C-reactive protein as a predictor of chorioamnionitis.
Chorioamnionitis (CAM) affects many pregnancies complicated by preterm premature rupture of membranes (PPROM). Finding a serum factor that could accurately predict the presence of CAM could potentially lead to more efficient management of PPROM and improved neonatal outcomes. To determine if C-reactive protein (CRP) is an effective early marker of CAM in patients with PPROM. A retrospective evaluation of pregnant women with PPROM at Geisinger Medical Center in Danville, Pennsylvania, between January 2005 and January 2009. Nonparametric statistical tests (ie, Wilcoxon rank sum and Spearman rank correlation) were used to compare distributions that were skewed. Characteristics of the study population were compared using 2-sample t tests for continuous variables and Fisher exact tests for discrete variables. Logistic regression analysis was used to generate receiver operating characteristic curves and obtain area under the curve estimates in stepwise fashion for predicting histologic CAM. A secondary analysis compared the characteristics among patients with clinical CAM, histologic CAM, or non-CAM. The total population of 73 women was subdivided into patients with histologic CAM (n=26) and patients without histologic CAM (ie, no evidence of CAM on placental pathology; n=47). There was no difference between groups in CRP levels, days of pregnancy latency, white blood cell count, smoking status, antibiotic administration, or steroid benefit. The group with histologic CAM delivered at earlier gestational ages: mean (standard deviation) age was 29.5 (4.4) weeks vs 31.9 (3.5) weeks (P=.02). For our primary analysis, we found no difference in CRP levels (P=.32). Receiver operating characteristic curve plots of CRP levels, temperature at delivery, and white blood cell count resulted in an area under the curve estimate of 0.696, which was 70% predictive of histologic CAM. In the secondary analysis, after adjusting for gestational age, the estimated hazard ratio for CRP change was 1.05 (95% confidence interval, 1.02-1.08; P=.001). Therefore, increasing CRP levels from PPROM was statistically significant in predicting clinical CAM development over time. C-reactive protein levels were not effective independent predictors of clinical or histologic CAM, nor was sequential CRP testing statistically significant for the identification of clinical or histologic CAM in patients with PPROM.


Assessment of 3D DCE-MRI of the kidneys using non-rigid image registration and segmentation of voxel time courses.
We have applied automated image analysis methods in the assessment of human kidney perfusion based on 3D dynamic contrast-enhanced MRI data. This approach consists of non-rigid 3D image registration of the moving kidney followed by k-means clustering of the voxel time courses with split between left and right kidney. This method was applied to four data sets acquired from healthy volunteers, using 1.5 T (2 exams) and 3 T scanners (2 exams). The proposed registration method reduced motion artifacts in the image time series and improved further analysis of the DCE-MRI data. The subsequent clustering to segment the kidney compartments was in agreement with manually delineations (similarity score of 0.96) in the same motion corrected images. The resulting mean intensity time curves clearly show the successive transition of contrast agent through kidney compartments (cortex, medulla, and pelvis). The proposed method for motion correction and kidney compartment segmentation might improve the validity and usefulness of further model-based pharmacokinetic analysis of kidney function in patients.


Functional outcome and complications following surgery for Dupuytren's disease: a multi-centre cross-sectional study.
Variables associated with recurrent Dupuytren's disease, or a 'diathesis', have been investigated, but those associated with functional outcome and complications are less well studied. Outcomes 1 or 5 years after an aponeurotomy, fasciectomy or dermofasciectomy were assessed by patient interview and examination at five UK centres. A total of 432 procedures were studied. The reoperation rate did not differ at 1 year ( p = 0.396, Chi-square test with Monte Carlo simulation), but was higher after aponeurotomy in the 5-year group (30%, versus 6% after fasciectomy and 0% after dermofasciectomy, p = 0.003, Chi square test with Monte Carlo simulation). Loss of function (DASH>15) did not differ between procedures at 5 years, even when reoperation and other variables were controlled. Diabetes, female gender and previous ipsilateral surgery were associated with poorer function in logistic regression analysis. The variables associated with poor function after treatments differ from diathesis variables. Aponeurotomy had lower complication rates than fasciectomy and dermofasciectomy. This may counterbalance the former's higher recurrence rate and explain why aponeurotomy demonstrated similar long-term functional outcome compared with excisional surgery in this study. III.


Population-Based Assessment of Determining Treatments for Prostate Cancer.
Many men with indolent prostate cancer often opt for radical prostatectomy or radiotherapy treatment for their disease. These men may experience considerable detriments of quality of life owing to sexual, urinary, and/or rectal toxic effects associated with these treatments. Without a better understanding of the mutable agents and predictors of treatment types, diffusion of expectant management among these men will be slow. To determine population-based predictors for treatment and use of watchful waiting or active surveillance for indolent prostate cancer. We used Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data. A total of 37,621 men in the general community diagnosed as having prostate cancer from 2004 to 2007 were followed until December 31, 2009. Watchful waiting or active surveillance, radiation therapy, or radical prostatectomy. We used mixed-effects logistic regression analysis to determine the factors associated with aggressive treatment and use of watchful waiting or active surveillance for men with prostate cancer. The most common treatment type is radiation therapy (57.9% [95% CI, 57.4%-58.4%]), followed by radical prostatectomy (19.1% [95% CI, 18.7%-19.5%]) and watchful waiting or active surveillance (9.6% [95% CI, 9.3%-9.9%]). Moreover, patients and providers significantly integrate age (odds ratio [OR], 0.32 [95% CI, 0.29-0.35]) and comorbidities (OR, 0.62 [95% CI, 0.56-0.68]) when determining radical prostatectomy, while regional variation (OR, 0.57 [95% CI, 0.47-0.68]) and referral patterns (OR, 44.46 [95% CI, 41.04-48.17]) influence the use of radiation therapy. Patient demographics and tumor characteristics significantly account for 40% of patients undergoing prostatectomy, 12% choosing watchful waiting or active surveillance, and only 3% undergoing radiotherapy. There is increased use of radiotherapy among patients with indolent prostate cancer with limited to no correlation with tumor biology. Active surveillance was underused, and a significant proportion of the variance was unexplained. Further research into qualitatively describing the contributing factors that drive decision-making recommendations for prostate cancer patients is needed.


Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery.
Preliminary reports of studies involving simple coronary lesions indicate that a sirolimus-eluting stent significantly reduces the risk of restenosis after percutaneous coronary revascularization. We conducted a randomized, double-blind trial comparing a sirolimus-eluting stent with a standard stent in 1058 patients at 53 centers in the United States who had a newly diagnosed lesion in a native coronary artery. The coronary disease in these patients was complex because of the frequent presence of diabetes (in 26 percent of patients), the high percentage of patients with longer lesions (mean, 14.4 mm), and small vessels (mean, 2.80 mm). The primary end point was failure of the target vessel (a composite of death from cardiac causes, myocardial infarction, and repeated percutaneous or surgical revascularization of the target vessel) within 270 days. The rate of failure of the target vessel was reduced from 21.0 percent with a standard stent to 8.6 percent with a sirolimus-eluting stent (P<0.001)--a reduction that was driven largely by a decrease in the frequency of the need for revascularization of the target lesion (16.6 percent in the standard-stent group vs. 4.1 percent in the sirolimus-stent group, P<0.001). The frequency of neointimal hyperplasia within the stent was also decreased in the group that received sirolimus-eluting stents, as assessed by both angiography and intravascular ultrasonography. Subgroup analyses revealed a reduction in the rates of angiographic restenosis and target-lesion revascularization in all subgroups examined. In this randomized clinical trial involving patients with complex coronary lesions, the use of a sirolimus-eluting stent had a consistent treatment effect, reducing the rates of restenosis and associated clinical events in all subgroups analyzed.


Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice.
Intraneuronal alpha-synuclein (alphaSYN) inclusions constitute the hallmark lesions of a number of neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies. In a transgenic mouse model expressing mutant [A30P]alphaSYN under control of the pan-neuronal Thy1 promoter, motor impairment became significant beyond 17 months of age. Cognitive performance was measured in the Morris water maze and upon fear conditioning. At 4 months of age, transgenic mice performed like controls. However, performance in these tasks was significantly impaired in (Thy1)-h[A30P]alphaSYN mice at 12 months of age. After completion of the cognition tests, mice were sacrificed and the regional distribution of neuropathology was examined. In contrast to 4 months old animals, 12 months old transgenic mice showed alpha-synucleinopathy in several brain regions, including the central nucleus of the amygdala, which is involved in cognitive behavior of mice, and is susceptible to alphaSYN pathology in human patients. Thus, age-dependent fibrillization of alphaSYN in specific cortical regions concomitant with cognitive decline may reflect dementia with Lewy bodies in a transgenic mouse model.


Cholera toxin B-subunit gene enhances mucosal immunoglobulin A, Th1-type, and CD8+ cytotoxic responses when coadministered intradermally with a DNA vaccine.
A plasmid vector encoding the cholera toxin B subunit (pCtB) was evaluated as an intradermal genetic adjuvant for a model DNA vaccine expressing the human papillomavirus type 16 L1 capsid gene (p16L1) in mice. p16L1 was coadministered with plasmid pCtB or commercial polypeptide CtB as a positive control. Coadministration of pCtB induced a significant increment of specific anti-L1 immunoglobulin A (IgA) antibodies in cervical secretions (P < 0.05) and fecal extracts (P < 0.005). Additionally, coadministration of pCtB enhanced the production of interleukin-2 and gamma interferon by spleen cells but did not affect the production of interleukin-4, suggesting a Th1-type helper response. Furthermore, improved CD8+ T-cell-mediated cytotoxic activity was observed in mice vaccinated with the DNA vaccine with pCtB as an adjuvant. This adjuvant effect was comparable to that induced by the CtB polypeptide. These results indicate that intradermal coadministration of pCtB is an adequate means to enhance the mucosa-, Th1-, and CD8(+)-mediated cytotoxic responses induced by a DNA vaccine.


