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1.  Loss of anti-contractile effect of perivascular adipose tissue in offspring of obese rats 
Maternal obesity pre-programmes offspring to develop obesity and associated cardiovascular disease. Perivascular adipose tissue (PVAT) exerts an anti-contractile effect on the vasculature, which is reduced in hypertension and obesity.
The objective of this study was to determine whether maternal obesity pre-programmes offspring to develop PVAT dysfunction in later life.
Female Sprague–Dawley rats were fed a diet containing 10% (control) or 45% fat (high fat diet, HFD) for 12 weeks prior to mating and during pregnancy and lactation. Male offspring were killed at 12 or 24 weeks of age and tension in PVAT-intact or -denuded mesenteric artery segments was measured isometrically. Concentration–response curves were constructed to U46619 and norepinephrine.
Only 24-week-old HFD offspring were hypertensive (P<0.0001), although the anti-contractile effect of PVAT was lost in vessels from HFD offspring of each age. Inhibition of nitric oxide (NO) synthase with 100 μM l-NMMA attenuated the anti-contractile effect of PVAT and increased contractility of PVAT-denuded arteries (P<0.05, P<0.0001). The increase in contraction was smaller in PVAT-intact than PVAT-denuded vessels from 12-week-old HFD offspring, suggesting decreased PVAT-derived NO and release of a contractile factor (P<0.07). An additional, NO-independent effect of PVAT was evident only in norepinephrine-contracted vessels. Activation of AMP-activated kinase (with 10 μM A769662) was anti-contractile in PVAT-denuded (P<0.0001) and -intact (P<0.01) vessels and was due solely to NO in controls; the AMPK effect was similar in HFD offspring vessels (P<0.001 and P<0.01, respectively) but was partially NO-independent.
The diminished anti-contractile effects of PVAT in offspring of HFD dams are primarily due to release of a PVAT-derived contractile factor and reduced NO bioavailability.
PMCID: PMC4973217  PMID: 27102050
2.  First description of the female of the jumping spider Balmaceda nigrosecta Mello-Leitão (Salticidae, Dendryphantini, Marpissina) 
ZooKeys  2016;11-19.
The female of Balmaceda nigrosecta Mello-Leitão, 1945 is described and illustrated for the first time. In addition, this paper further illustrates the male, and provides the first known observations on the natural history of this species, including habitat, cohabitation, and prey capturedata.
PMCID: PMC4797209  PMID: 27047236
Natural history; salticid; taxonomy
3.  Galanin Mediates Features of Neural and Behavioral Stress Resilience Afforded by Exercise 
Neuropharmacology  2014;89:255-264.
Exercise promotes resilience to stress and increases galanin in the locus coeruleus (LC), but the question of whether changes in galanin signaling mediate the stress-buffering effects of exercise has never been addressed. To test the contributions of galanin to stress resilience, male Sprague Dawley rats received intracerebroventricular (ICV) cannulation for drug delivery and frontocortical cannulation for microdialysis, and were housed with or without a running wheel for 21d. Rats were acutely injected with vehicle or the galanin receptor antagonist M40 and exposed to a single session of either footshock or no stress. Other groups received galanin, the galanin receptor antagonist M40, or vehicle chronically for 21d prior to the stress session. Microdialysis sampling occurred during stress exposure and anxiety-related behavior was measured on the following day in the elevated plus maze. Dendritic spines were visualized by Golgi impregnation in medial prefrontal cortex (mPFC) pyramidal neurons and quantified. Exercise increased galanin levels in the LC. Under non-stressed conditions, anxiety-related behavior and dopamine levels were comparable between exercised and sedentary rats. In contrast, exposure to stress reduced open arm exploration in sedentary rats but not in exercise rats or those treated chronically with ICV galanin, indicating improved resilience. Both exercise and chronic, ICV galanin prevented the increased dopamine overflow and loss of dendritic spines observed after stress in sedentary rats. Chronic, but not acute M40 administration blocked the resilience-promoting effects of exercise. The results indicate that increased galanin levels promote features of resilience at both behavioral and neural levels.
PMCID: PMC4250306  PMID: 25301278
Galanin; stress resilience; frontal cortex; locus coeruleus; plasticity; dopamine
4.  Caveolae in Ventricular Myocytes are Required for Stretch-Dependent Conduction Slowing 
Mechanical stretch of cardiac muscle modulates action potential propagation velocity, causing potentially arrhythmogenic conduction slowing. The mechanisms by which stretch alters cardiac conduction remain unknown, but previous studies suggest that stretch can affect the conformation of caveolae in myocytes and other cell types. We tested the hypothesis that slowing of action potential conduction due to cardiac myocyte stretch is dependent on caveolae.
