Association of Mycoplasma pneumoniae infection with coronary artery disease and its interaction with chlamydial infection.
Mycoplasma pneumoniae (MP) seropositivity was reported to be associated with coronary events. MP organisms were detected with Chlamydia pneumoniae (CP) in coronary plaques. We investigated MP and CP seropositivity in 549 patients undergoing coronary angiography. Coronary artery disease (CAD) was found in 396 patients, of whom 154 had myocardial infarction (MI). MP seropositivity was more prevalent in patients with CAD than without CAD (14% versus 6%, P < 0.01). The highest prevalence was found in patients with MI. In contrast, the prevalence of CP seropositivity was similar in patients with and without CAD (62% versus 59%). To clarify interaction with CP infection, 549 patients were divided into two groups with and without CP seropositivity. Among patients with CP seropositivity, MP seropositivity was more prevalent in patients with CAD than without CAD (17% versus 5%, P < 0.01), whereas among patients without CP seropositivity, MP seropositivity did not differ between patients with and without CAD (9% versus 6%). In multivariate analysis, MP seropositivity was associated with CAD only in patients with CP seropositivity (odds ratio = 5.1, 95% CI = 1.8-14.9). Thus, MP seropositivity was associated with CAD. However, this association was confined to patients with CP seropositivity. Coinfection by MP and CP may be an important cofactor for CAD.


Effect of Ruellia tuberosa L. on aorta endothelial damage-associated factors in high-fat diet and streptozotocin-induced type 2 diabetic rats.
Hyperglycemia plays crucial roles in vascular disease development, including macrovascular and microvascular diseases from diabetes mellitus (DM). Our previous study demonstrated that Ruellia tuberosa L. (RTL) aqueous and ethanol extracts alleviate hyperglycemia and inhibit insulin resistance in diabetic rats. This study investigated the protective effect of RTL ethanol extract against aorta dysfunction in high-fat diet (HFD) and streptozotocin (STZ)-induced type 2 DM (T2DM) rats. Results showed that RTL ethanol extract (100 and 400 mg/kg BW/day) ameliorated serum lipid profiles, including triglyceride, free fatty acid, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels. It also significantly reduced the level of serum cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 in T2DM rats. Additionally, RTL extract decreased endothelin-1 and endothelial nitric oxide contents, reduced the level of cell adhesion factors, including monocyte chemoattractant protein-1 and cell adhesion factor vascular cell adhesion molecule-1, while decreasing content of damage factors, namely tissue factor and von Willebrand factor in aortic tissues of diabetic rats. Equally noteworthy is that RTL extract enhanced the activity of aorta antioxidative enzymes, including superoxidase dismutase and catalase in diabetic rats, suggesting that RTL ethanol extract may ameliorate aorta dysfunction via enhancing aortic antioxidative enzyme activity, which subsequently suppresses aorta endothelial damage-associated factors in HFD with STZ-induced T2DM rats.


From clonal to sexual hybrids: genetic recombination via triploids in all-hybrid populations of water frogs.
Speciation via interspecific hybrids is very rare in animals, as compared to plants. Whereas most plants overcome the problem of meiosis between different chromosome sets by tetraploidization, animal hybrids often escape hybrid sterility by clonal reproduction. This comes at the expense of genetic diversity and the ability to purge deleterious mutations. However, here we show that all-hybrid populations of diploid (LR) and triploid (LLR and LRR) water frogs (Pelophylax esculentus) have secondarily acquired sexual reproduction. First, in a crossing experiment analyzed with microsatellite markers, triploid hybrids of both sexes and genotypes (LLR and LRR) recombined their homospecific genomes. Second, the great majority of natural populations investigated had low multilocus linkage disequilibrium, indicating a high recombination rate. As predicted from mating system models, the L genome had constant, low levels of linkage disequilibrium, whereas linkage disequilibrium in the R genome showed a significant reduction with increasing proportion of recombining triploids. This direct evidence of sexual reproduction in P. esculentus calls for a change of the conventional view of hybridogens as clonally reproducing diploids. Rather, hybridogens can be independent sexually reproducing units with an evolutionary potential.


Molecular dynamics simulations of retinal in rhodopsin: from the dark-adapted state towards lumirhodopsin.
The formation of photointermediates and conformational changes observed in the retinal chromophore of bilayer-embedded rhodopsin during the early steps of the protein activation have been studied by molecular dynamics (MD) simulation. In particular, the lysine-bound retinal has been examined, focusing on its conformation in the dark-adapted state (10 ns) and on the early steps after the isomerization of the 11-cis bond to trans (up to 10 ns). The parametrization for the chromophore is based on a recent quantum study [Sugihara, M., Buss, V., Entel, P., Elstner, M., and Frauenheim, T. (2002) Biochemistry 41, 15259-15266] and shows good conformational agreement with recent experimental results. The isomerization, induced by switching the function governing the dihedral angle for the C11=C12 bond, was repeated with several different starting conformations. From the repeated simulations, it is shown that the retinal model exhibits a conserved activation pattern. The conformational changes are sequential and propagate outward from the C11=C12 bond, starting with isomerization of the C11=C12 bond, then a rotation of methyl group C20, and followed by increased fluctuations at the beta-ionone ring. The dynamics of these changes suggest that they are linked with photointermediates observed by spectroscopy. The exact moment when these events occur after the isomerization is modulated by the starting conformation, suggesting that retinal isomerizes through multiple pathways that are slightly different. The amplitudes of the structural fluctuations observed for the protein in the dark-adapted state and after isomerization of the retinal are similar, suggesting a subtle mechanism for the transmission of information from the chromophore to the protein.


Developmental delays in emotion regulation strategies in preschoolers with autism.
Children with autism spectrum disorder (ASD) commonly present with difficulty regulating negative emotions, which has been found to impact their behavioral and mental health. Little research has documented the strategies that children with ASD use to regulate their emotion to understand whether they use qualitatively different strategies to children without ASD, whether these are developmentally delayed, or both. Forty-four children with ASD and 29 typically-developing children (2-4 years) were given tasks designed to mimic everyday life experiences requiring children to manage low-level stress (e.g., waiting for a snack) and children's emotion regulation strategies were coded. Parents reported on their child's mental health, wellbeing, and self-development. The results suggest differences in using emotion regulation strategies in children with ASD, reflecting a delay, rather than a deviance when compared to those used by children without ASD. Only children with ASD relied on their family members for physical and communicative soothing; the typically developing children relied on people outside of their family for help regulating their emotion. More frequent approach/less frequent avoidance was related to a higher self-evaluation in both groups, but was only additionally related to higher self-recognition and autonomy in the ASD group. These findings help to identify important emotion regulation intervention targets for this population, including supporting communication with people outside of the family and independence. Autism Res 2017, 10: 1808-1822. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Results suggest that children with autism had more difficulty using communication strategies to manage stress only with people outside the family; they used these strategies with family members as often as children without autism. For all children, more task approach/less avoidance was related to children's higher self-evaluation. These findings suggest targeting communication with people outside of the family and personality development as appropriate intervention goals.


Error minimization in lateral inhibition circuits.
The pattern of the sensory bristles in the fruit fly Drosophila is remarkably reproducible. Each bristle arises from a sensory organ precursor (SOP) cell that is selected, through a lateral inhibition process, from a cluster of proneural cells. Although this process is well characterized, the mechanism ensuring its robustness remains obscure. Using probabilistic modeling, we defined the sources of error in SOP selection and examined how they depend on the underlying molecular circuit. We found that rapid inhibition of the neural differentiation of nonselected cells, coupled with high cell-to-cell variability in the timing of selection, is crucial for accurate SOP selection. Cell-autonomous interactions (cis interactions) between the Notch receptor and its ligands Delta or Serrate facilitate accurate SOP selection by shortening the effective delay between the time when the inhibitory signal is initiated in one cell and the time when it acts on neighboring cells, suggesting that selection relies on competition between cis and trans interactions of Notch with its ligands. The cis interaction model predicts that the increase in ectopic SOP selections observed with reduced Notch abundance can be compensated for by reducing the abundance of the Notch ligands Delta and Serrate. We validated this prediction experimentally by quantifying the frequency of ectopic bristles in flies carrying heterozygous null mutations of Notch, Delta, or Serrate or combinations of these alleles. We propose that susceptibility to errors distinguishes seemingly equivalent designs of developmental circuits regulating pattern formation.


Retrieval of profile information from airborne multiaxis UV-visible skylight absorption measurements.
A recent development in ground-based remote sensing of atmospheric constituents by UV-visible absorption measurements of scattered light is the simultaneous use of several horizon viewing directions in addition to the traditional zenith-sky pointing. The different light paths through the atmosphere enable the vertical distribution of some atmospheric absorbers, such as NO2, BrO, or O3, to be retrieved. This approach has recently been implemented on an airborne platform. This novel instrument, the airborne multiaxis differential optical absorption spectrometer (AMAXDOAS), has been flown for the first time. In this study, the amount of profile information that can be retrieved from such measurements is investigated for the trace gas NO2. Sensitivity studies on synthetic data are performed for a variety of representative measurement conditions including two wavelengths, one in the UV and one in the visible, two different surface spectral reflectances, various lines of sight (LOSs), and for two different flight altitudes. The results demonstrate that the AMAXDOAS measurements contain useful profile information, mainly at flight altitude and below the aircraft. Depending on wavelength and LOS used, the vertical resolution of the retrieved profiles is as good as 2 km near flight altitude. Above 14 km the profile information content of AMAXDOAS measurements is sparse. Airborne multiaxis measurements are thus a promising tool for atmospheric studies in the troposphere and the upper troposphere and lower stratosphere region.


