPI (5-18 min), intermediate EPI (19-23 min), late EPI (24-29 min), and very late EPI (30-62 min), respectively. Multiple logistic regression analyses and adjusted odds ratios (AORs) were determined for CPC 1-2 at 1 month (primary outcome) and field return of spontaneous circulation (as secondary outcome) among the groups.Results: The EPI and non-EPI group had identical background, but EPI group shows higher incidence public access defibrillation and emergency medical technician defibrillation delivered than the non-EPI group. The differences were clinically negligible. Higher return of spontaneous circulation rate (18.0%) and lower CPC 1-2 (2.9%) shown in the EPI group than in the non-EPI group (9.4% and 5.2%). In the time dependent analysis, CPC 1 to 2 was greatest in the early EPI group (AOR, 2.49; 95% confidence interval [CI], 1.90-3.27), followed by the intermediate EPI group (AOR, 1.53; 95% CI, 1.14-2.05) then the late EPI group (AOR, 0.71; 95% CI, 0.47-1.08) as reference.Conclusion: Early EPI administration within 19 minutes after emergency medical service call independently improved the neurological outcome compared with late EPI (24-29 minutes) administration in patients with out-of-hospital cardiac arrest. [ABSTRACT FROM AUTHOR]

Murine nuclear factor of activated T cells (NFAT)2.α/β differ by 42 and 28 unique amino-terminal amino acids and are differentially expressed. Both isoforms share conserved domains that regulate DNA-binding and subcellular localization. A genetic "one-hybrid" assay was used to define two distinct transactivation (TA) domains: in addition to a conserved TAD present in both isoforms, a second, novel TAD exists within the β-specific amino terminus. Pharmacologic inhibitors Gö6976 and rottlerin demonstrate that both conventional and novel protein kinase C (PKC) family members regulate endogenous mast cell NFAT activity, and NFAT2 TA. Overexpression of dominant active PKCθ (which has been implicated in immune receptor signaling) induces NFAT2.β/β TA. Mutations within the smallest PKCθ-responsive transactivation domain demonstrate that the PKCθ effect is at least partially indirect. Significantly, the β-specific domain confers greater ability to TA in response to treatment with phorbol 12-myristate 13-acetate/ionomycin or lipopolysaccharide, and unique sensitivity to Fc∈RI signaling. Accordingly, overexpression of NFAT2.β results in significantly greater NFAT- and interleukin-4 reporter activity than NFAT2.α. These results suggest that whereas NFAT2 isoforms may share redundant DNA-binding preferences, there are specialized functional consequences of their isoform-specific domains. [ABSTRACT FROM AUTHOR]

Every year, 150-200 children are born with Down syndrome in Hungary, thus their number at preschool age is quite high. Our aim was to assess the passive range of motion, the muscle strength and the balance of preschool children with Down syndrome and to examine the effectiveness of a 12-week exercise program. Children showed a significant improvement in the passive range of motion p<0.001 (trunk flexion: 80 SP o sp , 96 SP o sp ; trunk extension: 20 SP o sp , 28 SP o sp ; trunk lateralflexion: 30 SP o sp , 35 SP o sp ; trunk rotation: 40 SP o sp , 46 SP o sp ; shoulder flexion: 165 SP o sp , 174 SP o sp ; shoulder abduction: 150 SP o sp , 159 SP o sp ; shoulder outward rotation: 25 SP o sp , 33 SP o sp ; p=0.001; elbow flexion: 120 SP o sp , 127 SP o sp ; lower arm supination: 80 SP o sp , 90 SP o sp ; p=0.004; lower arm pronation: 75 SP o sp , 84 SP o sp ; wrist palmarflexion: 70 SP o sp , 76 SP o sp ; wrist dorsalflexion: 50 SP o sp , 55 SP o sp ; hip flexion: 110 SP o sp , 125 SP o sp ; hip extension: 20 SP o sp , 32 SP o sp ; hip abduction: 30 SP o sp , 35 SP o sp ; p=0.001; hip outward rotation: 25 SP o sp , 33 SP o sp ; knee flexion: 110 SP o sp , 128 SP o sp ; ankle dorsalflexion: 20 SP o sp , 26 SP o sp ; wrist unlardeviation: 20 SP o sp ,26 SP o sp ; p=0.030; wrist radialdeviation: 10 SP o sp ,17 SP o sp , balance (Flamingo test) (47, 51 sec; p<0.001) and more difficult Flamingo test (35, 40 sec; p<0.001), as well as the muscle strength in the bigger muscle groups (trunk flexor-extensor, shoulder and elbow flexor, hip extensor, knee flexor-extensor, plantarflexor) also improved following the exercise program. [Extracted from the article]