Cardiac action potential propagation velocities, measured by optical mapping in isolated mouse hearts and in micropatterned mouse cardiomyocyte cultures, decreased reversibly with volume loading or stretch, respectively (by 19±5% and 26±4%). Stretch-dependent conduction slowing was not altered by stretch-activated channel blockade with gadolinium or by GsMTx-4 peptide, but was inhibited when caveolae were disrupted via genetic deletion of caveolin-3 (Cav3 KO) or membrane cholesterol depletion by methyl-β-cyclodextrin. In wild-type mouse hearts, stretch coincided with recruitment of caveolae to the sarcolemma, as observed by electron microscopy. In myocytes from wild-type but not Cav3 KO mice, stretch significantly increased cell membrane capacitance (by 98±64%), electrical time constant (by 285±149%), and lipid recruitment to the bilayer (by 84±39%).
Recruitment of caveolae to the sarcolemma during physiologic cardiomyocyte stretch slows ventricular action potential propagation by increasing cell membrane capacitance.
PMCID: PMC4250283  PMID: 25257915
cardiac mechanoelectric feedback; caveolae; capacitance
5.  Efficient national surveillance for health-care-associated infections 
BMC Public Health  2015;15:832.
Detecting novel healthcare-associated infections (HCAI) as early as possible is an important public health priority. However, there is currently no evidence base to guide the design of efficient and reliable surveillance systems. Here we address this issue in the context of a novel pathogen spreading primarily between hospitals through the movement of patients.
Using a mathematical modelling approach we compare the current surveillance system for a HCAI that spreads primarily between hospitals due to patient movements as it is implemented in Scotland with a gold standard to determine if the current system is maximally efficient or whether it would be beneficial to alter the number and choice of hospitals in which to concentrate surveillance effort.
We validated our model by demonstrating that it accurately predicts the risk of meticillin-resistant Staphylococcus aureus bacteraemia cases in Scotland.
Using the 29 (out of 182) sentinel hospitals that currently contribute most of the national surveillance effort results in an average detection time of 117 days. A reduction in detection time to 87 days is possible by optimal selection of 29 hospitals. Alternatively, the same detection time (117 days) can be achieved using just 22 optimally selected hospitals. Increasing the number of sentinel hospitals to 38 (teaching and general hospitals) reduces detection time by 43 days; however decreasing the number to seven sentinel hospitals (teaching hospitals) increases detection time substantially to 268 days.
Our results show that the current surveillance system as it is used in Scotland is not optimal in detecting novel pathogens when compared to a gold standard. However, efficiency gains are possible by better choice of sentinel hospitals, or by increasing the number of hospitals involved in surveillance. Similar studies could be used elsewhere to inform the design and implementation of efficient national, hospital-based surveillance systems that achieve rapid detection of novel HCAIs for minimal effort.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-2172-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4552460  PMID: 26316148
6.  Variation in the bovine FABP4 gene affects milk yield and milk protein content in dairy cows 
Scientific Reports  2015;5:10023.
Fatty acid binding proteins (FABPs) bind long-chain fatty acids and are involved in their intracellular transport. Of the known bovine FABP genes, FABP4 has been mapped to a region on chromosome 14 that contains quantitative trait loci for milk traits. This study investigated the association of FABP4 haplotypes with milk production traits in 719 Holstein-Friesian × Jersey cows. Polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis of a variable region of the gene revealed three haplotypes (A, B and C). Five single nucleotide polymorphisms (SNPs) were identified: two in exon 3 and three in intron 3. A was associated (P = 0.032) with increased milk protein percentage (present: 4.00 ± 0.02%; absent: 3.95 ± 0.02%) and B was associated (P = 0.009) with increased milk yield (present: 23.81 ± 0.23 kg/d; absent: 23.06 ± 0.21 kg/d), but tended to be associated with a decrease in protein percentage and an increase in protein yield. Cows with genotypes AA, AB and AC produced less milk, but with a higher protein percentage than BC cows. This suggest that FABP4 affects milk yield and milk protein content, both economically important traits, and that further study of this gene is warranted.
PMCID: PMC4464348  PMID: 26067182
7.  In vitro and in vivo comparison of two-, three- and four-point Dixon techniques for clinical intramuscular fat quantification at 3 T 
The British Journal of Radiology  2014;87(1036):20130761.
To compare Dixon-based MRI techniques for intramuscular fat quantification at 3 T with MR spectroscopy (MRS) in vitro and in vivo.
In vitro, two- three- and four-point mDixon (Philips Medical Systems, Best, Netherlands) sequences with 10°, 20° and 30° flip angles were acquired from seven test phantoms with sunflower oil–water percentages of 0–60% sunflower oil and calculated fat–water ratios compared with MRS. In vivo, two- three- and four-point mDixon sequences with 10° flip angle were acquired and compared with MRS in the vastus medialis of nine healthy volunteers (aged 30.6 ± 5.3 years; body mass index 22.2 ± 2.6).
