Aortoiliac hemodynamic and morphologic adaptation to chronic spinal cord injury

BackgroundReduced lower limb blood flow and resistive hemodynamic conditions potentially promote aortic inflammation and aneurysmal degeneration. We used abdominal ultrasonography, magnetic resonance imaging, and computational flow modeling to determine the relationship between reduced infrarenal aortic blood flow in chronic spinal cord injury (SCI) subjects and risk for abdominal aortic aneurysm (AAA) disease.MethodsAortic diameter in consecutive SCI subjects (n = 123) was determined via transabdominal ultrasonography. Aortic anatomic and physiologic data were acquired via magnetic resonance angiography (MRA; n = 5) and cine phase-contrast magnetic resonance flow imaging (n = 4) from SCI subjects whose aortic diameter was less than 3.0 cm by ultrasonography. Computational flow models were constructed from magnetic resonance data sets. Results were compared with those obtained from ambulatory control subjects (ultrasonography, n = 129; MRA/phase-contrast magnetic resonance flow imaging, n = 6) who were recruited at random from a larger pool of risk factor–matched individuals without known AAA disease.ResultsAge, sex distribution, and smoking histories were comparable between the SCI and control groups. In the SCI group, time since injury averaged 26 ± 13 years (mean ± SD). Aortic diameter was larger (P < .01), and the prevalence of large (≥2.5 cm; P < .01) or aneurysmal (≥3.0 cm; P < .05) aortas was greater in SCI subjects. Paradoxically, common iliac artery diameters were reduced in SCI subjects (<1.0 cm; 48% SCI vs 26% control; P < .0001). Focal preaneurysmal enlargement was noted in four of five SCI subjects by MRA. Flow modeling revealed normal flow volume, biphasic and reduced oscillatory flow, slower pressure decay, and reduced wall shear stress in the SCI infrarenal aorta.ConclusionsCharacteristic aortoiliac hemodynamic and morphologic adaptations occur in response to chronic SCI. Slower aortic pressure decay and reduced wall shear stress after SCI may contribute to mural degeneration, enlargement, and an increased prevalence of AAA disease

TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial

Background: Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm. Methods/Design: Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands. Discussion: Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms. Trial registration: Australian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976, registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084, registered on 5 September 2012

Melt Procedure Affects the Photosynthetic Response of Sea Ice Algae

The accuracy of sea ice algal production estimates is influenced by the range of melting procedures used in studies to obtain a liquid sample for incubation, particularly in relation to the duration of melt and the approach to buffering for osmotic shock. In this research, ice algal photophysiology from 14C incubations was compared in field samples prepared by three melt procedures: (i) a rapid 4 h melt of the bottommost ( < 1 cm) ice algal layer scraped into a large volume of filtered seawater (salinity 27–30), (ii) melt of a bottom 5 cm section diluted into a moderate volume of filtered seawater over 24 h (salinity 20–24), and (iii) melt of a bottom 5 cm section without any filtered seawater dilution over about 48 h (salinity 10–12). Maximum photosynthetic rate, photosynthetic efficiency and production at zero irradiance were significantly affected by the melt treatment employed in experiments. All variables were greatest in the highly diluted scrape sample and lowest in the bulk-ice samples melted in the absence of filtered seawater. Laboratory experiments exposing cultures of the common sea ice diatom Nitzschia frigida to different salinities and light conditions suggested that the field-based responses can be attributed to the rapid ( < 4 h) adverse effects of exposing cells to low salinities during melt without dilution. The observed differences in primary production between melt treatments were estimated to account for over 60% of the variability in production estimates reported for the Arctic. Future studies are strongly encouraged to replicate salinity conditions representative of in situ values during the melting process to minimize hypoosmotic stress, thereby most accurately estimating primary production

Fold change and p-value cutoffs significantly alter microarray interpretations

<p>Abstract</p> <p>Background</p> <p>As context is important to gene expression, so is the preprocessing of microarray to transcriptomics. Microarray data suffers from several normalization and significance problems. Arbitrary fold change (FC) cut-offs of >2 and significance p-values of <0.02 lead data collection to look only at genes which vary wildly amongst other genes. Therefore, questions arise as to whether the biology or the statistical cutoff are more important within the interpretation. In this paper, we reanalyzed a zebrafish (<it>D. rerio</it>) microarray data set using GeneSpring and different differential gene expression cut-offs and found the data interpretation was drastically different. Furthermore, despite the advances in microarray technology, the array captures a large portion of genes known but yet still leaving large voids in the number of genes assayed, such as leptin a pleiotropic hormone directly related to hypoxia-induced angiogenesis.</p> <p>Results</p> <p>The data strongly suggests that the number of differentially expressed genes is more up-regulated than down-regulated, with many genes indicating conserved signalling to previously known functions. Recapitulated data from Marques et al. (2008) was similar but surprisingly different with some genes showing unexpected signalling which may be a product of tissue (heart) or that the intended response was transient.</p> <p>Conclusions</p> <p>Our analyses suggest that based on the chosen statistical or fold change cut-off; microarray analysis can provide essentially more than one answer, implying data interpretation as more of an art than a science, with follow up gene expression studies a must. Furthermore, gene chip annotation and development needs to maintain pace with not only new genomes being sequenced but also novel genes that are crucial to the overall gene chips interpretation.</p

