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1.  Leptin regulates CD16 expression on human monocytes in a sex‐specific manner 
Physiological Reports  2014;2(10):e12177.
Abstract
Fat mass is linked mechanistically to the cardiovascular system through leptin, a 16 kDa protein produced primarily by adipocytes. In addition to increasing blood pressure via hypothalamic‐sympathetic pathways, leptin stimulates monocyte migration, cytokine secretion, and other functions that contribute to atherosclerotic plaque development. These functions are also characteristics of CD16‐positive monocytes that have been implicated in the clinical progression of atherosclerosis. This investigation sought to determine if leptin promoted the development of such CD16‐positive monocytes. Cells from 45 healthy men and women with age ranging from 20 to 59 years were analyzed. Circulating numbers of CD14++16++ monocytes, which are primary producers of TNFα, were positively related to plasma leptin concentrations (P < 0.0001), with a stronger correlation in men (P < 0.05 for leptin × sex interaction). In vitro, recombinant human leptin induced CD16 expression in a dose‐related manner (P = 0.02), with a stronger influence on monocytes from men (P = 0.03 for leptin × sex interaction). There were no sex‐related differences in total leptin receptor expression on any monocyte subtypes, relative expression of long versus short isoforms of the receptor, or soluble leptin receptor concentrations in the plasma. The number of circulating CD14+16++ monocytes, which preferentially migrate into nascent plaques, was positively related to systolic blood pressure (R = 0.56, P = 0.0008) and intima‐media thickness (R = 0.37, P = 0.03), and negatively related to carotid compliance (R = −0.39, P = 0.02). These observations indicate that leptin promotes the development of CD16‐positive monocyte populations in a sex‐specific manner and that these subpopulations are associated with diminished vascular function.
e12177
Recombinant leptin induced CD16 expression on human monocytes in vitro in a dose‐ and sex‐specific manner. In vivo, CD16 expression on human monocytes correlated with plasma leptin concentrations in a sex‐specific manner. Blood pressure, carotid intima‐media thickness and carotid compliance were related to the number of circulating CD16‐positive monocytes.
doi:10.14814/phy2.12177
PMCID: PMC4254102  PMID: 25303952
Blood pressure; carotid compliance; intima‐media thickness; leptin receptor
2.  The effect of sampling rate on observed statistics in a correlated random walk 
Tracking the movement of individual cells or animals can provide important information about their motile behaviour, with key examples including migrating birds, foraging mammals and bacterial chemotaxis. In many experimental protocols, observations are recorded with a fixed sampling interval and the continuous underlying motion is approximated as a series of discrete steps. The size of the sampling interval significantly affects the tracking measurements, the statistics computed from observed trajectories, and the inferences drawn. Despite the widespread use of tracking data to investigate motile behaviour, many open questions remain about these effects. We use a correlated random walk model to study the variation with sampling interval of two key quantities of interest: apparent speed and angle change. Two variants of the model are considered, in which reorientations occur instantaneously and with a stationary pause, respectively. We employ stochastic simulations to study the effect of sampling on the distributions of apparent speeds and angle changes, and present novel mathematical analysis in the case of rapid sampling. Our investigation elucidates the complex nature of sampling effects for sampling intervals ranging over many orders of magnitude. Results show that inclusion of a stationary phase significantly alters the observed distributions of both quantities.
doi:10.1098/rsif.2013.0273
PMCID: PMC4043159  PMID: 23740484
correlated random walk; sampling rate; tracking; animal migration; bacterial motility
3.  The cycling of organic nitrogen through the atmosphere 
Atmospheric organic nitrogen (ON) appears to be a ubiquitous but poorly understood component of the atmospheric nitrogen deposition flux. Here, we focus on the ON components that dominate deposition and do not consider reactive atmospheric gases containing ON such as peroxyacyl nitrates that are important in atmospheric nitrogen transport, but are probably not particularly important in deposition. We first review the approaches to the analysis and characterization of atmospheric ON. We then briefly summarize the available data on the concentrations of ON in both aerosols and rainwater from around the world, and the limited information available on its chemical characterization. This evidence clearly shows that atmospheric aerosol and rainwater ON is a complex mixture of material from multiple sources. This synthesis of available information is then used to try and identify some of the important sources of this material, in particular, if it is of predominantly natural or anthropogenic origin. Finally, we suggest that the flux of ON is about 25 per cent of the total nitrogen deposition flux.
doi:10.1098/rstb.2013.0115
PMCID: PMC3682737  PMID: 23713115
nitrogen; organic nitrogen; atmosphere
4.  The Tie-dyed pathway promotes symplastic trafficking in the phloem 
Plant Signaling & Behavior  2013;8(6):e24540.
