Structural damage burden and hypertrophic olivary degeneration in pediatric postoperative cerebellar mutism syndrome

Cerebellar mutism syndrome (CMS) occurs in one out of four children after posterior fossa tumor surgery, with open questions regarding risk factors, pathophysiology, and prevention strategies. Because of similarities between several cerebellar syndromes, a common pathophysiology with damage to the dentato-thalamo-cortical and dentato-rubro-olivary pathways has been proposed. Hypertrophic olivary degeneration (HOD) is an imaging correlate of cerebellar injury observed for instance in stroke patients. Aim of this study was to investigate whether the occurrence and severity of CMS correlates with the extent of damage to the relevant anatomical structures and whether HOD is a time-dependent postoperative neuroimaging correlate of CMS. We performed a retrospective single center study of CMS patients compared with matched non-CMS controls. CMS occurred in 10 children (13% of the overall cohort) with a median age of 8 years. Dentate nucleus (DN) injury significantly correlated with CMS, and superior cerebellar peduncle (SCP) injury was associated by tendency. HOD was observed as a dynamic neuroimaging phenomenon in the postoperative course and its presence significantly correlated with CMS and DN injury. Children who later developed HOD had an earlier onset and tended to have longer persistence of CMS. These findings can guide surgical measures to protect the DN and SCP during posterior fossa tumor resections and to avoid a high damage burden (i.e., bilateral damage). Development of intraoperative neuromonitoring of the cerebellar efferent pathways as well as improved preoperative risk stratification could help to establish a patient-specific strategy with optimal balance between degree of resection and functional integrity.

     

Functional antagonism between dopamine and noradrenaline within the caudate nucleus of cats: A phenomenon of rhythmically changing susceptibility

Two aspects of the functional interaction between the neurotransmitters dopamine (DA) and noradrenaline (NE) were studied: the role of NE within brain structures marked by DA terminals and the occurrence of annual changes in their functional interaction. The behavioral changes produced by single or combined administration of DA, (3,4-dihydroxyphenylamino)-2-imidazoline (DPI), ergometrine, ET-495, NE, oxymetazoline, and phentolamine into the caudate nucleus of freely moving cats were analyzed. NE and oxymetazoline produced effects that differed from those elicited by DA or DPI. NE-dependent effects were antagonized by phentolamine, and DA- or DPI-induced effects were antagonized by ergometrine. Ergometrine, NE, and oxymetazoline were effective in November, December, and January, lost their effectiveness in March, April, and May, regained it in July, and lost it again in August, September, and October. The annual pattern of DA, DPI, and phentolamine on the other hand, was just the opposite. DA agonists suppressed NE- or oxymetazoline-induced effects, while the DA antagonist suppressed phentolamine-induced effects. Noradrenergic agents were unable to modulate the DA-dependent effects under certain circumstances. It is concluded that (1) NE-dependent processes within the feline caudate nucleus inhibit DA-dependent processes within this structure, and (2) there exists a reciprocal relationship between the annual changes in the feline's susceptibility to DA, DPI, and phentolamine, on the one hand, and to ergometrine, NE, and oxymetazoline, on the other hand.     

Vestibulo-tactile interactions regarding motion perception and eye movements in yaw

This paper shows that tactile stimulation can override vestibular information regarding spinning sensations and eye movements. However, we conclude that the current data do not support the hypothesis that tactile stimulation controls eye movements directly. To this end, twenty-four subjects were passively disoriented by an abrupt stop after an increase in yaw velocity, about an Earth vertical axis, up to 120 degrees /s. Immediately thereafter, they had to actively maintain a stationary position despite a disturbance signal. Subjects wore a tactile display vest with 48 miniature vibrators, applied in different combinations with visual and vestibular stimuli. Their performance was quantified by RMS body velocity during self-control. Fast eye movement phases were analyzed by counting samples exceeding a velocity limit, slow phases by a novel method applying a first order model. Without tactile and visual information, subjects returned to a previous level of angular motion. Tactile stimulation decreased RMS self velocity considerably, though less than vision. No differences were observed between conditions in which the vest was active during the recovery phase only or during the disorienting phase as well. All effects of tactile stimulation found on the eye movement parameters could be explained by the vestibular stimulus.     

