A Brief Etymology of the Collateral Circulation

It is well known that the protective capacity of the collateral circulation falls short in many individuals with ischemic disease of the heart, brain and lower extremities. In the past fifteen years, opportunities created by molecular and genetic tools, together with disappointing outcomes in many “angiogenic” trials, has led to a significant increase in the number of studies that focus on: 1) understanding the basic biology of the collateral circulation; 2) identifying the mechanisms that limit the collateral circulation’s capacity in many individuals; 3) devising methods to measure collateral extent, which has been found to vary widely among individuals; and 4) developing treatments to increase collateral blood flow in obstructive disease. Unfortunately, accompanying this increase in reports has been a proliferation of vague terms used to describe the disposition and behavior of this unique circulation, as well as the increasing miss-use of well-ensconced ones by new (and old) students of the collateral circulation. With this in mind, we provide a brief glossary of readily understandable terms to denote the formation, adaptive growth, and mal-adaptive rarefaction of the collateral circulation. We also propose terminology for several newly discovered processes that occur in the collateral circulation. Finally, we include terms used to describe vessels that are sometimes confused with collaterals, as well as terms describing processes active in the general arterial-venous circulation when ischemic conditions engage the collateral circulation. We hope this brief review will help unify the terminology used in collateral research

The proteoglycan osteoglycin/mimecan is correlated with arteriogenesis

Arteriogenesis or collateral growth is able to compensate for the stenosis of major arteries. Using differential display RT-PCR on growing and quiescent collateral arteries in a rabbit femoral artery ligation model, we cloned the rabbit full-length cDNA of osteoglycin/mimecan. Osteoglycin was present in the adventitia of collateral arteries as a glycosylated protein without keratan sulfate side chains, mainly produced by smooth muscle cells (SMCs) and perivascular fibroblasts. Northern blot, Western blot, and immunohistochemistry confirmed a collateral artery-specific downregulation of osteoglycin from 6 h to 3 weeks after the onset of arteriogenesis. Treatment of primary SMCs with the arteriogenic protein fibroblast growth factor-2 (FGF-2) resulted in a similar reduction of osteoglycin expression as observed in vivo. Application of the FGF-2 inhibitor polyanethole sulfonic acid (PAS) blocked the downregulation of osteoglycin and interfered with arteriogenesis. From our study we conclude that downregulation of osteoglycin is a fundamental requirement for proper arteriogenesis

Versorgung und Reanimation des reifen Neugeborenen nach der Geburt : Basierend auf der aktuellen Leitlinie des European Resuscitation Council 2021

Zusammenfassung Die volle Reanimation eines Neugeborenen mit Beatmungen, Thoraxkompressionen und der Gabe von Medikamenten ist ein äußerst seltenes Ereignis, das selbst neonatologische Teams immer wieder vor Herausforderungen stellt. Gerade in diesen seltenen und häufig dramatischen Situationen ist schnelles und umsichtiges Handeln im Team gefragt. Dabei ist die effektivste und meist einzig notwendige Maßnahme für die erfolgreiche Versorgung eines nicht spontan atmenden Neugeborenen eine suffiziente Maskenbeatmung. Wird diese effektiv durchgeführt, sind beim Neugeborenen in den seltensten Fällen tatsächlich Thoraxkompressionen notwendig. Im März 2021 wurde vom European Resuscitation Council (ERC) die neue Leitlinie zur Reanimation von Neugeborenen publiziert. Auf Basis dieser Leitlinie beschreibt der vorliegende Beitrag detailliert den im Algorithmus der Versorgung und Reanimation von reifen Neugeborenen dargestellten Handlungsablauf. Er richtet sich damit einerseits insbesondere an NichtneonatologInnen, die für die Versorgung v. a. von reifen Neugeborenen nach der Geburt verantwortlich sind. Andererseits soll er auch jenen zur Unterstützung dienen, die medizinisches Personal in der Versorgung von lebensbedrohten Neugeborenen trainieren und den Algorithmus der Neugeborenenreanimation als didaktisches Konzept vermitteln. Abstract The resuscitation of a neonate with the need for ventilation, chest compressions and the administration of drugs is an extremely rare event that repeatedly challenges even neonatal teams. It is precisely in these rare and often dramatic situations that rapid and prudent team action is required. The most effective and usually the only necessary measure for the successful resuscitation of a neonate who is not breathing spontaneously is sufficient mask ventilation. If ventilation is performed effectively, chest compressions are rarely necessary in the neonate. In March 2021, the European Resuscitation Council (ERC) published the new guidelines for neonatal resuscitation. Based on these guidelines, this article describes in detail the course of action outlined in the algorithm for the stabilisation and resuscitation of term neonates. On the one hand, it is aimed at non-neonatologists who are responsible for the care of term neonates after birth. On the other hand, it is also intended to support those who train medical personnel in the care of life-threatened neonates and teach the algorithm of neonatal resuscitation as a didactic concept