The tie-dyed1 (tdy1) and tdy2 mutants of maize exhibit leaf regions with starch hyperaccumulation and display unusual genetic interactions, suggesting they function in the same physiological process. Tdy2 encodes a putative callose synthase and is expressed in developing vascular tissues of immature leaves. Radiolabelling experiments and transmission electron microscopy (TEM) revealed symplastic trafficking within the phloem was perturbed at the companion cell/sieve element interface. Here, we show that as reported for tdy2 mutants, tdy1 yellow leaf regions display an excessive oil-droplet phenotype in the companion cells. Based on the proposed function of Tdy2 as a callose synthase, our previous work characterizing Tdy1 as a novel, transmembrane-localized protein, and the present findings, we speculate how TDY1 and TDY2 might interact to promote symplastic transport of both solutes and developmentally instructive macromolecules during vascular development at the companion cell/sieve element interface.
doi:10.4161/psb.24540
PMCID: PMC3909061  PMID: 23603956
callose synthase; companion cell; maize; oil droplet; phloem; plasmodesmata; sieve element; symplastic trafficking; tie-dyed; xylem
5.  Fusobacterium necrophorum in an Abdominal Aortic Aneurysm, Treated by Once Daily Ertapenem 
Inflammatory aneurysms may make up a small percentage of the total number of abdominal aortic aneurysms, but they present their own unique challenges. We present a case of a 65-year-old man whose aneurysm was found to be colonized by Fusobacterium necrophorum.
doi:10.1055/s-0032-1325169
PMCID: PMC3578632  PMID: 23997565
abdominal aortic aneurysm; aneurysm; C-reactive protein; infection; mycotic aneurysm; risk factors; repair
6.  Myocardial Function after Fetal Cardiac Bypass in an Ovine Model 
Objective
Fetal cardiac surgery may improve the prognosis of certain complex congenital heart defects that have significant associated mortality and morbidity in utero or after birth. An important step in translating fetal cardiac surgery is identifying potential mechanisms leading to myocardial dysfunction following bypass. The hypothesis was that fetal cardiac bypass results in myocardial dysfunction, possibly due to perturbation of calcium cycling and contractile proteins.
Methods
Mid-term sheep fetuses (n=6) underwent 30 minutes of cardiac bypass and 120 minutes of monitoring after bypass. Sonomicrometry and pressure catheters inserted in left (LV) and right ventricles (RV) measured myocardial function. Cardiac contractile and calcium cycling proteins, along with calpain, were analyzed by immunoblot.
Results
Preload recruitable stroke work (slope of the regression line) was reduced at 120 min after bypass (RV – baseline vs. 120 min after bypass, 38.6±6.8 vs. 20.4±4.8 (P=.01); LV – 37±7.3 vs. 20.6±3.9 (P=.01). Tau (msec), a measure of diastolic relaxation, was elevated in both ventricles (RV – baseline vs. 120 min after bypass, 32.7±4.5 vs. 67.8±9.4 (P<.01); LV – 26.1±3.2 vs. 63.2±11.2 (P=.01). Cardiac output was lower and end-diastolic pressures were higher in the RV, but not the LV, after bypass compared with baseline. RV troponin I was degraded by elevated calpain activity and protein levels of sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) were reduced in both ventricles.