A mu-rhythm matched filter for continuous control of a brain-computer interface.
A brain-computer interface (BCI) is a system that provides an alternate nonmuscular communication/control channel for individuals with severe neuromuscular disabilities. With proper training, individuals can learn to modulate the amplitude of specific electroencephalographic (EEG) components (e.g., the 8-12 Hz mu rhythm and 18-26 Hz beta rhythm) over the sensorimotor cortex and use them to control a cursor on a computer screen. Conventional spectral techniques for monitoring the continuous amplitude fluctuations fail to capture essential amplitude/phase relationships of the mu and beta rhythms in a compact fashion and, therefore, are suboptimal. By extracting the characteristic mu rhythm for a user, the exact morphology can be characterized and exploited as a matched filter. A simple, parameterized model for the characteristic mu rhythm is proposed and its effectiveness as a matched filter is examined online for a one-dimensional cursor control task. The results suggest that amplitude/phase coupling exists between the mu and beta bands during event-related desynchronization, and that an appropriate matched filter can provide improved performance.


Actin Mechanics and Fragmentation.
Cell physiological processes require the regulation and coordination of both mechanical and dynamical properties of the actin cytoskeleton. Here we review recent advances in understanding the mechanical properties and stability of actin filaments and how these properties are manifested at larger (network) length scales. We discuss how forces can influence local biochemical interactions, resulting in the formation of mechanically sensitive dynamic steady states. Understanding the regulation of such force-activated chemistries and dynamic steady states reflects an important challenge for future work that will provide valuable insights as to how the actin cytoskeleton engenders mechanoresponsiveness of living cells.


IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex.
Activation of the transcription factor NF-kappaB is controlled by the sequential phosphorylation, ubiquitination, and degradation of its inhibitory subunit, IkappaB. We recently purified a large multiprotein complex, the IkappaB kinase (IKK) signalsome, which contains two regulated IkappaB kinases, IKK1 and IKK2, that can each phosphorylate IkappaBalpha and IkappaBbeta. The IKK signalsome contains several additional proteins presumably required for the regulation of the NFkappaB signal transduction cascade in vivo. In this report, we demonstrate reconstitution of IkappaB kinase activity in vitro by using purified recombinant IKK1 and IKK2. Recombinant IKK1 or IKK2 forms homo- or heterodimers, suggesting the possibility that similar IKK complexes exist in vivo. Indeed, in HeLa cells we identified two distinct IKK complexes, one containing IKK1-IKK2 heterodimers and the other containing IKK2 homodimers, which display differing levels of activation following tumor necrosis factor alpha stimulation. To better elucidate the nature of the IKK signalsome, we set out to identify IKK-associated proteins. To this end, we purified and cloned a novel component common to both complexes, named IKK-associated protein 1 (IKKAP1). In vitro, IKKAP1 associated specifically with IKK2 but not IKK1. Functional analyses revealed that binding to IKK2 requires sequences contained within the N-terminal domain of IKKAP1. Mutant versions of IKKAP1, which either lack the N-terminal IKK2-binding domain or contain only the IKK2-binding domain, disrupt the NF-kappaB signal transduction pathway. IKKAP1 therefore appears to mediate an essential step of the NF-kappaB signal transduction cascade. Heterogeneity of IKK complexes in vivo may provide a mechanism for differential regulation of NF-kappaB activation.


Are occupational physical activities tailored to the age of cleaners and manufacturing workers?
An ageing population will necessitate people to work for longer. High occupational physical activities (OPA) are a well-documented barrier to sustainable employment. Blue-collar workers are at high risk for early exit from the labour market, which may be prevented by improved tailoring of OPA to the capacities of ageing workers. However, little is known about the current approaches used in blue collar workplaces. This study investigated age and OPA using objective field measurements in the cleaning and manufacturing sector. Associations were examined between age and percentage of working time of three OPA: total time on feet, standing still and walking, among 615 cleaners and manufacturing workers from the Danish Physical Activity cohort with Objective measurements (DPhacto). OPA were measured over 3-4 days with accelerometers. Regression modeling was used to investigate the relationship between age and the respective OPA stratified by the two sectors after adjustment for potential confounders. No tendency for negative associations between age and OPA were found for either sector. To the contrary, a positive association between age and high levels of time on feet was found for male manufacturing workers (OR 1.05; 95% CI 1.02-1.08 per year). Using objective measurements of OPA, this study found that OPA are not tailored to the age of workers. To the contrary, some older workers are more likely to have higher OPA. A need exists for further investigation and development of guidelines to support job design that will enable older workers to remain employed.


Caulking polydimethylsiloxane molecular networks by thermal chemical vapor deposition of Parylene-C.
Surface functionalization of polydimethylsiloxane (PDMS) is important in developing high-performance microfluidic devices. This work applied the thermal chemical vapor deposition (t-CVD) of Parylene-C onto PDMS to caulk the molecular network while retaining the original surface properties for the oxygen plasma bonding. The very low deposition rates (for example, a nominal rate of 0.12 Å min-1 at 135 °C) of Parylene-C at elevated substrate temperatures enabled the reactive Parylene-C monomers to penetrate into the PDMS matrix up to 4.6 ± 0.1 μm (135 °C), which was verified for the first time by a scanning electron microscope with an energy dispersive X-ray analysis (SEM-EDAX). The Parylene-C caulked in the molecular network of PDMS matrix guaranteed an excellent resistance to small molecule permeations. Meanwhile, only discrete nucleation islands were formed on the top surface rather than a continuous Parylene-C layer as observed under the AFM scan, which made the processed PDMS surface ready for device assembly. This surface functionalization method has better long-term stability than the other wet-type rivals. The barrier for oxygen plasma bonding in previously reported dry surface treatments was also avoided, thereby, facilitating the device assembly. The present work successfully developed a novel pcPDMS (Parylene-C caulked PDMS) technique, which overcame the bonding difficulty in the previous works but retained the low small molecule permeability as before. Caulking a molecular network through the t-CVD of Parylene-C also demonstrated a new strategy of functionalizing polymer surfaces and preparing new hybrid materials for wide lab-on-a-chip applications.


Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site.
About 10% of all protein kinases are predicted to be enzymatically inactive pseudokinases, but the structural details of kinase inactivation have remained unclear. We present the first structure of a pseudokinase, VRK3, and that of its closest active relative, VRK2. Profound changes to the active site region underlie the loss of catalytic activity, and VRK3 cannot bind ATP because of residue substitutions in the binding pocket. However, VRK3 still shares striking structural similarity with VRK2, and appears to be locked in a pseudoactive conformation. VRK3 also conserves residue interactions that are surprising in the absence of enzymatic function; these appear to play important architectural roles required for the residual functions of VRK3. Remarkably, VRK3 has an "inverted" pattern of sequence conservation: although the active site is poorly conserved, portions of the molecular surface show very high conservation, suggesting that they form key interactions that explain the evolutionary retention of VRK3.


Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease.
Mutations that disrupt centrosome biogenesis or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet, how centrosome dysfunction results in the kidney disease phenotypes remains unknown. Here, we examined the consequences of conditional knockout of the ciliopathy gene Cep120, essential for centrosome duplication, in the nephron and collecting duct progenitor niches of the mouse embryonic kidney. Cep120 loss led to reduced abundance of both cap mesenchyme and ureteric bud populations, due to a combination of delayed mitosis, increased apoptosis, and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis, and decline in kidney function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in pathways essential for development, fibrosis, and cystogenesis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney morphogenesis, and identifies new therapeutic targets for patients with renal centrosomopathies.


Migraine surgery: a plastic surgery solution for refractory migraine headache.
Migraine headache can be a debilitating condition that confers a substantial burden to the affected individual and to society. Despite significant advancements in the medical management of this challenging disorder, clinical data have revealed a proportion of patients who do not adequately respond to pharmacologic intervention and remain symptomatic. Recent insights into the pathogenesis of migraine headache argue against a central vasogenic cause and substantiate a peripheral mechanism involving compressed craniofacial nerves that contribute to the generation of migraine headache. Botulinum toxin injection is a relatively new treatment approach with demonstrated efficacy and supports a peripheral mechanism. Patients who fail optimal medical management and experience amelioration of headache pain after injection at specific anatomical locations can be considered for subsequent surgery to decompress the entrapped peripheral nerves. Migraine surgery is an exciting prospect for appropriately selected patients suffering from migraine headache and will continue to be a burgeoning field that is replete with investigative opportunities.


Development of a Highly Effective African Swine Fever Virus Vaccine by Deletion of the I177L Gene Results in Sterile Immunity against the Current Epidemic Eurasia Strain.
African swine fever virus (ASFV) is the etiological agent of a contagious and often lethal disease of domestic pigs that has significant economic consequences for the swine industry. The disease is devastating the swine industry in Central Europe and East Asia, with current outbreaks caused by circulating strains of ASFV derived from the 2007 Georgia isolate (ASFV-G), a genotype II ASFV. In the absence of any available vaccines, African swine fever (ASF) outbreak containment relies on the control and culling of infected animals. Limited cross-protection studies suggest that in order to ensure a vaccine is effective, it must be derived from the current outbreak strain or at the very least from an isolate with the same genotype. Here, we report the discovery that the deletion of a previously uncharacterized gene, I177L, from the highly virulent ASFV-G produces complete virus attenuation in swine. Animals inoculated intramuscularly with the virus lacking the I177L gene, ASFV-G-ΔI177L, at a dose range of 102 to 106 50% hemadsorbing doses (HAD50), remained clinically normal during the 28-day observational period. All ASFV-G-ΔI177L-infected animals had low viremia titers, showed no virus shedding, and developed a strong virus-specific antibody response; importantly, they were protected when challenged with the virulent parental strain ASFV-G. ASFV-G-ΔI177L is one of the few experimental vaccine candidate virus strains reported to be able to induce protection against the ASFV Georgia isolate, and it is the first vaccine capable of inducing sterile immunity against the current ASFV strain responsible for recent outbreaks.IMPORTANCE Currently, there is no commercially available vaccine against African swine fever. Outbreaks of this disease are devastating the swine industry from Central Europe to East Asia, and they are being caused by circulating strains of African swine fever virus derived from the Georgia 2007 isolate. Here, we report the discovery of a previously uncharacterized virus gene, which when deleted completely attenuates the Georgia isolate. Importantly, animals infected with this genetically modified virus were protected from developing ASF after challenge with the virulent parental virus. Interestingly, ASFV-G-ΔI177L confers protection even at low doses (102 HAD50) and remains completely attenuated when inoculated at high doses (106 HAD50), demonstrating its potential as a safe vaccine candidate. At medium or higher doses (104 HAD50), sterile immunity is achieved. Therefore, ASFV-G-ΔI177L is a novel efficacious experimental ASF vaccine protecting pigs from the epidemiologically relevant ASFV Georgia isolate.


