The dynamic metabolism of hyaluronan regulates the cytosolic concentration of UDP-GlcNAc

Hyaluronan, a macromolecular glycosaminoglycan, is normally synthesized by hyaluronan synthases at the plasma membrane using cytosolic UDP-GlcUA and UDP-GlcNAc substrates and extruding the elongating chain into the extracellular space. The cellular metabolism (synthesis and catabolism) of hyaluronan is dynamic. UDP-GlcNAc is also the substrate for O-GlcNAc transferase, which is central to the control of many cytosolic pathways. This Perspective outlines recent data for regulation of hyaluronan synthesis and catabolism that support a model that hyaluronan metabolism can be a rheostat for controlling an acceptable normal range of cytosolic UDP-GlcNAc concentrations in order to maintain normal cell functions

Higher hematocrit improves cerebral outcome after deep hypothermic circulatory arrest

AbstractBackground: Various degrees of hemodilution are currently in clinical use during deep hypothermic circulatory arrest to counteract deleterious rheologic effects linked with brain injury by previous reports. Material and methods: Seventeen piglets were randomly assigned to three groups. Group I piglets (n = 7) received colloid and crystalloid prime (hematocrit < 10%), group II piglets (n = 5) received blood and crystalloid prime (hematocrit 20%), group III piglets (n = 5) received blood prime (hematocrit 30%). All groups underwent 60 minutes of deep hypothermic circulatory arrest at 15º C. with continuous magnetic resonance spectroscopy and near-infrared spectroscopy Neurologic recovery was evaluated for 4 days (neurologic deficit score 0, normal, to 500, brain death; overall performance category 1, normal, to 5, brain death). Neurohistologic score (0, normal, to 5+, necrosis) was assessed after the animals were euthanized on day 4. Results: Group I had significant loss of phosphocreatine and intracellular acidosis during early cooling (phosphocreatine in group I, 86.3% ± 26.8%; group II, 117.3% ± 8.6%; group III, 110.9% ± 2.68%; p = 0.0008; intracellular pH in group I, 6.95 ± 0.18; group II, 7.28 ± 0.04; group III, 7.49 ± 0.04; p = 0.0048). Final recovery was the same for all groups. Cytochrome aa3 was more reduced in group I during deep hypothermic circulatory arrest than in either of the other groups (group I, -43.6 ± 2.6; group II, -16.0 ± 5.2; group III, 1.3 ± 3.1; p < 0.0001). Neurologic deficit score was best preserved in group III (p < 0.05 group II vs group III) on the first postoperative day, although this difference diminished with time and all animals were neurologically normal after 4 days. Histologic assessment was worst among group I in neocortex area (group I, 1.33 ± 0.3; group II, 0.22 ± 0.1; group III, 0.40 ± 0.2, p < 0.05, group I vs group II; p = 0.0287, group I vs group III). Conclusion: Extreme hemodilution during cardiopulmonary bypass may cause inadequate oxygen delivery during early cooling. The higher hematocrit with a blood prime is associated with improved cerebral recovery after deep hypothermic circulatory arrest. (J Thorac Cardiovasc Surg 1996;112:1610-21

A novel sialyl lewis x analog attenuates cerebral injury after deep hypothermic circulatory arrest

AbstractBackground: The initial step in the inflammatory process, which can be initiated by cardiopulmonary bypass and by ischemia/reperfusion, is mediated by interactions between selectins on endothelial cells and on neutrophils. We studied the effects of selectin blockade using a novel Sialyl Lewis X analog (CY-1503) on recovery after deep hypothermic circulatory arrest in a piglet model. Methods: Twelve Yorkshire piglets were subjected to cardiopulmonary bypass, 30 minutes of cooling, 100 minutes of circulatory arrest at 15°C, and 40 minutes of rewarming. Five animals received a bolus of 60 mg/kg of CY-1503 and an infusion (3 mg/kg per hour) for 24 hours from reperfusion (group O), and 7 randomly selected control piglets received saline solution (group C). Body weight and total body water content were evaluated 3 hours and 24 hours after reperfusion by a bio-impedance technique. Neurologic recovery of animals was evaluated daily by neurologic deficit score (0 = normal, 500 = brain death) and overall performance categories (1 = normal, 5 = brain death). The brain was fixed in situ on the fourth postoperative day and examined by histologic score (0 = normal, 5+ = necrosis) in a blinded fashion. Results: Two of 7 animals in group C died. The neurologic deficit score was significantly lower in group O than in group C (postoperative day 1, P < .001; postoperative day 2, P = .02). The overall performance category was significantly lower in group O than in group C on postoperative day 2 (P = .01). Percentage total body water after cardiopulmonary bypass was significantly higher in group C than in group O (P = .03). Histologic score tended to be higher in group C than in group O, but this difference did not reach statistical significance (group O = 0.5 ± 0.7; group C = 1.3 ± 1.9). Conclusion: Blockade of selectin adhesion molecules by saturation with a Sialyl Lewisxanalog accelerates recovery after 100 minutes of deep hypothermic circulatory arrest in a piglet survival model. (J Thorac Cardiovasc Surg 1999; 117:1204-11

Interaction of temperature with hematocrit level and pH determines safe duration of hypothermic circulatory arrest