Conclusions
Fetal cardiac bypass was associated with myocardial dysfunction and disruption of calcium cycling and contractile proteins. Minimizing myocardial dysfunction after cardiac bypass is important for successful fetal surgery to repair complex congenital heart defects.
doi:10.1016/j.jtcvs.2010.08.031
PMCID: PMC3032026  PMID: 20884028
7.  Incidence and risk factors for fatal pulmonary embolism after major trauma: a nested cohort study† 
BJA: British Journal of Anaesthesia  2010;105(5):596-602.
Background
Venous thromboembolism is common after major trauma. Strategies to prevent fatal pulmonary embolism (PE) are widely utilized, but the incidence and risk factors for fatal PE are poorly understood.
Methods
Using linked data from the intensive care unit, trauma registry, Western Australian Death Registry, and post-mortem reports, the incidence and risk factors for fatal PE in a consecutive cohort of major trauma patients, admitted between 1994 and 2002, were assessed. Non-linear relationships between continuous predictors and risk of fatal PE were modelled by logistic regression.
Results
Of the 971 consecutive trauma patients considered in the study, 134 (13.8%) died after their injuries. Fatal PE accounted for 11.9% of all deaths despite unfractionated heparin prophylaxis being used in 44% of these patients. Fatal PE occurred in those who were older (mean age 51- vs 37-yr-old, P=0.01), with more co-morbidities (Charlson's co-morbidity index 1.1 vs 0.2, P=0.01), had a larger BMI (31.8 vs 24.5, P=0.01), and less severe head and systemic injuries when compared with those who died of other causes. Sites of injuries were not significantly related to the risk of fatal PE. Fatal PE occurred much later than deaths from other causes (median 18 vs 2 days, P=0.01), and the estimated attributable mortality of PE was 49% (95% confidence interval 36–62%).
Conclusions
Fatal PE appeared to be a potential preventable cause of late mortality after major trauma. Severity of injuries, co-morbidity, and BMI were important risk factors for fatal PE after major trauma.
doi:10.1093/bja/aeq254
PMCID: PMC2955535  PMID: 20861095
mortality; prevention; thromboembolism; traumatic injuries
8.  New relationships between breast microcalcifications and cancer 
British Journal of Cancer  2010;103(7):1034-1039.
Background:
Breast microcalcifications are key diagnostically significant radiological features for localisation of malignancy. This study explores the hypothesis that breast calcification composition is directly related to the local tissue pathological state.
Methods:
A total of 236 human breast calcifications from 110 patients were analysed by mid-Fouries transform infrared (FTIR) spectroscopy from three different pathology types (112 invasive carcinoma (IC), 64 in-situ carcinomas and 60 benign). The biochemical composition and the incorporation of carbonate into the hydroxyapatite lattice of the microcalcifications were studied by infrared microspectroscopy. This allowed the spectrally identified composition to be directly correlated with the histopathology grading of the surrounding tissue.
Results:
The carbonate content of breast microcalcifications was shown to significantly decrease when progressing from benign to malignant disease. In this study, we report significant correlations (P<0.001) between microcalcification chemical composition (carbonate content and protein matrix : mineral ratios) and distinct pathology grades (benign, in-situ carcinoma and ICs). Furthermore, a significant correlation (P<0.001) was observed between carbonate concentrations and carcinoma in-situ sub-grades. Using the two measures of pathology-specific calcification composition (carbonate content and protein matrix : mineral ratios) as the inputs to a two-metric discriminant model sensitivities of 79, 84 and 90% and specificities of 98, 82 and 96% were achieved for benign, ductal carcinoma in situ and invasive malignancies, respectively.
Conclusions:
We present the first demonstration of a direct link between the chemical nature of microcalcifications and the grade of the pathological breast disease. This suggests that microcalcifications have a significant association with cancer progression, and could be used for future objective analytical classification of breast pathology. A simple two-metric model has been demonstrated, more complex spectral analysis may yeild greater discrimination performance. Furthermore there appears to be a sequential progression of calcification composition.
doi:10.1038/sj.bjc.6605873
PMCID: PMC2965876  PMID: 20842116
breast cancer; calcifications; carbonate; DCIS; diagnose; FTIR; grade
9.  Dynamics of maternal and paternal effects on embryo and seed development in wild radish (Raphanus sativus) 
Annals of Botany  2010;106(2):309-319.