Sleep: a biological stimulus from our nearest celestial neighbor?
Three studies have retrospectively analysed different data-sets to assess whether there is an effect of lunar phase upon human sleep. The results and conclusions differ. Until specifically designed experiments, controlling for key variables, are undertaken this issue will remain open.


Structural and evolutionary bioinformatics of the SPOUT superfamily of methyltransferases.
SPOUT methyltransferases (MTases) are a large class of S-adenosyl-L-methionine-dependent enzymes that exhibit an unusual alpha/beta fold with a very deep topological knot. In 2001, when no crystal structures were available for any of these proteins, Anantharaman, Koonin, and Aravind identified homology between SpoU and TrmD MTases and defined the SPOUT superfamily. Since then, multiple crystal structures of knotted MTases have been solved and numerous new homologous sequences appeared in the databases. However, no comprehensive comparative analysis of these proteins has been carried out to classify them based on structural and evolutionary criteria and to guide functional predictions. We carried out extensive searches of databases of protein structures and sequences to collect all members of previously identified SPOUT MTases, and to identify previously unknown homologs. Based on sequence clustering, characterization of domain architecture, structure predictions and sequence/structure comparisons, we re-defined families within the SPOUT superfamily and predicted putative active sites and biochemical functions for the so far uncharacterized members. We have also delineated the common core of SPOUT MTases and inferred a multiple sequence alignment for the conserved knot region, from which we calculated the phylogenetic tree of the superfamily. We have also studied phylogenetic distribution of different families, and used this information to infer the evolutionary history of the SPOUT superfamily. We present the first phylogenetic tree of the SPOUT superfamily since it was defined, together with a new scheme for its classification, and discussion about conservation of sequence and structure in different families, and their functional implications. We identified four protein families as new members of the SPOUT superfamily. Three of these families are functionally uncharacterized (COG1772, COG1901, and COG4080), and one (COG1756 represented by Nep1p) has been already implicated in RNA metabolism, but its biochemical function has been unknown. Based on the inference of orthologous and paralogous relationships between all SPOUT families we propose that the Last Universal Common Ancestor (LUCA) of all extant organisms contained at least three SPOUT members, ancestors of contemporary RNA MTases that carry out m1G, m3U, and 2'O-ribose methylation, respectively. In this work we also speculate on the origin of the knot and propose possible 'unknotted' ancestors. The results of our analysis provide a comprehensive 'roadmap' for experimental characterization of SPOUT MTases and interpretation of functional studies in the light of sequence-structure relationships.


Neonatal circumcision model and competency evaluation for family medicine residents.
Neonatal circumcision is one of the most common procedures performed by family physicians and is a recommended procedure for resident training. Few models or simulators exist. A model of neonatal genitalia was constructed using a cocktail wiener covered by a surgical glove finger. A competency checklist was used to review the steps of the procedure. Posttest/pretest-posttest assessment found significant improvement in knowledge and comfort in three groups of learners. Ninety percent of participants were deemed competent in all 15 areas of the checklist. The easily replicable model was felt to reasonably model the neonatal genitalia for circumcision training.


The negative impact of tobacco smoking on survival after prostate cancer diagnosis.
Tobacco smoking has been found to increase prostate cancer (PCa) mortality in cohorts of healthy men, but its effects on prognosis of men with PCa are still unclear. This study investigated the role of smoking on long-term survival after PCa diagnosis. A retrospective cohort including 780 men with incident PCa previously enrolled (between 1995 and 2002) as cases in an Italian case-control study. Information on vital status up to 2013 (median follow-up 13 years) and cause of death were retrieved through health archives. Hazard ratios (HRs) of all-cause and PCa-specific death, and corresponding 95 % confidence intervals (CIs), were calculated using Cox models, adjusting for Gleason score and major confounders. Out of 263 PCa deceased patients, 81 died because of PCa. Smokers at PCa diagnosis reported increased risks of all-cause (HR = 1.5, 95% CI 1.1-2.2) and PCa death (HR = 2.0, 95% CI 1.0-3.8), as compared to never smokers. Dose-response effects emerged according to smoking intensity (HRs for >15 cigarettes/day: 1.9, 95% CI 1.3-3.0, for all causes and 2.3, 95% CI 1.1-4.9, for PCa) and duration (HRs for >45 years: 1.7, 95% CI 1.1-2.6, for all causes and 2.6, 95% CI 1.2-5.5, for PCa). Conversely, former smokers at PCa diagnosis showed no statistically significant higher risks of PCa death. The effects of smoking were consistent in strata of Gleason score. Current smoking at PCa diagnosis negatively impacted PCa-specific, long-term survival, regardless of Gleason score. Our findings suggest that smoking could be a modifiable risk factor to improve prognosis of men diagnosed with PCa.


Development of an Instrument for Measuring Self-Care Behaviors After Left Ventricular Assist Device Implantation.
Successful long-term left ventricular assist device (LVAD) therapy necessitates a high degree of self-care. We aimed to develop an instrument that measures self-care behaviors in adult patients living with an LVAD. We used the method to develop patient-reported outcomes recommended by the US Food and Drug Administration. Prior to developing the instrument, a literature review was conducted to generate items using the middle-range theory of self-care of chronic illness as a guiding framework. A 2-round Delphi method, involving 17 clinicians with expertise in heart failure and assist devices from the Netherlands, Israel, United States, Canada, and Japan, was used to generate and select items. In the first Delphi survey, the levels of importance, relevance, and clarity of items in the instrument were evaluated. The second Delphi survey was performed to gain consensus on the final selection of items. We also examined face validity. A preliminary 37-item version of the Self-Care Behavior Scale was produced. The first panel judged 33 items as important and relevant, taking out 4 items due to vague wording and duplication and adding in 4 items. In the final 33-item version, 19 items address self-care maintenance behaviors, 10 items address self-care monitoring behaviors, and 4 items address self-care management behaviors. Patients (N = 25) did not have any difficulties understanding items and report any missing items. The 33-item Self-Care Behavior Scale for patients with heart failure having an LVAD has been developed and is ready for further psychometric testing.


Neck Trauma: ENT Prospects.
Neck trauma is a very important surgical emergency faced by ENT surgeons in day to day practice. They are potentially life threatening conditions due to the presence of many vital structures in this area. Timely presentation to the referral centre and proper multidisciplinary approach towards management plays a pivotal role in the healing pattern of the wound and prevention of serious complication like shock, sepsis, laryngeal stenosis or fistula formation. A retrospective study was done in ENT Department, NSCB Medical College, Jabalpur, Madhya Pradesh, India during the period of 2014-2016. 17 patients were included in the study. All the records regarding symptoms at presentation, type and mode of injury, level of injury were analyzed. Management plan undertaken were thoroughly studied and post operative complications like hoarseness, stenosis or fistula formation were noted carefully. 14 out of 17 patients were male, all 17 patients belonged to lower socioeconomic status. Most common age group presenting with neck trauma was between 22 and 40 years. 7 case were homicidal, 5 cases were suicidal and 4 were of accidental injury. Most cases reached hospital within 2-6 h of injury except 3 cases which took more than 8 h. Bleeding from wound site was most common symptom at presentation. Most injuries in 13 out of 17 cases were at thyroid cartilage level. Penetrating neck trauma was most common followed by blunt neck trauma. Most cases required emergency tracheostomy along with primary laryngotracheal repair. Most common post operative complication seen was wound dehiscence, subglottic stenosis and fistula formation. Neck trauma and cut throat injuries are potentially life threatening emergency that require multidisciplinary approach. Timely intervention can be crucial in preventing fatal complications and reducing morbidity period of the patient.


Effects of bisphosphonates on lipid metabolism.
Bisphosphonates are widely used for the treatment of metabolic bone disorders and their effects on lipid metabolism have also been investigated. Some studies reported that bisphosphonates have beneficial effects on serum cholesterol levels. In this study we aimed to assess the effects of bisphosphonates on lipid levels in hyperlipidemic patients who received bisphosphonates because of osteoporosis. 49 female patients (age: 54.2+/-7.2 years) with diagnosis of osteoporosis and hyperlipidemia were enrolled. Patients received alendronate 10 mg/day and they were followed up for 6 months. Pretreatment total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, apolipoprotein A1 and apolipoprotein B levels were measured and compared with post-treatment levels. Pretreatment and post-treatment levels of total cholesterol were 255.2+/-34.3; 233.02+/-37.0 mg/dL, triglyceride levels were 153.0+/-57.3; 129.1+/-54.4 mg/dL, and LDL levels were 170.7+/-30.5; 160.0+/-34.2 mg/dL, respectively. Reductions in total cholesterol, triglyceride and LDL-cholesterol levels were statistically significant; whereas differences in HDL-cholesterol, apolipoprotein-A1 and apolipoprotein-B levels were not significant. Data from our study suggest that alendronate therapy may have beneficial effects on lipid metabolism. Thus, when hyperlipidemia is detected in patients receiving bisphosphonates, it is considered reasonable to follow the patient for a while before initiating antihyperlipidemic agent to prevent unnecessary use of drugs.