Pharmacologically informed machine learning approach for identifying pathological states of unconsciousness via resting-state fMRI.
Determining the level of consciousness in patients with disorders of consciousness (DOC) remains challenging. To address this challenge, resting-state fMRI (rs-fMRI) has been widely used for detecting the local, regional, and network activity differences between DOC patients and healthy controls. Although substantial progress has been made towards this endeavor, the identification of robust rs-fMRI-based biomarkers for level of consciousness is still lacking. Recent developments in machine learning show promise as a tool to augment the discrimination between different states of consciousness in clinical practice. Here, we investigated whether machine learning models trained to make a binary distinction between conscious wakefulness and anesthetic-induced unconsciousness would then be capable of reliably identifying pathologically induced unconsciousness. We did so by extracting rs-fMRI-based features associated with local activity, regional homogeneity, and interregional functional activity in 44 subjects during wakefulness, light sedation, and unresponsiveness (deep sedation and general anesthesia), and subsequently using those features to train three distinct candidate machine learning classifiers: support vector machine, Extra Trees, artificial neural network. First, we show that all three classifiers achieve reliable performance within-dataset (via nested cross-validation), with a mean area under the receiver operating characteristic curve (AUC) of 0.95, 0.92, and 0.94, respectively. Additionally, we observed comparable cross-dataset performance (making predictions on the DOC data) as the anesthesia-trained classifiers demonstrated a consistent ability to discriminate between unresponsive wakefulness syndrome (UWS/VS) patients and healthy controls with mean AUC's of 0.99, 0.94, 0.98, respectively. Lastly, we explored the potential of applying the aforementioned classifiers towards discriminating intermediate states of consciousness, specifically, subjects under light anesthetic sedation and patients diagnosed as having a minimally conscious state (MCS). Our findings demonstrate that machine learning classifiers trained on rs-fMRI features derived from participants under anesthesia have potential to aid the discrimination between degrees of pathological unconsciousness in clinical patients.


Histopathologic Characterization of the Expression of Vascular Endothelial Growth Factor in a Case of Retinopathy of Prematurity Treated With Ranibizumab.
To characterize the expression of vascular endothelial growth factor (VEGF) in a patient with retinopathy of prematurity (ROP) treated with ranibizumab (Case 1) and compare it with a case of ROP without treatment (Case 2), a case of a premature baby without ROP (Case 3), and a case of a baby without history of ROP or prematurity (Case 4). Observational case series. The eyes of the deceased babies were removed postmortem and were sent to the Florida Lions Ocular Pathology Laboratory, where they were processed. The specimens were immunostained using an antibody against VEGF. All eyes except for the eyes in Case 4 disclosed positive VEGF staining. Positive staining was present within the nerve fiber layer, inner plexiform layer, and inner and outer nuclear layers and within the spindle-shaped cell population in the vanguard in Case 1. In the posterior pole, positive staining was only observed at the level of the nerve fiber layer. This case also demonstrated less positive staining when compared with Case 2, where positive staining was found within all layers of the retina. Less VEGF staining was observed within the retina of the eyes treated with ranibizumab when compared with the VEGF staining in Case 2. This supports the idea that anti-VEGF agents are effective in reducing the amount of VEGF present in the retina. Furthermore, the fact that some expression of VEGF remains in the immature retina after injection supports the idea that anti-VEGF agents can suppress uncontrolled neovascularization without completely blocking the vascular drive for the vascularization of the immature retina.


Global systematic review of Indigenous community-led legal interventions to control alcohol.
The national and subnational governments of most developed nations have adopted cost-effective regulatory and legislative controls over alcohol supply and consumption with great success. However, there has been a lack of scrutiny of the effectiveness and appropriateness of these laws in shaping the health-related behaviours of Indigenous communities, who disproportionately experience alcohol-related harm. Further, such controls imposed unilaterally without Indigenous consultation have often been discriminatory and harmful in practice. In this systematic review of quantitative evaluations of Indigenous-led alcohol controls, we aim to investigate how regulatory responses have been developed and implemented by Indigenous communities worldwide, and evaluate their effectiveness in improving health and social outcomes. We included articles from electronic databases MEDLINE, EMBASE, CINAHL, PsycINFO and Web of Science from inception to December 2015. Our search yielded 1489 articles from which 18 met the inclusion criteria. Controls were implemented in rural and remote populations of high-income nations. Communities employed a range of regulatory options including alcohol rationing, prohibition of sale, importation or possession, restrictions on liquor sold, times of sale or mode of sale, Indigenous-controlled liquor licensing, sin tax and traditional forms of control. 11 studies reported interventions that were effective in reducing crime, injury deaths, injury, hospitalisations or lowering per capita consumption. In six studies interventions were found to be ineffective or harmful. The results were inconclusive in one. Indigenous-led policies that are developed or implemented by communities can be effective in improving health and social outcomes.


Deep Supervision with Intermediate Concepts.
Recent data-driven approaches to scene interpretation predominantly pose inference as an end-to-end black-box mapping, commonly performed by a Convolutional Neural Network (CNN). However, decades of work on perceptual organization in both human and machine vision suggest that there are often intermediate representations that are intrinsic to an inference task, and which provide essential structure to improve generalization. In this work, we explore an approach for injecting prior domain structure into neural network training by supervising hidden layers of a CNN with intermediate concepts that normally are not observed in practice. We formulate a probabilistic framework which formalizes these notions and predicts improved generalization via this deep supervision method. One advantage of this approach is that we are able to train only from synthetic CAD renderings of cluttered scenes, where concept values can be extracted, but apply the results to real images. Our implementation achieves the state-of-the-art performance of 2D/3D keypoint localization and image classification on real image benchmarks including KITTI, PASCAL VOC, PASCAL3D+, IKEA, and CIFAR100. We provide additional evidence that our approach outperforms alternative forms of supervision, such as multi-task networks.


Defining transcriptional networks through integrative modeling of mRNA expression and transcription factor binding data.
Functional genomics studies are yielding information about regulatory processes in the cell at an unprecedented scale. In the yeast S. cerevisiae, DNA microarrays have not only been used to measure the mRNA abundance for all genes under a variety of conditions but also to determine the occupancy of all promoter regions by a large number of transcription factors. The challenge is to extract useful information about the global regulatory network from these data. We present MA-Networker, an algorithm that combines microarray data for mRNA expression and transcription factor occupancy to define the regulatory network of the cell. Multivariate regression analysis is used to infer the activity of each transcription factor, and the correlation across different conditions between this activity and the mRNA expression of a gene is interpreted as regulatory coupling strength. Applying our method to S. cerevisiae, we find that, on average, 58% of the genes whose promoter region is bound by a transcription factor are true regulatory targets. These results are validated by an analysis of enrichment for functional annotation, response for transcription factor deletion, and over-representation of cis-regulatory motifs. We are able to assign directionality to transcription factors that control divergently transcribed genes sharing the same promoter region. Finally, we identify an intrinsic limitation of transcription factor deletion experiments related to the combinatorial nature of transcriptional control, to which our approach provides an alternative. Our reliable classification of ChIP positives into functional and non-functional TF targets based on their expression pattern across a wide range of conditions provides a starting point for identifying the unknown sequence features in non-coding DNA that directly or indirectly determine the context dependence of transcription factor action. Complete analysis results are available for browsing or download at http://bussemaker.bio.columbia.edu/papers/MA-Networker/.


Ultrahigh resolution optical coherence tomography in non-exudative age related macular degeneration.
To describe the appearance of the non-exudative forms of age related macular degeneration (AMD) as imaged by ultrahigh resolution optical coherence tomography (UHR-OCT). A UHR-OCT ophthalmic imaging system, which utilises a femtosecond laser light source capable of approximately 3 mum axial resolution, was employed to obtain retinal cross sectional images of patients with non-exudative AMD. Observational studies of the resulting retinal images were performed. 52 eyes of 42 patients with the clinical diagnosis of non-exudative AMD were imaged using the UHR-OCT system. 47 of the 52 (90%) eyes had the clinical diagnosis of drusen and/or retinal pigment epithelial (RPE) changes. In these patients, three patterns of drusen were apparent on UHR-OCT: (1) distinct RPE excrescences, (2) a saw toothed pattern of the RPE, and (3) nodular drusen. On UHR-OCT, three eyes (6%) with a clinical diagnosis of non-exudative AMD had evidence of fluid under the retina or RPE. Two of these three patients had findings suspicious for subclinical choroidal neovascularisation on UHR-OCT. With the increased resolution of UHR-OCT compared to standard OCT, the involvement of the outer retinal layers are more clearly defined. UHR-OCT may allow for the detection of early exudative changes not visible clinically or by angiography.


Restoring confidence in vaccines by explaining vaccine safety monitoring: is a targeted approach needed?
Public trust in childhood vaccines is crucial to achieving adequate immunisation coverage to ensure population-level immunity. However, in the UK, immunisation uptake has been adversely affected by vaccine safety scares, such as those surrounding whooping cough and measles, mumps and rubella (MMR). It is our belief that greater public awareness of safety surveillance schemes may play a key role in improving trust in vaccine safety. Many parents of vaccination-age children are unaware of the procedures in place for postmarketing surveillance of vaccines. Thus, we propose specific steps for generating such awareness, such as assisting parents to report suspected adverse reactions directly to the Medicines and Healthcare products Regulatory Agency (MHRA) via the Yellow Card scheme, providing information about adverse reaction reporting with vaccination information packs, and displaying posters and leaflets to convey the message that patient concerns and experiences are taken seriously by the MHRA and to generate further awareness about the scheme. In addition, healthcare staff should be encouraged to report suspected adverse reactions relating to vaccine products. Unresolved issues about the scientific usefulness of data reported by parents and the potential for these steps to increase parental concern and expectations require further investigation.


