It has been reported that disruption of the circadian clock may lead to increased risk of breast cancer in humans and to a high rate or ionizing radiation-induced tumors and mortality in mice. ...Cryptochrome 1 and cryptochrome 2 proteins are core components of the mammalian circadian clock and mice mutated in both genes are arrhythmic. We tested Cry1-/- Cry2-/- mice and fibroblasts derived from these mice for radiation-induced cancer and killing and DNA damage checkpoints and killing, respectively. We find that the mutant mice are indistinguishable from the wild-type controls with respect to radiation-induced morbidity and mortality. Similarly, the Cry1-/- Cry2-/-mutant fibroblasts are indistinguishable from the wild-type controls with respect to their sensitivity to ionizing radiation and UV radiation and ionizing radiation-induced DNA damage checkpoint response. Our data suggest that disruption of the circadian clock in itself does not compromise mammalian DNA repair and DNA damage checkpoints and does not predispose mice to spontaneous and ionizing radiation-induced cancers. We conclude that the effect of circadian clock disruption on cellular response to DNA damage and cancer predisposition in mice may depend on the mechanism by which the clock is disrupted.
The socio-economic transformations of the 1990s have forced many people in Poland into impoverishment. Hunters, Gatherers, and Practitioners of Powerlessness gives a dramatic account of life after ...this degradation, tracking the experiences of unemployed miners, scrap collectors, and poverty- stricken village residents. Contrary to the images of passivity, resignation, and helplessness that have become powerful tropes in Polish journalism and academic writing, Tomasz Rakowski traces the ways in which people actively reconfigure their lives. As it turns out, the initial sense of degradation and helplessness often gives way to images of resourcefulness that reveal unusual hunting-and-gathering skills.
The clinical usage of the resuscitative endovascular balloon occlusion of the aorta (REBOA) is limited by distal ischemia resulting from complete aortic occlusion. We hypothesized that animals would ...physiologically tolerate the prolonged partial occlusion using the novel partially occluding REBOA (pREBOA) with survivable downstream injuries.
This study used the pREBOA-PRO catheter in a previously established swine model. Female Yorkshire swine (n = 10) underwent a volume-controlled hemorrhage (40% estimated blood). After 1 hour of shock (mean arterial pressure, 28-32 mm Hg), animals were randomized to partial occlusion for either 2 hours or 4 hours. The pREBOA was inflated in zone 1 to achieve partial occlusion defined as a distal systolic blood pressure (SBP) of 20 ± 2 mm Hg. The balloon was deflated at the end of the occlusion period, and animals were resuscitated for 2 hours. Tissues were examined for gross and histologic injury. The primary endpoint was histologic organ injury, and secondary end points were hemodynamic variables and degree of distal organ ischemia.
All animals survived to the endpoint. Both groups had similar proximal and distal SBP at baseline, with a divergence of pressures ranging from 55 mm Hg to 90 mm Hg on inflation. The lactate levels increased throughout the occlusion and decreased approximately 40% during the observation period. More animals required norepinephrine and fluid in the 4-hour group compared with the 2-hour group. There was no gross small bowel ischemia noted in the 2-hour animals. The 4-hour group had surgically resectable patchy short segment ischemia. Neither group showed nonsurvivable organ ischemia on pathology or laboratory values.
This is the first study showing that the zone 1 aorta can be occluded for over 4 hours using a new pREBOA device without need for balloon titration. In conclusion, simple changes in balloon design offer reliable partial aortic occlusion, with potentially survivable and surgically manageable downstream injuries.