Background and Aims
Variability in embryo development can influence the rate of seed maturation and seed size, which may have an impact on offspring fitness. While it is expected that embryo development will be under maternal control, more controversial hypotheses suggest that the pollen donor and the embryo itself may influence development. These latter possibilities are, however, poorly studied. Characteristics of 10-d-old embryos and seeds of wild radish (Raphanus sativus) were examined to address: (a) the effects of maternal plant and pollen donor on development; (b) the effects of earlier reproductive events (pollen tube growth and fertilization) on embryos and seeds, and the influence of embryo size on mature seed mass; (c) the effect of water stress on embryos and seeds; (d) the effect of stress on correlations of embryo and seed characteristics with earlier and later reproductive events and stages; and (e) changes in maternal and paternal effects on embryo and seed characteristics during development.
Methods
Eight maternal plants (two each from four families) and four pollen donors were crossed and developing gynoecia were collected at 10 d post-pollination. Half of the maternal plants experienced water stress. Characteristics of embryos and seeds were summarized and also compared with earlier and later developmental stages.
Key Results
In addition to the expected effects of the maternal plants, all embryo characters differed among pollen donors. Paternal effects varied over time, suggesting that there are windows of opportunity for pollen donors to influence embryo development. Water-stress treatment altered embryo characteristics; embryos were smaller and less developed. In addition, correlations of embryo characteristics with earlier and later stages changed dramatically with water stress.
Conclusions
The expected maternal effects on embryo development were observed, but there was also evidence for an early paternal role. The relative effects of these controls may change over time. Thus, there may be times in development when selection on the maternal, paternal or embryo contributions to development are more and less likely.
doi:10.1093/aob/mcq110
PMCID: PMC2908165  PMID: 20519237
Raphanus sativus; embryo development; maternal effects; paternal effects; seed development; seed size; water stress; wild radish
10.  Optimal and robust control of invasive alien species spreading in homogeneous landscapes 
Government agencies lack robust modelling tools to manage the spread of invasive alien species (IAS). In this paper, we combine optimal control and simulation methods with biological invasion spread theory to estimate the type of optimal policy and switching point of control efforts against a spreading IAS. We employ information-gap (info-gap) theory to assess how the optimal solutions differ from a policy that is most robustly immune to unacceptable outcomes. The model is applied to the potential invasion of the Colorado potato beetle in the UK. Under no uncertainty, we demonstrate that for many of the parameter combinations the optimal control policy corresponds to slowing down the invasion. The info-gap analysis shows that eradication policies identified as optimal under no uncertainty are robustly the best policies even under severe uncertainty, i.e. even if they are likely to turn into slowing down policies. We also show that the control of satellite colonies, if identified as optimal under no uncertainty, will also be a robust slowing down policy for IAS that can spread by long distance dispersal even for relatively ineffective control measures. The results suggest that agencies adopt management strategies that are robustly optimal, despite the severe uncertainties they face.
doi:10.1098/rsif.2009.0266
PMCID: PMC2842796  PMID: 19740923
control theory; pest risk analysis; reaction–diffusion; stratified diffusion
12.  Acute Complete Heart Block in Dogs 
Circulation  1955;12(1):82-89.
A study has been conducted immediately and up to 18 days after the surgical production of complete heart block in dogs. Immediately after surgery cardiac output, coronary flow, and mean arterial pressure were reduced in rough proportion to the degree of bradycardia. In time, these measures began to return toward preoperative levels. Paralleling the diminished left ventricular work was a diminished left ventricular oxygen consumption with little consequent change in myocardial efficiency. Small rises were detected in central venous pressure. At autopsy, the only unequivocal abnormality was myocardial hypertrophy which became measurable between 2 and 18 days after operation.
PMCID: PMC2952508  PMID: 14390703
14.  Oral and Enteral Resuscitation of Burn Shock The Historical Record and Implications for Mass Casualty Care 
Eplasty  2010;10:e56.