Discovery and description of the "davtiani" morphotype for Teladorsagia boreoarcticus (Trichostrongyloidea: Ostertagiinae) abomasal parasites in muskoxen, Ovibos moschatus, and caribou, Rangifer tarandus, from the North American Arctic: implications for parasite faunal diversity.
Collections to explore helminth diversity among free-ranging ungulates in the North American Arctic revealed the occurrence of a third male, or " davtiani ," morphotype for Teladorsagia boreoarcticus . Designated as T. boreoarcticus forma (f.) minor B, the males occurred with T. boreoarcticus f. major and T. borearcticus f. minor A in endemic populations of muskoxen (Ovibos moschatus wardi) and barrenground caribou (Rangifer tarandus groenlandicus) on Victoria Island, Nunavut, Canada, and in muskoxen and Peary caribou ( Rangifer tarandus pearyi ) on Banks Island, Northwest Territories, Canada. These specimens differ from conspecific morphotypes in the structure of the genital cone and Sjöberg's organ. Relative to T. boreoarcticus f. minor A, specimens of T. boreoarcticus f. minor B are consistently smaller, and mean dimensions for the bursa and spicules do not overlap. The robust spicules are similar in form, particularly in the relative length of the dorsal and ventral processes, but mean total length is substantially less in specimens of T. boreoarcticus f. minor B. Differences that distinguish the minor morphotypes of T. boreoarcticus parallel those demonstrated for the T. trifurcata and T. davtiani morphotypes in association with T. circumcincta sensu stricto. New host and geographic records include the 3 morphotypes of T. boreoarcticus in muskoxen and Peary caribou from Banks Island and in barrenground caribou from Victoria Island. Recognition of the ubiquitous nature of cryptic species emphasizes the need to effectively develop and use our collections-based resources and museum archives to build a robust understanding of the biosphere. Field inventory should include provisions for integrative approaches that preserve specimens suitable for comparative morphology, multi-faceted molecular investigations, and population genetics.


Group B streptococcus in prosthetic hip and knee joint-associated infections.
The incidence of invasive group B streptococcus (GBS) infections in non-pregnant adults is increasing. Little is known about GBS in periprosthetic joint infections (PJIs). We aimed to analyse the clinical presentation of GBS PJI and its treatment in association with the outcome. The characteristics of 36 GBS PJIs collected from 10 centres were investigated. In 34 episodes, follow-up examination of ≥ 2 years was available, allowing treatment and outcome analysis. Most infections (75%) occurred ≥ 3 months after implantation. Most patients (91%) had at least one comorbidity; 69% presented with acute symptoms and 83% with damaged periprosthetic soft tissue. In 20 of 34 episodes debridement and retention of implant was attempted, but in five of these the prosthesis was ultimately removed. Hence, in 19 (56%) episodes, the implant was removed, including 14 immediate removals. In four episodes the removal was permanent. Penicillin derivatives and clindamycin were the most common antimicrobials administered (68%). In 94% the infection was cured, and in 82% functional mobility preserved. Debridement with implant retention was successful if the duration of symptoms was short, the prosthesis stable, and the tissue damage minor (10/10 vs 3/10 episodes, P = 0.003). Surgery that complied with a published algorithm was associated with a favourable outcome (P = 0.049).


Nisin penetration and efficacy against Staphylococcus aureus biofilms under continuous-flow conditions.
Biofilms may enhance the tolerance of bacterial pathogens to disinfectants, biocides and other stressors by restricting the penetration of antimicrobials into the matrix-enclosed cell aggregates, which contributes to the recalcitrance of biofilm-associated infections. In this work, we performed real-time monitoring of the penetration of nisin into the interior of Staphylococcus aureus biofilms under continuous flow and compared the efficacy of this lantibiotic against planktonic and sessile cells of S. aureus. Biofilms were grown in Center for Disease Control (CDC) reactors and the spatial and temporal effects of nisin action on S. aureus cells were monitored by real-time confocal microscopy. Under continuous flow, nisin caused loss of membrane integrity of sessile cells and reached the bottom of the biofilms within ~20 min of exposure. Viability analysis using propidium iodide staining indicated that nisin was bactericidal against S. aureus biofilm cells. Time-kill assays showed that S. aureus viability reduced 6.71 and 1.64 log c.f.u. ml-1 for homogenized planktonic cells in exponential and stationary phase, respectively. For the homogenized and intact S. aureus CDC biofilms, mean viability decreased 1.25 and 0.50 log c.f.u. ml-1, respectively. Our results demonstrate the kinetics of biofilm killing by nisin under continuous-flow conditions, and shows that alterations in the physiology of S. aureus cells contribute to variations in sensitivity to the lantibiotic. The approach developed here could be useful to evaluate the antibiofilm efficacy of other bacteriocins either independently or in combination with other antimicrobials.


Accuracy of an automated blood pressure device in stable inpatients: optimum vs routine use.
Despite widespread use of the automated blood pressure (BP) device (IVAC model 4200, IVAC Corporation, San Diego, Calif), there is little formal validation in the literature on its accuracy. To assess the accuracy of the IVAC 4200 device, both under standardized conditions and as routinely used by ward staff, compared with the true indirect BP measured by mercury manometer (MM). One hundred forty-five stable inpatients were randomly selected for BP measurements by 3 randomly ordered protocols: (1) MM performed by certified investigators, (2) IVAC 4200 BP performed by trained investigators (research automated [RA]), and (3) IVAC 4200 BP performed by ward personnel (ward automated [WA]). For RA compared with MM ("true" indirect BP), 59% of systolic and 54% of diastolic readings were within 5 mm Hg and 83% of systolic and 86% of diastolic were within 10 mm Hg for a British Hypertension Society grade C for both. For WA compared with MM, 40% of systolic and 50% of diastolic readings were within 5 mm Hg and 70% of systolic and 80% of diastolic readings were within 10 mm Hg for British Hypertension Society grades D and C, respectively. The presence of arrhythmias and/or low K5 values (fifth phase of Korotkoff sounds <30 mm Hg) significantly increased the inaccuracy for diastolic values. Inappropriate cuff selection significantly increased inaccuracy of systolic BP (WA vs MM). The IVAC 4200 yields substandard estimates of systolic and diastolic BP even under standardized, thus optimum conditions. The presence of arrhythmias or low K5 values and the selection of inappropriate cuff size by the ward staff also contributed to inaccuracy.


Frequent Detection and Genetic Diversity of Human Bocavirus in Urban Sewage Samples.
The prevalence and genetic diversity of human bocaviruses (HBoVs) in sewage water samples are largely unknown. In this study, 134 raw sewage samples from 25 wastewater treatment plants (WTPs) in Italy were analyzed by nested PCR and sequencing using species-specific primer pairs and broad-range primer pairs targeting the capsid proteins VP1/VP2. A large number of samples (106, 79.1 %) were positive for HBoV. Out of these, 49 were classified as HBoV species 2, and 27 as species 3. For the remaining 30 samples, sequencing results showed mixed electropherograms. By cloning PCR amplicons and sequencing, we confirmed the copresence of species 2 and 3 in 29 samples and species 2 and 4 in only one sample. A real-time PCR assay was also performed, using a newly designed TaqMan assay, for quantification of HBoVs in sewage water samples. Viral load quantification ranged from 5.51E+03 to 1.84E+05 GC/L (mean value 4.70E+04 GC/L) for bocavirus 2 and from 1.89E+03 to 1.02E+05 GC/L (mean value 2.27E+04 GC/L) for bocavirus 3. The wide distribution of HBoV in sewages suggests that this virus is common in the population, and the most prevalent are the species 2 and 3. HBoV-4 was also found, representing the first detection of this species in Italy. Although there is no indication of waterborne transmission for HBoV, the significant presence in sewage waters suggests that HBoV may spread to other water environments, and therefore, a potential role of water in the HBoV transmission should not be neglected.


Insulin therapy of hyperglycemia in intensive care.
Hyperglycemia is common among patients admitted to intensive care units, and carries the risk for complications and prolonged ICU stay. With intensive insulin control of blood glucose, morbidity and mortality can be reduced. To determine whether intensive or conventional insulin control of blood glucose in hyperglycemic ICU patients correlated with the prognosis. Following admission to the ICU, hyperglycemic patients were randomly assigned to a group treated intensively with insulin targeting glucose at 110-140 mg/dl, or to a conventional insulin therapy group, where glucose, upon exceeding 200 mg/dl, was controlled at 140-200 mg/dl. Rates of morbidity and mortality, hypoglycemic episodes, and insulin dosage were compared. In the 41 patients treated intensively with insulin the glucose level was 142 +/- 14 mg/dl, as compared to 174+/-20 mg/dl in the 48 patients on conventional insulin treatment. Both groups were similar in age, acute physiology and chronic health evaluation score. Morbidity was also similar, except for increased vascular damage in the conventional treatment group and slightly shorter ICU stay in the intensive therapy group. Both groups had similar in-ICU, in-hospital, and 28 day mortalities, and similar rates of hypoglycemic episodes. The daily dosage of insulin was significantly higher with the conventional treatment (P= 0.004). Intensive insulin treatment did not affect the mortality or morbidity rates in ICU patients. The increased insulin dosage of conventional insulin treatment was attributable to the group's higher prevalence of diabetes. Future studies should address this bias and determine the optimal glucose target.


