Potential role of histamine releasing factor (HRF) as a therapeutic target for treating asthma and allergy.
Histamine releasing factor (HRF), also known as translationally controlled tumor protein (TCTP), is a highly conserved, ubiquitous protein that has both intracellular and extracellular functions. Here, we will highlight the history of the molecule, its clinical implications with a focus on its extracellular functioning, and its potential role as a therapeutic target in asthma and allergy. The cells and cytokines produced when stimulated or primed by HRF/TCTP are detailed as well as the downstream signaling pathway that HRF/TCTP elicits. While it was originally thought that HRF/TCTP interacted with IgE, the finding that cells not binding IgE also respond to HRF/TCTP called this interaction into question. HRF/TCTP, or at least its mouse counterpart, appears to interact with some, but not all IgE and IgG molecules. HRF/TCTP has been shown to activate multiple human cells including basophils, eosinophils, T cells, and B cells. Since many of the cells activated by HRF/TCTP participate in the allergic response, extracellular functions of HRF/TCTP may exacerbate the allergic, inflammatory cascade. Particularly exciting is that small molecule agonists of Src homology 2-containing inositol phosphatase-1 have been shown to modulate the phosphoinositide 3-kinase/AKT pathway and may control inflammatory disorders. This review discusses this possibility in light of HRF/TCTP.


Nurse views on the cardiometabolic health nurse as an approach to improving the physical health of people with serious mental illness in Australia.
People with serious mental illness (SMI) die prematurely from common physical illnesses such as cardiovascular disease and diabetes. These cardiometabolic risks are preventable and manageable yet these aspects of health care have been neglected in mental health services. A potential nurse-based strategy to decisively improve cardiometabolic health of people with SMI is to introduce a cardiometabolic health nurse (CHN) into mental health services. The current study aimed to establish the views of nurses working in mental health care on the potential benefits and limits of CHN to improve physical health-care standards in Australia. All members of the Australian College of Mental Health Nurses were invited to participate in an online survey and 643 participated. Nurses generally agreed that a CHN role would provide a range of improvements to physical health care, such as increased detection, assessment on, and follow up of cardiometabolic risks, and decreased workload for other nurses. While participants were generally supportive of such a role, they felt it would not be suitable in all health-care settings in Australia.


Psychoeducation for depression, anxiety and psychological distress: a meta-analysis.
Given the high prevalence and burden associated with depression and anxiety disorders and the existence of treatment barriers, there is a clear need for brief, inexpensive and effective interventions such as passive psychoeducational interventions. There are no published meta-analyses of the effectiveness of passive psychoeducation in reducing symptoms of depression, anxiety or psychological distress. Cochrane, PsycInfo and PubMed databases were searched in September 2008. Additional materials were obtained from reference lists. Papers describing passive psychoeducational interventions for depression, anxiety and psychological distress were included if the research design was a randomized controlled trial and incorporated an attention placebo, no intervention or waitlist comparison group. In total, 9010 abstracts were identified. Of these, five papers which described four research studies targeting passive psychoeducation for depression and psychological distress met the inclusion criteria. The pooled standardized-effect size (four studies, four comparisons) for reduced symptoms of depression and psychological distress at post-intervention was d = 0.20 (95% confidence interval: 0.01-0.40; Z = 2.04; P = 0.04; the number needed to treat: 9). Heterogeneity was not significant among the studies (I2 = 32.77, Q:4.46; P = 0.22). Although it is commonly believed that psychoeducation interventions are ineffective, this meta-analysis revealed that brief passive psychoeducational interventions for depression and psychological distress can reduce symptoms. Brief passive psychoeducation interventions are easy to implement, can be applied immediately and are not expensive. They may offer a first-step intervention for those experiencing psychological distress or depression and might serve as an initial intervention in primary care or community models. The findings suggest that the quality of psychoeducation may be important.


Global pollution of surface waters from point and nonpoint sources of nitrogen.
Global 0.5- by 0.5-degree resolution estimates are presented on the fate of nitrogen (N) stemming from point and nonpoint sources, including plant uptake, denitrification, leaching from the rooting zone, rapid flow through shallow groundwater, and slow flow through deep groundwater to riverine systems. Historical N inputs are used to describe the N flows in groundwater. For nonpoint N sources (agricultural and natural ecosystems), calculations are based on local hydrology, climate, geology, soils, climate and land use combined with data for 1995 on crop production, N inputs from N fertilizers and animal manure, and estimates for ammonia emissions, biological N fixation, and N deposition. For point sources, our estimates are based on population densities and human N emissions, sanitation, and treatment. The results provide a first insight into the magnitude of the N losses from soil-plant systems and point sources in various parts of the world, and the fate of N during transport in atmosphere, groundwater, and surface water. The contribution to the river N load by anthropogenic N pollution is dominant in many river basins in Europe, Asia, and North Africa. Our model results explain much of the variation in measured N export from different world river basins.


Ethnic differences in mortality from cerebrovascular disease among New Mexico's Hispanics, Native Americans, and non-Hispanic whites, 1958 through 1987.
We analyzed vital statistics data collected from 1958 through 1987 to determine time trends and ethnic differences in cerebrovascular disease mortality rates in New Mexico's Hispanic, Native American, and non-Hispanic white populations. Over the 30-year period of our study, cerebrovascular disease mortality rates decreased in all three major ethnic groups in the state, comparable to national trends. We found that Native Americans of both sexes had the lowest cerebrovascular disease mortality rates, followed by Hispanics, during the initial 25-year span of our data. In the most recent 5-year period that we examined, 1983 through 1987, Hispanics had the highest cerebrovascular disease mortality rates of the three groups. Our data suggest that Hispanics in New Mexico are now at higher risk for cerebrovascular disease-related mortality than are non-Hispanic whites, and that prevention strategies aimed at decreasing cerebrovascular disease rates should be focused on this segment of the state's population.


Determinants of Intention to Use Mobile Phone Caller Tunes to Promote Voluntary Blood Donation: Cross-Sectional Study.
Voluntary blood donation rates are low in sub-Saharan Africa. Sociobehavioral factors such as a belief that donated blood would be used for performing rituals deter people from donating blood. There is a need for culturally appropriate communication interventions to encourage individuals to donate blood. Health care interventions that use mobile phones have increased in developing countries, although many of them focus on SMS text messaging (short message service, SMS). A unique feature of mobile phones that has so far not been used for aiding blood donation is caller tunes. Caller tunes replace the ringing sound heard by a caller to a mobile phone before the called party answers the call. In African countries such as Ghana, instead of the typical ringing sound, a caller may hear a message or song. Despite the popularity of such caller tunes, there is a lack of empirical studies on their potential use for promoting blood donation. The aim of this study was to use the technology acceptance model to explore the influence of the factors-perceived ease of use, perceived usefulness, attitude, and free of cost-on intentions of blood or nonblood donors to download blood donation-themed caller tunes to promote blood donation, if available. A total of 478 blood donors and 477 nonblood donors were purposively sampled for an interviewer-administered questionnaire survey at blood donation sites in Accra, Ghana. Data were analyzed using descriptive statistics, exploratory factor analysis, and confirmatory factory analysis or structural equation modeling, leading to hypothesis testing to examine factors that determine intention to use caller tunes for blood donation among blood or nonblood donors who use or do not use mobile phone caller tunes. Perceived usefulness had a significant effect on intention to use caller tunes among blood donors with caller tunes (beta=.293, P<.001), blood donors without caller tunes (beta=.165, P=.02, nonblood donors with caller tunes (beta=.278, P<.001), and nonblood donors without caller tunes (beta=.164, P=.01). Attitudes had significant effect on intention to use caller tunes among blood donors without caller tunes (beta=.351, P<.001), nonblood donors with caller tunes (beta=.384, P<.001), nonblood donors without caller tunes (beta=.539, P<.001) but not among blood donors with caller tunes (beta=.056, P=.44). The effect of free-of-cost caller tunes on the intention to use for blood donation was statistically significant (beta=.169, P<.001) only in the case of nonblood donors without caller tunes, whereas this path was statistically not significant in other models. Our results provide empirical evidence for designing caller tunes to promote blood donation in Ghana. The study found that making caller tunes free is particularly relevant for nonblood donors with no caller tunes.


Auditory-visual aversive stimuli modulate the conscious experience of fear.
In a natural environment, affective information is perceived via multiple senses, mostly audition and vision. However, the impact of multisensory information on affect remains relatively undiscovered. In this study, we investigated whether the auditory-visual presentation of aversive stimuli influences the experience of fear. We used the advantages of virtual reality to manipulate multisensory presentation and to display potentially fearful dog stimuli embedded in a natural context. We manipulated the affective reactions evoked by the dog stimuli by recruiting two groups of participants: dog-fearful and non-fearful participants. The sensitivity to dog fear was assessed psychometrically by a questionnaire and also at behavioral and subjective levels using a Behavioral Avoidance Test (BAT). Participants navigated in virtual environments, in which they encountered virtual dog stimuli presented through the auditory channel, the visual channel or both. They were asked to report their fear using Subjective Units of Distress. We compared the fear for unimodal (visual or auditory) and bimodal (auditory-visual) dog stimuli. Dog-fearful participants as well as non-fearful participants reported more fear in response to bimodal audiovisual compared to unimodal presentation of dog stimuli. These results suggest that fear is more intense when the affective information is processed via multiple sensory pathways, which might be due to a cross-modal potentiation. Our findings have implications for the field of virtual reality-based therapy of phobias. Therapies could be refined and improved by implicating and manipulating the multisensory presentation of the feared situations.


Ancient papillomavirus-host co-speciation in Felidae.
Estimating evolutionary rates for slowly evolving viruses such as papillomaviruses (PVs) is not possible using fossil calibrations directly or sequences sampled over a time-scale of decades. An ability to correlate their divergence with a host species, however, can provide a means to estimate evolutionary rates for these viruses accurately. To determine whether such an approach is feasible, we sequenced complete feline PV genomes, previously available only for the domestic cat (Felis domesticus, FdPV1), from four additional, globally distributed feline species: Lynx rufus PV type 1, Puma concolor PV type 1, Panthera leo persica PV type 1, and Uncia uncia PV type 1. The feline PVs all belong to the Lambdapapillomavirus genus, and contain an unusual second noncoding region between the early and late protein region, which is only present in members of this genus. Our maximum likelihood and Bayesian phylogenetic analyses demonstrate that the evolutionary relationships between feline PVs perfectly mirror those of their feline hosts, despite a complex and dynamic phylogeographic history. By applying host species divergence times, we provide the first precise estimates for the rate of evolution for each PV gene, with an overall evolutionary rate of 1.95 x 10(-8) (95% confidence interval 1.32 x 10(-8) to 2.47 x 10(-8)) nucleotide substitutions per site per year for the viral coding genome. Our work provides evidence for long-term virus-host co-speciation of feline PVs, indicating that viral diversity in slowly evolving viruses can be used to investigate host species evolution. These findings, however, should not be extrapolated to other viral lineages without prior confirmation of virus-host co-divergence.