In the aftermath of a mass disaster, standard care methods for treatment of burn injury will often not be available for all victims. A method of fluid resuscitation for burns that has largely been forgotten by contemporary burn experts is enteral resuscitation. We identified 12 studies with over 700 patients treated with enteral resuscitation, defined as drinking or gastric infusion of salt solutions, from the literature. These studies suggest that enteral resuscitation can be an effective treatment for burn shock under conditions in which the standard IV therapy is unavailable or delayed, such as in mass disasters and combat casualties. Enteral resuscitation of burn shock was effective in patients with moderate (10–40% TBSA) and in some patients with more severe injuries. The data suggests that some hypovolemic burn and trauma patients can be treated exclusively with enteral resuscitation, and others might benefit from enteral resuscitation as an initial alternative and a supplement to IV therapy. A complication of enteral resuscitation was vomiting, which occurred less in children and much less when therapy was initiated within the first postburn hour. Enteral resuscitation is contra-indicated when the patient is in “peripheral circulatory collapse”. The optimal enteral solution and regimen has not yet been defined, nor has its efficacy been tested against modern IV resuscitation. The oldest studies used glucose-free solutions of buffered isotonic and hypotonic saline. Studies that are more recent show benefit of adding glucose to electrolyte solutions similar to those used in the treatment of cholera. If IV therapy for mass casualty care is delayed due to logistical constraints, enteral resuscitation should be considered.
PMCID: PMC2933130  PMID: 20827301
15.  Patterns of Chromosomal Evolution in Sigmodon, Evidence from Whole Chromosome Paints 
Cytogenetic and Genome Research  2009;125(1):54-66.
Of the superfamily Muroidea (31 genera, 1578 species), the Sigmodontinae (74 genera, 377 species) is the second largest subfamily in number of species and represents a significant radiation of rodent biodiversity. Only 2 of the 74 genera are found in both North and South America (Sigmodon and Oryzomys) and the remainder are exclusively from South America. In recent molecular studies, the genus Sigmodon (Cricetidae, Sigmodontinae) has been considered sister to many other South American Sigmodontines [Steppan et al., 2004]. We examine the chromosomal evolution of 9 species of Sigmodon utilizing chromosomal paints isolated from S. hispidus, proposed to be similar to the ancestral karyotype [Elder, 1980]. Utilizing a phylogenetic hypothesis of a molecular phylogeny of Sigmodon [Henson and Bradley, 2009], we mapped shared chromosomal rearrangements of taxa on a molecular tree to estimate the evolutionary position of each rearrangement. For several species (S. hirsutus, S. leucotis, S. ochrognathus, S. peruanus, and S. toltecus), the karyotype accumulated few or no changes, but in three species (S. arizonae, S. fulviventer, and S. mascotensis) numerous karyotype rearrangements were observed. These rearrangements involved heterochromatic additions, centric fusions, tandem fusions, pericentric inversions, as well as the addition of interstitial DNA not identified by chromosome paints or C-banding. The hypothesis that the ancestral karyotype for this complex had a diploid number of 52, a fundamental number of 52, and a G-band pattern of which most, if not all are similar to that present in modern day S. hispidus fails to be rejected. This hypothesis remains viable as an explanation of chromosomal evolution in Sigmodontine rodents.
doi:10.1159/000218747
PMCID: PMC2918645  PMID: 19617697
Ancestral karyotype; Comparative cytogenetics; DAPI banding; Karyotype conservation; Muroid rodents; Phylogeny; Sigmodontinae; Tandem fusions
16.  Breast calcification: the 'Cinderella' breast element? 
Breast Cancer Research : BCR  2010;12(Suppl 1):P36.
doi:10.1186/bcr2533
PMCID: PMC2875598
17.  The Adapter Protein SLP-76 Mediates “Outside-In” Integrin Signaling and Function in T Cells▿ †  
Molecular and Cellular Biology  2009;29(20):5578-5589.