Quantitative plant proteomics.
Quantitation is an inherent requirement in comparative proteomics and there is no exception to this for plant proteomics. Quantitative proteomics has high demands on the experimental workflow, requiring a thorough design and often a complex multi-step structure. It has to include sufficient numbers of biological and technical replicates and methods that are able to facilitate a quantitative signal read-out. Quantitative plant proteomics in particular poses many additional challenges but because of the nature of plants it also offers some potential advantages. In general, analysis of plants has been less prominent in proteomics. Low protein concentration, difficulties in protein extraction, genome multiploidy, high Rubisco abundance in green tissue, and an absence of well-annotated and completed genome sequences are some of the main challenges in plant proteomics. However, the latter is now changing with several genomes emerging for model plants and crops such as potato, tomato, soybean, rice, maize and barley. This review discusses the current status in quantitative plant proteomics (MS-based and non-MS-based) and its challenges and potentials. Both relative and absolute quantitation methods in plant proteomics from DIGE to MS-based analysis after isotope labeling and label-free quantitation are described and illustrated by published studies. In particular, we describe plant-specific quantitative methods such as metabolic labeling methods that can take full advantage of plant metabolism and culture practices, and discuss other potential advantages and challenges that may arise from the unique properties of plants.


Genomic insights into strategies used by Xanthomonas albilineans with its reduced artillery to spread within sugarcane xylem vessels.
Xanthomonas albilineans causes leaf scald, a lethal disease of sugarcane. X. albilineans exhibits distinctive pathogenic mechanisms, ecology and taxonomy compared to other species of Xanthomonas. For example, this species produces a potent DNA gyrase inhibitor called albicidin that is largely responsible for inducing disease symptoms; its habitat is limited to xylem; and the species exhibits large variability. A first manuscript on the complete genome sequence of the highly pathogenic X. albilineans strain GPE PC73 focused exclusively on distinctive genomic features shared with Xylella fastidiosa-another xylem-limited Xanthomonadaceae. The present manuscript on the same genome sequence aims to describe all other pathogenicity-related genomic features of X. albilineans, and to compare, using suppression subtractive hybridization (SSH), genomic features of two strains differing in pathogenicity. Comparative genomic analyses showed that most of the known pathogenicity factors from other Xanthomonas species are conserved in X. albilineans, with the notable absence of two major determinants of the "artillery" of other plant pathogenic species of Xanthomonas: the xanthan gum biosynthesis gene cluster, and the type III secretion system Hrp (hypersensitive response and pathogenicity). Genomic features specific to X. albilineans that may contribute to specific adaptation of this pathogen to sugarcane xylem vessels were also revealed. SSH experiments led to the identification of 20 genes common to three highly pathogenic strains but missing in a less pathogenic strain. These 20 genes, which include four ABC transporter genes, a methyl-accepting chemotaxis protein gene and an oxidoreductase gene, could play a key role in pathogenicity. With the exception of hypothetical proteins revealed by our comparative genomic analyses and SSH experiments, no genes potentially involved in any offensive or counter-defensive mechanism specific to X. albilineans were identified, supposing that X. albilineans has a reduced artillery compared to other pathogenic Xanthomonas species. Particular attention has therefore been given to genomic features specific to X. albilineans making it more capable of evading sugarcane surveillance systems or resisting sugarcane defense systems. This study confirms that X. albilineans is a highly distinctive species within the genus Xanthomonas, and opens new perpectives towards a greater understanding of the pathogenicity of this destructive sugarcane pathogen.


Nurture trumps nature in a longitudinal survey of salivary bacterial communities in twins from early adolescence to early adulthood.
Variation in the composition of the human oral microbiome in health and disease has been observed. We have characterized inter- and intra-individual variation of microbial communities of 107 individuals in one of the largest cohorts to date (264 saliva samples), using culture-independent 16S rRNA pyrosequencing. We examined the salivary microbiome in up to three time-points during 10 yr spanning adolescence, and determined the influence of human genotype, gender, age, and weight class. Participants, including 27 monozygotic and 18 dizygotic twin pairs, were sampled mainly at ages 12-13, 17-18, and 22-24, with a few sampled as early as 8 yr of age. In contrast to gut or skin microbiomes, there is a core genus-level salivary microbiome. Individuals are more similar to themselves and their co-twins in the 12-17 and in the 17-22 cohorts than to the whole sample population, but not over the 10 yr from 12 to 22; and monozygotic twin pairs are statistically not more similar than dizygotic twin pairs. The data are most consistent with shared environment serving as the main determinant of microbial populations. Twins resemble each other more closely than the whole population at all time-points, but become less similar to each other when they age and no longer cohabit. Several organisms have age-specific abundance profiles, including members of the genera Veillonella, Actinomyces, and Streptococcus. There is no clear effect of weight class and gender. The results of this work will provide a basis to further study oral microbes and human health.


Does repeatedly viewing overweight versus underweight images change perception of and satisfaction with own body size?
Body dissatisfaction is associated with subsequent eating disorders and weight gain. One-off exposure to bodies of different sizes changes perception of others' bodies, and perception of and satisfaction with own body size. The effect of repeated exposure to bodies of different sizes has not been assessed. We randomized women into three groups, and they spent 5 min twice a day for a week completing a one-back task using images of women modified to appear either under, over, or neither over- nor underweight. We tested the effects on their perception of their own and others' body size, and satisfaction with own size. Measures at follow-up were compared between groups, adjusted for baseline measurements. In 93 women aged 18-30 years, images of other women were perceived as larger following exposure to underweight women (and vice versa) (p < 0.001). There was no evidence for a difference in our primary outcome measure (visual analogue scale own size) or in satisfaction with own size. Avatar-constructed ideal (p = 0.03) and avatar-constructed perceived own body size (p = 0.007) both decreased following exposure to underweight women, possibly due to adaptation affecting how the avatar was perceived. Repeated exposure to different sized bodies changes perception of the size of others' bodies, but we did not find evidence that it changes perceived own size.


Similarities and differences of graduate entry-level competencies of chiropractic councils on education: a systematic review.
Councils of Chiropractic Education (CCE) indirectly influence patient care and safety through their role of ensuring the standards of training delivered by chiropractic educational institutions. This is achieved by CCEs defining competence and creating lists of descriptive statements to establish the necessary standards for students to attain before graduating. A preliminary review suggested that these definitions and descriptive lists lacked consensus. This creates the potential for variations in standards between the CCE jurisdictions and may compromise patient care and safety and also inter-jurisdictional mutual recognition. The purposes of this study were 1) to investigate similarities and differences between the CCEs in their definitions of competence, domains of educational competencies, components of the domains of competencies, as represented by assessment and diagnosis, ethics, intellectual development, and 2) to make recommendations, if significant deficiencies were found. We undertook a systematic review of the similarities and differences between various CCEs definitions of competence and the descriptive lists of educational competencies they have adopted. CCEs were selected on the basis of WHO recommendations. Blinded investigators selected the data from CCE websites and direct contact with CCEs. This information was tabulated for a comparative analysis. All CCEs' definitions of competence included the elements of "knowledge", "skills" and "attitudes" whereas only one CCE included the expected "abilities" element. The educational application of the definition of competency among CCEs varied. A high level of similarity when comparing the domains of competence adopted by CCEs was found despite variations in the structure. Differences between CCEs became increasingly apparent when the three selected representative domains were compared. CCEs were found to stipulate varying levels of prescriptiveness for graduate entry level standards. A series of recommendations are proposed to create uniform and high quality international standards of care. Future research should compare the levels of CCEs enforcement of standards to see if similarities and differences exist.


Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells.
Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyte-erythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGFβ signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term self-renewal were impaired as a consequence of activated TGFβ signaling. In accordance, TGFβ levels in the BM extracellular fluid were elevated and mesenchymal stromal cells (MSCs) had a reduced capacity to support long-term hematopoiesis of HSPCs that completely recovered on blockade of TGFβ signaling. Furthermore, we found defective actin assembly and down-regulation of the adhesion receptor CD44 in MM HSPCs functionally reflected by impaired migration and adhesion. Still, transplantation into myeloma-free NOG mice revealed even enhanced engraftment and normal differentiation capacities of MM HSPCs, which underlines that functional impairment of HSPCs depends on MM-related microenvironmental cues and is reversible. Taken together, these data implicate that hematopoietic suppression in MM emerges from the HSPCs as a result of MM-related microenvironmental alterations.


The clinical challenge of bridging anticoagulation with low-molecular-weight heparin in patients with mechanical prosthetic heart valves: an evidence-based comparative review focusing on anticoagulation options in pregnant and nonpregnant patients.
Recent labeling changes for enoxaparin, a low-molecular-weight heparin (LMWH), have prompted a reexamination of its role in patients with mechanical prosthetic heart valves (MPHVs). Healthcare providers are faced with the challenge of weighing favorable trial results with LMWHs and balancing their clinical experiences with these agents as a bridge to oral anticoagulation in patients with prosthetic heart valves. This review will provide evidence-based guidance on issues surrounding the use of LMWH that require bridging anticoagulant therapy in the setting of cardiac surgery (MPHVs), cardiovascular disease, and during temporary interruption of oral anticoagulants in patients requiring periprocedural bridging therapy. A Medline search was conducted of articles appearing in the medical literature published in English between 1992 and 2004. Approximately 120 clinical trials, case reports, editorials, and/or guideline statements were retrieved and reviewed by the authors as to their relevance for the subject under review, ie, bridging anticoagulation in patients with MPHVs. Approximately 80 of these publications were selected for detailed review, analysis, and discussion in a consensus format. This review addresses the controversy surrounding the divergence between the new labeling recommending against the use of LMWH in patients with MPHVs as well as the ongoing clinical experience and evidence in the medical literature. The clinical challenges in the use of LMWH and unfractioned heparin (UFH) in pregnant patients with MPHVs are presented; the evidence for LMWHs in nonpregnant patients with prosthetic valves is described; and the role of LMWH for bridging immediately after mechanical valve surgery and its periprocedural and perioperative uses are discussed. Based on an expert consensus panel, clinical algorithms for the use of LMWH in pregnant and nonpregnant patients with MPHVs are also illustrated. Based on the available data sets, clinical trials, reviews, and registry data, the evidence suggests that LMWH compared to UFH may be a safe and effective agent in patients with MPHVs. Future large-scale, randomized trials are warranted.