Pip6-PMO, A New Generation of Peptide-oligonucleotide Conjugates With Improved Cardiac Exon Skipping Activity for DMD Treatment.
Antisense oligonucleotides (AOs) are currently the most promising therapeutic intervention for Duchenne muscular dystrophy (DMD). AOs modulate dystrophin pre-mRNA splicing, thereby specifically restoring the dystrophin reading frame and generating a truncated but semifunctional dystrophin protein. Challenges in the development of this approach are the relatively poor systemic AO delivery and inefficient dystrophin correction in affected non-skeletal muscle tissues, including the heart. We have previously reported impressive heart activity including high-splicing efficiency and dystrophin restoration following a single administration of an arginine-rich cell-penetrating peptide (CPPs) conjugated to a phosphorodiamidate morpholino oligonucleotide (PMO): Pip5e-PMO. However, the mechanisms underlying this activity are poorly understood. Here, we report studies involving single dose administration (12.5 mg/kg) of derivatives of Pip5e-PMO, consecutively assigned as Pip6-PMOs. These peptide-PMOs comprise alterations to the central hydrophobic core of the Pip5e peptide and illustrate that certain changes to the peptide sequence improves its activity; however, partial deletions within the hydrophobic core abolish its efficiency. Our data indicate that the hydrophobic core of the Pip sequences is critical for PMO delivery to the heart and that specific modifications to this region can enhance activity further. The results have implications for therapeutic PMO development for DMD.


Fixation of supraglenoid tubercle fractures using distal femoral locking plates in three Warmblood horses.
Three horses that were presented with supraglenoid tubercle fractures were treated with open reduction and internal fixation using distal femoral locking plates (DFLP). Placing the DFLP caudal to the scapular spine in order to preserve the suprascapular nerve led to a stable fixation, however, it resulted in infraspinatus muscle atrophy and mild scapulohumeral joint instability (case 1). Placing the DFLP cranial to the scapular spine and under the suprascapular nerve resulted in a stable fixation, however, it resulted in severe atrophy of the supraspinatus and infraspinatus muscles and scapulohumeral joint instability (case 2). Placing the DFLP cranial to the scapular spine and slightly overbending it at the suprascapular nerve passage site resulted in the best outcome (case 3). Only a mild degree of supraspinatus and infraspinatus muscle atrophy was apparent, which resolved quickly and with no effect on scapulohumeral joint stability. In all cases, fixation of supraglenoid tubercle fractures using DFLP in slightly different techniques led to stable fixations with good long-term outcome. One case suffered from a mild incisional infection and plates were removed in two horses. Placement of the DFLP cranial to the scapular spine and slightly overbending it at the suprascapular nerve passage prevented major nerve damage. Further cases investigating the degree of muscle atrophy following the use of the DFLP placed in the above-described technique are justified to improve patient outcome.


Detection of middle cerebral artery emboli during carotid endarterectomy using transcranial Doppler ultrasonography.
The purpose of our study was to define the signal characteristics and clinical circumstances associated with emboli detected in the middle cerebral artery using 2-MHz pulsed transcranial Doppler ultrasound in patients undergoing carotid endarterectomy. Signals designating emboli were transients displaying harmonic qualities the signatures of which were clearly different from those of mechanical and electronic artifacts. We reviewed the audio/video tape recordings from 91 patients for signals of air bubble emboli occurring upon release of common carotid artery crossclamps; recordings from 35 patients (38%) demonstrated air bubble emboli. Transients with signatures identical to those of air bubble emboli were also discovered when bubbles in the bloodstream were improbable; we defined these transients as representing formed-element emboli. Such signals were found in recordings from 24 patients (26%), and they occurred before (both spontaneously and upon common carotid artery compression), during, and after surgical dissection. Signals indicating formed-element emboli were associated with intraluminal platelet thrombus, with ulcerations in the carotid artery, and with transient ischemic attacks or stroke. Most postoperative formed-element emboli did not cause symptoms but, when persisting for hours, they were associated with strokes and cerebral infarction. This Doppler ultrasound method of detecting emboli will be useful in the study of stroke mechanisms and as a clinical test to guide the medical and surgical treatment of patients at risk of stroke.


Mouse MRI shows brain areas relatively larger in males emerge before those larger in females.
Sex differences exist in behaviors, disease and neuropsychiatric disorders. Sexual dimorphisms however, have yet to be studied across the whole brain and across a comprehensive time course of postnatal development. Here, we use manganese-enhanced MRI (MEMRI) to longitudinally image male and female C57BL/6J mice across 9 time points, beginning at postnatal day 3. We recapitulate findings on canonically dimorphic areas, demonstrating MEMRI's ability to study neuroanatomical sex differences. We discover, upon whole-brain volume correction, that neuroanatomical regions larger in males develop earlier than those larger in females. Groups of areas with shared sexually dimorphic developmental trajectories reflect behavioral and functional networks, and expression of genes involved with sex processes. Also, post-pubertal neuroanatomy is highly individualized, and individualization occurs earlier in males. Our results demonstrate the ability of MEMRI to reveal comprehensive developmental differences between male and female brains, which will improve our understanding of sex-specific predispositions to various neuropsychiatric disorders.


Direct Measurements of Unimolecular and Bimolecular Reaction Kinetics of the Criegee Intermediate (CH3)2COO.
The Criegee intermediate acetone oxide, (CH3)2COO, is formed by laser photolysis of 2,2-diiodopropane in the presence of O2 and characterized by synchrotron photoionization mass spectrometry and by cavity ring-down ultraviolet absorption spectroscopy. The rate coefficient of the reaction of the Criegee intermediate with SO2 was measured using photoionization mass spectrometry and pseudo-first-order methods to be (7.3 ± 0.5) × 10-11 cm3 s-1 at 298 K and 4 Torr and (1.5 ± 0.5) × 10-10 cm3 s-1 at 298 K and 10 Torr (He buffer). These values are similar to directly measured rate coefficients of anti-CH3CHOO with SO2, and in good agreement with recent UV absorption measurements. The measurement of this reaction at 293 K and slightly higher pressures (between 10 and 100 Torr) in N2 from cavity ring-down decay of the ultraviolet absorption of (CH3)2COO yielded even larger rate coefficients, in the range (1.84 ± 0.12) × 10-10 to (2.29 ± 0.08) × 10-10 cm3 s-1. Photoionization mass spectrometry measurements with deuterated acetone oxide at 4 Torr show an inverse deuterium kinetic isotope effect, kH/kD = (0.53 ± 0.06), for reactions with SO2, which may be consistent with recent suggestions that the formation of an association complex affects the rate coefficient. The reaction of (CD3)2COO with NO2 has a rate coefficient at 298 K and 4 Torr of (2.1 ± 0.5) × 10-12 cm3 s-1 (measured with photoionization mass spectrometry), again similar to rate for the reaction of anti-CH3CHOO with NO2. Cavity ring-down measurements of the acetone oxide removal without added reagents display a combination of first- and second-order decay kinetics, which can be deconvolved to derive values for both the self-reaction of (CH3)2COO and its unimolecular thermal decay. The inferred unimolecular decay rate coefficient at 293 K, (305 ± 70) s-1, is similar to determinations from ozonolysis. The present measurements confirm the large rate coefficient for reaction of (CH3)2COO with SO2 and the small rate coefficient for its reaction with water. Product measurements of the reactions of (CH3)2COO with NO2 and with SO2 suggest that these reactions may facilitate isomerization to 2-hydroperoxypropene, possibly by subsequent reactions of association products.


Increased angiotensin II contraction of the uterine artery at early gestation in a transgenic model of hypertensive pregnancy is reduced by inhibition of endocannabinoid hydrolysis.
Increased vascular sensitivity to angiotensin II (Ang II) is a marker of a hypertensive human pregnancy. Recent evidence of interactions between the renin-angiotensin system and the endocannabinoid system suggests that anandamide and 2-arachidonoylglycerol may modulate Ang II contraction. We hypothesized that these interactions may contribute to the enhanced vascular responses in hypertensive pregnancy. We studied Ang II contraction in isolated uterine artery (UA) at early gestation in a rat model that mimics many features of preeclampsia, the transgenic human angiotensinogen×human renin (TgA), and control Sprague-Dawley rats. We determined the role of the cannabinoid receptor 1 by blockade with SR171416A, and the contribution of anandamide and 2-arachidonoylglycerol degradation to Ang II contraction by inhibiting their hydrolyzing enzyme fatty acid amide hydrolase (with URB597) or monoacylglycerol lipase (with JZL184), respectively. TgA UA showed increased maximal contraction and sensitivity to Ang II that was inhibited by indomethacin. Fatty acid amide hydrolase blockade decreased Ang IIMAX in Sprague-Dawley UA, and decreased both Ang IIMAX and sensitivity in TgA UA. Monoacylglycerol lipase blockade had no effect on Sprague-Dawley UA and decreased Ang IIMAX and sensitivity in TgA UA. Blockade of the cannabinoid receptor 1 in TgA UA had no effect. Immunolocalization of fatty acid amide hydrolase and monoacylglycerol lipase showed a similar pattern between groups; fatty acid amide hydrolase predominantly localized in endothelium and monoacylglycerol lipase in smooth muscle cells. We demonstrated an increased Ang II contraction in TgA UA before initiation of the hypertensive phenotype. Anandamide and 2-arachidonoylglycerol reduced Ang II contraction in a cannabinoid receptor 1-independent manner. These renin-angiotensin system-endocannabinoid system interactions may contribute to the enhanced vascular reactivity in early stages of hypertensive pregnancy.