Injuries lead to an early systemic inflammatory state with innate immune system activation. Neutrophil extracellular traps (NETs) are a complex of chromatin and proteins released from the activated ...neutrophils. Although initially described as a response to bacterial infections, NETs have also been identified in the sterile postinjury inflammatory state. Peptidylarginine deiminases (PADs) are a group of isoenzymes that catalyze the conversion of arginine to citrulline, termed citrullination or deimination. PAD2 and PAD4 have been demonstrated to play a role in NET formation through citrullinated histone 3. PAD2 and PAD4 have a variety of substrates with variable organ distribution. Preclinical and clinical studies have evaluated the role of PADs and NETs in major trauma, hemorrhage, burns, and traumatic brain injury. Neutrophil extracellular trap formation and PAD activation have been shown to contribute to the postinjury inflammatory state leading to a detrimental effect on organ systems. This review describes our current understanding of the role of PAD and NET formation following injury and burn. This is a new field of study, and the emerging data appear promising for the future development of targeted biomarkers and therapies in trauma.
Background Microbial skin colonization with Staphylococcus aureus is known to play an important role in atopic eczema (AE). Recently, an antibacterial effect of silver‐coated textiles on S. aureus ...colonization has been demonstrated.
Objectives To investigate clinical efficacy and functionality of silver‐coated textiles in AE, a multicentre, double‐blind, placebo‐controlled trial was conducted.
Patients/methods From November 2001 to August 2002, 68 consecutive outpatients clinically diagnosed with generalized AE were included in the study. Inclusion criteria were the clinical diagnosis of AE with a moderate severity as measured by the scoring of atopic dermatitis (SCORAD) index with at least 20. Patients were instructed to wear either silver‐coated (verum, 35 patients + 2 dropouts) or cotton garments (placebo, 22 patients + 9 dropouts) directly on the skin for 2 weeks. Only basic skin care and ongoing therapy with topical steroids or oral antihistamines was permitted. Clinical severity was assessed using the ‘SCORAD’ before, during and at the end of study. Quality of life (QOL), wearing comfort (WC) and functionality (FU) of study clothes were measured in parallel. Patients documented their subjective and objective symptoms daily.
Results In the verum group, eczema improved significantly after 1 week with further enhancement until the end of study (P = 0.03 and P < 0.001). Silver‐coated textiles were comparable to cotton in WC and FU. Pruritus and self‐assigned skin condition improved significantly more than with placebo (P < 0.001 and P = 0.003).
Conclusions In conclusion, silver‐coated textiles are able to improve objective and subjective symptoms of AE significantly within 2 weeks, showing a good wearing comfort and functionality comparable to cotton.
Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the ...efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism.
In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed.
From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio HR 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths.
In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants.
Bayer AG and Janssen Research & Development.
Summary
Background Influences of microbial pathogens are crucial for the maturation of the immune system. Caspase‐recruitment domain containing protein 15 (CARD15) is a cytosolic receptor involved in ...bacterial recognition by antigen‐presenting cells. CARD15 polymorphisms have been associated with Crohn's disease. Recently, associations with atopic phenotypes have been reported in children.
Objective Within a large population of German adults (n=1875), we evaluated eight CARD15 polymorphisms for associations with atopic phenotypes.
Methods Subjects were phenotyped by standardized questionnaires and interviews as well as total and allergen‐specific IgE measurements. Genotyping was performed using matrix‐assisted laser desorption ionization – time of flight mass spectrometry. Haplotypes were estimated using the SAS/Genetics module.
Results Subjects with a T allele at rs1077861 had a decreased risk of developing asthma (odds ratio OR=0.648, P=0.013), whereas the presence of an A allele at rs3135500 was significantly associated with an increased risk (OR=1.374, P=0.023). In addition, a CARD15 haplotype revealed to be protective against the development of asthma (OR=0.326, P=0.003). Subjects with an A allele at position rs5743266 or a T allele at rs2066842 had a significantly decreased risk of developing allergic rhinoconjunctivitis with ORs of 0.820 (P=0.049) and 0.801 (P=0.025). Polymorphism rs2066845 showed a significant association with increased total serum IgE (OR=2.155, P=0.006).