Analytic and clinical utility of a next-generation, highly sensitive cardiac troponin I assay for early detection of myocardial injury.
Improvements in cardiac troponin (cTn) assays have increased the rapidity with which clinicians can identify patients with changing cTn concentrations (rise or fall) indicative of acute myocardial injury. The aim of the present study was to characterize a new, high-sensitivity cTnI (hs-cTnI) assay and examine whether increased sensitivity can result in still earlier detection of evolving injury. We determined the limit of detection, precision profiles, and preliminary estimates of the 99th percentile for the Beckman Coulter hs-cTnI assay in 125 healthy individuals (age <55 years, 54% male). We compared AccuTnI and hs-cTnI to assess whether change criteria for early concentration changes (i.e., > or =3SD for low concentrations and 20% difference for concentrations >0.10 microg/L) were exceeded in the first 2 specimens (median time between specimens, 1 h; 25th-75th percentile, 1-3 h) from subjects with symptoms suggestive of cardiac ischemia (n = 290). The limit of detection for the hs-cTnI assay was 2.06 ng/L, and the 20% CV and 10% CV concentrations were 2.95 and 8.66 ng/L, respectively. The preliminary 99th percentile estimates in lithium heparin, serum, and EDTA plasma were 9.20, 8.00, and 8.60 ng/L, respectively. In 108 patients with myocardial injury based on the peak AccuTnI concentration, applying the change criteria on the 2 earliest specimens identified 81% (95% CI 73%-88%) of patients using the hs-cTnI assay compared to 62% (53%-71%) using the AccuTnI assay (P < 0.001). Although more extensive validation studies are required, this Beckman Coulter hs-cTnI assay appears to detect patients with evolving myocardial injury earlier.


Listeria and autophagy escape: involvement of InlK, an internalin-like protein.
Autophagy is a cell-autonomous mechanism of innate immunity that protects the cytosol against bacterial infection. Invasive bacteria, including Listeria monocytogenes, have thus evolved strategies to counteract a process that limits their intracellular growth. ActA is a surface protein produced by L. monocytogenes to polymerize actin and mediate intra- and intercellular movements, which plays a critical role in autophagy escape. We have recently investigated the role of another L. monocytogenes surface protein, the internalin InlK, in the infection process. We showed that in the cytosol of infected cells, InlK interacts with the Major Vault Protein (MVP), the main component of cytoplasmic ribonucleoprotein particles named vaults. Although MVP has been implicated in a variety of key cellular process, its role remains elusive. We demonstrated that L. monocytogenes is able, via InlK, to decorate its surface with MVP in order to escape autophagic recognition. Strikingly, this new strategy used by L. monocytogenes to avoid autophagy is independent of ActA, suggesting that InlK-MVP interactions and actin polymerization are two processes that favor in the same manner the infection process. Understanding the role of MVP may provide new insights into bacterial infection and autophagy.


Influence of glass-ceramic thickness on Hertzian and bulk fracture mechanisms.
The objective of this study was to test the hypothesis that bulk fracture of glass-ceramic disks of variable thickness originates at the inner, resin-bonded surface and is dominant over Hertzian fracture at the lower range of thickness values. Eight groups of seven glass-ceramic disks (Dicor, Dentsply), 12 mm in diameter with thicknesses ranging from 0.4 to 2.4 mm, were cast, cerammed (to produce approximately 55 vol% of tetrasilicic fluormica crystals), air abraded, etched, and silane coated according to the manufacturer's instructions. The disks were bonded to an epoxy die substrate (with an elastic modulus comparable to that of dentin) using a light-activated resin cement. The bonded samples were supported on a flat surface and loaded at the top center of each disk until crack initiation occurred. All disks exhibited an initial crack within the bonded surface. Three randomly selected samples for each thickness were loaded beyond the point of crack initiation until Hertzian failure occurred. Although the crack-initiation force increased with increasing thickness, the failure stress approached a maximum level at a thickness of approximately 1.6 mm. These results suggest that the estimated maximum occlusal load for each patient should be used to select the minimum thickness of ceramic crowns rather than using the arbitrary traditional selection of a 1.5-mm thickness. The authors conclude that bulk fracture is initiated within the bonded surface of a glass-ceramic specimen (for samples 0.4 to 2.4 mm in thickness) when the glass-ceramic is supported by a substrate with an elastic modulus similar to that of dentin. Furthermore, a Hertzian failure mechanism is unlikely to cause bulk fracture for these conditions.


Significance of metastasis detected by molecular techniques in sentinel nodes of patients with gastrointestinal cancer.
The clinical significance of micrometastasis in sentinel nodes (SNs) may differ in various organs. In particular, the prognostic value of SN micrometastases detected by reverse transcriptase-polymerase chain reaction (RT-PCR) is still controversial. We investigated the diagnostic and therapeutic significance of nodal molecular metastasis detected by nested RT-PCR for cytokeratin (CK) 19 mRNA in gastrointestinal cancer. In 51 cases with GI tract cancer treated by standard curative resection, SNs were identified by a radio-guided method. In 10 of 51 patients, 25 SNs and 3 non-SNs were histologically negative and RT-PCR positive. Three non-SNs with positive CK19 mRNA were randomly sampled from the same basin where histologically positive SNs were identified. Immunohistochemical analysis of six additional step sections obtained at 30- micro m intervals with use of an anticytokeratin antibody showed clearly recognizable histological metastases in 4 of 25 histologically negative/RT-PCR-positive SNs (16%). In one case of esophageal squamous cell carcinoma with nodal micrometastasis identified by CK19 RT-PCR, extranodal local recurrence in the SN basin (left supraclavicular basin) was observed 6 months postoperatively. These findings suggest that nodal micrometastasis detected by nested RT-PCR has some clinical significance in GI cancer. Molecular assessment of the SN may be a valuable tool to complement routine histological examination for GI cancers.


Acousto-optic tunable filter sidelobe analysis and reduction with telecentric confocal optics.
The acousto-optic tunable filter (AOTF) has optical sidelobes that are due to the acoustic field produced by the transducer. These sidelobes were analyzed by wave-vector phase matching between the optical and acoustic fields, which correlated with measurements made with a TeO2 AOTF. A white-light point source was filtered and imaged, showing reasonably large and slowly decreasing sidelobes covering a large spectral range. This effect reduces the image quality of an AOTF system by producing faint secondary images of bright objects. The image quality can be improved with a telecentric confocal optical arrangement in which the angular shift of the sidelobes is greatly reduced, producing a much sharper image. This effect was also demonstrated experimentally with the point source.


Erdosteine prevents bleomycin-induced pulmonary fibrosis in rats.
Oxidative stress plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. Therefore, erdosteine, an antioxidant, is expected to have an inhibitor potential against the disease. Rats were given one dose of bleomycin in pulmonary fibrosis groups and saline in controls. The first dose of oral erdosteine (10 mg/kg/day) was given 2 days before the bleomycin injection to achieve the plateau level in blood and continued until killing. At day 14, fibrotic changes were evaluated, using Aschoft's criteria and lung hydroxyproline content. Bleomycin produced a fivefold increase in fibrosis score that was decreased by 87% by erdosteine (P>0.001) and almost twofold increases in hydroxyproline content which were completely prevented by erdosteine. Myeloperoxidase activities and MDA levels, which were significantly higher in the bleomycin group, were then significantly attenuated by erdosteine. These results revealed that oral erdosteine may prevent the development of acute pulmonary inflammation caused by bleomycin injection via the repression of neutrophil accumulation and lipid peroxidation, resulting in the inhibition of subsequent lung fibrosis.


The Changing Epidemiology of Human T-Cell Lymphotropic Virus Type 1 Infection in Peruvian Female Sex Workers, 1993-2010.
Human T-cell lymphotropic virus type 1 (HTLV-1) was the first human retrovirus to be reported and is associated with neoplastic, neurological, autoimmune, and infectious complications. HTLV-1 is endemic in Peru, with the highest prevalence reported among commercial sex workers. Seroprevalence data collected from Peruvian female sex workers (FSWs) working in Callao over three study periods between 1993 and 2010 were used to examine the secular trend in HTLV-1 prevalence. Between 1993 and 2010, the prevalence of HTLV-1 decreased significantly from 14.5% to 3.1% (P < 0.01). The prevalence of HTLV-1 seropositivity differed significantly by birth cohort (1922-1959, 1960-1969, 1970-1979, and 1980-1992), and for each of the four birth cohorts, the prevalence did not significantly decrease by screening year (P > 0.07). There were no cases of HTLV-1 detected among FSW born after 1979 (N = 224). Participant characteristics associated with HTLV-1 seropositivity were birth in the Andes Mountains region, age, increased time in sex work, younger age of starting sex work, and human immunodeficiency virus (HIV) seropositivity. The secular trend in declining prevalence persisted after adjustment for age, time in sex work, place of birth, and HIV serostatus, with the odds of HTLV-1 infection decreasing approximately 16% per year (adjusted odds ratio = 0.84, 95% confidence interval = 0.78, 0.90). The increasing use of condoms by later birth cohorts noted in our analysis, as well as the increasing availability of free condoms provided by the Peruvian government-which started in the late 1980s before this study-may have been responsible for declining HTLV seroprevalence.