Altered DNA methylation associated with a translocation linked to major mental illness

Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions

Melt Procedure Affects the Photosynthetic Response of Sea Ice Algae

The accuracy of sea ice algal production estimates is influenced by the range of melting procedures used in studies to obtain a liquid sample for incubation, particularly in relation to the duration of melt and the approach to buffering for osmotic shock. In this research, ice algal photophysiology from 14C incubations was compared in field samples prepared by three melt procedures: (i) a rapid ≤ 4 h melt of the bottommost ( &lt; 1 cm) ice algal layer scraped into a large volume of filtered seawater (salinity 27–30), (ii) melt of a bottom 5 cm section diluted into a moderate volume of filtered seawater over 24 h (salinity 20–24), and (iii) melt of a bottom 5 cm section without any filtered seawater dilution over about 48 h (salinity 10–12). Maximum photosynthetic rate, photosynthetic efficiency and production at zero irradiance were significantly affected by the melt treatment employed in experiments. All variables were greatest in the highly diluted scrape sample and lowest in the bulk-ice samples melted in the absence of filtered seawater. Laboratory experiments exposing cultures of the common sea ice diatom Nitzschia frigida to different salinities and light conditions suggested that the field-based responses can be attributed to the rapid ( &lt; 4 h) adverse effects of exposing cells to low salinities during melt without dilution. The observed differences in primary production between melt treatments were estimated to account for over 60% of the variability in production estimates reported for the Arctic. Future studies are strongly encouraged to replicate salinity conditions representative of in situ values during the melting process to minimize hypoosmotic stress, thereby most accurately estimating primary production

Perinatal Asphyxia Reduces Dentate Granule Cells and Exacerbates Methamphetamine-Induced Hyperlocomotion in Adulthood

Background: Obstetric complications have been regarded as a risk factor for schizophrenia later in life. One of the mechanisms underlying the association is postulated to be a hypoxic process in the brain in the offspring around the time of birth. Hippocampus is one of the brain regions implicated in the late-onset dopaminergic dysfunction associated with hypoxic obstetric complications. Methodology/Principal Findings: We used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Cesarean section birth. At 6 and 12 weeks after birth, the behavior of the pups was assessed using a methamphetamine-induced locomotion test. In addition, the histopathology of the hippocampus was examined by means of stereology. At 6 weeks, there was no change in the methamphetamine-induced locomotion. However, at 12 weeks of age, we found an elevation in methamphetamine-induced locomotor activity, which was associated with an increase of dopamine release in the nucleus accumbens. At the same age, we also found a reduction of the dentate granule cells of the hippocampus. Conclusions/Significance: These results suggest that the dopaminergic dysregulation after perinatal asphyxia is associated with a reduction in hippocampal dentate granule cells, and this may partly contribute to the pathogenesis of schizophrenia.浜松医科大学学位論文　医博第548号(平成２１年３月１８日

Differential expression of presynaptic genes in a rat model of postnatal hypoxia: relevance to schizophrenia

Obstetric complications play a role in the pathophysiology of schizophrenia. However, the biological consequences during neurodevelopment until adulthood are unknown. Microarrays have been used for expression profiling in four brain regions of a rat model of neonatal hypoxia as a common factor of obstetric complications. Animals were repeatedly exposed to chronic hypoxia from postnatal (PD) day 4 through day 8 and killed at the age of 150 days. Additional groups of rats were treated with clozapine from PD 120–150. Self-spotted chips containing 340 cDNAs related to the glutamate system (“glutamate chips”) were used. The data show differential (up and down) regulations of numerous genes in frontal (FR), temporal (TE) and parietal cortex (PAR), and in caudate putamen (CPU), but evidently many more genes are upregulated in frontal and temporal cortex, whereas in parietal cortex the majority of genes are downregulated. Because of their primary presynaptic occurrence, five differentially expressed genes (CPX1, NPY, NRXN1, SNAP-25, and STX1A) have been selected for comparisons with clozapine-treated animals by qRT-PCR. Complexin 1 is upregulated in FR and TE cortex but unchanged in PAR by hypoxic treatment. Clozapine downregulates it in FR but upregulates it in PAR cortex. Similarly, syntaxin 1A was upregulated in FR, but downregulated in TE and unchanged in PAR cortex, whereas clozapine downregulated it in FR but upregulated it in PAR cortex. Hence, hypoxia alters gene expression regionally specific, which is in agreement with reports on differentially expressed presynaptic genes in schizophrenia. Chronic clozapine treatment may contribute to normalize synaptic connectivity