Cooperation in networks where the learning environment differs from the interaction environment.
We study the evolution of cooperation in a structured population, combining insights from evolutionary game theory and the study of interaction networks. In earlier studies it has been shown that cooperation is difficult to achieve in homogeneous networks, but that cooperation can get established relatively easily when individuals differ largely concerning the number of their interaction partners, such as in scale-free networks. Most of these studies do, however, assume that individuals change their behaviour in response to information they receive on the payoffs of their interaction partners. In real-world situations, subjects do not only learn from their interaction partners, but also from other individuals (e.g. teachers, parents, or friends). Here we investigate the implications of such incongruences between the 'interaction network' and the 'learning network' for the evolution of cooperation in two paradigm examples, the Prisoner's Dilemma game (PDG) and the Snowdrift game (SDG). Individual-based simulations and an analysis based on pair approximation both reveal that cooperation will be severely inhibited if the learning network is very different from the interaction network. If the two networks overlap, however, cooperation can get established even in case of considerable incongruence between the networks. The simulations confirm that cooperation gets established much more easily if the interaction network is scale-free rather than random-regular. The structure of the learning network has a similar but much weaker effect. Overall we conclude that the distinction between interaction and learning networks deserves more attention since incongruences between these networks can strongly affect both the course and outcome of the evolution of cooperation.


Hyponatraemia: etiology, management and outcome.
To determine the etiology of hyponatraemia, the treatment instituted and the outcome of treatment in a tertiary care hospital setting. Case series. The Aga Khan University Hospital, Karachi, between January and June 2004. Case records of 220 patients admitted to the medical service were identified through computerized hospital patients' data. All patients (3) 15 years with a sodium level on admission of (2) 130 mmol/litre were included. The records of those patients were reviewed for relevant demographic, clinical and laboratory data, in addition to the diagnosis, treatment and outcome of hospitalization. The data was analyzed through SPSS software version 11.0. Over a 6-month period, 220 patients were admitted with hyponatraemia (serum sodium (2) 130 mmol/L). Of those 127 females and 93 males, the mean age was 65 + 13.29 years. Neurological symptoms were the presenting feature in 25% patients. The mean serum sodium level on admission was 119.46 mmol/L. The rate of correction was >10 mmol/L/ 24 hours in 17% patients. The average duration of stay was 4 days. The mortality was 6.8%. Medicines accounted for 30% cases of hyponatraemia, of which diuretics, angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARBs) were top of the list. Other causes were gastrointestinal in 25%, chest infection in 11% patients, depletional hyponatraemia in 10% patients, SIADH (Syndrome of Inappropriate Antidiuretic Hormone) in 6% patients, congestive cardiac failure and malignancy in 5% each and chronic liver disease in 3.6% patients. Hyponatraemia was seen more commonly in the elderly, major causes being gastrointestinal losses and use of drugs. Serum sodium correction should be less than 10 mmol/L/24 hours. The treatment plan be directed to correction of the underlying cause. Diagnosis of SIADH should be sought with appropriate investigation.


PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis.
Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα (Ppara-/-) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara-/- mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with Ppara-/- mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara-/- mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality. In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-α (PPARα) results in reduced cardiac performance and fatty acid oxidation in sepsis.


Polycomb mediates Myc autorepression and its transcriptional control of many loci in Drosophila.
Aberrant accumulation of the Myc oncoprotein propels proliferation and induces carcinogenesis. In normal cells, however, an abundance of Myc protein represses transcription at the c-myc locus. Cancer cells often lose this autorepression. We examined the control of myc in Drosophila and show here that the Drosophila ortholog, dmyc, also undergoes autorepression. We find that the developmental repressor Polycomb (Pc) is required for dmyc autorepression, and that this Pc-dMyc-mediated repression spreads across an 875-kb region encompassing the dmyc gene. To further investigate the relationship between Myc and Polycomb, we used microarrays to identify genes regulated by each, and identify a striking relationship between the two: A large set of dMyc activation targets is normally repressed by Pc, and 73% of dMyc repression targets require Pc for this repression. Chromatin immunoprecipitation confirmed that many dMyc-Pc-repressed loci have an epigenetic mark recognized by Pc. Our results suggest a novel relationship between Myc and Polycomb, wherein Myc enhances Polycomb repression in order to repress targets, and Myc suppresses Polycomb repression in order to activate targets.


Differential geminin requirement for proliferation of thymocytes and mature T cells.
Stem/progenitor cells coordinate proliferation and differentiation, giving rise to appropriate cell numbers of functionally specialized cells during organogenesis. In different experimental systems, Geminin was shown to maintain progenitor cells and participate in fate determination decisions and organogenesis. Although the exact mechanisms are unclear, Geminin has been postulated to influence proliferation versus differentiation decisions. To gain insight into the in vivo role of Geminin in progenitor cell division and differentiation, we have generated mice that specifically lack Geminin in cells of lymphoid lineage through Cre-mediated recombination. T cells lacking Geminin expression upregulate early activation markers efficiently upon TCR stimulation in vitro and are able to enter the S phase of cell cycle, but show a marked defect in completing the cycle, leading to a large proportion of T cells accumulating in S/G2/M phases. Accordingly, T cells deficient in Geminin show a reduced ability to repopulate lymphopenic hosts in vivo. Contrary to expectations, Geminin deficiency does not alter development and differentiation of T cells in vivo. Our data suggest that Geminin is required for the proliferation events taking place either in vitro upon TCR receptor activation or during homeostatic expansion, but appears to be redundant for the proliferation and differentiation of the majority of progenitor T cell populations.


An evaluation of strategies to improve the quality and content of hospital-based postnatal care in a metropolitan Australian hospital.
This study aimed to design, implement and evaluate strategies to improve the quality and content of hospital-based postnatal care. Following birth, women report physical health problems, difficulties with breastfeeding, a lack of parenting self-efficacy and there is high occurrence of postnatal distress and depression. Despite these significant needs, women are frequently dissatisfied with the advice and support they receive from hospital-based postnatal care. A pre/post test design compared the effect of multifaceted strategies on perceptions of quality and content of postnatal care, knowledge and experience of postnatal problems, parenting self-efficacy and breastfeeding outcomes. The key strategy, 'one-to-one time', focused on providing women an uninterrupted period of time each day when a midwife would be available to discuss women's concerns about their health and that of their baby. A convenience sample of 146 women at baseline and 148 women postintervention completed a postal self-report questionnaire between 2-4 weeks postpartum. There were no significant differences between baseline and postintervention groups in perceived quality of care, breastfeeding outcomes and maternal self-efficacy. Women experiencing health issues, including insufficient milk supply, backache, abnormal bleeding and urinary incontinence, were more likely to report that they received good or excellent care and advice in the postintervention group. Strategies to increase rest appeared effective with women less likely to report excessive tiredness postintervention. The key strategy, 'one-to-one time' was not consistently implemented, 57% of women reported they received 10 minutes or less of uninterrupted time with a midwife and only 11% reported that they were provided with 20 minutes or more. There is the potential for individualised care to impact on outcomes for women but established routines and institutional priorities are difficult to change. Midwives require both skill development and time to be able to sensitively listen to women's needs in the hospital postnatal setting.


The soft mechanical signature of glial scars in the central nervous system.
Injury to the central nervous system (CNS) alters the molecular and cellular composition of neural tissue and leads to glial scarring, which inhibits the regrowth of damaged axons. Mammalian glial scars supposedly form a chemical and mechanical barrier to neuronal regeneration. While tremendous effort has been devoted to identifying molecular characteristics of the scar, very little is known about its mechanical properties. Here we characterize spatiotemporal changes of the elastic stiffness of the injured rat neocortex and spinal cord at 1.5 and three weeks post-injury using atomic force microscopy. In contrast to scars in other mammalian tissues, CNS tissue significantly softens after injury. Expression levels of glial intermediate filaments (GFAP, vimentin) and extracellular matrix components (laminin, collagen IV) correlate with tissue softening. As tissue stiffness is a regulator of neuronal growth, our results may help to understand why mammalian neurons do not regenerate after injury.


Inequalities in Alcohol-Related Mortality in 17 European Countries: A Retrospective Analysis of Mortality Registers.
Socioeconomic inequalities in alcohol-related mortality have been documented in several European countries, but it is unknown whether the magnitude of these inequalities differs between countries and whether these inequalities increase or decrease over time. We collected and harmonized data on mortality from four alcohol-related causes (alcoholic psychosis, dependence, and abuse; alcoholic cardiomyopathy; alcoholic liver cirrhosis; and accidental poisoning by alcohol) by age, sex, education level, and occupational class in 20 European populations from 17 different countries, both for a recent period and for previous points in time, using data from mortality registers. Mortality was age-standardized using the European Standard Population, and measures for both relative and absolute inequality between low and high socioeconomic groups (as measured by educational level and occupational class) were calculated. Rates of alcohol-related mortality are higher in lower educational and occupational groups in all countries. Both relative and absolute inequalities are largest in Eastern Europe, and Finland and Denmark also have very large absolute inequalities in alcohol-related mortality. For example, for educational inequality among Finnish men, the relative index of inequality is 3.6 (95% CI 3.3-4.0) and the slope index of inequality is 112.5 (95% CI 106.2-118.8) deaths per 100,000 person-years. Over time, the relative inequality in alcohol-related mortality has increased in many countries, but the main change is a strong rise of absolute inequality in several countries in Eastern Europe (Hungary, Lithuania, Estonia) and Northern Europe (Finland, Denmark) because of a rapid rise in alcohol-related mortality in lower socioeconomic groups. In some of these countries, alcohol-related causes now account for 10% or more of the socioeconomic inequality in total mortality. Because our study relies on routinely collected underlying causes of death, it is likely that our results underestimate the true extent of the problem. Alcohol-related conditions play an important role in generating inequalities in total mortality in many European countries. Countering increases in alcohol-related mortality in lower socioeconomic groups is essential for reducing inequalities in mortality. Studies of why such increases have not occurred in countries like France, Switzerland, Spain, and Italy can help in developing evidence-based policies in other European countries.