AbstractObjectivePrevious studies have demonstrated that both hematocrit level and pH influence the protection afforded by deep hypothermic circulatory arrest. The current study examines how temperature modulates the effect of hematocrit level and pH in determining a safe duration of circulatory arrest. The study also builds on previous work investigating the utility of near-infrared spectroscopy as a real-time monitor of cerebral protection during circulatory arrest.MethodsSeventy-six piglets (9.3 ± 1.2 kg) underwent circulatory arrest under varying conditions with continuous monitoring by means of near-infrared spectroscopy (hematocrit level of 20% or 30%; pH-stat or alpha-stat strategy; temperature of 15°C or 25°C; arrest time of 60, 80, or 100 minutes). Neurologic recovery was evaluated daily by a veterinarian, and the brain was fixed in situ on postoperative day 4 to be examined on the basis of histologic score in a blinded fashion.ResultsMultivariable analysis of total histologic score revealed that higher temperature, lower hematocrit level, more alkaline pH, and longer hypothermic circulatory arrest duration were predictive of more severe damage to the brain (P < .01). Regression modeling revealed that higher temperature exacerbated the disadvantage of a lower hematocrit level and longer arrest times but not pH strategy. Normalized oxyhemoglobin nadir time, derived from near-infrared spectroscopy, was positively correlated with neurologic recovery on the fourth postoperative day and with total histologic injury score (P < .0001).ConclusionHematocrit level and pH, as well as temperature, determine the safe duration of hypothermic circulatory arrest. Near-infrared spectroscopy is a useful real-time monitor of safe duration of circulatory arrest

Preceding rule induction with instance reduction methods

A new prepruning technique for rule induction is presented which applies instance reduction before rule induction. An empirical evaluation records the predictive accuracy and size of rule-sets generated from 24 datasets from the UCI Machine Learning Repository. Three instance reduction algorithms (Edited Nearest Neighbour, AllKnn and DROP5) are compared. Each one is used to reduce the size of the training set, prior to inducing a set of rules using Clark and Boswell's modification of CN2. A hybrid instance reduction algorithm (comprised of AllKnn and DROP5) is also tested. For most of the datasets, pruning the training set using ENN, AllKnn or the hybrid significantly reduces the number of rules generated by CN2, without adversely affecting the predictive performance. The hybrid achieves the highest average predictive accuracy

Comparisons of Supergranule Characteristics During the Solar Minima of Cycles 22/23 and 23/24

Supergranulation is a component of solar convection that manifests itself on the photosphere as a cellular network of around 35 Mm across, with a turnover lifetime of 1-2 days. It is strongly linked to the structure of the magnetic field. The horizontal, divergent flows within supergranule cells carry local field lines to the cell boundaries, while the rotational properties of supergranule upflows may contribute to the restoration of the poloidal field as part of the dynamo mechanism that controls the solar cycle. The solar minimum at the transition from cycle 23 to 24 was notable for its low level of activity and its extended length. It is of interest to study whether the convective phenomena that influences the solar magnetic field during this time differed in character to periods of previous minima. This study investigates three characteristics (velocity components, sizes and lifetimes) of solar supergranulation. Comparisons of these characteristics are made between the minima of cycles 22/23 and 23/24 using MDI Doppler data from 1996 and 2008, respectively. It is found that whereas the lifetimes are equal during both epochs (around 18 h), the sizes are larger in 1996 (35.9 +/- 0.3 Mm) than in 2008 (35.0 +/- 0.3 Mm), while the dominant horizontal velocity flows are weaker (139 +/- 1 m/s in 1996; 141 +/- 1 m/s in 2008). Although numerical differences are seen, they are not conclusive proof of the most recent minimum being inherently unusual.Comment: 22 pages, 5 figures. Solar Physics, in pres

Mutations in the Satellite Cell Gene MEGF10 Cause a Recessive Congenital Myopathy with Minicores

We ascertained a nuclear family in which three of four siblings were affected with an unclassified autosomal recessive myopathy characterized by severe weakness, respiratory impairment, scoliosis, joint contractures, and an unusual combination of dystrophic and myopathic features on muscle biopsy. Whole genome sequence from one affected subject was filtered using linkage data and variant databases. A single gene, MEGF10, contained nonsynonymous mutations that co-segregated with the phenotype. Affected subjects were compound heterozygous for missense mutations c.976T > C (p.C326R) and c.2320T > C (p.C774R). Screening the MEGF10 open reading frame in 190 patients with genetically unexplained myopathies revealed a heterozygous mutation, c.211C > T (p.R71W), in one additional subject with a similar clinical and histological presentation as the discovery family. All three mutations were absent from at least 645 genotyped unaffected control subjects. MEGF10 contains 17 atypical epidermal growth factor-like domains, each of which contains eight cysteine residues that likely form disulfide bonds. Both the p.C326R and p.C774R mutations alter one of these residues, which are completely conserved in vertebrates. Previous work showed that murine Megf10 is required for preserving the undifferentiated, proliferative potential of satellite cells, myogenic precursors that regenerate skeletal muscle in response to injury or disease. Here, knockdown of megf10 in zebrafish by four different morpholinos resulted in abnormal phenotypes including unhatched eggs, curved tails, impaired motility, and disorganized muscle tissue, corroborating the pathogenicity of the human mutations. Our data establish the importance of MEGF10 in human skeletal muscle and suggest satellite cell dysfunction as a novel myopathic mechanism

AIFM1 mutation presenting with fatal encephalomyopathy and mitochondrial disease in an infant

Apoptosis-inducing factor mitochondrion-associated 1 (AIFM1), encoded by the gene AIFM1, has roles in electron transport, apoptosis, ferredoxin metabolism, reactive oxygen species generation, and immune system regulation. Here we describe a patient with a novel AIFM1 variant presenting unusually early in life with mitochondrial disease, rapid deterioration, and death. Autopsy, at the age of 4 mo, revealed features of mitochondrial encephalopathy, myopathy, and involvement of peripheral nerves with axonal degeneration. In addition, there was microvesicular steatosis in the liver, thymic noninvolution, follicular bronchiolitis, and pulmonary arterial medial hypertrophy. This report adds to the clinical and pathological spectrum of disease related to AIFM1 mutations and provides insights into the role of AIFM1 in cellular function