In vitro, all mDixon sequences correlated significantly with MRS (r > 0.97, p < 0.002). The measured phantom percentage fat depended significantly on the flip angle (p ≤ 0.001) and mDixon sequence (p = 0.005). Flip angle was the dominant factor influencing agreement with MRS. Increasing the flip angle significantly increased the overestimation of the mDixon sequences compared with MRS. In vivo, a significant difference was observed between sequences (p < 0.001), with all mDixon sequences overestimating the intramuscular fat content of the vastus medialis muscle compared with MRS. Two-point mDixon agreed best with MRS and had comparable variability with the other mDixon sequences.
This study demonstrates that mDixon techniques have good linearity and low variability for use in intramuscular fat quantification. To avoid significant fat overestimation with short repetition time, a low flip angle should be used to reduce T1 effects.
Advances in knowledge:
This is the first study investigating the optimal mDixon parameters for intramuscular fat quantification compared with MRS in vivo and in vitro.
PMCID: PMC4067022  PMID: 24641314
8.  Novel age-dependent learning deficits in a mouse model of Alzheimer’s disease: implications for translational research 
Neurobiology of aging  2009;32(7):1273-1285.
Computational modeling predicts that the hippocampus plays an important role in the ability to apply previously learned information to novel problems and situations (referred to as the ability to generalize information or simply as ‘transfer learning’). These predictions have been tested in humans using a computer-based task on which individuals with hippocampal damage are able to learn a series of complex discriminations with two stimulus features (shape and color), but are impaired in their ability to transfer this information to newly configured problems in which one of the features is altered. This deficit occurs despite the fact that the feature predictive of the reward (the relevant information) is not changed. The goal of the current study was to develop a mouse analog of transfer learning and to determine if this new task was sensitive to pathological changes in a mouse model of AD. We describe a task in which mice were able to learn a series of concurrent discriminations that contained two stimulus features (odor and digging media) and could transfer this learned information to new problems in which the irrelevant feature in each discrimination pair was altered. Moreover, we report age-dependent deficits specific to transfer learning in APP+PS1 mice relative to nontransgenic littermates. The robust impairment in transfer learning may be more sensitive to AD-like pathology than traditional cognitive assessments in that no deficits were observed in the APP+PS1 mice on the widely used Morris water maze task. These data describe a novel and sensitive paradigm to evaluate mnemonic decline in AD mouse models that has unique translational advantages over standard species-specific cognitive assessments (e.g. water maze for rodent and delayed paragraph recall for humans).
PMCID: PMC4334376  PMID: 19720431
aging; AD; APP+PS1; hippocampus; transfer Learning; Spatial Learning; cognitive decline
9.  Time-Scaled Evolutionary Analysis of the Transmission and Antibiotic Resistance Dynamics of Staphylococcus aureus Clonal Complex 398 
Applied and Environmental Microbiology  2014;80(23):7275-7282.
Staphylococcus aureus clonal complex 398 (CC398) is associated with disease in humans and livestock, and its origins and transmission have generated considerable interest. We performed a time-scaled phylogenetic analysis of CC398, including sequenced isolates from the United Kingdom (Scotland), along with publicly available genomes. Using state-of-the-art methods for mapping traits onto phylogenies, we quantified transitions between host species to identify sink and source populations for CC398 and employed a novel approach to investigate the gain and loss of antibiotic resistance in CC398 over time. We identified distinct human- and livestock-associated CC398 clades and observed multiple transmissions of CC398 from livestock to humans and between countries, lending quantitative support to previous reports. Of note, we identified a subclade within the livestock-associated clade comprised of isolates from hospital environments and newborn babies, suggesting that livestock-associated CC398 is capable of onward transmission in hospitals. In addition, our analysis revealed significant differences in the dynamics of resistance to methicillin and tetracycline related to contrasting historical patterns of antibiotic usage between the livestock industry and human medicine. We also identified significant differences in patterns of gain and loss of different tetracycline resistance determinants, which we ascribe to epistatic interactions between the resistance genes and/or differences in the modes of inheritance of the resistance determinants.
PMCID: PMC4249192  PMID: 25239891
10.  Stimulated release of a hyperpolarizing factor (ADHF) from mesenteric artery perivascular adipose tissue: involvement of myocyte BKCa channels and adiponectin 
British Journal of Pharmacology  2013;169(7):1500-1509.
Background and Purpose
Perivascular adipose tissue (PVAT) releases adipocyte-derived hyperpolarizing factors (ADHFs) that may partly act by opening myocyte K+ channels. The present study in rat and mouse mesenteric arteries aimed to identify the myocyte K+ channel activated by PVAT and to determine whether adiponectin contributed to the hyperpolarizing effects of PVAT.