Demonstration of the Pericallosal Artery at 11-13 Weeks of Gestation Using 3D Ultrasound.
To assess the sonographic visualization of the pericallosal arteries in normal fetuses at 11-13 weeks of gestation using 3D ultrasound. We prospectively enrolled women with a singleton pregnancy undergoing ultrasound at 11-13 weeks of gestation. A 3D volume with high-definition power Doppler was acquired starting from the sagittal view of the fetal head and stored in the spatiotemporal image correlation mode. The images of the pericallosal arteries were assigned a score of 0 (no visualization), 1 (visualization of the origin) or 2 (visualization of the whole course). A follow-up scan was performed in all cases at 20 weeks of gestation to assess the presence of the corpus callosum. 70 patients were included and the pericallosal arteries were sonographically detectable in all cases. Image scores of 1 and 2 were obtained in 8 and 62 cases, respectively. The whole length of the vessel was between 3.5 and 4.5 mm. The vast majority of those with a score of 2 were beyond 12 completed weeks of gestation. All fetuses showed a normal corpus callosum at midtrimester and no abnormal brain findings after birth. The pericallosal arteries are sonographically visible since the first trimester in 3D ultrasound scans of fetuses found to have a normal corpus callosum at follow-up.


Her-2/neu gene amplification in paraffin-embedded tissue sections of meningioma patients.
Meningiomas arise from the meningoendothelial cells and are one of the most common tumors of the central nervous system. The HER-2/neu gene is located on the 17q11.2-q12 chromosome region and encodes an epidermal growth factor receptor. HER- 2/neu gene amplification and/or over expression have been studied most widely in breast carcinomas. Previous studies have shown the importance of HER-2/neu gene amplification on the prognosis of meningioma cases. In this study, we aimed to detect HER-2/neu gene copy number in archive materials of 55 meningioma patients by fluorescent in situ hybridization (FISH). The patients included in the study had undergone surgery in the neurosurgery department of our hospital between 1999 and 2002. Tissue samples were classified histologically according to WHO 2007 guidelines. Interphase FISH was performed on 3 to 4microm thick paraffin embedded tissue sections for the detection of HER- 2/neu gene amplification status. We found HER-2/neu gene amplification in 7 (12.73%) patients. Another 2 patients had only one signal for the HER-2/neu region. We confirmed this finding by a second hybridization with the chromosome 17p13.1 (p53) probe. According to our results, HER-2/neu amplification could be regarded as an additional genetic factor playing role in meningioma pathogenesis together with known chromosomal abnormalities.


Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.
TNK-S2B, an innovative, randomized, seamless phase II/III trial of tenecteplase versus rt-PA for acute ischemic stroke, terminated for slow enrollment before regulatory approval of use of phase II patients in phase III. (1) To review the trial design and comprehensive type I error rate simulations and (2) to discuss issues raised during regulatory review, to facilitate future approval of similar designs. In phase II, an early (24-h) outcome and adaptive sequential procedure selected one of three tenecteplase doses for phase III comparison with rt-PA. Decision rules comparing this dose to rt-PA would cause stopping for futility at phase II end, or continuation to phase III. Phase III incorporated two co-primary hypotheses, allowing for a treatment effect at either end of the trichotomized Rankin scale. Assuming no early termination, four interim analyses and one final analysis of 1908 patients provided an experiment-wise type I error rate of <0.05. Over 1,000 distribution scenarios, each involving 40,000 replications, the maximum type I error in phase III was 0.038. Inflation from the dose selection was more than offset by the one-half continuity correction in the test statistics. Inflation from repeated interim analyses was more than offset by the reduction from the clinical stopping rules for futility at the first interim analysis. Design complexity and evolving regulatory requirements lengthened the review process. (1) The design was innovative and efficient. Per protocol, type I error was well controlled for the co-primary phase III hypothesis tests, and experiment-wise. (2a) Time must be allowed for communications with regulatory reviewers from first design stages. (2b) Adequate type I error control must be demonstrated. (2c) Greater clarity is needed on (i) whether this includes demonstration of type I error control if the protocol is violated and (ii) whether simulations of type I error control are acceptable. (2d) Regulatory agency concerns that protocols for futility stopping may not be followed may be allayed by submitting interim analysis results to them as these analyses occur.


Combined use of clofibrate and cholestyramine or DEAE sephadex in hypercholesterolaemia.
A comparison was made of the effect of DEAE (diethylaminoethyl) Sephadex (an anion exchange resin) and cholestyramine (Questran) with and without the addition of clofibrate in normal and hypercholesterolaemic patients. DEAE Sephadex (12-15 g/day) alone appeared to be as effective as cholestyramine in lowering the plasma cholesterol by 12-15%. Clofibrate acted synergistically with DEAE Sephadex and increased the activity of the latter by over twofold. This combination proved superior to that of clofibrate and cholestyramine and has the greatest potential use in the treatment of type II pattern hyperlipoproteinaemia.


Employing a combinatorial expression approach to characterize xylose utilization in Saccharomyces cerevisiae.
Fermentation of xylose, a major constituent of lignocellulose, will be important for expanding sustainable biofuel production. We sought to better understand the effects of intrinsic (genotypic) and extrinsic (growth conditions) variables on optimal gene expression of the Scheffersomyces stipitis xylose utilization pathway in Saccharomyces cerevisiae by using a set of five promoters to simultaneously regulate each gene. Three-gene (xylose reductase, xylitol dehydrogenase (XDH), and xylulokinase) and eight-gene (expanded with non-oxidative pentose phosphate pathway enzymes and pyruvate kinase) promoter libraries were enriched under aerobic and anaerobic conditions or with a mutant XDH with altered cofactor usage. Through characterization of enriched strains, we observed (1) differences in promoter enrichment for the three-gene library depending on whether the pentose phosphate pathway genes were included during the aerobic enrichment; (2) the importance of selection conditions, where some aerobically-enriched strains underperform in anaerobic conditions compared to anaerobically-enriched strains; (3) improved growth rather than improved fermentation product yields for optimized strains carrying the mutant XDH compared to the wild-type XDH.


Adjunctive thrombectomy and distal protection in primary percutaneous coronary intervention: impact on microvascular perfusion and outcomes.
A significant proportion of patients with ST-elevation myocardial infarction have persistent impairment of microvascular blood flow despite successful reperfusion of epicardial vessels. Microvascular dysfunction has been associated with larger infarct size, increased predisposition to ventricular arrhythmias, heart failure, cardiogenic shock, recurrent myocardial infarction, and death. It remains unclear whether this association is of direct mechanistic significance or whether the microcirculatory injury is an epiphenomenon and a manifestation of greater ischemic insult to the myocardium. Although several potential mechanisms have been proposed for the microvascular dysfunction, distal microembolization during mechanical reperfusion is likely to be an important contributor. Consequently, there has been increasing interest in the concept of adjunctive mechanical thrombectomy to improve outcomes in primary percutaneous coronary intervention. Until recently, randomized trials of thrombectomy and distal protection devices during primary percutaneous coronary intervention have provided conflicting results with no definitive evidence for efficacy. The recently published Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction Study has rekindled the interest in this area. This trial is the largest randomized study of a thrombectomy device published to date and demonstrates that adjunctive treatment with aspiration thrombectomy during primary percutaneous coronary intervention improves surrogate and clinical end points. The aim of the present report is to review the evidence to date on the role of mechanical thrombectomy and embolic protection in native coronary arteries during primary percutaneous coronary intervention.


Anticoagulant synergism of heparin and activated protein C in vitro. Role of a novel anticoagulant mechanism of heparin, enhancement of inactivation of factor V by activated protein C.
Interactions between standard heparin and the physiological anticoagulant plasma protein, activated protein C (APC) were studied. The ability of heparin to prolong the activated partial thromboplastin time and the factor Xa- one-stage clotting time of normal plasma was markedly enhanced by addition of purified APC to the assays. Experiments using purified clotting factors showed that heparin enhanced by fourfold the phospholipid-dependent inactivation of factor V by APC. In contrast to factor V, there was no effect of heparin on inactivation of thrombin-activated factor Va by APC. Based on SDS-PAGE analysis, heparin enhanced the rate of proteolysis of factor V but not factor Va by APC. Coagulation assays using immunodepleted plasmas showed that the enhancement of heparin action by APC was independent of antithrombin III, heparin cofactor II, and protein S. Experiments using purified proteins showed that heparin did not inhibit factor V activation by thrombin. In summary, heparin and APC showed significant anticoagulant synergy in plasma due to three mechanisms that simultaneously decreased thrombin generation by the prothrombinase complex. These mechanisms include: first, heparin enhancement of antithrombin III-dependent inhibition of factor V activation by thrombin; second, the inactivation of membrane-bound FVa by APC; and third, the proteolytic inactivation of membrane-bound factor V by APC, which is enhanced by heparin.


Palladium(ii) and platinum(ii) saccharinate complexes with bis(diphenylphosphino)methane/ethane: synthesis, S-phase arrest and ROS-mediated apoptosis in human colon cancer cells.
New neutral [M(sac)2(diphos)] and cationic [M(diphos)2](sac)2 complexes, where M = PdII or PtII, sac = saccharinate, and diphos = 1,1-bis(diphenylphosphino)methane (dppm) or 1,2-bis(diphenylphosphino)ethane (dppe), were synthesized and structurally characterized. The anticancer activity of the complexes was investigated against MCF-7 (breast), A549 (lung), HCT116 (colon), DU145 (prostate) cancer and BEAS-2B (normal bronchial epithelial) cells. Neutral Pt-dppm (2) and Pd-dppe complexes (5) did not show any biological activity. The cationic Pd-dppe (7) complex displayed antiproliferative activity, while the rest of the complexes exhibited potent cytotoxicity compared with cisplatin. The active Pd(ii)/Pt(ii) complexes were then included in further studies including interaction with DNA/HSA, nuclease activity, cellular uptake and lipophilicity. The potent complexes induced the apoptotic cell death as probed through annexin V positivity and caspase activation. Mechanistic studies on HCT116 cells showed that the complexes cause cell cycle arrest at the DNA synthesis (S) phase and excessive generation of reactive oxygen species (ROS), damaging to both mitochondria and DNA.


Higher qualifications, first-birth timing, and further childbearing in England and Wales.
This article examines how strong the association is between the obtaining of higher educational qualifications and later entry to motherhood, and how these are associated with levels and pace of second and subsequent childbearing. Data from the ONS Longitudinal Study are used to estimate these associations for women born in England and Wales between 1954 and 1958. Average age of entry to motherhood is found to be five years later for women with higher qualifications than for those without. Increasing age of motherhood is always associated with a lower likelihood of going on to have another child, but the decline with age is less pronounced for women with a higher qualification. Moreover, for any given age of childbearing, mothers with a higher qualification are more likely than those without to have another child, and are more likely to do so quickly.