The adapter protein SH2 domain-containing leukocyte protein of 76 kDa (SLP-76) is an essential mediator of signaling from the T-cell antigen receptor (TCR). We report here that SLP-76 also mediates signaling downstream of integrins in T cells and that SLP-76-deficient T cells fail to support adhesion to integrin ligands. In response to both TCR and integrin stimulation, SLP-76 relocalizes to surface microclusters that colocalize with phosphorylated signaling proteins. Disruption of SLP-76 recruitment to the protein named LAT (linker for activation of T cells) inhibits SLP-76 clustering downstream of the TCR but not downstream of integrins. Conversely, an SLP-76 mutant unable to bind ADAP (adhesion and degranulation-promoting adapter protein) forms clusters following TCR but not integrin engagement and fails to support T-cell adhesion to integrin ligands. These findings demonstrate that SLP-76 relocalizes to integrin-initiated signaling complexes by a mechanism different from that employed during TCR signaling and that SLP-76 relocalization corresponds to SLP-76-dependent integrin function in T cells.
doi:10.1128/MCB.00283-09
PMCID: PMC2756887  PMID: 19667077
18.  Low level mercury speciation in freshwaters by isotope dilution GC-ICP-MS 
Environmental science & technology  2009;43(7):2463-2469.
Atmospheric deposition of anthropogenic Hg has led to increased Hg concentrations in many ecosystems. Modeling is an effective method for predicting the complex dynamics of Hg fate and transport in watersheds; such models require accurate concentrations for water column methylmercury, CH3Hg+, as input parameters, yet these concentrations are very difficult to measure precisely as they are so low. We developed a method for aqueous CH3Hg+ quantification in Lake Champlain VT, where ambient CH3Hg+ concentrations are < 0.04 ng l-1. The analysis utilized species specific isotope dilution, purge and trap, gas chromatography ICP-MS and provided instrument detection limits of ca 0.2 fM (0.04 pg l-1) and method detection limits of 15 fM (0.003 ng l-1) for CH3Hg+ which are amongst the lowest reported. Artifactual methylation of inorganic Hg2+ was shown to be minor and the precision of the isotope dilution method was generally < 5% relative standard deviation; much lower than would have been the case for an external calibration approach. The method is accurate even at low concentrations of ca. 0.025 ng l-1. This combination of precision, accuracy and low detection allow for quantification of significant differences in CH3Hg+ concentration between bays and over time within bays of Lake Champlain where mean CH3Hg+ concentrations differ by only 0.006 ng l-1 at concentrations as low as 0.014 ng l-1.
PMCID: PMC2692077  PMID: 19452902
19.  Enzyme-induced posterior vitreous detachment in the rat produces increased lens nuclear pO2 levels* 
Experimental eye research  2008;88(2):286-292.
It has been proposed that disruption of normal vitreous humor may permit O2 to travel more easily from the retina to the center of the lens where it may cause nuclear cataract (Barbazetto et al., 2004; Harocopos et al., 2004). In the present study, we injected enzymes intravitreally into guinea pigs (which possess an avascular retina) and rats (which possess a vascular retina) to produce either vitreous humor liquefaction plus a posterior vitreous detachment (PVD) (with use of microplasmin) or vitreous humor liquefaction only (with use of hyaluronidase), and 1–2 weeks later measured lens nuclear pO2 levels in vivo using a platinum-based fluorophore O2 sensor (Oxford-Optronix, Ltd.). Experiments were also conducted in which the animals were allowed to breathe 100% O2 following intravitreal injection with either microplasmin or hyaluronidase in order to investigate possible effects on O2 exchange within the eye. Injection of guinea pigs with either of the two enzymes produced no significant differences in lens pO2 levels 1–2 weeks later, compared to controls. However, for the rat, injection of microplasmin produced a 68% increase in O2 level in the center of the lens, compared to the controls (5.6 mmHg increasing to 9.4 mmHg, p<0.05), with no corresponding effect observed following similar use of hyaluronidase. Treatment of guinea pigs with microplasmin dramatically accelerated movement of O2 across the vitreal space when the animals were later allowed to breathe 100% O2 (for example, O2 traveled to a location directly behind the lens 5 times faster than control; p<0.01); however, the effect following treatment with hyaluronidase was significantly less. When microplasmin-injected rats breathed 100% O2, the time required for O2 to reach the center of the lens was 3 times faster than control (0.4 min compared to 1.4 min, p<0.01). The results have implication with regard to the occurrence of age-related PVD in the human, and a possible acceleration of maturity-onset nuclear cataract. In addition, enzymatic creation of a PVD to increase the rate of O2 exchange within the vitreal space may have potential application for treatment of retinal ischemic disease.