Experimental Approach
Myocyte membrane potential was recorded from de-endothelialized, non-contracted rat and mouse mesenteric arteries in the presence and absence of PVAT.
Key Results
The β3-adrenoceptor agonist, CL-316,243 (10 μM), generated PVAT-dependent, iberiotoxin-sensitive myocyte hyperpolarizations resulting from BKCa channel opening and which were partially blocked by L-NMMA (100 μM). Adiponectin (5 μg·mL−1) also produced iberiotoxin-sensitive hyperpolarizations in PVAT-denuded arterioles. Activation of myocyte AMP-activated protein kinase (AMPK) using 5 μM A-769662 also induced BKCa-mediated hyperpolarizations. Dorsomorphin abolished hyperpolarizations to CL-316,243, adiponectin and A-769662. In vessels from Adipo−/− mice, hyperpolarizations to CL-316,243 were absent whereas those to A-769662 and adiponectin were normal. In rat vessels, adipocyte-dependent hyperpolarizations were blocked by glibenclamide and clotrimazole but those to NS1619 (33 μM) were unaltered.
Conclusions and Implications
Under basal, non-contracted conditions, β3-adrenoceptor stimulation of PVAT releases an ADHF, which is probably adiponectin. This activates AMPK to open myocyte BKCa channels indirectly and additionally liberates NO, which also contributes to the observed PVAT-dependent myocyte hyperpolarizations. Clotrimazole and glibenclamide each reversed hyperpolarizations to adiponectin and A-769662, suggesting the involvement of myocyte TRPM4 channels in the ADHF-induced myocyte electrical changes mediated via the opening of BKCa channels.
PMCID: PMC3724107  PMID: 23488724
BKCa channels; adipose tissue; vascular myocytes; membrane potential; CL-316; 243; iberiotoxin; AMP kinase; adipocyte-derived hyperpolarizing factor; adiponectin; β3-adrenoceptors
11.  The prevalence and impact of Fusarium head blight pathogens and mycotoxins on malting barley quality in UK 
Fusarium head blight (FHB) caused by Fusarium and Microdochium species can significantly affect the yield of barley grain as well as the quality and safety of malt and beer. The present study provides new knowledge on the impacts of the FHB pathogen complex on the malting and brewing quality parameters of naturally infected barley. Quantitative real-time PCR and liquid chromatography double mass spectrometry were used to quantify the predominant FHB pathogens and Fusarium mycotoxins, respectively, in commercially grown UK malting barley samples collected between 2007 and 2011. The predominant Fusarium species identified across the years were F. poae, F. tricinctum and F. avenaceum. Microdochium majus was the predominant Microdochium species in 2007, 2008, 2010 and 2011 whilst Microdochium nivale predominated in 2009. Deoxynivalenol and zearalenone quantified in samples collected between 2007 and 2009 were associated with F. graminearum and F. culmorum, whilst HT-2 and T-2, and nivalenol in samples collected between 2010 and 2011 correlated positively with F. langsethiae and F. poae, respectively. Analysis of the regional distribution and yearly variation in samples from 2010 to 2011 showed significant differences in the composition of the FHB species complex. In most regions (Scotland, the South and North of England) the harvest in 2010 had higher concentrations of Fusarium spp. than in 2011, although no significant difference was observed in the Midlands between the two years. Microdochium DNA was significantly higher in 2011 and in the North of England and Scotland compared to the South or Midlands regions. Pathogens of the FHB complex impacted negatively on grain yield and quality parameters. Thousand grain weight of malting barley was affected significantly by M. nivale and M. majus whilst specific weight correlated negatively with F. avenaceum and F. graminearum. To determine the impact of sub-acute infections of the identified Fusarium and Microdochium species on malting and brewing quality of naturally infected samples, selected malting barley cultivars (Optic, Quench and Tipple) were micromalted and subjected to malt and wort analysis of key quality parameters. F. poae and M. nivale decreased germinative energy and increased water sensitivity of barley. The fungal biomass of F. poae and F. langsethiae correlated with increased wort free amino nitrogen and with decreased extract of malt. DNA of M. nivale correlated with increased malt friability as well as decreased wort filtration volume. The findings of this study indicate that the impact of species such as the newly emerging F. langsethiae, as well as F. poae and the two non-toxigenic Microdochium species should be considered when evaluating the quality of malting barley.
•First report of the impact of naturally occurring FHB species on brewing quality•Diverse FHB complex comprised of Fusarium and Microdochium spp. in UK barley•Strong positive correlations found between mycotoxins and relevant producers•Toxigenic Fusarium and non-toxigenic Microdochium reduce yield quality parameters.•Brewing quality significantly impaired by M. nivale, F. poae and F. langsethiae
PMCID: PMC4018669  PMID: 24727381
Fusarium; Microdochium; Malting barley; Mycotoxins; Malting; Brewing
12.  The newly described mecA homologue, mecALGA251, is present in methicillin-resistant Staphylococcus aureus isolates from a diverse range of host species 
Journal of Antimicrobial Chemotherapy  2012;67(12):2809-2813.