Survey based investigation into general practitioner referral patterns for spinal manipulative therapy.
In the UK Physiotherapy, Chiropractic and Osteopathy are all statutory regulated professions. Though guidelines have supported the use of Spinal Manipulative Therapy (SMT) for low back pain (LBP), General Practitioners (GP) referral patterns to the 3 registered professions that perform SMT are generally unknown. A short questionnaire was designed and piloted. Demographic information, patient referral to SMT and the GPs own personal utilisation of SMT were obtained. 385 GP's were contacted representing approximately 20% of the GP's in Wales Autumn 2007. 182 (50.8%) completed questionnaires were returned. Profile characteristics: 2/3 of respondents were male, 79% were 40 years old or older (statistically reflective of the total population of GPs in Wales at that time) and 62% had 20 years or less in practise. Personal use of SMT by GP's: 48 respondents had sought SMT treatment and a further 56% of those that had not previously sought SMT indicated that they would consider doing so. Patient referral to SMT by GP's: 131 respondents (72%) had referred patients to SMT and of those who had not a further 13% would consider referring. The general referral pattern and utilisation pattern was Physiotherapy: Osteopathy: Chiropractic. 21% who had never referred patients neither had, nor would consider it for themselves. A small subgroup appeared to manage personal choice differently from patient referral: 5 individuals who had not referred patients either had or would consider it for themselves and 23 of the group that would refer patients neither had nor would seek it for themselves. This limited investigation indicates that GP's do practise consistently with guidelines on back pain and utilise SMT as a care option. Although the main option for referral was physiotherapy, slightly over 40% of respondents who expressed a preference would refer to either osteopathy or chiropractic, or both in preference to physiotherapy. There was a small proportion that did not and would not refer patients for SMT regardless of personal use of SMT; these suggested use of acupuncture. Further investigation is needed to determine the alternatives to SMT offered to patients and the decision-making criteria for patient referral to subtypes of SMT practitioner.


Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2.
Oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor (HIF) by a set of closely related prolyl hydroxylase domain enzymes (PHD1, 2 and 3) regulates a range of transcriptional responses to hypoxia. This raises important questions about the role of these oxygen-sensing enzymes in integrative physiology. We investigated the effect of both genetic deficiency and pharmacological inhibition on the change in ventilation in response to acute hypoxic stimulation in mice. Mice exposed to chronic hypoxia for 7 days manifest an exaggerated hypoxic ventilatory response (HVR) (10.8 ± 0.3 versus 4.1 ± 0.7 ml min(-1) g(-1) in controls; P < 0.01). HVR was similarly exaggerated in PHD2(+/-) animals compared to littermate controls (8.4 ± 0.7 versus 5.0 ± 0.8 ml min(-1) g(-1); P < 0.01). Carotid body volume increased (0.0025 ± 0.00017 in PHD2(+/-) animals versus 0.0015 ± 0.00019 mm(3) in controls; P < 0.01). In contrast, HVR in PHD1(-/-) and PHD3(-/-) mice was similar to littermate controls. Acute exposure to a small molecule PHD inhibitor (PHI) (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetic acid) did not mimic the ventilatory response to hypoxia. Further, 7 day administration of the PHI induced only modest increases in HVR and carotid body cell proliferation, despite marked stimulation of erythropoiesis. This was in contrast with chronic hypoxia, which elicited both exaggerated HVR and cellular proliferation. The findings demonstrate that PHD enzymes modulate ventilatory sensitivity to hypoxia and identify PHD2 as the most important enzyme in this response. They also reveal differences between genetic inactivation of PHDs, responses to hypoxia and responses to a pharmacological inhibitor, demonstrating the need for caution in predicting the effects of therapeutic modulation of the HIF hydroxylase system on different physiological responses.


Atlas of the Global Burden of Stroke (1990-2013): The GBD 2013 Study.
World mapping is an important tool to visualize stroke burden and its trends in various regions and countries. To show geographic patterns of incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke and hemorrhagic stroke in the world for 1990-2013. Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated following the general approach of the Global Burden of Disease (GBD) 2010 with several important improvements in methods. Data were updated for mortality (through April 2014) and stroke incidence, prevalence, case fatality and severity through 2013. Death was estimated using an ensemble modeling approach. A new software package, DisMod-MR 2.0, was used as part of a custom modeling process to estimate YLDs. All rates were age-standardized to new GBD estimates of global population. All estimates have been computed with 95% uncertainty intervals. Age-standardized incidence, mortality, prevalence and DALYs/YLDs declined over the period from 1990 to 2013. However, the absolute number of people affected by stroke has substantially increased across all countries in the world over the same time period, suggesting that the global stroke burden continues to increase. There were significant geographical (country and regional) differences in stroke burden in the world, with the majority of the burden borne by low- and middle-income countries. Global burden of stroke has continued to increase in spite of dramatic declines in age-standardized incidence, prevalence, mortality rates and disability. Population growth and aging have played an important role in the observed increase in stroke burden.


Relationship between endocrine changes and bone markers in pediatric thalassemic patients after hematopoietic stem cell transplantation.
Beta thalassemia major and its treatment by hematopoietic stem cell transplantation can have deleterious effects on bone integrity and a main part of such effects is due to their deleterious effects on endocrine systems. So, we assessed the effects of endocrine changes during HSCT (Hematopoietic Stem Cell Transplantation) on growing bones of pediatric thalassemic patients. Bone-specific alkaline phosphatase and osteocalcin (bone formation markers), N-terminal telopeptide (NTX, bone resorption marker), calcium (Ca), phosphorus (P), alkaline phosphatase (Alk ph), parathyroid hormone (PTH), vitamin D (vit D), prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroxine (T4), triiodothyronine (T3), thyroid-stimulating hormone (TSH), insulin-like growth factor 1 (IGF-1), testosterone (in males) or estradiol (in females), measured in 20 major thalassemic patients with mean age of 10.8±3.9 years. Parameters at the baseline (before HSCT), and 1 month and 3 months after HSCT. After stem cell transplantation, changes of mean serum levels of NTX, osteocalcin, prolactin, LH, T4, IGF-1, testosterone (in males), Ca, Alk ph, PTH, and vit D were not significant, but bone specific Alk ph, P, T3, TSH, FSH and estradiol changed significantly (P=0.013, P=0.001, P=0.48, P=0.02, P=0.04 and P=0.001, respectively). After one month, there was a significant positive relationship between osteocalcine and T3 (p= 0.009). After 3 months, also, there was a significant positive relationship between osteocalcine and T3 and T4 as well as a negative one with IGF-1 (P<0.001, P<0.02 and P<0.03, respectively). Endocrine disorders do not appear to have an overall positive or negative effect on bone metabolism (anabolism or catabolism) in HSCT pediatric thalassemic patients in short term (three months).


Transcranial Alternating Current Stimulation Has Frequency-Dependent Effects on Motor Learning in Healthy Humans.
It is well established that the primary motor cortex (M1) plays a significant role in motor learning in healthy humans. It is unclear, however, whether mechanisms of motor learning include M1 oscillatory activity. In this study, we aimed to test whether M1 oscillations, entrained by transcranial Alternating Current Stimulation (tACS) at motor resonant frequencies, have any effect on motor acquisition and retention during a rapid learning task, as assessed by kinematic analysis. We also tested whether the stimulation influenced the corticospinal excitability changes after motor learning. Sixteen healthy subjects were enrolled in the study. Participants performed the motor learning task in three experimental conditions: sham-tACS (baseline), β-tACS and γ-tACS. Corticospinal excitability was assessed with single-pulse TMS before the motor learning task and 5, 15, and 30 min thereafter. Motor retention was tested 30 min after the motor learning task. During training, acceleration of the practiced movement improved in the baseline condition and the enhanced performance was retained when tested 30 min later. The β-tACS delivered during training inhibited the acquisition of the motor learning task. Conversely, the γ-tACS slightly improved the acceleration of the practiced movement during training but it reduced motor retention. At the end of training, corticospinal excitability had similarly increased in the three sessions. The results are compatible with the hypothesis that entrainment of the two major motor resonant rhythms through tACS over M1 has different effects on motor learning in healthy humans. The effects, however, were unrelated to corticospinal excitability changes.


Non-small cell lung cancer is characterised by a distinct inflammatory signature in serum compared with chronic obstructive pulmonary disease.
Development of lung cancer is closely related to smoking in a majority of patients. Most smokers, however, do not develop lung cancer in spite of a high mutational load accumulating in the lung tissue. Here we investigate whether a cancer-specific footprint can be revealed by investigating circulating inflammatory markers in patients with non-small cell lung cancer (NSCLC) compared with patients with chronic obstructive pulmonary disease (COPD), both cohorts characterised by similar smoking history. Serum concentrations of 57 cytokines and matrix metalloproteinases (MMPs) from 43 patients with advanced NSCLC were evaluated by multiplex immunoassays and compared with serum samples from 35 patients with COPD. Unsupervised hierarchical clustering and non-parametric analyses were performed. False discovery rate was used to adjust for multiple testing. Clustering of cytokine and MMP concentrations in the serum revealed a distinct separation of the NSCLC patients from the COPD group. Individual concentrations of thymus and activation-regulated cytokine (C-C motif chemokine ligand 17), Gro-b (C-X-C motif chemokine ligand 2 (CXCL2)), CXCL13, interleukin (IL)-1ra, IL-6, IL-8 (CXCL8), IL-16, IL-17A, macrophage migration inhibitory factor (MIF), granulocyte colony-stimulating factor, platelet-derived growth factor subunit B, MMP-2, MMP-8 and MMP-12 were significantly different in serum from NSCLC and COPD patients. Moreover, the interferon-γ/IL-10 ratio was lower in cancer patients compared with COPD patients, consistent with a cytokine milieu favouring tumour tolerance. Our results suggest that NSCLC is characterised by a distinct inflammatory signature in serum. The different cytokine profiles in NSCLC and COPD patients may represent tumour-promoting and tumour-suppressing immune responses developing in response to mucosal inflammation and mutations induced by smoking.