Prevalence of depressive symptoms as elicited by Patient Health Questionnaire (PHQ-9) among medical trainees in Oman.
Despite the increasing recognition that medical training tends to coincide with markedly high levels of stress and distress, there is a dearth of validated measures that are capable of gauging the prevalence of depressive symptoms among medical residents in the Arab/Islamic part of the world. The aim of the present study is two-fold. First is to examine the diagnostic validity of the Patient Health Questionnaire (PHQ-9) using an Omani medical resident population in order to establish a cut-off point. Second is to compare gender, age, and residency level among Omani Medical residents who report current depressive symptomatology versus those who report as non-depressed according to PHQ-9 cut-off threshold. A total of 132 residents (42 males and 90 females) consented to participate in this study. The cut-off score of 12 on the PHQ-9 revealed a sensitivity of 80.6% and a specificity of 94.0%. The rate of depression, as elicited by PHQ-9, was 11.4%. The role of gender, age, and residency level was not significant in endorsing depression. This study indicated that PHQ-9 is a reliable measure among this cross-cultural population. More studies employing robust methodology are needed to confirm this finding.


First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies.
The influence of cytochrome P450 (CYP) 2C19 genotype on platelet function in patients treated with ticagrelor versus clopidogrel is unknown. CYP2C19 (*1, *2, *3, *4, *5, *6, *7, *8, *17) genotyping was performed in patients with coronary artery disease treated with ticagrelor (180-mg load, 90 mg BID) (n=92) or clopidogrel (600-mg load, 75 mg/d) (n=82). All patients received 75 to 100 mg/d aspirin. Platelet function was measured by aggregometry, VerifyNow P2Y12 assay, and vasodilator-stimulated phosphoprotein-phosphorylation assay at predose, 8 hours postloading, and maintenance. In each treatment group, patients were categorized according to 2C19 genotype carrier status (loss-of-function, gain-of-function) and metabolizer status. Kruskal-Wallis test was used to compare platelet function among these categories for each treatment, and Wilcoxon rank sum test was used to compare platelet function between the clopidogrel and ticagrelor groups for each category. There was no statistically significant influence of genotype on platelet function during aspirin therapy alone. Ticagrelor exhibited lower platelet reactivity than clopidogrel by all assays irrespective of 2C19 genotype or metabolizer status (P<0.01). Loss-of-function carriers had greater platelet reactivity during clopidogrel therapy. The influence of genotype on platelet reactivity was greatest during clopidogrel maintenance and best demonstrated by the VerifyNow P2Y12 assay. This report is the first to demonstrate the superior pharmacodynamic effect of ticagrelor compared with clopidogrel irrespective of CYP2C19 genotype. Whereas CYP2C19 genotype influenced the antiplatelet effect of clopidogrel, there was no effect of CYP2C19 genotype during ticagrelor therapy.


Heparanase and coagulation-new insights.
Heparanase, a β-D-endoglucuronidase abundant in platelets that was discovered 30 years ago, is an enzyme that cleaves heparan sulfate side chains on the cell surface and in the extracellular matrix. It was later recognized as being a pro-inflammatory and pro-metastatic protein. We had earlier demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. We had shown that heparanase up-regulated the expression of the blood coagulation initiator tissue factor (TF) and interacted with the tissue factor pathway inhibitor (TFPI) on the cell surface membrane of endothelial and tumor cells, leading to dissociation of TFPI and resulting in increased cell surface coagulation activity. Moreover, we have demonstrated that heparanase directly enhanced TF activity which led to increased factor Xa production and subsequent activation of the coagulation system. Recently, heparanase inhibitory peptides derived of TFPI-2 were demonstrated by us to inhibit heparanase procoagulant activity and attenuate sepsis in mouse models.


Cranberry proanthocyanidins are cytotoxic to human cancer cells and sensitize platinum-resistant ovarian cancer cells to paraplatin.
Polyphenolic extracts of the principal flavonoid classes present in cranberry were screened in vitro for cytotoxicity against solid tumor cells lines, identifying two fractions composed principally of proanthocyanidins (PACs) with potential anticancer activity. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) analysis of the proanthocyanidins (PACs) fractions indicated the presence of A-type PACs with 1-4 linkages containing between 2-8 epicatechin units with a maximum of 1 epigallocatechin unit. PACs exhibited in vitro cytotoxicity against platinum-resistant human ovarian, neuroblastoma and prostate cancer cell lines (IC50 = 79-479 microg/mL) but were non-cytotoxic to lung fibroblast cells (IC50 > 1000 microg/ml). SKOV-3 ovarian cancer cells treated with PACs exhibited classic apoptotic changes. PACs acted synergistically with paraplatin in SKOV-3 cells. Pretreatment of SKOV-3 cells with PACs (106 microg/ml) resulted in a significant reduction of the paraplatin IC50 value. Similarly, in a BrdU incorporation assay, co-treatment of SKOV-3 cells with PACs and paraplatin revealed reduced cell proliferation at lower concentrations than with either individually. In SKOV-3 cell cultures co-treated with PAC-1 and paraplatin, an HPLC analysis indicated differential quantitative presence of various PAC oligomers such as DP-8, -9, -11 and -14 indicating either selective binding or uptake. Cranberry proanthocyanidins exhibit cell-line specific cytotoxicity, induce apoptotic markers and augment cytotoxicity of paraplatin in platinum-resistant SKOV-3 ovarian cancer cells.


Investigation of hexagonal and cubic GaN by high-resolution electron energy-loss spectroscopy and density functional theory.
High-resolution electron energy-loss spectroscopy in a transmission electron microscope is a very powerful method for the study of electronic structure of materials. The fine structure of Ga L(2,3) and N ionization edges in c-GaN and h-GaN was studied using a TEM equipped with a monochromator and high-resolution energy spectrometer. The experimental results were compared with the results of calculation based on the density functional theory using the Wien2k code and show that the best fit is achieved when the core hole effect is taken into account. The effect of the core hole value and the supercell size on the energy-loss near-edge structure have been investigated. A different behaviour was found for c-GaN and h-GaN: better agreement is obtained for a 0.5 core hole for h-GaN and for a full core hole for c-GaN. The anisotropic behaviour of the experimental spectra and calculated spectra for h-GaN have been studied and the "magic" angle was determined.


Adsorption differences between low coverage enantiomers of alanine on the chiral Cu{421}R surface.
Chiral separation using heterogeneous methods has long been sought after. Chiral metal surfaces have the potential to make it possible to model these systems using small amino acids, the building blocks for proteins. A comparison of submonolayer concentrations of alanine enantiomers adsorbed onto Cu{421}R has revealed a large geometrical differences between the two molecules as compared to the saturated coverage. Large differences were observed in HR-XPS and NEXAFS and complemented by theoretical DFT calculations. At approximately one third of a monolayer a comparison of the C1s XPS signal showed a shift in the methyl group of more than 300 meV indicating that the two enantiomers are in different chemical environments. NEXAFS spectroscopy confirmed the XPS variations and showed large differences in the orientation of the adsorbed molecules. Our DFT results show that the l-enantiomer is energetically the most stable in the {311} microfacet configuration. In contrast to the full monolayer coverage, these lower coverages showed enhanced selectivity.


The cellular effects of carbon monoxide in the airway.
The notion of inhaled carbon monoxide (CO) being a toxic chemical under all circumstances is currently being challenged, as recent research has suggested that low concentrations of CO may have therapeutic value, especially in the airway. This review evaluates CO's effects on cellular functions that may result in beneficial outcomes in the settings of airway disease, inflammation, and injury. CO can modulate the stress response system of the cell by decreasing levels of reactive intermediates over time, produced by mitochondrial iNOS and NADPH oxidase. Intracellular stress-induced response factors (e.g., HIF-1 and HSP- 70) are induced in response to CO, possibly facilitating more rapid and effective defenses, in response to subsequent stressors. CO also can trigger changes in cellular functions downstream, protecting the cells from stress-associated events promoted in the airway, as a result of disease or injury, including reducing rates of apoptosis, proliferation, and inflammatory cellular infiltration, as well as preventing an imbalance in the extracellular matrix composition. CO has also been associated with maintaining homeostasis of ions essential for normal cellular functions (e.g., Na+, Fe2+,3+). CO also targets cell-specific functions of the airway, such as reduction of contractility of airway smooth muscle cells, and preservation of the innate defense mechanism of airway epithelial cells. Further understanding of CO's effects on fundamental cellular functions in the airway will likely hold significant value in future considerations of CO's role in airway therapy and health.


Regulation of MLL1 H3K4 methyltransferase activity by its core components.
Histone H3 Lys4 (H3K4) methylation is a prevalent mark associated with transcription activation. A common feature of several H3K4 methyltransferase complexes is the presence of three structural components (RbBP5, Ash2L and WDR5) and a catalytic subunit containing a SET domain. Here we report the first biochemical reconstitution of a functional four-component mixed-lineage leukemia protein-1 (MLL1) core complex. This reconstitution, combined with in vivo assays, allows direct analysis of the contribution of each component to MLL1 enzymatic activity and their roles in transcriptional regulation. Moreover, taking clues from a crystal structure analysis, we demonstrate that WDR5 mediates interactions of the MLL1 catalytic unit both with the common structural platform and with the histone substrate. Mechanistic insights gained from this study can be generalized to the whole family of SET1-like histone methyltransferases in mammals.


Varicella in the first year after renal transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).
Prior reports document that children with renal transplants are at risk of severe varicella, with a 5-25% mortality rate. We have examined the current incidence and mortality of varicella requiring hospitalization in pediatric patients in the first year after kidney transplantation through a multi-center retrospective cohort study. Data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) for 2320 pediatric patients who received renal transplants between 1987 and 1993 and were followed until 1995 were examined. Varicella requiring hospitalization in the first post-transplant year occurred in 44 children. Characteristics of the patients who developed varicella were compared to the rest of the NAPRTCS cohort using chi-square analysis. Kaplan-Meier estimates of graft survival were used to compare graft survival in varicella patients and other NAPRTCS patients. Varicella patients tended to be younger (p=0.09) and more often male (p=0.07, chi-square) than other NAPRTCS patients. None of the 44 patients with varicella in their first post-transplant year died from this infection. The number of episodes of acute rejection per transplant and the time to first rejection was not different in patients with varicella compared to the other NAPRTCS patients. Five-year graft survival was not different for varicella cases when compared to other NAPRTCS patients with grafts surviving at least 6 months post-transplant. We conclude that the mortality rate of patients hospitalized with varicella in the first post-transplant year and the risk of subsequent graft dysfunction may be significantly lower than previously described. However, varicella remains a significant cause of potentially avoidable hospitalization in the first post-transplant year. Further study of the safety and efficacy of varicella vaccination in children with renal insufficiency and those post-transplant is warranted.