A previously unidentified mecA homologue, mecALGA251, has recently been described in methicillin-resistant Staphylococcus aureus (MRSA) from humans and dairy cattle. The origin and epidemiology of this novel homologue are unclear. The objective of this study was to provide basic descriptive information of MRSA isolates harbouring mecALGA251 from a range of host animal species.
A number of S. aureus isolates from historical animal isolate collections were chosen for investigation based on their similarity to known mecALGA251 MRSA isolates. The presence of mecALGA251 was determined using a multiplex PCR and antimicrobial susceptibility testing performed by disc diffusion.
MRSA harbouring mecALGA251 were found in isolates from a domestic dog, brown rats, a rabbit, a common seal, sheep and a chaffinch. All of the isolates were phenotypically MRSA, although this depended on which test was used; some isolates would be considered susceptible with certain assays. All isolates were susceptible to linezolid, rifampicin, kanamycin, norfloxacin, erythromycin, clindamycin, fusidic acid, tetracycline, trimethoprim/sulfamethoxazole and mupirocin. Five multilocus sequence types were represented (2273, 130, 425, 1764 and 1245) and six spa types (t208, t6293, t742, t6594, t7914 and t843).
The discovery of MRSA isolates possessing mecALGA251 from a diverse range of host species, including different taxonomic classes, has important implications for the diagnosis of MRSA in these species and our understanding of the epidemiology of this novel mecA homologue.
PMCID: PMC3494845  PMID: 22941897
animal infections; animal reservoirs; wildlife; MRSA
13.  Emergent properties during dorsal closure in Drosophila morphogenesis 
Physical biology  2008;5(1):015004.
Dorsal closure is an essential stage of Drosophila development that is a model system for research in morphogenesis and biological physics. Dorsal closure involves an orchestrated interplay between gene expression and cell activities that produce shape changes, exert forces and mediate tissue dynamics. We investigate the dynamics of dorsal closure based on confocal microscopic measurements of cell shortening in living embryos. During the mid-stages of dorsal closure we find that there are fluctuations in the width of the leading edge cells but the time-averaged analysis of measurements indicate that there is essentially no net shortening of cells in the bulk of the leading edge, that contraction predominantly occurs at the canthi as part of the process for zipping together the two leading edges of epidermis and that the rate constant for zipping correlates with the rate of movement of the leading edges. We characterize emergent properties that regulate dorsal closure, i.e., a velocity governor and the coordination and synchronization of tissue dynamics.
PMCID: PMC3747517  PMID: 18403825
14.  The genus Myrmarachne (Araneae, Salticidae) in Flores, Indonesia 
ZooKeys  2013;1-20.
Two new species of the genus Myrmarachne are described (Myrmarachne acutidens sp. n., Myrmarachne epigealis sp. n.), and Myrmarachne macrognatha and Myrmarachne melanocephala are redescribed from Flores specimens. The females of Myrmarachne macrognatha are recorded for the first time.
PMCID: PMC3689102  PMID: 23794886
New species; ant-mimicking jumping spiders; Java; Malay Archipelago
16.  Intermediate-conductance calcium-activated potassium channels participate in neurovascular coupling 
British Journal of Pharmacology  2011;164(3):922-933.
Controlling vascular tone involves K+ efflux through endothelial cell small- and intermediate-conductance calcium-activated potassium channels (KCa2.3 and KCa3.1, respectively). We investigated the expression of these channels in astrocytes and the possibility that, by a similar mechanism, they might contribute to neurovascular coupling.
Transgenic mice expressing enhanced green fluorescent protein (eGFP) in astrocytes were used to assess KCa2.3 and KCa3.1 expression by immunohistochemistry and RT-PCR. KCa currents in eGFP-positive astrocytes were determined in situ using whole-cell patch clamp electrophysiology. The contribution of KCa3.1 to neurovascular coupling was investigated in pharmacological experiments using electrical field stimulation (EFS) to evoke parenchymal arteriole dilatation in FVB/NJ mouse brain slices and whisker stimulation to evoke changes in cerebral blood flow in vivo, measured by laser Doppler flowmetry.