Labeling and exocytosis of secretory compartments in RBL mastocytes by polystyrene and mesoporous silica nanoparticles.
For a safe 'in vivo' biomedical utilization of nanoparticles, it is essential to assess not only biocompatibility, but also the potential to trigger unwanted side effects at both cellular and tissue levels. Mastocytes (cells having secretory granules containing cytokines, vasoactive amine, and proteases) play a pivotal role in the immune and inflammatory responses against exogenous toxins. Mastocytes are also recruited in the tumor stroma and are involved in tumor vascularization and growth. In this work, mastocyte-like rat basophilic leukemia (RBL) cells were used to investigate whether carboxyl-modified 30 nm polystyrene (PS) nanoparticles (NPs) and naked mesoporous silica (MPS) 10 nm NPs are able to label the secretory inflammatory granules, and possibly induce exocytosis of these granules. Uptake, cellular retention and localization of fluorescent NPs were analyzed by cytofluorometry and microscope imaging. OUR FINDINGS WERE THAT: (1) secretory granules of mastocytes are accessible by NPs via endocytosis; (2) PS and MPS silica NPs label two distinct subpopulations of inflammatory granules in RBL mastocytes; and (3) PS NPs induce calcium-dependent exocytosis of inflammatory granules. These findings highlight the value of NPs for live imaging of inflammatory processes, and also have important implications for the clinical use of PS-based NPs, due to their potential to trigger the unwanted activation of mastocytes.


Role of hemodynamic factors in osmoregulatory alterations of rat pregnancy.
Plasma osmolality (Posmol) decreases in pregnancy, possibly because of hemodynamically mediated arginine vasopressin (AVP) secretion, i.e., inadequate vascular filling and/or decreased blood pressure. This hypothesis was tested in Sprague-Dawley rats treated on gestational days 1-18 or 13-18 with 1) deoxycorticosterone acetate (DOCA) + standard chow (0.5% Na), 2) vehicle + standard chow, or 3) high-Na (1.25%) diet. Renal sodium "escape" and suppression of the renin-aldosterone system suggested "effective volume expansion," yet Posmol was similar in all pregnant groups, 7-10 mosmol/kg below levels in virgin controls, and plasma AVP was unaltered. Apparent osmotic thresholds for AVP secretion, similar in control and DOCA-treated gravid animals, were 8-10 mosmol/kg below those of untreated virgin rats. Norepinephrine + DOCA, administered to gravid animals consuming normal or high-Na chow, increased blood pressure approximately 10% above control levels, but this also failed to alter Posmol. These data suggest that mechanisms other than hemodynamically mediated AVP secretion are responsible for the osmoregulatory alterations accompanying rodent pregnancy.


Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation.
Cytosine methylation of mammalian DNA is essential for the proper epigenetic regulation of gene expression and maintenance of genomic integrity. To define the mechanism through which demethylated cells die, and to establish a paradigm for identifying genes regulated by DNA methylation, we have generated mice with a conditional allele for the maintenance DNA methyltransferase gene Dnmt1. Cre-mediated deletion of Dnmt1 causes demethylation of cultured fibroblasts and a uniform p53-dependent cell death. Mutational inactivation of Trp53 partially rescues the demethylated fibroblasts for up to five population doublings in culture. Oligonucleotide microarray analysis showed that up to 10% of genes are aberrantly expressed in demethylated fibroblasts. Our results demonstrate that loss of Dnmt1 causes cell-type-specific changes in gene expression that impinge on several pathways, including expression of imprinted genes, cell-cycle control, growth factor/receptor signal transduction and mobilization of retroelements.


E. coli cells expressing the Baeyer-Villiger monooxygenase 'MO14' (ro03437) from Rhodococcus jostii RHA1 catalyse the gram-scale resolution of a bicyclic ketone in a fermentor.
The Baeyer-Villiger monooxygenase (BVMO) 'MO14' from Rhodococcus jostii RHA1, is an enantioselective BVMO that catalyses the resolution of the model ketone substrate bicyclo[3.2.0]hept-2-en-6-one to the (1S,5R)-2-oxa lactone and the residual (1S,5R)-substrate enantiomer. This regio-plus enantioselective behaviour is highly unusual for BVMOs, which often perform enantiodivergent biotransformations of this substrate. The scaleability of the transformation was investigated using fermentor-based experiments, in which variables including gene codon optimisation, temperature and substrate concentration were investigated. E. coli cells expressing MO14 catalysed the resolution of bicyclo[3.2.0]hept-2-en-6-one to yield (1S,5R)-2-oxa lactone of >99% ee and (1S,5R)-ketone of 96% ee after 14 h at a temperature of 16 °C and a substrate concentration of 0.5 g L(-1) (4.5 mM). MO14 is thus a promising biocatalyst for the production of enantio-enriched ketones and lactones derived from the [3.2.0] platform.


Extended wakefulness: compromised metabolics in and degeneration of locus ceruleus neurons.
Modern society enables a shortening of sleep times, yet long-term consequences of extended wakefulness on the brain are largely unknown. Essential for optimal alertness, locus ceruleus neurons (LCns) are metabolically active neurons that fire at increased rates across sustained wakefulness. We hypothesized that wakefulness is a metabolic stressor to LCns and that, with extended wakefulness, adaptive mitochondrial metabolic responses fail and injury ensues. The nicotinamide adenine dinucleotide-dependent deacetylase sirtuin type 3 (SirT3) coordinates mitochondrial energy production and redox homeostasis. We find that brief wakefulness upregulates SirT3 and antioxidants in LCns, protecting metabolic homeostasis. Strikingly, mice lacking SirT3 lose the adaptive antioxidant response and incur oxidative injury in LCns across brief wakefulness. When wakefulness is extended for longer durations in wild-type mice, SirT3 protein declines in LCns, while oxidative stress and acetylation of mitochondrial proteins, including electron transport chain complex I proteins, increase. In parallel with metabolic dyshomeostasis, apoptosis is activated and LCns are lost. This work identifies mitochondrial stress in LCns upon wakefulness, highlights an essential role for SirT3 activation in maintaining metabolic homeostasis in LCns across wakefulness, and demonstrates that extended wakefulness results in reduced SirT3 activity and, ultimately, degeneration of LCns.


Immune cytopenia post-cord transplant in Hurler syndrome is a forme fruste of graft rejection.
Umbilical cord blood (UCB) is the preferred donor cell source for children with Hurler syndrome undergoing transplant, and its use has been associated with improved "engrafted survival" rates. However, as in other pediatric recipients of UCB transplants for nonmalignant disease, immune-mediated cytopenia (IMC) is a significant complication. This article describes 8 episodes of IMC in 36 patients with Hurler syndrome undergoing UCB transplant. The incidence of IMC was increased in those with a higher preconditioning absolute lymphocyte count and in those conditioned with fludarabine-containing regimens rather than cyclophosphamide, and it included red cell alloantibodies directed at cord blood group antigens that are novel to the recipient. In several cases, IMC was a precursor to immune-mediated complete graft rejection. We describe IMC as part of a spectrum of graft rejection by a residual competent host immune system and a forme fruste of complete graft rejection.


Pedicled lateral nasal wall flap for the reconstruction of the nasal septum perforation. A radio-anatomical study.
The aim of this radio-anatomical study is to ensure that the potential donor area of the pedicled lateral nasal wall flap (PLNW) is adequate to reconstruct nasal perforation. Analysis was conducted on 40 de-identified CT angiographies. The area and length of the PLNW, the septum, and the nasal floor were measured. In a cadaver study, 20 hemi-cranial sagittal sections were also analyzed. The anterior-posterior length of the PLNW flap and the distance between the sphenopalatine foramen and piriform aperture were measured. A clinical study with endoscopic closure of a large perforation was conducted in three patients. The CT angiographies demonstrated an average PLNW area of 10.80±1.13 cm2 and a nasal floor area of 3.78±0.58 cm2. The septal area (22.54±21.32 cm2) was significantly larger than the total PLNW flap area (14.59±1.21 cm2). The average length of the flap was 5.58±0.39 cm, while the septum was 6.66±0.42 cm; therefore the PLNW flap is insufficient to reconstruct the entire septum. The cadaver study showed that the length of the PLNW flap was 5.28±0.40 cm. These results demonstrate that measurements obtained from CT scans are reliable data and similar to those found in the radiological study. Complete closure was achieved in all three patients. The PLNW flap does not render enough tissue to reconstruct a total septal perforation; however, up to 84% of the septum could be repaired with a PLNW. The potential donor area obtained by CT scan and clinical practice support the approachability of PLNW to repair large septal perforation.


The use of non-narcotic pain medication in pediatric gastroenterology.
The perception of pain in children is easily influenced by environmental factors and psychological comorbidities that are known to play an important role in its origin and response to therapy. Chronic abdominal pain is one of the most commonly treated conditions in modern pediatric gastroenterology and is the hallmark of 'functional' disorders that include irritable bowel syndrome, functional dyspepsia, and functional abdominal pain. The development of pharmacological therapies for these disorders in adults and children has been limited by the lack of understanding of the putative, pathophysiological mechanisms that underlie them. Peripheral and central pain-signaling mechanisms are known to be involved in chronic pain originating from the gastrointestinal tract, but few therapies have been developed to target specific pathways or enhance correction of the underlying pathophysiology. The responses to therapy have been variable, potentially reflecting the heterogeneity of the disorders for which they are used. Only a few small, randomized clinical trials have evaluated the benefit of pain medications for chronic abdominal pain in children and thus, the decision on the most appropriate treatment is often based on adult studies and empirical data. This review discusses the most common, non-narcotic pharmacological treatments for chronic abdominal pain in children and includes a thorough review of the literature to support or refute their use. Because of the dearth of pediatric studies, the focus is on pharmacological and alternative therapies where there is sufficient evidence of benefit in either adults or children with chronic abdominal pain.