Among acrobatic rock and roll dancers, the exercises for core muscle strengthening are kept in the background because the dancers learn several acrobatics and choreography and they keep preparing for the competitions. Outcome measurement included Core Test (CT), Flamingo Balance Test (FBT), Lumbar Motor Control Test (LMCT) and the Roland-Morris questionnaire. Based on the international literature and on the results what we achieved, we concluded that a core-strengthening training programme has a beneficial effect on the acrobatic rock and roll dancers, therefore it is worth using such programmes. [Extracted from the article]

In the intervention group at the 1st (5.20, 6.18 cm/s; p=0.005), 8th (5.82, 7.12 cm/s; p=0.040) and 16th (6.48, 7.5cm/s; p=0.004) training occasion the post-exercise VFV was significantly higher than the pre-exercise in the left leg. At the 16th training occasion, the measured pre-exercise VFV was significantly higher than the pre-exercise VFV measured at the 1st occasion (left leg: 6.48, 5.20 cm/s; p=0.007), (right leg: 6.50, 5.22 cm/s; p=0.010). The post-exercise circumference of the thigh was significantly lower at the 8th (right leg: 51.60, 48.20 cm; p=0.028) and 16th (left leg: 51.40, 49.60 cm; right leg: 51.00, 49.20 cm; p=0.009) occasion than prior to the exercise. [Extracted from the article]

The immunogenicity risk assessment and bioanalytical strategy for novel therapeutics should account for both unique biophysical properties and potential consequences of immunogenicity. When assessing the immunogenicity risk of etelcalcetide, a peptide agonist of the calcium-sensing receptor, we considered the potential that the d -amino acid ‘backbone’ and biotransformation of etelcalcetide could allow the drug to act as a hapten. As a consequence, we validated and implemented a surface plasmon resonance immunoassay platform with both etelcalcetide and etelcalcetide-‘carrier’ surfaces to detect anti-drug antibodies (ADA). No evidence of in-vitro neutralizing activity with surrogate controls was detected despite multiple immunization approaches and a sensitive cell-based activity assay. Therefore, a neutralizing assay was not implemented for clinical support. We conducted an integrated analysis of immunogenicity data pooled from two pivotal placebo-controlled trials to define the clinical impact of anti-etelcalcetide antibodies. While both pre-existing and developing anti-etelcalcetide antibodies were detected, we show here that they have no consequences for clinical exposure, efficacy, or safety of etelcalcetide. [ABSTRACT FROM AUTHOR]

Abstract: Immunoglobulin E (IgE) is the least abundant immunoglobulin in serum. However, development of an IgE immune response can induce IgE receptor-expressing cells to carry out potent effector functions. A reliable antigen-specific IgE biomarker method for use in non-human primate studies would facilitate (i) confirmation of Type-I hypersensitivity reactions during safety toxicology testing, and (ii) a better understanding of non-human primate models of allergic disease. We cloned and expressed a recombinant cynomolgus monkey IgE molecule in order to screen a panel of commercially available detection reagents raised against human IgE for cross-reactivity. The reagent most reactive to cynomolgus IgE was confirmed to be specific for IgE and did not bind recombinant cynomolgus monkey IgG1-4. A drug-specific IgE assay was developed on the MSD electrochemiluminescent (ECL) platform. The assay is capable of detecting 10ng/mL drug-specific IgE. Importantly, the assay is able to detect IgE in the presence of excess IgG, the scenario likely to be present in a safety toxicology study. Using our ECL assay, we were able to confirm that serum from cynomolgus monkeys that had experienced clinical symptoms consistent with hypersensitivity responses contained IgE specific for a candidate therapeutic antibody. In addition, a bioassay for mast cell activation was developed using CD34+-derived cynomolgus monkey mast cells. This assay confirmed that plasma from animals identified as positive in the drug-specific IgE immunoassay contained biologically active IgE (i.e. could sensitize cultured mast cells), resulting in histamine release after exposure to the therapeutic antibody. These sensitive assays for Type-I hypersensitivity in the NHP can confirm that secondary events are downstream of immunogenicity. [Copyright &y& Elsevier]

Three groups: a. patients receiving radiotherapy; b. patients receiving chemotherapy while having in hospital ward placement; c. patients receiving ambulant chemotherapy. The 3 subgroups: 41 persons (35%) radiotherapy, 44 (38%) chemotherapy in in-patient hospital care, 31 (27%) ambulant chemotherapy. Significant relationship between treatment types and quality of life scores (p<0.006), between radiotherapy participants and ambulant chemotherapy participants (p=0.008), marginal significant difference between radiotherapy and class chemotherapy (p=0.077). [Extracted from the article]