KCa3.1 immunoreactivity was restricted to astrocyte processes and endfeet and RT-PCR confirmed astrocytic KCa2.3 and KCa3.1 mRNA expression. With 200 nM [Ca2+]i, the KCa2.1-2.3/KCa3.1 opener NS309 increased whole-cell currents. CyPPA, a KCa2.2/KCa2.3 opener, was without effect. With 1 µM [Ca2+]i, the KCa3.1 inhibitor TRAM-34 reduced currents whereas apamin (KCa2.1-2.3 blocker) had no effect. CyPPA also inhibited currents evoked by NS309 in HEK293 cells expressing KCa3.1. EFS-evoked Fluo-4 fluorescence confirmed astrocyte endfoot recruitment into neurovascular coupling. TRAM-34 inhibited EFS-evoked arteriolar dilatation by 50% whereas charybdotoxin, a blocker of KCa3.1 and the large-conductance KCa channel, KCa1.1, inhibited dilatation by 82%. TRAM-34 reduced the cortical hyperaemic response to whisker stimulation by 40%.
Astrocytes express functional KCa3.1 channels, and these contribute to neurovascular coupling.
This article is part of a themed issue on Vascular Endothelium in Health and Disease. To view the other articles in this issue visit
PMCID: PMC3195915  PMID: 21506954
astrocyte; brain slice; KCa2.3; KCa3.1; electrical field stimulation; laser Doppler flowmetry; neurovascular coupling; CyPPA; NS309
17.  Methicillin-Resistant Staphylococcus aureus in Northeastern Scotland in 2003 to 2007: Evolving Strain Distribution and Resistance Patterns▿ 
Journal of Clinical Microbiology  2011;49(5):1975-1978.
This study explored strain distribution and resistance patterns of methicillin-resistant Staphylococcus aureus (MRSA) over a 5-year period in northeastern Scotland. We noted a shift in the relative rates of epidemic strains and an increase in community-associated strains. Use of oral antibiotics to eradicate throat carriage may have contributed to trimethoprim resistance, which was observed to increase 10-fold.
PMCID: PMC3122644  PMID: 21411588
18.  Elevated Incidence of Fractures in Solid-Organ Transplant Recipients on Glucocorticoid-Sparing Immunosuppressive Regimens 
Journal of Osteoporosis  2011;2011:591793.
This study was conducted to assess the occurrence of fractures in solid-organ transplant recipients. Methods. Medical record review and surveys were performed. Patients received less than 6 months of glucocorticoids. Results. Of 351 transplant patients, 175 patients provided fracture information, with 48 (27.4%) having fractured since transplant (2–6 years). Transplants included 19 kidney/liver (50% male), 47 kidney/pancreas (53% male), 92 liver (65% male), and 17 pancreas transplants (41% male). Age at transplant was 50.8 ± 10.3 years. Fractures were equally seen across both genders and transplant types. Calcium supplementation (n = 94) and bisphosphonate therapy (n = 52) were observed, and an association with a lower risk of fractures was noted for bisphosphonate users (OR = 0.45 95% C.I. 0.24, 0.85). Fracture location included 8 (16.7%) foot, 12 (25.0%) vertebral, 3 (6.3%) hand, 2 (4.2%) humerus, 5 (10.4%) wrist, 10 (20.8%) fractures at other sites, and 7 (14.6%) multiple fractures. The estimated relative risk of fracture was nearly seventeen-times higher in male liver transplant recipients ages 45–64 years compared with the general male population, and comparable to fracture rates on conventional immunosuppressant regimens. Conclusion. We identify a high frequency of fractures in transplant recipients despite limited glucocorticoid use.
PMCID: PMC3172972  PMID: 21922049
19.  Impairment of endothelial SKCa channels and of downstream hyperpolarizing pathways in mesenteric arteries from spontaneously hypertensive rats 
British Journal of Pharmacology  2010;160(4):836-843.
Background and purpose:
Previous studies have shown that endothelium-dependent hyperpolarization of myocytes is reduced in resistance arteries from spontaneously hypertensive rats (SHRs). The aim of the present study was to determine whether this reflects down-regulation of endothelial K+ channels or their associated pathways.
Experimental approach:
Changes in vascular K+ channel responses and expression were determined by a combination of membrane potential recordings and Western blotting.
Key results:
Endothelium-dependent myocyte hyperpolarizations induced by acetylcholine, 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309) (opens small- and intermediate-conductance calcium-sensitive K+ channels, SKCa and IKCa, respectively) or cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (SKCa opener) were reduced in mesenteric arteries from SHRs. After blocking SKCa channels with apamin, hyperpolarizations to acetylcholine and NS309 in SHR arteries were similar to those of controls. Hyperpolarization to 5 mM KCl was reduced in SHR arteries due to loss of the Ba2+-sensitive, inward-rectifier channel (KIR) component; the contribution of ouabain-sensitive, Na+/K+-ATPases was unaffected. Protein expression of both SKCa and KIR channels was reduced in SHR arteries; the caveolin-1 monomer/dimer ratio was increased.