Distinct fission signatures predict mitochondrial degradation or biogenesis.
Mitochondrial fission is a highly regulated process that, when disrupted, can alter metabolism, proliferation and apoptosis1-3. Dysregulation has been linked to neurodegeneration3,4, cardiovascular disease3 and cancer5. Key components of the fission machinery include the endoplasmic reticulum6 and actin7, which initiate constriction before dynamin-related protein 1 (DRP1)8 binds to the outer mitochondrial membrane via adaptor proteins9-11, to drive scission12. In the mitochondrial life cycle, fission enables both biogenesis of new mitochondria and clearance of dysfunctional mitochondria through mitophagy1,13. Current models of fission regulation cannot explain how those dual fates are decided. However, uncovering fate determinants is challenging, as fission is unpredictable, and mitochondrial morphology is heterogeneous, with ultrastructural features that are below the diffraction limit. Here, we used live-cell structured illumination microscopy to capture mitochondrial dynamics. By analysing hundreds of fissions in African green monkey Cos-7 cells and mouse cardiomyocytes, we discovered two functionally and mechanistically distinct types of fission. Division at the periphery enables damaged material to be shed into smaller mitochondria destined for mitophagy, whereas division at the midzone leads to the proliferation of mitochondria. Both types are mediated by DRP1, but endoplasmic reticulum- and actin-mediated pre-constriction and the adaptor MFF govern only midzone fission. Peripheral fission is preceded by lysosomal contact and is regulated by the mitochondrial outer membrane protein FIS1. These distinct molecular mechanisms explain how cells independently regulate fission, leading to distinct mitochondrial fates.


Effectiveness of anaerobic biomass in adsorbing heavy metals.
This study focuses on the effectiveness of waste anaerobic dead biomass (ADB) in adsorbing heavy metals, namely Pb(II), Cr(VI), Cu(II), Ni(II) and Zn(II). The metal uptake capacity of ADB was investigated and compared with the values for various biomass types from the literature. The biomass, which was grown under laboratory conditions using a synthetic wastewater, was used throughout the study after sterilization. The maximum metal adsorptive capacities were evaluated by running isotherm tests at 25 degrees C and initial pH of 4. It was observed that Pb(II) was adsorbed with the highest capacity. The maximum adsorptive capacity of ADB for Pb(II), Zn(II), Cu(II), Ni(II) and Cr(VI) was determined as 1250, 625, 357, 227 and 384 mg/g dry biomass, respectively. These values were significantly higher than the corresponding capacities reported in the literature for other types of biomass. In describing the adsorption equilibrium, both the Langmuir and Freundlich isotherm models were examined. The experimental data for Pb(II), Zn(II), Cr(VI), and Ni(II) fitted both the Langmuir and Freundlich models with correlation coefficients of 0.80-0.99 while Cu(II) only fitted the Langmuir model with a correlation coefficient of 0.99. Therefore, different and distinct aspects of the interactions between the cell surfaces and the metal ions might have occurred for Cu(II) and the rest of the metals. The equilibrium pH values attained were all higher than the initial pH value of 4.0, and this indicated that both the type and the initial concentration of the metal influenced the equilibrium pH. Furthermore, there was a decrease in equilibrium pH with increasing initial metal concentration at varying levels.


How delays matter in an oscillatory whole-brain spiking-neuron network model for MEG alpha-rhythms at rest.
In recent years the study of the intrinsic brain dynamics in a relaxed awake state in the absence of any specific task has gained increasing attention, as spontaneous neural activity has been found to be highly structured at a large scale. This so called resting-state activity has been found to be comprised by nonrandom spatiotemporal patterns and fluctuations, and several Resting-State Networks (RSN) have been found in BOLD-fMRI as well as in MEG signal power envelope correlations. The underlying anatomical connectivity structure between areas of the brain has been identified as being a key to the observed functional network connectivity, but the mechanisms behind this are still underdetermined. Theoretical large-scale brain models for fMRI data have corroborated the importance of the connectome in shaping network dynamics, while the importance of delays and noise differ between studies and depend on the models' specific dynamics. In the current study, we present a spiking neuron network model that is able to produce noisy, distributed alpha-oscillations, matching the power peak in the spectrum of group resting-state MEG recordings. We studied how well the model captured the inter-node correlation structure of the alpha-band power envelopes for different delays between brain areas, and found that the model performs best for propagation delays inside the physiological range (5-10 m/s). Delays also shift the transition from noisy to bursting oscillations to higher global coupling values in the model. Thus, in contrast to the asynchronous fMRI state, delays are important to consider in the presence of oscillation.


A double-blind, randomized study comparing the efficacy and safety of sertindole and risperidone in patients with treatment-resistant schizophrenia.
The comparative efficacy of second-generation antipsychotics has yet to be fully elucidated in patients with treatment-resistant schizophrenia. The objective of this study was to examine the efficacy and safety of sertindole, compared to risperidone, in this patient population. In this multicenter, phase 3, randomized, double-blind, parallel-group study, only patients with DSM-IV schizophrenia who had failed an adequate antipsychotic treatment within the previous 6 months and who had not responded positively to haloperidol during screening were eligible for enrollment. The primary efficacy variable was change in Positive and Negative Syndrome Scale (PANSS) from baseline to final assessment. Weekly assessments included the PANSS, the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and the Clinical Global Impressions (CGI) scale. The study was conducted between June 1996 and April 1998. Of the 321 patients randomly assigned to double-blind treatment, 217 patients completed the study (sertindole, n/n = 142/216 [66%]; risperidone, n/n = 75/105 [71%]). The main reason for withdrawal in both groups was ineffective therapy. The between-group difference in PANSS total score was not statistically significant and both groups showed improvement, with mean changes of -18.6 in the sertindole group and -20.9 in the risperidone group based on observed cases and -12.0 and -19.0, respectively, based on the last-observation-carried-forward method for inputing missing data. There were no statistically significant differences between the groups in any of the secondary end points: PANSS positive and negative subscales, CGI scores, BPRS total scores and positive symptom subscale scores, and SANS total scores. Patients reported similar levels of adverse events and treatment-emergent adverse events (TEAEs), except for extrapyramidal syndrome-related TEAEs, which were more common in the risperidone-treated group. Prolongation of the QTc interval was observed significantly more frequently with sertindole treatment. Sertindole and risperidone are effective and well-tolerated in patients with treatment-resistant schizophrenia. Sertindole offers an alternative treatment option for refractory patients in Europe given its good EPS profile, favorable metabolic profile, and comparable efficacy to risperidone.


Deoxycytidine: a morphine antagonist.
Deoxycytidine antagonizes the analgesic action of morphine in the rat, morphine-induced respiratory depression in the rabbit and mitigates withdrawal in the dependent mouse. Administration of deoxycytidine does not precipitate the abstinence syndrome in dependent mice, a property shared by certain other endogenous morphine antagonsits. Cytidine and thymidine closely related in structure to deoxycytidine, are interchangeable with saline as controls, indicating a high degree of specificity in the receptor involved in the "action-effects" sequence. The requirement for deoxycytidine in countering the effects of morphine parallels the requirement for certain other DNA pyrimidines in the antagonism of barbiturate and alcohol. The rapidity of antogonist action suggests that such a DNA species would presumably be localized in the synaptosome, at outer membrane or the synaptic junction.


Reactivity of avian RNA tumor viruses with lectins.
The infectivity of avian RNA tumor viruses was inactivated to varying degrees by treatment with either concanavalin A (Con A) or phytohemagglutinin but not by treatment with wheat germ agglutinin. In general, leukosis viruses reacted preferentially with Con A, whereas sarcoma viruses showed more affinity for phytohemagglutinin. In a more extensive study with subgroup A of Prague Rous sarcoma virus (PR-A), the effect of inactivation by Con A could be specifically prevented by the addition of alpha-methyl-D-mannoside, alpha-methyl-D-glucoside, and N-acetyl-D-glucosamine. These sugars were also capable of eluting [3H]glucosamine-labeled material from disrupted PR-A virus, which was bound to a Con A-sepharose affinity column. A major viral glycoprotein recovered from the column had the same mobility as gp85 in polyacrylamide gel electrophoresis and could be immunoprecipitated with anti-gp85 antiserum. These results suggest that the material reacting with Con A is present on the gp85 component of the viral glycoprotein. The diversity in the reactivity of the glycoproteins of transforming and nontransforming viruses with plant lectins is discussed.


Increased excitatory synaptic input to granule cells from hilar and CA3 regions in a rat model of temporal lobe epilepsy.
One potential mechanism of temporal lobe epilepsy is recurrent excitation of dentate granule cells through aberrant sprouting of their axons (mossy fibers), which is found in many patients and animal models. However, correlations between the extent of mossy fiber sprouting and seizure frequency are weak. Additional potential sources of granule cell recurrent excitation that would not have been detected by markers of mossy fiber sprouting in previous studies include surviving mossy cells and proximal CA3 pyramidal cells. To test those possibilities in hippocampal slices from epileptic pilocarpine-treated rats, laser-scanning glutamate uncaging was used to randomly and focally activate neurons in the granule cell layer, hilus, and proximal CA3 pyramidal cell layer while measuring evoked EPSCs in normotopic granule cells. Consistent with mossy fiber sprouting, a higher proportion of glutamate-uncaging spots in the granule cell layer evoked EPSCs in epileptic rats compared with controls. In addition, stimulation spots in the hilus and proximal CA3 pyramidal cell layer were more likely to evoke EPSCs in epileptic rats, despite significant neuron loss in those regions. Furthermore, synaptic strength of recurrent excitatory inputs to granule cells from CA3 pyramidal cells and other granule cells was increased in epileptic rats. These findings reveal substantial levels of excessive, recurrent, excitatory synaptic input to granule cells from neurons in the hilus and proximal CA3 field. The aberrant development of these additional positive-feedback circuits might contribute to epileptogenesis in temporal lobe epilepsy.


Mutual solubilities of water and hydrophobic ionic liquids.
The ionic nature of ionic liquids (ILs) results in a unique combination of intrinsic properties that produces increasing interest in the research of these fluids as environmentally friendly "neoteric" solvents. One of the main research fields is their exploitation as solvents for liquid-liquid extractions, but although ILs cannot vaporize leading to air pollution, they present non-negligible miscibility with water that may be the cause of some environmental aquatic risks. It is thus important to know the mutual solubilities between ILs and water before their industrial applications. In this work, the mutual solubilities of hydrophobic yet hygroscopic imidazolium-, pyridinium-, pyrrolidinium-, and piperidinium-based ILs in combination with the anions bis(trifluoromethylsulfonyl)imide, hexafluorophosphate, and tricyanomethane with water were measured between 288.15 and 318.15 K. The effect of the ILs structural combinations, as well as the influence of several factors, namely cation side alkyl chain length, the number of cation substitutions, the cation family, and the anion identity in these mutual solubilities are analyzed and discussed. The hydrophobicity of the anions increases in the order [C(CN)(3)] < [PF(6)] < [Tf(2)N] while the hydrophobicity of the cations increases from [C(n)mim] < [C(n)mpy] < or = [C(n)mpyr] < [C(n)mpip] and with the alkyl chain length increase. From experimental measurements of the temperature dependence of ionic liquid solubilities in water, the thermodynamic molar functions of solution, such as Gibbs energy, enthalpy, and entropy at infinite dilution were determined, showing that the solubility of these ILs in water is entropically driven and that the anion solvation at the IL-rich phase controls their solubilities in water. The COSMO-RS, a predictive method based on unimolecular quantum chemistry calculations, was also evaluated for the description of the water-IL binary systems studied, where it showed to be capable of providing an acceptable qualitative agreement with the experimental data.


