Betamethasone effects on fetal sheep cerebral blood flow are not dependent on maturation of cerebrovascular system and pituitary–adrenal axis

Synthetic glucocorticoids are administered to pregnant women in premature labour to accelerate fetal lung maturation at a time when fetal cerebrovascular and endocrine systems are maturing. Exposure to glucocorticoids at 0.8–0.9 of gestation increases peripheral and cerebrovascular resistance (CVR) in fetal sheep. We examined whether the increase of CVR and its adverse effect on cerebral blood flow (CBF) depend on the current level of maturation of the pituitary–adrenal axis and the cerebrovascular system. Using fluorescent microspheres, regional CBF was measured in 11 brain regions before and 24 h and 48 h after the start of 3.3 μg kg⁻¹ h⁻¹ betamethasone ( n = 8) or vehicle ( n = 7) infusions to fetal sheep at 0.73 of gestation. Hypercapnic challenges were performed before and 24 h after the onset of betamethasone exposure to examine betamethasone effects on cerebrovascular reactivity. Betamethasone exposure decreased CBF by approximately 40% in all brain regions after 24 h of infusion ( P < 0.05). The decline in CBF was mediated by a CVR increase of 111 ± 16% in the cerebral cortex and 129 ± 29% in subcortical regions ( P < 0.05). Hypercapnic cerebral vasodilatation and associated increase in CBF were blunted ( P < 0.05). Fetal CBF recovered after 48 h of betamethasone administration. There were no differences in glucocorticoid induced CBF and CVR changes compared with our previous findings at 0.87 of gestation. We conclude that the cerebrovascular effects of antenatal glucocorticoids are independent of cerebrovascular maturation and preparturient increase in activity of the fetal pituitary–adrenal axis.     

IP-10 and type 1 diabetes: a question of time and location

Chemokines are key signal molecules that attract cells of the host immune system to the site of a potential threat. Virus infections usually induce a massive chemokine and cytokine burst and therefore recruit a large plethora of leukocytes to the site of infection with the goal to restrict and abrogate viral spread. The down side of this massive excitation of the human defense system is non-specific activation of potentially self-reactive lymphocytes. Coupled with an antigen-specific event, for example molecular mimicry between host components and viral proteins, autoimmunity might be the consequence in susceptible individuals. However, activated immune components with autoaggressive potential must find their target and must remain in one site sufficiently long in order to cause chronic tissue damage. In this review we will focus on the influence of the chemokine IP-10 (CXCL10) on the trafficking of autoaggressive cells during the immunopathogenesis of type 1 diabetes (T1D) and explain why IP-10 can have a dual effect on T1D depending on time and location of expression.     

The effect of the interferon-gamma-inducible processing machinery on the generation of a naturally tumor-associated human cytotoxic T lymphocyte epitope within a wild-type and mutant p53 sequence context

The human wild-type (wt) p53.264-272 peptide is a universal tumor antigen and recognized by HLA-A*0201 (A2.1)-restricted CTL. Generation of this epitope by constitutive 20S proteasomes is prevented by a p53 R to H hotspot mutation at the C-terminal flanking residue 273. We report on the impact of the interferon-gamma (IFN-gamma)-inducible proteasomal activator PA28 (11S regulator) and the immunoproteasome on the in vitro and cellular processing of wt and mutant (mut) p53 substrates. We found that production of the antigenic 264-272 peptide from wt p53 by constitutive as well as immunoproteasomes is accelerated and amplified by the PA28 activator. PA28 and (immuno)proteasomes were not capable to reconvert the resistance of epitope release from mut p53. Maximum and accelerated antigen production in vitro and on the cellular level required the IFN-gamma-inducible interaction of immunoproteasomes and PA28. We conclude that efficient processing of p53.264272 from wt p53 is governed by the proteasome/PA28 complex. These studies have important implications for p53-specific cancer immunotherapy and demonstrate that the effects of the immunoproteasome and PA28 are influenced by the individual epitope and its flanking sequence context.     

Vortex Shaped Current Sources in a Physical Torso Phantom

Recent studies reported differential information in human magnetocardiogram and in electrocardiogram. Vortex currents have been discussed as a possible source of this divergence. With the help of physical phantom experiments, we quantified the influence of active vortex currents on the strength of electric and magnetic signals, and we tested the ability of standard source localization algorithms to reconstruct vortex currents. The active vortex currents were modeled by a set of twelve single current dipoles arranged in a circle and mounted inside a phantom that resembles a human torso. Magnetic and electric data were recorded simultaneously while the dipoles were switched on stepwise one after the other. The magnetic signal strength increased continuously for an increasing number of dipoles switched on. The electric signal strength increased up to a semicircle and decreased thereafter. Source reconstruction with unconstrained focal source models performed well for a single dipole only (less than 3-mm localization error). Minimum norm source reconstruction yielded reasonable results only for a few of the dipole configurations. In conclusion active vortex currents might explain, at least in part, the difference between magnetically and electrically acquired data, but improved source models are required for their reconstruction.     

Human papillomavirus type 16 DNA sequence

The complete nucleotide sequence of HPV16 DNA (7904 bp) cloned from an invasive cervical carcinoma was determined. Homology comparisons allowed us to align the major open reading frames with the other published papilloma virus DNA sequences. The general organization of the open reading frames is similar to that of the other four papillomavirus (BPV1, HPV1a, HPV6b, CRPV) already sequenced. The sequence reveals an interruption of the reading frame coding for a suspected E1 protein.     

Cytogenetic analysis of the Asian Plethodontid salamander, Karsenia koreana: Evidence for karyotypic conservation, chromosome repatterning, and genome size evolution

A cytogenetic analysis, including the karyotype, C-bands, silver-stained nucleolus organizer regions and genome size, was performed on the recently discovered species, Karsenia koreana, the first plethodontid salamander from Asia. The karyotype consists of 14 pairs of bi-armed chromosomes, with no evidence of heteromorphic sex chromosomes. C-banding reveals a concentration of heterochromatin at the centromeres as well as at interstitial locations. The smallest chromosome (pair number 14) has symmetrical interstitial C-bands in each arm, resembling chromosome no. 14 of North American species of its sister group taxon, supergenus Hydromantes. Acomparative analysis of C-band heterochromatin and silver-stained nucleolus organizer regions of Karsenia and other plethodontid genera reveals that chromosomal evolution may have featured chromosome 'repatterning' within the context of conserved chromosome number and shape in this clade. Genome size is correlated with geographic distribution in plethodontids and appears to have important phenotypic correlates as well. The genome size of Karsenia is relatively large, and resembles that of the geographically closest plethodontids from western North America, especially species of the genus Hydromantes. The biological significance of these cytogenetic characteristics of plethodontid salamanders is discussed within an evolutionary context.