Conclusions and implications:
In SHRs, the distinct pathway that generates endothelium-dependent hyperpolarization in vascular myocyte by activation of IKCa channels and Na+/K+-ATPases remains intact. The second pathway, initiated by endothelial SKCa channel activation and amplified by KIR opening on both endothelial cells and myocytes is compromised in SHRs due to down-regulation of both SKCa and KIR and to changes in caveolin-1 oligomers. These impairments in the SKCa–KIR pathway shed new light on vascular control mechanisms and on the underlying vascular changes in hypertension.
This article is commented on by Garland, pp. 833–835 of this issue. To view this commentary visit
PMCID: PMC2935991  PMID: 20233221
hypertension; EDHF; acetylcholine; apamin; TRAM-34; CyPPA; NS309; KCa3.1; KCa2.3; caveolin-1
20.  Comparison of Two Multilocus Variable-Number Tandem-Repeat Methods and Pulsed-Field Gel Electrophoresis for Differentiating Highly Clonal Methicillin-Resistant Staphylococcus aureus Isolates▿  
Journal of Clinical Microbiology  2010;48(10):3600-3607.
In the United Kingdom, EMRSA-15 and EMRSA-16 account for the majority (∼90%) of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infections. Currently, the standard typing technique, pulsed-field gel electrophoresis (PFGE), is laborious and insufficient for discriminating between closely related subtypes of EMRSA-15 and -16. The objective of the present study was to compare the usefulness of multilocus variable-number tandem-repeat fingerprinting (MLVF) and multilocus variable-number tandem-repeat analysis (MLVA) with PFGE for subtyping these highly clonal MRSA lineages. A panel of 85 MRSA isolates (41 EMRSA-15, 20 EMRSA-16, and 24 MRSA isolates with diverse PFGE patterns) was investigated. In addition, a further 29 EMRSA-15s with identical PFGE patterns from two geographically linked but epidemiologically distinct outbreaks and several sporadic cases were analyzed. PFGE, MLVF, and MLVA resolved 66 (Simpson's index of diversity [SID] = 0.984), 51 (SID = 0.95), and 42 (SID = 0.881) types, respectively, among the 85 MRSA isolates. MLVF was more discriminatory than MLVA for EMRSA-15 and -16 strains, but both methods had comparable discriminatory powers for distinguishing isolates in the group containing diverse PFGE types. MLVF was comparable to PFGE for resolving the EMRSA-15s but had a lower discriminatory power for the EMRSA-16s. MLVF and MLVA resolved the 29 isolates with identical PFGE patterns into seven and six subtypes, respectively. Importantly, both assays indicated that the two geographically related outbreaks were caused by distinct subtypes of EMRSA-15. Taken together, the data suggest that both methods are suitable for identifying and tracking specific subtypes of otherwise-indistinguishable MRSA. However, due to its greater discriminatory power, MLVF would be the most suitable alternative to PFGE for hospital outbreak investigations.
PMCID: PMC2953104  PMID: 20702668
21.  Survival of HIV‐infected patients in the intensive care unit in the era of highly active antiretroviral therapy 
Thorax  2007;62(11):964-968.
Several studies have described improved outcomes for HIV‐infected patients admitted to the intensive care unit (ICU) since the introduction of highly active antiretroviral therapy (HAART). A study was undertaken to examine the outcome from the ICU for HIV‐infected patients and to identify prognostic factors.
A retrospective study of HIV‐infected adults admitted to a university affiliated hospital ICU between January 1999 and December 2005 was performed. Information was collected on patient demographics, receipt of HAART (no patient began HAART on the ICU), reason for ICU admission and hospital course. Outcomes were survival to ICU discharge and to hospital discharge.
102 patients had 113 admissions to the ICU; HIV infection was newly diagnosed in 31 patients. Survival (first episode ICU discharge and hospital discharge) was 77% and 68%, respectively, compared with 74% and 65% for general medical patients. ICU and hospital survival was 78% and 67% in those receiving HAART, and 75% and 66% in those who were not. In univariate analysis, factors associated with survival were: haemoglobin (OR = 1.25, 95% CI 1.03 to 1.51, for an increase of 1 g/dl), CD4 count (OR = 1.59, 95% CI 0.98 to 2.58, for a 10‐fold increase in cells/µl), APACHE II score (OR = 0.51, 95% CI 0.29 to 0.90, for a 10 unit increase) and mechanical ventilation (OR = 0.29, 95% CI 0.10 to 0.83).
The outcome for HIV‐infected patients admitted to the ICU was good and was comparable to that in general medical patients. More than a quarter of patients had newly diagnosed HIV infection. Patients receiving HAART did not have a better outcome.