Myth or reality: hematocrit and hemoglobin differ in trauma

BACKGROUND: Estimating blood loss in trauma patients usually involves the determination of hematocrit (Ht) or hemoglobin (Hb). However, in trauma patients, a poorly substantiated habit exists to determine both Ht and Hb in assessing acute blood loss. This suggests that Ht and Hb provide different information. Moreover, a survey of the literature showed a significant association of the subject trauma with the use of Ht. We investigated whether Ht and Hb differ in trauma patients. METHODS: Trauma patients with an Injury Severity Score>15 admitted from 1996 to 2004 to the University Medical Center Groningen were analyzed. All blood samples obtained during the first 7 days postinjury in which both Ht and Hb were determined were studied. Ht and Hb were measured with a Coulter Counter. The relation between Ht and Hb was analyzed with linear regression. The potential effect of hemolysis was studied by analyzing lactate dehydrogenase levels. RESULTS: In 671 patients 2,461 paired Ht levels and Hb levels were obtained. The mean Ht was 30.9%+/-6.9% (interquartile range 25.8%-35.8%). The mean concentration of Hb was 10.4+/-2.3 g/dL (interquartile range 8.7-12.1 g/dL). Ht and Hb had a Pearson's R of 0.99 and the following relations applied: Ht (%)=2.953xHb (g/dL) or Hb (g/dL)=0.334xHt (%). Lactate dehydrogenase was not related with Ht and Hb, indicating hemolysis was not relevant. CONCLUSIONS: In a large series of trauma patients, Ht and Hb behaved as identical parameters. The idea that Ht is different from or even superior to Hb is a misconception. There is no reason for determining both Ht and Hb in trauma patients.     

Relative immunogenicity of PorA subtypes in a multivalent Neisseria meningitidis vaccine is not dependent on presentation form

The hexavalent meningococcal vaccine HexaMen, containing six PorAs on two vesicles, was tested in clinical studies. Although fourfold increases in serum bactericidal activity (SBA) titers against all of the PorAs were observed, there were significant differences between PorA-specific SBA titers. SBA titers were mainly directed against one PorA from each vesicle, P1.5-2,10 and P1.5-1,2-2, and were lower against the other PorAs, especially P1.7-2,4 and P1.19,15-1. We investigated whether these differences were due to immunological interference that resulted in competition between the three PorAs on the same vesicle or whether they were caused by a difference in the immunogenicities of the separate PorAs. Therefore, mice were immunized either with HexaMen, with six monovalent outer membrane vesicles (OMVs) representing the same six PorAs simultaneously (HexaMix), or with only one of the monovalent OMVs. The immunoglobulin G and SBA titers after HexaMen immunization in mice resembled the results obtained in clinical studies. Although immunization with HexaMix gave higher titers than immunization with HexaMen for some PorAs, the pattern of high and low titers was the same. Similar differences in immunogenicity between subtypes were seen after monovalent immunization when interference was eliminated as a cause of the differences. Monovalent immunization resulted in higher titers for P1.5-1,2-2 and P1.7,16 than immunization with HexaMen. However, no significant differences were found for the weakly immunogenic PorAs, P1.7-2,4 and P1.19,15-1. Since immunization with the six PorAs in the trivalent presentation form (HexaMen) and in the mixture of monovalent vesicles (HexaMix) resulted in the same pattern of high and low titers, we concluded that the differences between the PorA-specific responses are due to differences in the immunogenicities of the various PorAs and not due to interference that results in competition between different PorAs.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Strong signatures of selection in the domestic pig genome