doi:10.1016/j.exer.2008.09.003
PMCID: PMC2694186  PMID: 18835558
guinea pig; lens; microplasmin; nuclear cataract; oxygen; posterior vitreous detachment; rat; vitreous humor
20.  Association between phosphodiesterase 4D gene and ischaemic stroke 
Background
An association between the phosphodiesterase 4D (PDE4D) gene and risk of ischaemic stroke in an Icelandic population has been suggested by the deCODE group.
Methods
A case–control study of 151 hospitalised patients with first‐ever ischaemic stroke and 164 randomly selected age‐matched and sex‐matched community controls was conducted. PDE4D genotypes for the six single‐nucleotide polymorphisms (SNPs) previously reported to be independently associated with stroke were determined, common haplotypes were inferred using the expectation‐maximisation algorithm, and SNP and haplotype associations with stroke were examined. A meta‐analysis of published studies examining the association between PDE4D and stroke was also carried out.
Results
Our study of Australian patients with stroke showed an independent association between ischaemic stroke and PDE4D SNP 89 (CC: odds ratio (OR) 5.55, 95% confidence interval (CI) 1.02 to 30.19; CA: OR 1.68, 95% CI 0.96 to 2.96; AA: OR 1 (reference)), SNP 87 (CC: OR 2.13, 95% CI 1.08 to 4.20; TC: OR 1.64, 95% CI 0.89 to 3.00; TT: OR 1 (reference)) and SNP 83 (TT: OR 2.16, 95% CI 1.08 to 4.32; TC: OR 1.37, 95% CI 0.77 to 2.43; CC: OR 1 (reference)), and between ischaemic stroke and PDE4D haplotypes at SNP 89–87–83 (A–C–C: OR 2.13, 95% CI 1.15 to 3.96; C–C–T: OR 2.25, 95% CI 1.29 to 3.92), but no association between ischaemic stroke and PDE4D SNP 56, SNP 45 or SNP 41, or with PDE4D haplotypes at SNP 56–45–41. A meta‐analysis of nine case–control studies (including our current results) of 3808 stroke cases and 4377 controls confirmed a significant association between stroke and PDE SNP 87 (pooled p = 0.002), SNP 83 (0.003) and SNP 41 (0.003). However, there was statistical heterogeneity (p<0.1) among the studies in the direction of association for each of the individual SNPs tested.
Conclusions
Our results and the pooled analyses from all the studies indicate a strong association between PDE4D and ischaemic stroke. This strengthens the evidence that PDE4D plays a key part in the pathogenesis of ischaemic stroke. Heterogeneity among the studies in the direction of association between individual SNPs and stroke suggests that the SNPs tested are in linkage disequilibrium with the causal allele(s).
doi:10.1136/jnnp.2006.092106
PMCID: PMC2077747  PMID: 16914755
21.  Impact of Single pMOSFET Dielectric Degradation on NAND Circuit Performance 
Microelectronics and reliability  2008;48(3):354-363.
Degradation of CMOS NAND logic circuits resulting from dielectric degradation of a single pMOSFET using constant voltage stress has been examined by means of a switch matrix technique. As a result, the NAND gate rise time increases by greater than 65%, which may lead to timing errors in high frequency digital circuits. In addition, the NAND gate DC switching point voltage shifts by nearly 11% which may be of consequence for analog or mixed signal applications. Experimental results for the degraded pMOSFET reveal a decrease in drive current by approximately 43%. There is also an increase in threshold voltage by 23%, a decrease in source to drain conductance of 30%, and an increase in channel resistance of about 44%. A linear relationship between the degradation of the pMOSFET channel resistance and the increase in NAND gate rise time is demonstrated, thereby providing experimental evidence of the impact of a single degraded pMOSFET on NAND circuit performance.
doi:10.1016/j.microrel.2007.09.002
PMCID: PMC2564826  PMID: 19255611
Gate oxide; dielectric degradation; pMOSFET; NAND logic gate; constant voltage stress; oxide wear out
22.  A syndromal analysis of neuropsychological outcome following coronary artery bypass graft surgery 
Background: Studies of neuropsychological outcome following coronary artery bypass graft surgery (CABG) have traditionally dichotomised patients as "impaired" or "unimpaired". This conceals the potential heterogeneity of deficits due to different mechanisms and sites of brain injury.