PMCID: PMC2117109  PMID: 17517829
23.  Temporal Analysis of Invasive Pneumococcal Clones from Scotland Illustrates Fluctuations in Diversity of Serotype and Genotype in the Absence of Pneumococcal Conjugate Vaccine▿  
In September 2006, the seven-valent pneumococcal conjugate vaccine (PCV7; Prevenar) was introduced into the childhood vaccination schedule in the United Kingdom. We monitored the population of invasive pneumococci in Scotland in the 5 years preceding the introduction of PCV7 by using serogrouping, multilocus sequence typing (MLST), and eBURST analysis. Here, we present a unique analysis of a complete national data set of invasive pneumococci over this time. We observed an increase in invasive pneumococcal disease (IPD) caused by serotypes 1, 4, and 6 and a decrease in serogroup 14-, 19-, and 23-associated disease. Analysis of sequence type (ST) data shows a significant increase in ST306, associated with serotype 1, and a decrease in ST124, associated with serotype 14. There have also been increases in the amounts of IPD caused by ST227 (serotype 1) and ST53 (serotype 8), although these increases were not found to reach significance (P = 0.08 and 0.06, respectively). In the course of the study period preceding the introduction of PCV7, we observed considerable and significant changes in serogroup and clonal distribution over time.
PMCID: PMC2812259  PMID: 19923488
24.  Behavioural predictors of subsequent hepatitis C diagnosis in a UK clinic sample of HIV positive men who have sex with men 
Sexually Transmitted Infections  2006;82(4):298-300.
To explore the associations between self reported high risk sexual behaviours and subsequent diagnosis with hepatitis C virus (HCV) infection.
The Sex, Health and Anti‐Retrovirals Project (SHARP) was a cross sectional study of sexual behaviour in HIV positive, men who have sex with men (MSM) attending a London outpatient clinic. From July 1999 to August 2000 participants completed a computer assisted self interview questionnaire (CASI) on recent sexual behaviour, recreational drug use, and detailed reporting of the last two sexual episodes involving different partners. Results were combined with routine clinic data and subsequent testing for HCV up to 21 April 2005. A new HCV diagnosis was defined as anti‐HCV antibody seroconversion or positive HCV RNA following a previous negative. Incident rate ratios (IRR) were calculated using Poisson regression in Stata (version 9). Men contributed time at risk from interview until either their diagnosis or their last negative test result.
Of the 422 men who completed questionnaires, 308 (73%) had sufficient clinical and HCV testing data available for analysis. Incident HCV infection was identified in 11 men. Unprotected anal intercourse, more than 30 sex partners in the past year, higher numbers of new anal sex partners, rimming (oro‐anal sex), fisting, use of sex toys, and intranasal recreational drug use were associated with HCV. In multivariate analysis only fisting remained associated with HCV (adjusted IRR 6.27, p = 0.005).
In this study of HIV positive MSM, fisting is strongly associated with HCV infection. Where individuals report high risk sexual behaviours, clinicians should offer appropriate testing for HCV infection.
PMCID: PMC2564713  PMID: 16877578
hepatitis C virus infection; sexual behaviour; MSM; HIV positive
25.  Improved survival for HIV infected patients with severe Pneumocystis jirovecii pneumonia is independent of highly active antiretroviral therapy 
Thorax  2006;61(8):716-721.
Despite a decline in incidence of Pneumocystis jirovecii pneumonia (PCP), severe PCP continues to be a common cause of admission to the intensive care unit (ICU) where mortality remains high. A study was undertaken to examine the outcome from intensive care for patients with PCP and to identify prognostic factors.
A retrospective cohort study was conducted of HIV infected adults admitted to a university affiliated hospital ICU between November 1990 and October 2005. Case note review collected information on demographic variables, use of prophylaxis and highly active antiretroviral therapy (HAART), and hospital course. The main outcome was 1 month mortality, either on the ICU or in hospital.
Fifty nine patients were admitted to the ICU on 60 occasions. Thirty four patients (57%) required mechanical ventilation. Overall mortality was 53%. No patient received HAART before or during ICU admission. Multivariate analysis showed that the factors associated with mortality were the year of diagnosis (before mid 1996 (mortality 71%) compared with later (mortality 34%; p = 0.008)), age (p = 0.016), and the need for mechanical ventilation and/or development of pneumothorax (p = 0.031). Mortality was not associated with sex, ethnicity, prior receipt of sulpha prophylaxis, haemoglobin, serum albumin, CD4 count, Pao2, A‐ao2 gradient, co‐pathology in bronchoscopic lavage fluid, medical co‐morbidity, APACHE II score, or duration of mechanical ventilation.
Observed improved outcomes from severe PCP for patients admitted to the ICU occurred in the absence of intervention with HAART and probably reflect general improvements in ICU management of respiratory failure and ARDS rather than improvements in the management of PCP.
PMCID: PMC2104703  PMID: 16601092
AIDS; intensive care; mechanical ventilation;  Pneumocystis jirovecii ; opportunistic infections; respiratory failure

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