Polymorphisms of two histamine-metabolizing enzymes genes and childhood allergic asthma: a case control study

<p>Abstract</p> <p>Background</p> <p>Histamine-metabolizing enzymes (N-methyltransferase and amiloride binding protein 1) are responsible for histamine degradation, a biogenic amine involved in allergic inflammation. Genetic variants of <it>HNMT </it>and <it>ABP1 </it>genes were found to be associated with altered enzyme activity. We hypothesized that alleles leading to decreased enzyme activity and, therefore, decreased inactivation of histamine may be responsible for altered susceptibility to asthma.</p> <p>Methods</p> <p>The aim of this study was to analyze polymorphisms within the <it>HNMT </it>and <it>ABP1 </it>genes in the group of 149 asthmatic children and in the group of 156 healthy children. The genetic analysis involved four polymorphisms of the <it>HNMT </it>gene: rs2071048 (-1637T/C), rs11569723 (-411C/T), rs1801105 (Thr105Ile = 314C/T) and rs1050891 (1097A/T) and rs1049793 (His645Asp) polymorphism for <it>ABP1 </it>gene. Genotyping was performed with use of PCR-RFLP. Statistical analysis was performed using Statistica software; linkage disequilibrium analysis was done with use of Haploview software.</p> <p>Results</p> <p>We found an association of TT genotype and T allele of Thr105Ile polymorphism of <it>HNMT </it>gene with asthma. For other polymorphisms for <it>HNMT </it>and <it>ABP1 </it>genes, we have not observed relationship with asthma although the statistical power for some SNPs might not have been sufficient to detect an association. In linkage disequilibrium analysis, moderate linkage was found between -1637C/T and -411C/T polymorphisms of <it>HNMT </it>gene. However, no significant differences in haplotype frequencies were found between the group of the patients and the control group.</p> <p>Conclusions</p> <p>Our results indicate modifying influence of histamine N-methyltransferase functional polymorphism on the risk of asthma. The other HNMT polymorphisms and ABP1 functional polymorphism seem unlikely to affect the risk of asthma.</p

Quantitative Analysis of Protein Phosphorylations and Interactions by Multi-Colour IP-FCM as an Input for Kinetic Modelling of Signalling Networks

BACKGROUND: To understand complex biological signalling mechanisms, mathematical modelling of signal transduction pathways has been applied successfully in last few years. However, precise quantitative measurements of signal transduction events such as activation-dependent phosphorylation of proteins, remains one bottleneck to this success. METHODOLOGY/PRINCIPAL FINDINGS: We use multi-colour immunoprecipitation measured by flow cytometry (IP-FCM) for studying signal transduction events to unrivalled precision. In this method, antibody-coupled latex beads capture the protein of interest from cellular lysates and are then stained with differently fluorescent-labelled antibodies to quantify the amount of the immunoprecipitated protein, of an interaction partner and of phosphorylation sites. The fluorescence signals are measured by FCM. Combining this procedure with beads containing defined amounts of a fluorophore allows retrieving absolute numbers of stained proteins, and not only relative values. Using IP-FCM we derived multidimensional data on the membrane-proximal T-cell antigen receptor (TCR-CD3) signalling network, including the recruitment of the kinase ZAP70 to the TCR-CD3 and subsequent ZAP70 activation by phosphorylation in the murine T-cell hybridoma and primary murine T cells. Counter-intuitively, these data showed that cell stimulation by pervanadate led to a transient decrease of the phospho-ZAP70/ZAP70 ratio at the TCR. A mechanistic mathematical model of the underlying processes demonstrated that an initial massive recruitment of non-phosphorylated ZAP70 was responsible for this behaviour. Further, the model predicted a temporal order of multisite phosphorylation of ZAP70 (with Y319 phosphorylation preceding phosphorylation at Y493) that we subsequently verified experimentally. CONCLUSIONS/SIGNIFICANCE: The quantitative data sets generated by IP-FCM are one order of magnitude more precise than Western blot data. This accuracy allowed us to gain unequalled insight into the dynamics of the TCR-CD3-ZAP70 signalling network