Objectives: To explore neuropsychological outcome following CABG and determine to what extent it conforms to prototypic cortical and/or subcortical neurobehavioral syndromes and whether different intraoperative physiologic measures are associated with different subtypes of neuropsychological outcome.
Methods: Neuropsychological tests were administered to 85 patients before and after elective CABG and to 50 matched normal control subjects. Pre- to postoperative change scores were computed using standardised regression based norms. Change scores on selected memory measures were subjected to cluster analysis to identify qualitatively distinct subtypes of memory outcome. Emergent clusters were compared on non-memory measures, intraoperative physiologic measures, and demographic variables.
Results: Three subtypes of memory outcome were identified: memory spared (48% of patients), retrieval deficit (35%), and encoding/storage deficit (17%). Contrary to expectation, the subgroups were indistinguishable on measures of confrontation naming and manual dexterity and on intraoperative cardiac surgical physiologic measures and demographic variables. The encoding/storage deficit subgroup exhibited executive dysfunction.
Conclusions: Heterogeneous profiles of neuropsychological dysfunction were found following CABG although they did not tightly conform to prototypic cortical and subcortical neurobehavioral syndromes. This challenges the value and appropriateness of the common practice of collapsing individual test scores to arrive at a single figure to define "impairment". Whether different subtypes of neuropsychological outcome are caused by different pathophysiologic mechanisms remains unknown.
doi:10.1136/jnnp.2004.047456
PMCID: PMC1739759  PMID: 16024891
23.  Tie-dyed1 and Sucrose export defective1 act independently to promote carbohydrate export from maize leaves 
Planta  2007;227(3):527-538.
tie-dyed1 (tdy1) and sucrose export defective1 (sxd1) are recessive maize (Zea mays) mutants with nonclonal chlorotic leaf sectors that hyperaccumulate starch and soluble sugars. In addition, both mutants display similar growth-related defects such as reduced plant height and inflorescence development due to the retention of carbohydrates in leaves. As tdy1 and sxd1 are the only variegated leaf mutants known to accumulate carbohydrates in any plant, we investigated whether Tdy1 and Sxd1 function in the same pathway. Using aniline blue staining for callose and transmission electron microscopy to inspect plasmodesmatal ultrastructure, we determined that tdy1 does not have any physical blockage or alteration along the symplastic transport pathway as found in sxd1 mutants. To test whether the two genes function in the same genetic pathway, we constructed F2 families segregating both mutations. Double mutant plants showed an additive interaction for growth related phenotypes and soluble sugar accumulation, and expressed the leaf variegation pattern of both single mutants indicating that Tdy1 and Sxd1 act in separate genetic pathways. Although sxd1 mutants lack tocopherols, we determined that tdy1 mutants have wild-type tocopherol levels, indicating that Tdy1 does not function in the same biochemical pathway as Sxd1. From these and other data we conclude that Tdy1 and Sxd1 function independently to promote carbon export from leaves. Our genetic and cytological studies implicate Tdy1 functioning in veins, and a model discussing possible functions of TDY1 is presented.
Electronic supplementary material
The online version of this article (doi:10.1007/s00425-007-0636-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s00425-007-0636-6
PMCID: PMC2249615  PMID: 17924136
Carbohydrate accumulation; Carbon partitioning; Maize; sucrose export defective1; tie-dyed1
24.  Getting to Grips with Clinical Governance 
doi:10.1136/qshc.2004.010512
PMCID: PMC1743908
25.  Implications of Harold Shipman for general practice 
Postgraduate Medical Journal  2004;80(944):303-306.
doi:10.1136/pgmj.2003.013110
PMCID: PMC1743029  PMID: 15192157

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