Conclusion Genetic variants of CARD15 that might result in inappropriate immunomodulation are not only associated with autoimmune diseases but also with atopic disorders.
Background: Atopic disorders are the result of complex interactions between genetic and environmental factors. Associations analyses between the promoter polymorphism rs1800875 in the mast cell ...chymase gene (CMA1) and atopy‐related phenotypes have yielded inconsistent results.
Methods: We sequenced the CMA1 locus in 24 unrelated healthy individuals with serum IgE levels <50% percentile and 24 individuals with atopic eczema and serum IgE levels >90% percentile. Seven CMA1 single nucleotide polymorphisms (SNPs) were evaluated for evidence of associations with atopic phenotypes within a large population of German adults (n = 1875). Subjects were phenotyped by standardized questionnaires and interviews, skin prick testing and serum IgE measurements. Genotyping was performed using MALDI‐TOF MS (Matrix‐Assisted Laser Desorption Ionization–Time of Flight mass spectrometry).
Results: Promoter polymorphism rs1800875 was significantly associated with atopic eczema. No associations between any other single SNP and atopic phenotypes could be detected. Haplotype reconstruction revealed four of 128 possible haplotypes reaching estimated frequencies of 3% or more. Two of these haplotypes showed a borderline‐significant association with atopic eczema, which did not remain significant after correction for multiple testing.
Conclusions: Results confirm previous observations of a significant association between the CMA1 promoter polymorphism rs1800875 and atopic eczema, but not with serum IgE levels, and support the hypothesis that CMA1 serves as candidate gene for atopic eczema.
Kinesin light chain (KLC) complexes with the kinesin heavy chain (KHC) to form native kinesin. Proposed functions of KLC include coupling of cargo to KHC or modulation of KHC ATPase activity. In this ...paper we use the KHC tail, which binds specifically to KLC in blot overlays, as a probe to clone a cDNA encoding KLC from a Drosophila expression library. The identified clone encodes a protein with 70% amino acid identity to rat KLC. Drosophila KLC is predicted to form an alpha-helical coiled-coil between residues 34 and 129, followed by five imperfect tandem repeats of unknown function and a sixth shorter motif. These repeats are highly conserved across species. The Drosophila KLC gene is located at 69D on the third chromosome and is widely expressed, with 1.8-kb transcripts in most tissues, and slightly smaller transcripts in gonads. Finally, we present evidence that the heptad repeats of KLC are required for interaction with the KHC tail. Since the KHC tail used in our assay includes about 20 heptad repeats, this result suggests that KHC and KLC interact via coiled-coils. Such an interaction could provide stability to the KHC-KLC complex in vivo
Reports published in 1996 concerning the protein MIA proposed it as a useful tumor marker for patients suffering from malignant melanoma. Therefore we systematically started to measure MIA levels in ...patients with malignant melanoma. It was and still is questionable whether MIA in the serum of melanoma patients is a reliable tumor marker in terms of course of disease, therapy-monitoring and prognostic value. Previous studies have already confirmed the specifity of MIA as a tumor marker for malignant melanoma.
Using an ELISA- System, we examined over 830 blood samples of 326 melanoma patients. The cut-off was determined at 9.8 ng/ml.
5.6% (n = 17) of melanoma patients at stage I/II (n = 302) showed increased MIA levels, whereas at stage III/IV (n = 5/n = 19) high levels were found in 60.0% and 89.5% respectively. Patients at stage III/IV with MIA levels below the cut-off turned out to be the ones after metastatic surgery, irradiation or chemotherapy. None of these patients developed further metastases during follow-up, just as patients at stage I/II without increased MIA levels. After a distinct rise of MIA levels, metastases could be detected at the same time or shortly after. On the other hand we saw decreasing levels after or during therapy.
Our data showed that MIA is a suitable serum marker to detect metastases and to monitor course and therapy of disease. The prognostic value (increased MIA levels at stage I/II), however, requires further investigation.
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