The prevalence of cardiovascular disease risk factors of Hong Kong Chinese.
In Hong Kong, the prevalence of cardiovascular heart disease (CHD) increased from 38.6% in 1972 to 59.4% in 1992 and has become an area of concern. The present study intended to identify the CHD risk factors of 18-60 year old Hong Kong Chinese and recommend primary prevention programmes accordingly. Subjects (N=1432) were systemically recruited from community and sports centres in urban and rural districts in order to balance the effects of age, gender and economic status. Eight major CHD factors were identified and criteria used for classifying them as high risk were as follows: high blood pressure (SBP: over 160 mmHg or DBP: over 95 mmHg); total blood cholesterol (over 6.2 mmol/L) or high density lipoprotein (HDL) under 0.9 mmol/L; cigarette smoking; overweight (BMI over 27.5, or percent body fat over 25 for men and 30 for women); exercise habit (no exercise or exercise less than once per week); alcohol consumption (over 6 drinks or 90 ml ethanol per week); diabetes mellitus; and family history (one or both parents died of CHD before the age of 60 years). All testings and data collection were conducted at the laboratory in 1997-98. Differences in the prevalence of CHD risk factors due to age and gender were then investigated. It was found that the percentages of subjects with high risk factors were substantially lower than those reported in other countries e.g., Australia and the People's Republic of China. The prevalence of CHD risk factors increased with age and it was also higher in the male subjects. There were more men with three or more CHD risk factors than women (23.5 vs 9.9%). It was suggested that the Hong Kong SAR Government should launch primary prevention programmes to eliminate the five behaviour-related CHD risk factors identified in the present study and monitor their prevalence in the future.


Defining a standardized methodology for the determination of the antioxidant capacity: case study of Pistacia atlantica leaves.
Antioxidant activity can be measured by a variety of methods, that include hydrogen atom transfer (HAT) and single electron transfer (ET) methods. Most of these techniques are spectrophotometric, and thus incapable of quantifying or indicting individual antioxidant compounds. Nowadays, the integration of chromatographic and chemometric approaches allows a high-throughput identification and activity prediction of herbal products. The ethyl acetate fraction from the aqueous-acetone extract of Pistacia atlantica leaves is frequently used for the isolation of antioxidants. In this study it is investigated for its antioxidant properties in order to define a potential methodology for the determination of the antioxidant capacity of herbal extracts (which need to be confirmed by future studies). The seven free radical assays evaluated can be divided into two groups depending on the oxidizing reagent. Three methods use stable, non-biological radicals, i.e. the diphenyl-1-picrylhydrazyl (DPPH) assay, the azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay, and the N,N-dimethyl-p-phenylenediamine (DMPD) assay, which have no direct physiological importance. Four methods work with biological radical producers, including superoxide anion (O2˙-), hydroxyl (˙OH), nitric oxide (NO˙) and peroxyl (ROO˙) are produced metabolically in living organisms, and thus direct information on an extract's protective action is obtained. Furthermore, the reducing power method by potassium ferricyanide (RPC), and the iron (ferrous) ion chelating activity also have been investigated. The antioxidant activities of the samples were measured according to the different methods and modelled as a function of the HPLC fingerprints using the partial least squares (PLS) technique. The regression coefficients of the models were studied to indicate the peaks potentially responsible for the antioxidant activity. From the combined results of the different PLS models, we recommend using the DPPH, RPC and ROO˙ assays, to evaluate the overall antioxidant capacity; in the case study of P. atlantica leaves.


Molecular characterization and expression of two ovarian lipoprotein receptors in the rainbow trout, Oncorhynchus mykiss.
Partial cDNAs encoding two lipoprotein receptors were isolated and sequenced from the ovary in the rainbow trout (rt), Oncorhynchus mykiss. One of the cDNAs (rt-LPR) contained the 5 domains characteristic of receptors belonging to the low-density lipoprotein receptor superfamily. The second cDNA (rt-LP[OS]R) was similar to rt-LPR but lacked 105 base pairs encoding the O-linked sugar domain. The deduced amino acid sequences of the rt-LPR and rt-LP[OS]R had between 75% and 80% identity with very-low-density lipoprotein and vitellogenin receptors of other species. The rt-lipoprotein receptor mRNAs were approximately 3.5 kilobases in size. The rt-LPR was expressed in both the ovary and somatic tissues, whereas the rt-LP[OS]R was ovary-specific. Messenger RNA for the lipoprotein receptor(s) was expressed at high levels in both pre-vitellogenic (< 0.3 mm) and early vitellogenic (up to 1 mm) follicles. Using reverse transcription-polymerase chain reaction, expression of rt-LPR and rt-LP[OS]R mRNA was also detected in larger vitellogenic follicles (up to 2.5 mm in diameter) but not in follicles in late vitellogenesis or in ovulated eggs. The sequence, ovary specificity, and pattern of ovarian expression of the rt-LPR mRNA suggest that it encodes the receptor that mediates vitellogenin uptake into the ovary.


Exogenous glucose administration impairs glucose tolerance and pancreatic insulin secretion during acute sepsis in non-diabetic mice.
The development of hyperglycemia and the use of early parenteral feeding are associated with poor outcomes in critically ill patients. We therefore examined the impact of exogenous glucose administration on the integrated metabolic function of endotoxemic mice using our recently developed frequently sampled intravenous glucose tolerance test (FSIVGTT). We next extended our findings using a cecal ligation and puncture (CLP) sepsis model administered early parenteral glucose support. Male C57BL/6J mice, 8-12 weeks, were instrumented with chronic indwelling arterial and venous catheters. Endotoxemia was initiated with intra-arterial lipopolysaccharide (LPS; 1 mg/kg) in the presence of saline or glucose infusion (100 µL/hr), and an FSIVGTT was performed after five hours. In a second experiment, catheterized mice underwent CLP and the impact of early parenteral glucose administration on glucose homeostasis and mortality was assessed over 24 hrs. AND MAIN RESULTS: Administration of LPS alone did not impair metabolic function, whereas glucose administration alone induced an insulin sensitive state. In contrast, LPS and glucose combined caused marked glucose intolerance and insulin resistance and significantly impaired pancreatic insulin secretion. Similarly, CLP mice receiving parenteral glucose developed fulminant hyperglycemia within 18 hrs (all > 600 mg/dl) associated with increased systemic cytokine release and 40% mortality, whereas CLP alone (85 ± 2 mg/dL) or sham mice receiving parenteral glucose (113 ± 3 mg/dL) all survived and were not hyperglycemic. Despite profound hyperglycemia, plasma insulin in the CLP glucose-infused mice (3.7 ± 1.2 ng/ml) was not higher than sham glucose infused mice (2.1 ± 0.3 ng/ml). The combination of parenteral glucose support and the systemic inflammatory response in the acute phase of sepsis induces profound insulin resistance and impairs compensatory pancreatic insulin secretion, leading to the development of fulminant hyperglycemia.


A pilot randomized controlled trial comparing prenatal yoga to perinatal health education for antenatal depression.
We conducted a pilot randomized controlled trial (RCT) comparing a prenatal yoga intervention to perinatal-focused health education in pregnant women with depression. Findings document acceptability and feasibility of the yoga intervention: no yoga-related injuries were observed, instructors showed fidelity to the yoga manual, and women rated interventions as acceptable. Although improvements in depression were not statistically different between groups, they favored yoga. This study provides support for a larger scale RCT examining prenatal yoga to improve mood during pregnancy.


Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation.
Autophagy that is induced by starvation or cellular stress can enable cancer cell survival by sustaining energy homeostasis and eliminating damaged organelles and proteins. In response to stress, cancer cells have been reported to accumulate the protein p62/SQSTM1 (p62), but its role in the regulation of autophagy is controversial. Here, we report that the plant phytoalexin resveratrol (RSV) triggers autophagy in imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia (CML) cells via JNK-dependent accumulation of p62. JNK inhibition or p62 knockdown prevented RSV-mediated autophagy and antileukemic effects. RSV also stimulated AMPK, thereby inhibiting the mTOR pathway. AMPK knockdown or mTOR overexpression impaired RSV-induced autophagy but not JNK activation. Lastly, p62 expression and autophagy in CD34+ progenitors from patients with CML was induced by RSV, and disrupting autophagy protected CD34+ CML cells from RSV-mediated cell death. We concluded that RSV triggered autophagic cell death in CML cells via both JNK-mediated p62 overexpression and AMPK activation. Our findings show that the JNK and AMPK pathways can cooperate to eliminate CML cells via autophagy.


Chemical signals that regulate mammalian oocyte maturation.
The nature and functions of the chemical signals involved in the acquisition of competence to resume meiosis, and the maintenance of meiotic arrest in antral follicles are the subjects of this paper. Evidence indicating that gonadotropins are not required for the development of competence to undergo spontaneous maturation is discussed. However, gonadotropins may promote optimal conditions for oocyte development via an estrogen-dependent action on follicular cells. Evidence for the participation of cyclic AMP (cAMP), steroids and a putative maturation-inhibiting factor in the maintenance of meiotic arrest in mammalian oocytes is discussed. Cyclic AMP seems to play a critical role in the maintenance of meiotic arrest by actions in both granulosa/cumulus cells and oocytes. However, cAMP does not appear to equilibrate between cumulus cells and oocytes. In the granulosa/cumulus cells, cAMP may promote the generation/activation of a maturation-inhibiting factor which is transferred to the oocyte. Oocyte cAMP appears to be produced in the oocyte itself. The putative maturation-inhibiting factor may be maintained in an active form by a cAMP-dependent process in the oocyte. Alternatively, the putative maturation-inhibiting factor may play a role in maintaining oocyte cAMP levels. Some steroid hormones act synergistically with a cAMP-dependent process in the oocyte to maintain meiotic arrest. However, the physiological significance of this observation remains in question.