Domestication of wild boar (Sus scrofa) and subsequent selection have resulted in dramatic phenotypic changes in domestic pigs for a number of traits, including behavior, body composition, reproduction, and coat color. Here we have used whole-genome resequencing to reveal some of the loci that underlie phenotypic evolution in European domestic pigs. Selective sweep analyses revealed strong signatures of selection at three loci harboring quantitative trait loci that explain a considerable part of one of the most characteristic morphological changes in the domestic pig—the elongation of the back and an increased number of vertebrae. The three loci were associated with the NR6A1, PLAG1, and LCORL genes. The latter two have repeatedly been associated with loci controlling stature in other domestic animals and in humans. Most European domestic pigs are homozygous for the same haplotype at these three loci. We found an excess of derived nonsynonymous substitutions in domestic pigs, most likely reflecting both positive selection and relaxed purifying selection after domestication. Our analysis of structural variation revealed four duplications at the KIT locus that were exclusively present in white or white-spotted pigs, carrying the Dominant white, Patch, or Belt alleles. This discovery illustrates how structural changes have contributed to rapid phenotypic evolution in domestic animals and how alleles in domestic animals may evolve by the accumulation of multiple causative mutations as a response to strong directional selection.Several subspecies of wild boars have contributed to the development of the domestic pig, and there is a considerable divergence time between them (on the order of 1 million y) (1–4). The domestication process has, to a large extent, been going on in parallel in Asia and Europe. For instance, black coat color in Asian and European domestic pigs is caused by independent missense mutations in the melanocortin 1 receptor (MC1R) that occurred on haplotypes originating from the Asian and European wild boar, respectively (5). Since animal breeding became more organized in the 18th century, the selection goals in pigs have evolved in response to demand. The early focus on selection for fatness was driven by demand for energy-rich food and tallow for candles. In contrast, there has been very strong selection for lean growth (high protein and low fat content) during the last 60 y, driven by the demand for reduced caloric intake in modern society. Several mutations with major effects on lean growth have already been identified, including a missense mutation in Ryanodine receptor 1 (RYR1) (6), a missense mutation in PRKAG3 encoding the gamma 3 subunit of AMP-activated protein kinase (7), and a single base change at a repressor binding site in intron 3 of insulin-like growth factor 2 (IGF2) (8).Here we used the pig draft genome sequence (Sscrofa10.2) (4) and whole-genome resequencing to reveal loci that have been under selection during and since pig domestication. We searched for selective sweeps and genetic variants showing marked allele frequency differences between pig and wild boar populations. The results are based on the combined analyses of two datasets: (i) mate pair reads from eight different pools of pigs and wild boars sequenced to ∼5× coverage/pool, and (ii) paired-end fragment reads (100 + 100 bp) from 37 individual pigs and 11 wild boars, each sequenced to ∼10× coverage (

Genome-wide assessment of worldwide chicken SNP genetic diversity indicates significant absence of rare alleles in commercial breeds

Breed utilization, genetic improvement, and industry consolidation are predicted to have major impacts on the genetic composition of commercial chickens. Consequently, the question arises as to whether sufficient genetic diversity remains within industry stocks to address future needs. With the chicken genome sequence and more than 2.8 million single-nucleotide polymorphisms (SNPs), it is now possible to address biodiversity using a previously unattainable metric: missing alleles. To achieve this assessment, 2551 informative SNPs were genotyped on 2580 individuals, including 1440 commercial birds. The proportion of alleles lacking in commercial populations was assessed by (1) estimating the global SNP allele frequency distribution from a hypothetical ancestral population as a reference, then determining the portion of the distribution lost, and then (2) determining the relationship between allele loss and the inbreeding coefficient. The results indicate that 50% or more of the genetic diversity in ancestral breeds is absent in commercial pure lines. The missing genetic diversity resulted from the limited number of incorporated breeds. As such, hypothetically combining stocks within a company could recover only preexisting within-breed variability, but not more rare ancestral alleles. We establish that SNP weights act as sentinels of biodiversity and provide an objective assessment of the strains that are most valuable for preserving genetic diversity. This is the first experimental analysis investigating the extant genetic diversity of virtually an entire agricultural commodity. The methods presented are the first to characterize biodiversity in terms of allelic diversity and to objectively link rate of allele loss with the inbreeding coefficient.