Pelvic floor muscle function in a general female population in relation with age and parity and the relation between voluntary and involuntary contractions of the pelvic floor musculature

Contains fulltext : 80525.pdf (publisher's version ) (Closed access

Childhood socioeconomic position and adult mental wellbeing:Evidence from four British birth cohort studies

There is much evidence showing that childhood socioeconomic position is associated with physical health in adulthood; however existing evidence on how early life disadvantage is associated with adult mental wellbeing is inconsistent. This paper investigated whether childhood socioeconomic position (SEP) is associated with adult mental wellbeing and to what extent any association is explained by adult SEP using harmonised data from four British birth cohort studies.The sample comprised 20,717 participants with mental wellbeing data in the Hertfordshire Cohort Study (HCS), the MRC National Survey of Health and Development (NSHD), the National Child Development Study (NCDS), and the British Cohort Study (BCS70). Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) scores at age 73 (HCS), 60-64 (NSHD), 50 (NCDS), or 42 (BCS70) were used. Harmonised socioeconomic position (Registrar General's Social Classification) was ascertained in childhood (age 10/11) and adulthood (age 42/43). Associations between childhood SEP, adult SEP, and wellbeing were tested using linear regression and multi-group structural equation models.More advantaged father's social class was associated with better adult mental wellbeing in the BCS70 and the NCDS. This association was independent of adult SEP in the BCS70 but fully mediated by adult SEP in the NCDS. There was no evidence of an association between father's social class and adult mental wellbeing in the HCS or the NSHD.Socioeconomic conditions in childhood are directly and indirectly, through adult socioeconomic pathways, associated with adult mental wellbeing, but findings from these harmonised data suggest this association may depend on cohort or age

JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors

The JAK2 V617F mutation present in over 95% of Polycythemia Vera patients and in 50% of Essential Thrombocythemia and Primary Myelofibrosis patients renders the kinase constitutively active. In the absence of a three-dimensional structure for the full-length protein, the mechanism of activation of JAK2 V617F has remained elusive. In this study, we used functional mutagenesis to investigate the involvement of the JH2 αC helix in the constitutive activation of JAK2 V617F. We show that residue F595, located in the middle of the αC helix of JH2, is indispensable for the constitutive activity of JAK2 V617F. Mutation of F595 to Ala, Lys, Val or Ile significantly decreases the constitutive activity of JAK2 V617F, but F595W and F595Y are able to restore it, implying an aromaticity requirement at position 595. Substitution of F595 to Ala was also able to decrease the constitutive activity of two other JAK2 mutants, T875N and R683G, as well as JAK2 K539L, albeit to a lower extent. In contrast, the F595 mutants are activated by erythropoietin-bound EpoR. We also explored the relationship between the dimeric conformation of EpoR and several JAK2 mutants. Since residue F595 is crucial to the constitutive activation of JAK2 V617F but not to initiation of JAK2 activation by cytokines, we suggest that small molecules that target the region around this residue might specifically block oncogenic JAK2 and spare JAK2 wild-type

RhoH Regulates Subcellular Localization of ZAP-70 and Lck in T Cell Receptor Signaling

RhoH is an hematopoietic-specific, GTPase-deficient Rho GTPase that plays a role in T development. We investigated the mechanisms of RhoH function in TCR signaling. We found that the association between Lck and CD3ζ was impaired in RhoH-deficient T cells, due to defective translocation of both Lck and ZAP-70 to the immunological synapse. RhoH with Lck and ZAP-70 localizes in the detergent-soluble membrane fraction where the complex is associated with CD3ζ phosphorylation. To determine if impaired translocation of ZAP-70 was a major determinant of defective T cell development, Rhoh-/- bone marrow cells were transduced with a chimeric myristoylation-tagged ZAP-70. Myr-ZAP-70 transduced cells partially reversed the in vivo defects of RhoH-associated thymic development and TCR signaling. Together, our results suggest that RhoH regulates TCR signaling via recruitment of ZAP-70 and Lck to CD3ζ in the immunological synapse. Thus, we define a new function for a RhoH GTPase as an adaptor molecule in TCR signaling pathway