Azúcar y nervios: explanatory models and treatment experiences of Hispanics with diabetes and depression.
This study examined the explanatory models of depression, perceived relationships between diabetes and depression, and depression treatment experiences of low-income, Spanish-speaking, Hispanics with diabetes and depression. A purposive sample (n=19) was selected from participants enrolled in a randomized controlled trial conducted in Los Angeles, California (United States) testing the effectiveness of a health services quality improvement intervention. Four focus groups followed by 10 in-depth semi-structured qualitative interviews were conducted. Data were analyzed using the methodology of coding, consensus, co-occurrence, and comparison, an analytical strategy rooted in grounded theory. Depression was perceived as a serious condition linked to the accumulation of social stressors. Somatic and anxiety-like symptoms and the cultural idiom of nervios were central themes in low-income Hispanics' explanatory models of depression. The perceived reciprocal relationships between diabetes and depression highlighted the multiple pathways by which these two illnesses impact each other and support the integration of diabetes and depression treatments. Concerns about depression treatments included fears about the addictive and harmful properties of antidepressants, worries about taking too many pills, and the stigma attached to taking psychotropic medications. This study provides important insights about the cultural and social dynamics that shape low-income Hispanics' illness and treatment experiences and support the use of patient-centered approaches to reduce the morbidity and mortality associated with diabetes and depression.


Reduced stability of mRNA secondary structure near the translation-initiation site in dsDNA viruses.
Recent studies have demonstrated a selection pressure for reduced mRNA secondary-structure stability near the start codon of coding sequences. This selection pressure can be observed in bacteria, archaea, and eukaryotes, and is likely caused by the requirement of efficient translation initiation in cellular organism. Here, we surveyed the complete genomes of 650 dsDNA virus strains for signals of reduced stability of mRNA secondary structure near the start codon. Our analysis included viruses infecting eukaryotic, prokaryotic, and archaeic hosts. We found that many viruses showed evidence for reduced mRNA secondary-structure stability near the start codon. The effect was most pronounced in viruses infecting prokaryotes, but was also observed in viruses infecting eukaryotes and archaea. The reduction in stability generally increased with increasing genomic GC content. For bacteriophage, the reduction was correlated with a corresponding reduction of stability in the phage hosts. We conclude that reduced stability of the mRNA secondary structure near the start codon is a common feature for dsDNA viruses, likely driven by the same selective pressures that cause it in cellular organisms.


Construction of homogeneous antibody-drug conjugates using site-selective protein chemistry.
Systemic chemotherapy, the current standard of care for the treatment of cancer, is rarely curative and is often accompanied by debilitating side effects. Targeted drug delivery stands as an alternative to chemotherapy, with the potential to improve upon its low efficacy and systemic toxicity. Among targeted therapeutic options, antibody-drug conjugates (ADCs) have emerged as the most promising. These conjugates represent a new class of biopharmaceuticals that selectively deliver potent cytotoxic drugs to cancer cells, sparing healthy tissue throughout the body. Despite this promise, early heterogenous ADCs suffered from stability, pharmacokinetic, and efficacy issues that hindered clinical development. Recent advances in antibody engineering, linkers for drug-release, and chemical site-selective antibody conjugation have led to the creation of homogenous ADCs that have proven to be more efficacious than their heterogeneous predecessors both in vitro and in vivo. In this minireview, we focus on and discuss recent advances in chemical site-selective modification strategies for the conjugation of drugs to antibodies and the resulting potential for the development of a new generation of homogenous ADCs.


Cost-effectiveness of interventions to prevent alcohol-related disease and injury in Australia.
To evaluate cost-effectiveness of eight interventions for reducing alcohol-attributable harm and determine the optimal intervention mix. Interventions include volumetric taxation, advertising bans, an increase in minimum legal drinking age, licensing controls on operating hours, brief intervention (with and without general practitioner telemarketing and support), drink driving campaigns, random breath testing and residential treatment for alcohol dependence (with and without naltrexone). Cost-effectiveness is modelled over the life-time of the Australian population in 2003, with all costs and health outcomes evaluated from an Australian health sector perspective. Each intervention is compared with current practice, and the most cost-effective options are then combined to determine the optimal intervention mix. Cost-effectiveness is measured in 2003 Australian dollars per disability adjusted life year averted. Although current alcohol intervention in Australia (random breath testing) is cost-effective, if the current spending of $71 million could be invested in a more cost-effective combination of interventions, more than 10 times the amount of health gain could be achieved. Taken as a package of interventions, all seven preventive interventions would be a cost-effective investment that could lead to substantial improvement in population health; only residential treatment is not cost-effective. Based on current evidence, interventions to reduce harm from alcohol are highly recommended. The potential reduction in costs of treating alcohol-related diseases and injuries mean that substantial improvements in population health can be achieved at a relatively low cost to the health sector.


Two-dimensional spatiotemporal coding of linear acceleration in vestibular nuclei neurons.
Response properties of vertical (VC) and horizontal (HC) canal/otolith-convergent vestibular nuclei neurons were studied in decerebrate rats during stimulation with sinusoidal linear accelerations (0.2-1.4 Hz) along different directions in the head horizontal plane. A novel characteristic of the majority of tested neurons was the nonzero response often elicited during stimulation along the "null" direction (i.e., the direction perpendicular to the maximum sensitivity vector, Smax). The tuning ratio (Smin gain/Smax gain), a measure of the two-dimensional spatial sensitivity, depended on stimulus frequency. For most vestibular nuclei neurons, the tuning ratio was small at the lowest stimulus frequencies and progressively increased with frequency. Specifically, HC neurons were characterized by a flat Smax gain and an approximately 10-fold increase of Smin gain per frequency decade. Thus, these neurons encode linear acceleration when stimulated along their maximum sensitivity direction, and the rate of change of linear acceleration (jerk) when stimulated along their minimum sensitivity direction. While the Smax vectors were distributed throughout the horizontal plane, the Smin vectors were concentrated mainly ipsilaterally with respect to head acceleration and clustered around the naso-occipital head axis. The properties of VC neurons were distinctly different from those of HC cells. The majority of VC cells showed decreasing Smax gains and small, relatively flat, Smin gains as a function of frequency. The Smax vectors were distributed ipsilaterally relative to the induced (apparent) head tilt. In type I anterior or posterior VC neurons, Smax vectors were clustered around the projection of the respective ipsilateral canal plane onto the horizontal head plane. These distinct spatial and temporal properties of HC and VC neurons during linear acceleration are compatible with the spatiotemporal organization of the horizontal and the vertical/torsional ocular responses, respectively, elicited in the rat during linear translation in the horizontal head plane. In addition, the data suggest a spatially and temporally specific and selective otolith/canal convergence. We propose that the central otolith system is organized in canal coordinates such that there is a close alignment between the plane of angular acceleration (canal) sensitivity and the plane of linear acceleration (otolith) sensitivity in otolith/canal-convergent vestibular nuclei neurons.


Commentary on "Autism, oxytocin and interoception": Alexithymia, not Autism Spectrum Disorders, is the consequence of interoceptive failure.
In "Autism, oxytocin and interoception" (Neuroscience and Biobehavioral Reviews 47, 410-430) Quattrocki and Friston present their theory of the role of oxytocin in interoception from multiple perspectives. The arguments contained therein are compelling, and highlight the fact that interoception, and the role of oxytocin in interoception, should receive more research attention. However, in addition to outlining the role of oxytocin in interoception the authors also suggest that Autism Spectrum Disorder (ASD) is a result of a failure of this system. It is this latter claim that we disagree with, instead suggesting that alexithymia, rather than autism, is most accurately characterised as a general failure of interoception. We review positive evidence that alexithymia produces several of the deficits identified as indicating a failure of interoception, and negative evidence that ASD (in the absence of comorbid alexithymia) is associated with these deficits. We highlight implications for the model, for oxytocin research, and for the clinical management of psychiatric conditions more generally.


Existing capacity to manage pharmaceuticals and related commodities in East Africa: an assessment with specific reference to antiretroviral therapy.
East African countries have in the recent past experienced a tremendous increase in the volume of antiretroviral drugs. Capacity to manage these medicines in the region remains limited. Makerere University, with technical assistance from the USAID supported Rational Pharmaceutical Management Plus (RPM Plus) Program of Management Sciences for Health (MSH) established a network of academic institutions to build capacity for pharmaceutical management in the East African region. The initiative includes institutions from Uganda, Tanzania, Kenya and Rwanda and aims to improve access to safe, effective and quality-assured medicines for the treatment of HIV/AIDS, TB and Malaria through spearheading in-country capacity. The initiative conducted a regional assessment to determine the existing capacity for the management of antiretroviral drugs and related commodities. Heads and implementing workers of fifty HIV/AIDS programs and institutions accredited to offer antiretroviral services in Uganda, Kenya, Tanzania and Rwanda were key informants in face-to-face interviews guided by structured questionnaires. The assessment explored categories of health workers involved in the management of ARVs, their knowledge and practices in selection, quantification, distribution and use of ARVs, nature of existing training programs, training preferences and resources for capacity building. Inadequate human resource capacity including, inability to select, quantify and distribute ARVs and related commodities, and irrational prescribing and dispensing were some of the problems identified. A competence gap existed in all the four countries with a variety of healthcare professionals involved in the supply and distribution of ARVs. Training opportunities and resources for capacity development were limited particularly for workers in remote facilities. On-the-job training and short courses were the preferred modes of training. There is inadequate capacity for managing medicines and related commodities in East Africa. There is an urgent need for training in aspects of pharmaceutical management to different categories of health workers. Skills building activities that do not take healthcare workers from their places of work are preferred.