Potential role of parasitism in the evolution of mutualism in astigmatid mites: Hemisarcoptes cooremani as a model.
Phoresy is a symbiotic interaction that results in dispersal, benefiting the relocated organism without negatively impacting the phoretic host. It has long been considered that phoresy among astigmatid mites is somehow an intermediate precursor to the evolution of parasitism within the group. In astigmatid mites, only the heteromorphic deutonymph (hypopode) participates in phoretic dispersal, and the plesiomorphic hypopode may be the key to understanding the dynamics of the evolution of that parasitism. Hypopodes of Hemisarcoptes cooremani (Acari: Acariformes) and their phoretic beetle host Chilocorus cacti (Coleoptera: Coccinellidae) have become the experimental focus for studies concerned with the potential forces that influence the transition of a free-living life style into various coevolved relationships. Previous radiolabeling studies applied to H. cooremani and C. cacti determined that hypopodes of H. cooremani acquired resources from adults of C. cacti while in transit, negating the paradigm that the heteromorphy was purely phoretic. To further probe this relationship, we tested whether materials could be passed from the mites to their hosts. We report here a study using a tritium radiolabel, which indicated that beetles also acquire resources from the hypopodes. These results have implications for understanding the complex relationship between H. cooremani and C. cacti. We propose that this relationship should now correctly be defined as mutualistic (not phoretic) and develop a general model for the potential role of parasitism in the evolution of mutualism among the Astigmata.


Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses.
DNA mismatch repair (MMR) is an efficient system for the detection and repair of mismatched and unpaired bases in DNA. Deficiencies in MMR are commonly found in both hereditary and sporadic colorectal cancers, as well as in cancers of other tissues. Because fluorinated thymidine analogues (which through their actions might generate lesions recognizable by MMR) are widely used in the treatment of colorectal cancer, we investigated the role of MMR in cellular responses to 5-fluorouracil and 5-fluoro-2'-deoxyuridine (FdUrd). Human MLH1(-) and MMR-deficient HCT116 colon cancer cells were 18-fold more resistant to 7.5 microM 5-fluorouracil (continuous treatment) and 17-fold more resistant to 7.5 microM FdUrd in clonogenic survival assays compared with genetically matched, MLH1(+) and MMR-proficient HCT116 3-6 cells. Likewise, murine MLH1(-) and MMR-deficient CT-5 cells were 3-fold more resistant to a 2-h pulse of 10 microM FdUrd than their MLH1(+) and MMR-proficient ME-10 counterparts. Decreased cytotoxicity in MMR-deficient cells after treatment with various methylating agents and other base analogues has been well reported and is believed to reflect a tolerance to DNA damage. Synchronized HCT116 3-6 cells treated with a low dose of FdUrd had a 2-fold greater G(2) cell cycle arrest compared with MMR-deficient HCT116 cells, and asynchronous ME-10 cells demonstrated a 4-fold greater G(2) arrest after FdUrd treatment compared with CT-5 cells. Enhanced G(2) arrest in MMR-proficient cells in response to other agents has been reported and is believed to allow time for DNA repair. G(2) cell cycle arrest as determined by propidium iodide staining was not a result of mitotic arrest, but rather a true G(2) arrest, as indicated by elevated cyclin B1 levels and a lack of staining with mitotic protein monoclonal antibody 2. Additionally, p53 and GADD45 levels were induced in FdUrd-treated HCT116 3-6 cells. DNA double-strand break (DSB) formation was 2-fold higher in MMR-proficient HCT116 3-6 cells after FdUrd treatment, as determined by pulsed-field gel electrophoresis. The formation of DSBs was not the result of enhanced apoptosis in MMR-proficient cells. FdUrd-mediated cytotoxicity was caused by DNA-directed and not RNA-directed effects, because administration of excess thymidine (and not uridine) prevented cytotoxicity, cell cycle arrest, and DSB formation. hMLH1-dependent responses to fluoropyrimidine treatment, which may involve the action of p53 and the formation of DSBs, clearly have clinical relevance for the use of this class of drugs in the treatment of tumors with MMR deficiencies.


N- and C-terminal modifications of nociceptin/orphanin FQ generate highly potent NOP receptor ligands.
Previous structure-activity studies on nociceptin/orphanin FQ (N/OFQ) identified [Phe(1)Psi(CH(2)NH)Gly(2)]N/OFQ(1-13)-NH(2) and [Nphe(1)]N/OFQ(1-13)-NH(2) as a N/OFQ peptide receptor (NOP) partial agonist and pure antagonist, respectively. The addition of fluorine to the Phe(4) or the insertion of a further pair of basic amino acids Arg(14)-Lys(15) generate potent agonists. On the basis of these findings, we combined in the N/OFQ-NH(2) template the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) that increase the agonist potency with those conferring partial agonist (Phe(1)Psi(CH(2)NH)Gly(2)) or pure antagonist (Nphe(1)) properties. Twelve peptides were synthesized and pharmacologically evaluated in Chinese hamster ovary cells expressing the human recombinant NOP and in electrically stimulated mouse vas deferens and guinea pig ileum assays. All peptides behaved as NOP ligands; the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) increased ligand affinity/potency. Peptides with the normal Phe(1)-Gly(2) peptide bond behaved as full agonists, and those with the Phe(1)Psi(CH(2)NH)Gly(2) modification behaved as partial agonists, while those with the Nphe(1) modification behaved as partial agonists or pure antagonists depending on the presence or absence of the (pF)Phe(4) modification, respectively. The full agonist [(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), the partial agonist [Phe(1)Psi(CH(2)NH)Gly(2),(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), and the pure antagonist [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) represent the most potent peptide ligands for NOP.


Wilms tumor suppressor 1 (WT1) and early growth response 1 (EGR1) are regulators of STIM1 expression.
Store-operated calcium entry (SOCE) is a key evolutionarily conserved process whereby decreases in endoplasmic reticulum Ca(2+) content lead to the influx of Ca(2+) across the plasma membrane. How this process is regulated in specific tumor cell types is poorly understood. In an effort to address this concern, we obtained and tested primary Wilms tumor cells, finding no detectable SOCE in this cell type. Analysis of the expression levels of STIM1 and ORAI1 (the molecular mediators of SOC) revealed poor STIM1 expression. Analysis of the STIM1 promoter using the TESS search system (University of Pennsylvania) revealed four putative response elements to the zinc-finger proteins WT1 (Wilms tumor suppressor 1) and EGR1 (early growth response 1). Either overexpression of WT1 or knockdown of EGR1 resulted in loss of STIM1 expression and a resultant decrease in SOCE. Furthermore, examination of Egr1 knock-out animals revealed loss of STIM1 expression in multiple tissues. Finally, using chromatin immunoprecipitation, we reveal direct binding of both WT1 and EGR1 to putative response elements located within 500 bp of the transcriptional start site of STIM1. Considering that WT1 and EGR1 are well described oncogenes and tumor suppressors, these observations may reveal new mechanisms responsible for distinct Ca(2+) signals in cancer cells.


Community-acquired bacterial pneumonia in adults: An update.
Community-acquired pneumonia (CAP) is the prominent cause of mortality and morbidity with important clinical impact across the globe. India accounts for 23 per cent of global pneumonia burden with case fatality rates between 14 and 30 per cent, and Streptococcus pneumoniae is considered a major bacterial aetiology. Emerging pathogens like Burkholderia pseudomallei is increasingly recognized as an important cause of CAP in Southeast Asian countries. Initial management in the primary care depends on clinical assessment while the hospitalized patients require combinations of clinical scores, chest radiography and various microbiological and biomarker assays. This comprehensive diagnostic approach together with additional sampling and molecular tests in selected high-risk patients should be practiced. Inappropriate therapy in CAP in hospitalized patients lengthens hospital stay and increases cost and mortality. In addition, emergence of multidrug-resistant organisms poses tough challenges in deciding empirical as well as definitive therapy. Developing local evidence on the cause and management should be a priority to improve health outcomes in CAP.


An adaptive link position tracking controller for rigid-link flexible-joint robots without velocity measurements.
This paper presents an adaptive partial state feedback controller for rigid-link flexible-joint (RLFJ) robots. The controller compensates for parametric uncertainty throughout the entire mechanical system while only requiring measurement of link position and actuator position. To eliminate the need for measuring link velocity and actuator velocity a set of filters is utilized as a surrogate for the unmeasurable quantities. Based on this set of filters, an adaptive integrator backstepping procedure is used to develop a torque input controller which guarantees semiglobal asymptotic link position tracking while also ensuring that all signals remain bounded during closed-loop operation. Simulation results for a two-link RLFJ robot are utilized to validate the performance of the proposed controller.