Effects of Peanut Processing on Masticatory Performance during Variable Appetitive States.
Background. Current evidence indicates that peanut consumption reduces cardiovascular disease risk, while posing little threat to positive energy balance. However, questions have been raised as to whether inter- and intraindividual variability in mastication in response to peanut form and processing properties may influence these health effects, since mastication has the potential to alter the bioaccessibility of nutrients within the nut matrix. Objective. To explore the relationship between peanut form and processing and masticatory function. Subjects/Methods. Thirty nine adults (16 M, 23 F; BMI: 30.4 +/- 4.0 kg/m(2); age: 27 +/- 8 y) with healthy dentition chewed four different forms of peanuts until they would normally swallow and then expectorated the bolus. Surface electromyograms (EMGs) were obtained from the masseter and temporalis muscles during chewing of the four test foods. The maximum and mean bite forces, duration of chewing sequence, number of chews, and total muscle work for the complete chewing cycle were measured on the integrated EMG in fasted and sated states. Results. While no significant differences were noted in response to appetitive state, peanut form and processing had a significant influence on masticatory efficiency, as measured by proportional particle size distributions. The processed peanuts (honey roasted, roasted salted, and roasted unsalted) were chewed significantly fewer times compared to the unprocessed form (raw). Further, the proportional particle sizes within the swallowing bolus were significantly larger for the processed forms compared to the unprocessed form. Conclusion. These observations may have implications for bioaccessibility of energy and cardioprotective nutrients as well as endocrine responses, following peanut consumption.


Identification of genes and gene pathways associated with major depressive disorder by integrative brain analysis of rat and human prefrontal cortex transcriptomes.
Despite moderate heritability estimates, progress in uncovering the molecular substrate underpinning major depressive disorder (MDD) has been slow. In this study, we used prefrontal cortex (PFC) gene expression from a genetic rat model of MDD to inform probe set prioritization in PFC in a human post-mortem study to uncover genes and gene pathways associated with MDD. Gene expression differences between Flinders sensitive (FSL) and Flinders resistant (FRL) rat lines were statistically evaluated using the RankProd, non-parametric algorithm. Top ranking probe sets in the rat study were subsequently used to prioritize orthologous selection in a human PFC in a case-control post-mortem study on MDD from the Stanley Brain Consortium. Candidate genes in the human post-mortem study were then tested against a matched control sample using the RankProd method. A total of 1767 probe sets were differentially expressed in the PFC between FSL and FRL rat lines at (q⩽0.001). A total of 898 orthologous probe sets was found on Affymetrix's HG-U95A chip used in the human study. Correcting for the number of multiple, non-independent tests, 20 probe sets were found to be significantly dysregulated between human cases and controls at q⩽0.05. These probe sets tagged the expression profile of 18 human genes (11 upregulated and seven downregulated). Using an integrative rat-human study, a number of convergent genes that may have a role in pathogenesis of MDD were uncovered. Eighty percent of these genes were functionally associated with a key stress response signalling cascade, involving NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), AP-1 (activator protein 1) and ERK/MAPK, which has been systematically associated with MDD, neuroplasticity and neurogenesis.


The T cell receptor resides in ordered plasma membrane nanodomains that aggregate upon patching of the receptor.
Two related models for T cell signalling initiation suggest either that T cell receptor (TCR) engagement leads to its recruitment to ordered membrane domains, often referred to as lipid rafts, where signalling molecules are enriched or that ordered TCR-containing membrane nanodomains coalesce upon TCR engagement. That ordered domains form upon TCR engagement, as they do upon lipid raft marker patching, has not been considered. The target of this study was to differentiate between those three options. Plasma membrane order was followed in live T cells at 37 °C using laurdan to report on lipid packing. Patching of the TCR that elicits a signalling response resulted in aggregation, not formation, of ordered plasma membrane domains in both Jurkat and primary T cells. The TCR colocalised with actin filaments at the plasma membrane in unstimulated Jurkat T cells, consistent with it being localised to ordered membrane domains. The colocalisation was most prominent in cells in G1 phase when the cells are ready to commit to proliferation. At other cell cycle phases the TCR was mainly found at perinuclear membranes. Our study suggests that the TCR resides in ordered plasma membrane domains that are linked to actin filaments and aggregate upon TCR engagement.


Budget impact analysis of surfactant therapy for bronchiolitis in critically ill infants: the Colombian National Health System perspective.
Severe bronchiolitis requiring mechanical ventilation was associated with an absence of surfactant activity and phosphatidylglycerol, causing airway obstruction in acute bronchiolitis. Exogen surfactant in mechanically ventilated infants decreased duration of stay in the intensive care unit and had favorable effects on oxygenation and carbon dioxide removal. This study aimed to evaluate the budget impact of surfactant therapy for bronchiolitis in critically ill infants in Colombia. Budget impact analysis was performed to estimate the economic impact of surfactant therapy (ST) for the treatment of infants with a diagnosis of bronchiolitis, requiring mechanical ventilation. The analysis considered a 4-year time horizon and Colombian National Health System perspective. The model estimated drug costs associated with current scenario using humidified oxygen or adrenaline nebulization, and new scenario adding exogen surfactant. The size of the target population was calculated using epidemiological national data. Univariate one-way sensitivity analyses and scenario analyses were performed. In the base-case analysis the 4-year costs associated to ST and no-ST were estimated to be US$ 55,188,132 and US$ 55,972,082 respectively, indicating savings for Colombian National Health equal to US$ 783,950 if ST is adopted for the routine management of patients with bronchiolitis requiring mechanical ventilation. In the one-way sensitivity analysis, only increases in the cost of the surfactant drug and cost or length of stay in the pediatric intensive unit reduce the potential savings of ST. ST was cost-saving in emergency settings for treating infants with severe bronchiolitis requiring mechanical ventilation. This shift in treatment approach proved to be economically favorable in the Colombian context.


Mineralocorticoid escape during kallikrein inhibition.
Kinins have been considered to be involved in the escape from the sodium retaining effects of mineralocorticoids. In a metabolic study in rats, the importance of the kallikrein-kinin system for sodium and potassium excretion was evaluated by aprotinin-induced kallikrein inhibition under basal conditions and during DOCA administration. Kallikrein inhibition was accompanied by a transient sodium retention. The escape from the sodium retaining effect of DOCA was not affected. However, the DOCA-induced potassium loss was enhanced. Kallikrein inhibition decreased urinary prostaglandin (PG) E2 and prevented the DOCA-induced rise in PGE2. Plasma renin activity was stimulated after 10 days of aprotinin administration. The kallikrein-kinin system is not an important mediator of the escape phenomenon but it may play a role in the regulation of sodium and potassium excretion.


Generation of cAMP-activated chloride currents by expression of CFTR.
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis. In order to evaluate its function, CFTR was expressed in HeLa, Chinese hamster ovary (CHO), and NIH 3T3 fibroblast cells, and anion permeability was assessed with a fluorescence microscopic assay and the whole-cell patch-clamp technique. Adenosine 3',5'-monophosphate (cAMP) increased anion permeability and chloride currents in cells expressing CFTR, but not in cells expressing a mutant CFTR (delta F508) or in nontransfected cells. The simplest interpretation of these observations is that CFTR is itself a cAMP-activated chloride channel. The alternative interpretation, that CFTR directly or indirectly regulates chloride channels, requires that these cells have endogenous cryptic, chloride channels that are stimulated by cAMP only in the presence of CFTR.


Quantitative Polymerase Chain Reaction-based Analyses of Murine Intestinal Microbiota After Oral Antibiotic Treatment.
The gut microbiota has a central influence on human health. Microbial dysbiosis is associated with many common immunopathologies such as inflammatory bowel disease, asthma and arthritis. Thus, understanding the mechanisms underlying microbiota-immune system crosstalk is of crucial importance. Antibiotic administration, while aiding pathogen clearance, also induces drastic changes in the size and composition of intestinal bacterial communities which can have an impact on human health. Antibiotic treatment in mice recapitulates the impact and long-term changes in human microbiota from antibiotic treated patients, and enables investigation of the mechanistic links between changes in microbial communities and immune cell function. While several methods for antibiotic treatment of mice have been described, some of them induce severe dehydration and weight-loss complicating the interpretation of the data. Here, we provide two protocols for oral antibiotic administration which can be used for long-term treatment of mice without inducing major weight-loss. These protocols make use of a combination of antibiotics that target both Gram-positive and Gram-negative bacteria and can be provided either ad libitum in the drinking water or by oral gavage. Moreover, we describe a method for the quantification of microbial density in fecal samples by qPCR which can be used to validate the efficacy of the antibiotic treatment. The combination of these approaches provides a reliable methodology for the manipulation of the intestinal microbiota and the study of the effects of antibiotic treatment in mice.