Bimodular auxin response controls organogenesis in Arabidopsis.
Like animals, the mature plant body develops via successive sets of instructions that determine cell fate, patterning, and organogenesis. In the coordination of various developmental programs, several plant hormones play decisive roles, among which auxin is the best-documented hormonal signal. Despite the broad range of processes influenced by auxin, how such a single signaling molecule can be translated into a multitude of distinct responses remains unclear. In Arabidopsis thaliana, lateral root development is a classic example of a developmental process that is controlled by auxin at multiple stages. Therefore, we used lateral root formation as a model system to gain insight into the multifunctionality of auxin. We were able to demonstrate the complementary and sequential action of two discrete auxin response modules, the previously described Solitary Root/indole-3-Acetic Acid (IAA)14-Auxin Response Factor (ARF)7-ARF19-dependent lateral root initiation module and the successive Bodenlos/IAA12-Monopteros/ARF5-dependent module, both of which are required for proper organogenesis. The genetic framework in which two successive auxin response modules control early steps of a developmental process adds an extra dimension to the complexity of auxin's action.


Expert Programmers Have Fine-Tuned Cortical Representations of Source Code.
Expertise enables humans to achieve outstanding performance on domain-specific tasks, and programming is no exception. Many studies have shown that expert programmers exhibit remarkable differences from novices in behavioral performance, knowledge structure, and selective attention. However, the underlying differences in the brain of programmers are still unclear. We here address this issue by associating the cortical representation of source code with individual programming expertise using a data-driven decoding approach. This approach enabled us to identify seven brain regions, widely distributed in the frontal, parietal, and temporal cortices, that have a tight relationship with programming expertise. In these brain regions, functional categories of source code could be decoded from brain activity and the decoding accuracies were significantly correlated with individual behavioral performances on a source-code categorization task. Our results suggest that programming expertise is built on fine-tuned cortical representations specialized for the domain of programming.


Evaluating skin care problems in people with stomas.
This study aimed to identify actual and potential peristomal skin problems in relation to the use of different types of stoma appliances and accessories. It also compared ostomists' perceptions of their peristomal skin condition with those of stoma care nurse specialists. Maintaining skin integrity is a basic skill that ensures good stoma management. It is widely accepted that from time to time a patient with a stoma will seek clinical advice about a peristomal skin problem. Little is known about how often patients present with these problems, the clinical course of peristomal skin problems, and how patients manage them. A multi-centred descriptive study was conducted among 80 ostomists. Fieldwork took place over 13 months. The sample was drawn from a UK home care delivery database. Using structured questionnaires, ostomists were interviewed by a stoma care nurse specialist. A digital photograph was taken of their peristomal skin and their answers compared with nurse assessment using the Stoma Care Ostomy Research index scoring system. Of the interviewees 32% had healthy peristomal skin both via questionnaire and at observation. At observation, 68% were observed to have peristomal skin problems, of whom 44% had irritated skin, 12% had ulcerated skin, 9% had an apparent allergy and 3% had macerated/eroded skin. In addition, 21% had an ill-fitting appliance at observation. Half (50%) were observed to have a parastomal hernia, although only 24% reported having one. These findings demonstrate significant differences between the perception of skin problems among ostomists and actual skin problems observed by stoma care nurse specialists. Peristomal skin problems are common among ostomists. The difference between ostomists' and nurses' perceptions of peristomal skin condition led to the identification of educational needs for the new ostomist. Education and regular follow-up by the stoma care nurse specialist is imperative.


Open reduction internal fixation has fewer short-term complications than shoulder arthroplasty for proximal humeral fractures.
Open reduction and internal fixation (ORIF), hemiarthroplasty (HA), and anatomic or reverse total shoulder arthroplasty (TSA/RTSA) are surgical treatment options for proximal humeral fractures (PHFx). Little is known about comparative complication rates. We aimed to determine whether ORIF for PHFx has fewer 30-day complications than HA and TSA/RTSA and to define independent risk factors for 30-day complications. Patients who underwent ORIF, HA, or TSA/RTSA for PHFx between 2006 and 2013 were identified from the National Surgical Quality Improvement Program database. Potential patient and surgical risk factors and 30-day postoperative complications were extracted. Univariate and multivariate analyses were conducted. We identified 1791 patients (1262 ORIF, 404 HA, and 125 TSA/RTSA). The overall complication rate was 13.0% in ORIF, 22.0% in HA, and 23.2% in TSA/RTSA (P < .001), driven primarily by rates of blood transfusion. Multivariate analyses demonstrated ORIF was an independent protective factor against minor complications (P = .009) and overall complications (P = .028) but not against major complications (P = .351). Risk factors for overall complications included preoperative sepsis (P < .001), higher American Society of Anesthesiologists Physical Status Classification (P < .001), dependent functional status (P = .002), transfusion of at least 5 units in the 72 hours before surgery (P = .002), longer operative time (P = .003), and a history of chronic obstructive pulmonary disease (P = .028). After adjusting for patient factors, ORIF for PHFx remains an independent protective factor against overall complications and minor complications compared with HA and TSA/RTSA, primarily due to lower rates of blood transfusion. Patient comorbidities play a larger role than the procedure selected in predicting short-term complications.


Preparation of iridescent colloidal crystal coatings with variable structural colors.
Iridescent colloidal crystal coatings with variable structural colors were fabricated by incorporating carbon black nanoparticles (CB-NPs) into the voids of polystyrene (PS) colloidal crystals. The structural color of the colloid crystal coatings was not only greatly enhanced after the composition but also varied with observation angles. By changing the diameter of monodisperse PS colloids in the composites, colloidal crystal coatings with three primary colors for additive or subtractive combination were obtained. After incorporation of the PS/CB-NPs hybrid coatings into polydimethylsiloxane (PDMS) matrix, manmade opal jewelry with variable iridescent colors was made facilely.


Functional epitope analysis of the human CD4 molecule. The MHC class II-dependent activation of resting T cells is inhibited by monoclonal antibodies to CD4 regardless whether or not they recognize epitopes involved in the binding of MHC class II or HIV gp120.
This study was designed to define regions on the human CD4 molecule important for the class II-dependent activation of resting, polyclonal CD4 T cells. With the use of mAb to known epitopes on CD4, we assayed the degree of CD4 saturation and functional effects on T cell activation over a range of antibody concentrations in parallel titration experiments. This approach allows a quantitative comparison of different reagents, regardless of parameters such as affinity for CD4. In sharp contrast to results reported for preactivated T cells and CD4 transfected T cell hybridomas, all 22 CD4 mAb tested did inhibit proliferative responses of freshly isolated CD4 T cells to MHC class II Ag. At the lowest saturating concentration of each antibody, T cell proliferation was reduced by 45 to 82%. Inhibition did not depend on antibody-induced modulation of CD4 expression. Strikingly, no correlation was found between the functional effects and the specificity of the mAb for different epitopes on CD4, such as the putative binding sites for MHC class II or HIV glycoprotein gp120.


Selectivity for multiple stimulus features in retinal ganglion cells.
Under normal viewing conditions, retinal ganglion cells transmit to the brain an encoded version of the visual world. The retina parcels the visual scene into an array of spatiotemporal features, and each ganglion cell conveys information about a small set of these features. We study the temporal features represented by salamander retinal ganglion cells by stimulating with dynamic spatially uniform flicker and recording responses using a multi-electrode array. While standard reverse correlation methods determine a single stimulus feature--the spike-triggered average--multiple features can be relevant to spike generation. We apply covariance analysis to determine the set of features to which each ganglion cell is sensitive. Using this approach, we found that salamander ganglion cells represent a rich vocabulary of different features of a temporally modulated visual stimulus. Individual ganglion cells were sensitive to at least two and sometimes as many as six features in the stimulus. While a fraction of the cells can be described by a filter-and-fire cascade model, many cells have feature selectivity that has not previously been reported. These reverse models were able to account for 80-100% of the information encoded by ganglion cells.


Human rhinoviruses in Chinese adults with acute respiratory tract infection.
To evaluate the roles of human rhinoviruses (HRVs) in acute respiratory tract infections (ARTIs) in Chinese adults and determine the association between species of HRV and clinical presentations. RT-PCR methods were used to detect HRVs in throat and nasal swabs collected from 6104 adult patients with ARTIs from December 2005 to April 2008 in Beijing, China. HRV strains were detected in 271 ARTIs cases, 65% of which tested positive for HRV-A, 25% for HRV-B, and 10% for HRV-C. Aside from fever, pharyngeal congestion and headache were the most common clinical symptoms observed in the HRVs infected patients. HRV-A infected patients had a higher percentage of upper respiratory symptoms than patients infected by the two other HRV species. Systemic symptoms such as chilliness and myalgia were more frequent in people infected by HRV-B. The three HRV species exhibited unique infection timing when analyzed monthly. HRV-C can be detected in adult patients with acute upper respiratory tract infections, but is not the predominant species in this population.


CCN1, a candidate target for zoledronic acid treatment in breast cancer.
CCN1, also known as CYR61, is a survival and proangiogenic factor overexpressed in about 30% of invasive breast carcinomas, and particularly in triple-negative breast carcinomas (TNBC). CCN1 expression in breast cancer promotes tumorigenicity, metastasis, antihormone, and chemoresistance. TNBCs often develop bone metastasis, thus the vast majority of patients receive bisphosphonate treatment as a companion to chemotherapy. Zoledronic acid (ZOL), a bisphosphonate currently in use, inhibits bone resorption, prevents development of new osteolytic lesions induced by tumor metastasis, and has a direct antitumor activity in breast cancer cells and tumors. We have shown that ZOL inhibits anchorage independent growth as well as branching and morphogenesis in CCN1 overexpressing cells. However, the mechanism is not yet well understood. In this study, we investigate the effect of ZOL in breast cancer cells with high and undetectable CCN1 expression levels. We show that CCN1-expressing cells are more sensitive to ZOL, that ZOL induces downregulation of the CCN1 promoter activity and CCN1 protein expression in a dose-dependent manner, and that ZOL is associated with a decrease in phosphorylated Akt and translocation of FOXO3a, a negative regulator of CCN1 expression, to the nucleus. Deletion of the FOXO3a binding site in the CCN1 promoter prevents ZOL inhibition of the CCN1 promoter activity showing that FOXO3a transcriptional activation is necessary for ZOL to induce CCN1 inhibition. This study provides evidence that ZOL targets the proangiogenic factor (CCN1) through FOXO3a and reveals a new mechanism of ZOL action in breast cancer cells.