CLAVATA1 dominant-negative alleles reveal functional overlap between multiple receptor kinases that regulate meristem and organ development.
The CLAVATA1 (CLV1) receptor kinase controls stem cell number and differentiation at the Arabidopsis shoot and flower meristems. Other components of the CLV1 signaling pathway include the secreted putative ligand CLV3 and the receptor-like protein CLV2. We report evidence indicating that all intermediate and strong clv1 alleles are dominant negative and likely interfere with the activity of unknown receptor kinase(s) that have functional overlap with CLV1. clv1 dominant-negative alleles show major differences from dominant-negative alleles characterized to date in animal receptor kinase signaling systems, including the lack of a dominant-negative effect of kinase domain truncation and the ability of missense mutations in the extracellular domain to act in a dominant-negative manner. We analyzed chimeric receptor kinases by fusing CLV1 and BRASSINOSTEROID INSENSITIVE1 (BRI1) coding sequences and expressing these in clv1 null backgrounds. Constructs containing the CLV1 extracellular domain and the BRI1 kinase domain were strongly dominant negative in the regulation of meristem development. Furthermore, we show that CLV1 expressed within the pedicel can partially replace the function of the ERECTA receptor kinase. We propose the presence of multiple receptors that regulate meristem development in a functionally related manner whose interactions are driven by the extracellular domains and whose activation requires the kinase domain.


Rabies in South Africa between 1993 and 2005--what has been achieved?
Epidemiological analyses in time and space were carried out on all animal rabies cases reported in South Africa for the period 1993-2005. Validation of state veterinary records was done by comparing these with data from the 2 diagnostic laboratories mandated to test for animal rabies. A discrepancy between state veterinary records and laboratory results was found and is discussed. The total number of positive rabies cases reported to veterinary services between 1993 and 2005 was 4767. During this period the proportion of domestic animal rabies had increased to 79% (19% more than for the period 1980-1994), with 59% of the total cases being domestic dogs. Of the domestic animal cases 74 % were canine and only 21% were bovine; when compared to the data from 1985-1994 there was an increase of 6% of rabies in canine and a 3% decrease in bovine cases. A disturbing trend is the increase in the incidence of rabies over the last 16 years in provinces neighbouring KwaZulu-Natal province, where rabies used to be concentrated, and in Limpopo province.


Prosthetic management for edentulous glossectomy patients.
The prosthetic treatment of edentulous glossectomy patients is very difficult. The tongue defect results in oral dysfunction and affects the stability of the mandibular denture. The appropriate denture form and occlusion can be established by using the modified functional impression technique. Through the use of x-ray television and an image-processing system in clinical experiments, it was shown that a wide buccolingual table, an occlusal table height matched to that of the tongue body, and close adherence of the tongue and the lingual flange are effective means of preventing food from dropping to the oral floor, keeping the food on the occlusal table, and crushing the food.


The impact of night shift work on breast cancer: Results from the Burden of Occupational Cancer in Canada Study.
We estimated the proportion and number of female breast cancer cases in Canada attributable to night shift work, a probable cause of breast cancer. Levin's equation was used to calculate population attributable fractions (PAFs) among Canadian women who ever worked night/rotating shifts from 1961 to 2000, accounting for labor turnover and survival to the year 2011. The calculated PAFs were applied to 2011 Canadian breast cancer incidence statistics to obtain the number of attributable cases. Approximately 1.5 million women ever worked night/rotating shifts during 1961-2000 and survived to 2011. The PAFs ranged from 2.0% (95% confidence interval [CI]: 1.4-6.2) to 5.2% (95% CI: 3.7-13.6), and 470 to 1200 incident breast cancer cases in 2011 were likely due to shift work, of which 38% would have been diagnosed among women in health-related occupations. More research is needed to increase the certainty of this association, but current evidence supports workplace-based prevention.


Depolarized resonance light scattering by porphyrin and chlorophyll a aggregates.
A quantum mechanical model is developed for the observed resonance enhancement of light scattering by aggregates of electronically interacting chromophores. Aggregate size, monomer oscillator strength, extent of electronic coupling, and aggregate geometry are all important determinants of intensity in resonance light scattering (RLS) spectra. The theory also predicts the value of the depolarization ratio (rho(v)(90)) of RLS for a given aggregate geometry. These results are used to interpret the RLS depolarization ratios of four aggregates: tetrakis(4-sulfonatophenyl)porphine aggregated at low pH (rho(v)(90) = 0.17 at 488 nm), trans-bis(N-methylpyridinium-4-yl)-diphenylporphinato copper(II) aggregated in 0.2 M NaCl solution (rho(v)(90) = 0.13 at 450 nm) and on calf thymus DNA (rho(v)(90) = 0.20 at 454 nm), and chlorophyll a aggregates in formamide/water (rho(v)(90) = 0.23 and 0.32 at 469 and 699 nm, respectively). The analysis is consistent with a J-aggregate geometry for all four systems. Furthermore, the specific values of rho(v)(90) allow us to estimate the orientation of the monomer transition dipoles with respect to the long axis of the aggregate. We conclude that depolarized resonance light scattering spectroscopy is a powerful probe of the geometric and electronic structures of extended aggregates of strong chromophores.


A qualitative study of older adults' and family caregivers' perspectives regarding their preoperative care transitions.
To explore how older patients with multiple chronic conditions and their family caregivers perceive their engagement and overall care experience throughout the preoperative phase of elective orthopaedic hip or knee joint replacement. Patient engagement is a critical component of care necessary for improving patient outcomes. Little is known about how older adults with multiple chronic conditions and their family caregivers engage in preoperative care transitions and the subsequent impact of this experience on postoperative health outcomes. Prospective qualitative descriptive design was used. Semi-structured telephone interviews with a convenience sample of older adults coping with multiple chronic conditions and their family caregivers. Interviews were conducted prior to surgery and, again 21 days postsurgery, were audio-recorded and transcribed for qualitative content analysis. The Quality Health Outcomes Model was used to categorise study findings. Eleven patients and five family caregivers participated. Guided by the Quality Health Outcomes Model, four major themes were identified. (i) Older adults perceive that joint replacement is about quality of life. (ii) Standardised interventions often fail to address the unique needs of complex older adults. (iii) Family caregivers perceive they are the primary care coordinators. (iv) Postoperative outcomes and resource utilisation vary widely in complex older adults. Findings suggest that current preoperative care interventions are often not designed to effectively engage complex older patients and their family caregivers. Coordinated patient-centred preoperative care that reflects the needs and goals of complex older patients and their family caregivers may positively influence perioperative care transitions and outcomes beyond this episode of care. The current research documents the need for more in-depth knowledge about the relationship between older adults' and their family caregivers' engagement preoperatively and postoperative outcomes and resource utilisation.


Estrogen-induced upregulation and 3'-UTR shortening of CDC6.
3'-Untranslated region (UTR) shortening of mRNAs via alternative polyadenylation (APA) has important ramifications for gene expression. By using proximal APA sites and switching to shorter 3'-UTRs, proliferating cells avoid miRNA-mediated repression. Such APA and 3'-UTR shortening events may explain the basis of some of the proto-oncogene activation cases observed in cancer cells. In this study, we investigated whether 17 β-estradiol (E2), a potent proliferation signal, induces APA and 3'-UTR shortening to activate proto-oncogenes in estrogen receptor positive (ER+) breast cancers. Our initial probe based screen of independent expression arrays suggested upregulation and 3'-UTR shortening of an essential regulator of DNA replication, CDC6 (cell division cycle 6), upon E2 treatment. We further confirmed the E2- and ER-dependent upregulation and 3'UTR shortening of CDC6, which lead to increased CDC6 protein levels and higher BrdU incorporation. Consequently, miRNA binding predictions and dual luciferase assays suggested that 3'-UTR shortening of CDC6 was a mechanism to avoid 3'-UTR-dependent negative regulations. Hence, we demonstrated CDC6 APA induction by the proliferative effect of E2 in ER+ cells and provided new insights into the complex regulation of APA. E2-induced APA is likely to be an important but previously overlooked mechanism of E2-responsive gene expression.


Speciation in ancient lakes.
About a dozen lakes in the world are up to three orders of magnitude older than most others. Lakes Tanganyika (East Africa) and Baikal (Siberia) have probably existed in some form for 12-20 million years, maybe more. Such lakes can have different origins, sizes, shapes, depths and limnologies, but, in contrast to short-lived (mostly post-glacial) lakes, they have exceptionally high faunal diversity and levels of endemicity. A multitude of and processes accounting for these explosive radiations have recently been documented, most of them based on particular groups in certain lakes, but comparative research can detect repeated patterns. No special speciafion mechanism, exclusive to ancient lakes has been demonstrated, although cases of ultra-rapid speciation have been documented. Extant diversity results not by simple accumulation, but by a complex process of immigration, speciation and extinction.


Diversity and inclusion training in pediatric departments.
The diversifying US population of children necessitates assessing the diversity of the pediatric academic workforce and its level of cultural competency training. Such data are essential for workforce and educational policies. An 8-question survey was sent to 131 US pediatric chairs to assess plans for diversity, targeted groups, departmental diversity, diversity measures, perceived success in diversity, and presence and type of cultural competency training. In all, 49.6% of chairs responded, and three-quarters of them reported having a plan for diversity, which targeted racial; ethnic; gender; lesbian, gay, bisexual, and transgender; disabled; and social class groups. Of the residents, 75% were women, as compared with 54% of faculty and 26% of chairs. Racial and ethnic diversity was limited among trainees, faculty, and leaders; <10% of each group was African American, Hispanic, or Native American. Asian Americans were more common among trainees (15%-33%) but were less common in faculty and leadership positions (0%-14%). Lesbian, gay, bisexual, and transgender physicians were represented in some groups. Measures of diversity included the number of trainees and faculty, promotion success, climate assessments, and exit interviews. Overall, 69% of chairs reported being successful in diversity efforts. A total of 90% reported cultural competency training for trainees, and 74% reported training for faculty and staff. Training in cultural competency included linguistic training, primarily in Spanish. Pipeline issues for minorities are ongoing challenges. Pediatric leadership needs more representation of racial and ethnic minorities, women, and LGBT. Suggestions for workforce and educational policies are made.