Assessment of chronic sublethal effects of imidacloprid on honey bee colony health.
Here we present results of a three-year study to determine the fate of imidacloprid residues in hive matrices and to assess chronic sublethal effects on whole honey bee colonies fed supplemental pollen diet containing imidacloprid at 5, 20 and 100 μg/kg over multiple brood cycles. Various endpoints of colony performance and foraging behavior were measured during and after exposure, including winter survival. Imidacloprid residues became diluted or non-detectable within colonies due to the processing of beebread and honey and the rapid metabolism of the chemical. Imidacloprid exposure doses up to 100 μg/kg had no significant effects on foraging activity or other colony performance indicators during and shortly after exposure. Diseases and pest species did not affect colony health but infestations of Varroa mites were significantly higher in exposed colonies. Honey stores indicated that exposed colonies may have avoided the contaminated food. Imidacloprid dose effects was delayed later in the summer, when colonies exposed to 20 and 100 μg/kg experienced higher rates of queen failure and broodless periods, which led to weaker colonies going into the winter. Pooled over two years, winter survival of colonies averaged 85.7, 72.4, 61.2 and 59.2% in the control, 5, 20 and 100 μg/kg treatment groups, respectively. Analysis of colony survival data showed a significant dose effect, and all contrast tests comparing survival between control and treatment groups were significant, except for colonies exposed to 5 μg/kg. Given the weight of evidence, chronic exposure to imidacloprid at the higher range of field doses (20 to 100 μg/kg) in pollen of certain treated crops could cause negative impacts on honey bee colony health and reduced overwintering success, but the most likely encountered high range of field doses relevant for seed-treated crops (5 μg/kg) had negligible effects on colony health and are unlikely a sole cause of colony declines.


Chemometric evaluation of trace metal concentrations in some nuts and seeds.
Seventeen trace metals in acid digests of nuts and seeds were determined using inductively coupled plasma-atomic emission spectrometry and inductively coupled plasma-mass spectrometry. The data were subjected to chemometric evaluation using principal component analysis (PCA), linear discriminant analysis (LDA) and cluster analysis (CA) in an attempt to classify the samples. Hazelnuts (raw and dry roasted), almonds (raw and dry roasted), sunflower seeds (black and white), peanuts (raw and dry roasted), cashew nuts, Brazil nuts, walnuts, chickpeas (raw and dry roasted), pumpkin seeds (raw and dry roasted), and pistachio nuts were used as samples. The samples were classified into seven groups by PCA and CA. All group members determined using PCA and CA were found by LDA to be correctly classified in the predicted groups. Interestingly, the chemometric evaluation indicated that the raw and roasted nuts are very close to each other even though some originated from different countries.


Manual lymphatic drainage for lymphedema following breast cancer treatment.
More than one in five patients who undergo treatment for breast cancer will develop breast cancer-related lymphedema (BCRL). BCRL can occur as a result of breast cancer surgery and/or radiation therapy. BCRL can negatively impact comfort, function, and quality of life (QoL). Manual lymphatic drainage (MLD), a type of hands-on therapy, is frequently used for BCRL and often as part of complex decongestive therapy (CDT). CDT is a fourfold conservative treatment which includes MLD, compression therapy (consisting of compression bandages, compression sleeves, or other types of compression garments), skin care, and lymph-reducing exercises (LREs). Phase 1 of CDT is to reduce swelling; Phase 2 is to maintain the reduced swelling. To assess the efficacy and safety of MLD in treating BCRL. We searched Medline, EMBASE, CENTRAL, WHO ICTRP (World Health Organization's International Clinical Trial Registry Platform), and Cochrane Breast Cancer Group's Specialised Register from root to 24 May 2013. No language restrictions were applied. We included randomized controlled trials (RCTs) or quasi-RCTs of women with BCRL. The intervention was MLD. The primary outcomes were (1) volumetric changes, (2) adverse events. Secondary outcomes were (1) function, (2) subjective sensations, (3) QoL, (4) cost of care. We collected data on three volumetric outcomes. (1) LE (lymphedema) volume was defined as the amount of excess fluid left in the arm after treatment, calculated as volume in mL of affected arm post-treatment minus unaffected arm post-treatment. (2) Volume reduction was defined as the amount of fluid reduction in mL from before to after treatment calculated as the pretreatment LE volume of the affected arm minus the post-treatment LE volume of the affected arm. (3) Per cent reduction was defined as the proportion of fluid reduced relative to the baseline excess volume, calculated as volume reduction divided by baseline LE volume multiplied by 100. We entered trial data into Review Manger 5.2 (RevMan), pooled data using a fixed-effect model, and analyzed continuous data as mean differences (MDs) with 95% confidence intervals (CIs). We also explored subgroups to determine whether mild BCRL compared to moderate or severe BCRL, and BCRL less than a year compared to more than a year was associated with a better response to MLD. Six trials were included. Based on similar designs, trials clustered in three categories.(1) MLD + standard physiotherapy versus standard physiotherapy (one trial) showed significant improvements in both groups from baseline but no significant between-groups differences for per cent reduction.(2) MLD + compression bandaging versus compression bandaging (two trials) showed significant per cent reductions of 30% to 38.6% for compression bandaging alone, and an additional 7.11% reduction for MLD (MD 7.11%, 95% CI 1.75% to 12.47%; two RCTs; 83 participants). Volume reduction was borderline significant (P = 0.06). LE volume was not significant. Subgroup analyses was significant showing that participants with mild-to-moderate BCRL were better responders to MLD than were moderate-to-severe participants.(3) MLD + compression therapy versus nonMLD treatment + compression therapy (three trials) were too varied to pool. One of the trials compared compression sleeve plus MLD to compression sleeve plus pneumatic pump. Volume reduction was statistically significant favoring MLD (MD 47.00 mL, 95% CI 15.25 mL to 78.75 mL; 1 RCT; 24 participants), per cent reduction was borderline significant (P=0.07), and LE volume was not significant. A second trial compared compression sleeve plus MLD to compression sleeve plus self-administered simple lymphatic drainage (SLD), and was significant for MLD for LE volume (MD -230.00 mL, 95% CI -450.84 mL to -9.16 mL; 1 RCT; 31 participants) but not for volume reduction or per cent reduction. A third trial of MLD + compression bandaging versus SLD + compression bandaging was not significant (P = 0.10) for per cent reduction, the only outcome measured (MD 11.80%, 95% CI -2.47% to 26.07%, 28 participants).MLD was well tolerated and safe in all trials.Two trials measured function as range of motion with conflicting results. One trial reported significant within-groups gains for both groups, but no between-groups differences. The other trial reported there were no significant within-groups gains and did not report between-groups results. One trial measured strength and reported no significant changes in either group.Two trials measured QoL, but results were not usable because one trial did not report any results, and the other trial did not report between-groups results.Four trials measured sensations such as pain and heaviness. Overall, the sensations were significantly reduced in both groups over baseline, but with no between-groups differences. No trials reported cost of care.Trials were small ranging from 24 to 45 participants. Most trials appeared to randomize participants adequately. However, in four trials the person measuring the swelling knew what treatment the participants were receiving, and this could have biased results. MLD is safe and may offer additional benefit to compression bandaging for swelling reduction. Compared to individuals with moderate-to-severe BCRL, those with mild-to-moderate BCRL may be the ones who benefit from adding MLD to an intensive course of treatment with compression bandaging. This finding, however, needs to be confirmed by randomized data.In trials where MLD and sleeve were compared with a nonMLD treatment and sleeve, volumetric outcomes were inconsistent within the same trial. Research is needed to identify the most clinically meaningful volumetric measurement, to incorporate newer technologies in LE assessment, and to assess other clinically relevant outcomes such as fibrotic tissue formation.Findings were contradictory for function (range of motion), and inconclusive for quality of life.For symptoms such as pain and heaviness, 60% to 80% of participants reported feeling better regardless of which treatment they received.One-year follow-up suggests that once swelling had been reduced, participants were likely to keep their swelling down if they continued to use a custom-made sleeve.


Crossover from three- to six-fold symmetry of colloidal aggregates in circular traps.
At sufficiently low temperatures and high densities, repulsive spherical particles in two-dimensions (2d) form close-packed structures with six-fold symmetry. By contrast, when the interparticle interaction has an attractive anisotropic component, the structure may exhibit the symmetry of the interaction. We consider a suspension of spherical particles interacting through an isotropic repulsive potential and a three-fold symmetric attractive interaction, confined in circular potential traps in 2d. We find that, due to the competition between the interparticle and the external potentials, the particles self-organize into structures with three- or six-fold symmetry, depending on the width of the traps. For intermediate trap widths, a core-shell structure is formed, where the core has six-fold symmetry and the shell is three-fold symmetric. When the width of the trap changes periodically in time, the symmetry of the colloidal structure also changes, but it does not necessarily follow that of the corresponding static trap.


Reproducibility, bioinformatic analysis and power of the SAGE method to evaluate changes in transcriptome.
The serial analysis of gene expression (SAGE) method is used to study global gene expression in cells or tissues in various experimental conditions. However, its reproducibility has not yet been definitively assessed. In this study, we have evaluated the reproducibility of the SAGE method and identified the factors that affect it. The determination coefficient (R2 ) for the reproducibility of SAGE is 0.96. However, there are some factors that can affect the reproducibility of SAGE, such as the replication of concatemers and ditags, the number of sequenced tags and double PCR amplification of ditags. Thus, corrections for these factors must be made to ensure the reproducibility and accuracy of SAGE results. A bioinformatic analysis of SAGE data is also presented in order to eliminate these artifacts. Finally, the current study shows that increasing the number of sequenced tags improves the power of the method to detect transcripts and their regulation by experimental conditions.


Primary pancreatic lymphoma evaluated by fine-needle aspiration: findings in 14 cases.
Fine-needle aspiration (FNA) is a popular method for evaluating pancreatic lesions. There is considerable literature on FNA evaluation of primary pancreatic carcinomas, but few studies address the FNA diagnosis of primary pancreatic lymphoma. We reviewed 14 cases of atypical lymphoid processes diagnosed by FNA during a 5-year period, constituting 1.3% of a total of 1,050 pancreatic FNA cases. The diagnoses were as follows: 6 large B-cell lymphomas, 4 follicular lymphomas, 3 suggestive of lymphoma, and 1 unclassified B-cell lymphoma. Lymphoid neoplasms manifested in older people (mean age, 64.7 years) as a solitary mass in the pancreatic head, mimicking primary carcinoma. Clonality was confirmed by flow cytometry in 11 cases and immunohistochemical analysis on cell block material in 2. Obtaining diagnostic material often required several passes (average, 3.9 passes; range, 1-8 passes). We conclude that primary pancreatic lymphomas rarely are diagnosed by FNA, tend to be high grade, and clinically and radiographically might mimic primary carcinoma.