Synaptic connections between spiny neurons of the direct and indirect pathways in the neostriatum of the rat: evidence from dopamine receptor and neuropeptide immunostaining.
The flow of cortical information through the basal ganglia occurs through the so-called 'direct pathway' and 'indirect pathways'. The object of the present work was to attempt to determine whether spiny neurons in the neostriatum that give rise to the direct pathway (i.e. the striatonigral/entopeduncular pathway) and those giving rise to the indirect pathways (i.e. striatopallidal pathway) are synaptically interconnected. The approach was to carry out double immunocytochemistry at the electron microscopic level using antibodies against peptides or dopamine receptor subtypes that are selectively associated with the neurons that give rise to the direct (substance P or D1 receptors) and indirect pathways (enkephalin or D2 receptors). Sections of perfuse-fixed rat neostriatum were immunostained to reveal both substance P immunoreactivity and D2 receptor immunoreactivity or enkephalin and D1 receptor immunoreactivity, respectively. Double peroxidase methods were employed using different chromogens that were distinguishable at both the light and electron microscopic levels. In the electron microscope substance P-immunoreactive terminals were seen in synaptic contact with dendritic structures that displayed immunoreactivity for D2 receptor. Similarly, enkephalin-immunoreactive terminals were seen in synaptic contact with D1-immunoreactive dendritic structures. Thus, axon collaterals of neurons giving rise to the direct pathway form synaptic contacts with neurons that give rise to the indirect pathway and axon collaterals of neurons giving rise to the indirect pathway form synaptic contact with neurons that give rise to the direct pathway. These results indicate that the two pathways of information flow through the basal ganglia are synaptically linked at the level of the neostriatum. spiny neurons, direct pathway,indirect pathways, rat neostriatum


[Which integrative and disorder specific treatment approaches are considered in research papers? An analysis on psychotherapeutic treatments in German journals].
In the current discussion on optimizing psychotherapeutic approaches, two important developments have to be considered: a tendency towards integrative and a tendency towards disorder specific approaches. For the years 2005 and 2006, an analysis of three German journals (covering the fields of psychosomatics, psychiatry and clinical psychology) was conducted on the question whether these two developments can be identified in current empirical and conceptual publications. Contrary to the expectations, there are only very few papers dealing with integrative approaches. As expected, there is a major emphasis on psychodynamic and cognitive behavioural approaches; other approaches are only marginally considered. A disorder specific approach can be identified not only for cognitive behavioural, but also for psychodynamic papers.


A case of recurrent epilepsy-associated rosette-forming glioneuronal tumor with anaplastic transformation in the absence of therapy.
Rosette-forming glioneuronal tumor (RGNT) most commonly occurs adjacent to the fourth ventricle and therefore rarely presents with epilepsy. Recent reports describe RGNT occurrence in other anatomical locations with considerable morphologic and genetic overlap with the epilepsy-associated dysembryoplastic neuroepithelial tumor (DNET). Examples of RGNT or DNET with anaplastic change are rare, and typically occur in the setting of radiation treatment. We present the case of a 5-year-old girl with seizures, who underwent near total resection of a cystic temporal lobe lesion. Pathology showed morphologic and immunohistochemical features of RGNT, albeit with focally overlapping DNET-like patterns. Resections of residual or recurrent tumor were performed 1 year and 5 years after the initial resection, but no adjuvant radiation or chemotherapy was given. Ten years after the initial resection, surveillance imaging identified new and enhancing nodules, leading to another gross total resection. This specimen showed areas similar to the original tumor, but also high-grade foci with oligodendroglial morphology, increased cellularity, palisading necrosis, microvascular proliferation, and up to 13 mitotic figures per 10 high power fields. Ancillary studies the status by sequencing showed wild-type of the isocitrate dehydrogenase 1 (IDH1), IDH2, and human histone 3.3 (H3F3A) genes, and BRAF studies were negative for mutation or rearrangement. Fluorescence in situ hybridization (FISH) showed codeletion of 1p and 19q limited to the high-grade regions. By immunohistochemistry there was loss of nuclear alpha-thalassemia mental retardation syndrome, X-linked (ATRX) expression only in the high-grade region. Next-generation sequencing showed an fibroblast growth factor receptor receptor 1 (FGFR1) kinase domain internal tandem duplication in three resection specimens. ATRX mutation in the high-grade tumor was confirmed by sequencing which showed a frameshift mutation (p.R1427fs), while the apparent 1p/19q-codeletion by FISH was due to loss of chromosome arm 1p and only partial loss of 19q. Exceptional features of this case include the temporal lobe location, 1p/19q loss by FISH without true whole-arm codeletion, and anaplastic transformation associated with ATRX mutation without radiation or chemotherapy.


The barber-surgeons of London.
The Company of the Barber-Surgeons of London was formed by the union of the Company of Barbers and the Fellowship of Surgeons in 1540. It marked one of the great milestones in English surgery. The barbers had carried out minor surgery such as bleeding and lancing of abscesses, while the more erudite surgeons attempted to evolve some principles in surgery, and were involved in the mutilating surgery of warfare. The Barber-Surgeons became responsible for instigating teaching programs and the licensing of men to practice the art of surgery; they also appointed surgeons to the armed forces. An inevitable rift between these two different types of people occurred in 1745. The surgeons broke away and formed the Company of Surgeons, which, in 1800, became the Royal College of Surgeons.


Bloodstream infections in pediatric oncology outpatients: a new healthcare systems challenge.
To investigate a perceived increase in central venous catheter (CVC)-associated bloodstream infections (BSIs) among pediatric hematology-oncology outpatients. A case-control study. A pediatric hematology-oncology outpatient clinic at Fresno Children's Hospital. Pediatric hematology-oncology clinic outpatients with CVCs at Fresno Children's Hospital between November 1994 and October 1997. A case-patient was defined as any hematology-oncology outpatient with a CVC-associated BSI at Fresno Children's Hospital from November 1996 to October 1997 (study period) without a localizable infection. To identify case-patients, we reviewed Fresno Children's Hospital records for all hematology-oncology clinic patients, those with CVCs and those with CVCs and BSIs. Control-patients were randomly selected hematology-oncology outpatients with a CVC but no BSI during the study period. Case-patient and control-patient demographics, diagnoses, caretakers, catheter types, catheter care, and water exposure were compared. Twenty-five case-patients had 42 CVC-associated BSIs during the study period. No significant increase in CVC-associated BSI rates occurred among pediatric hematology-oncology patients. However, there was a statistically significant increase in nonendogenous, gram-negative (eg, Pseudomonas species) BSIs during summer months (May-October) compared with the rest of the year. Case-patients and control-patients differed only in catheter type; case-patients were more likely than control-patients to have a transcutaneous CVC. Summertime recreational water exposures were similar and high in the two groups. Hematology-oncology clinic patients with transcutaneous CVCs are at greater risk for CVC-associated BSI, particularly during the summer. Caretakers should be instructed on proper care of CVCs, particularly protection of CVCs during bathing and recreational summer water activities, to reduce the risk of nonendogenous, gram-negative BSIs.


Clinical-angiographic correlation of ophthalmodynamometry in patients with suspected carotid artery disease: a prospective study.
A prospective, clinical study was performed on patients with suspected carotid artery disease to compare the accuracy of compression and suction ophthalmodynamometry with carotid artery stenosis as determined by arteriography. Results were analyzed with respect to current criteria for classification and determination of "significant" carotid artery disease. Although our results suggest that the best correlation for both procedures with arteriography is a ratio of the corrected intraocular pressure to the systolic brachial blood pressure, these results were not statistically improved over those obtained using uncorrected systolic or diastolic values. Both suction and compression ophthalmodynamometry are equally accurate with levels approaching 80 percent; however, neither test is sensitive enough to be used alone as a screening technique. Arteriography remains the best procedure for the determination of carotid artery disease.


From living systematic reviews to meta-analytical research domains.
Because of the rapidly increasing number of randomised controlled trials (RCTs) and meta-analyses in many fields, there is an urgent need to step up from meta-analyses to higher levels of aggregation of outcomes of RCTs. Network meta-analyses and umbrella reviews allow higher levels of aggregation of RCT outcomes, but cannot adequately cover the evidence for a whole field. The 'Meta-Analytic Research Domain' (MARD) may be a new methodology to aggregate RCT data of a whole field. A MARD is a living systematic review of a research domain that cannot be covered by one PICO. For example, a MARD of psychotherapy for depression covers all RCTs comparing the effects of all types of psychotherapy to control conditions, to each other, to pharmacotherapy and combined treatment. It also covers all RCTs comparing treatment formats, the effects in different target groups, subtypes of depression and secondary outcomes. Although the time and resources needed to build a MARD are considerable, they offer many advantages, including a comprehensive and consistent overview of a research field and important meta-analytic studies that cannot be conducted with conventional methods. MARDs are a promising method to step up the aggregation of RCTs to a next level and it is highly relevant to work out the methods of this approach in a more detailed way.


Effects of a Dicalcium and Tetracalcium Phosphate-Based Desensitizer on In Vitro Dentin Permeability.
The present study evaluated the effectiveness of a dicalcium and tetracalcium phosphate-based desensitizer in reducing dentin permeability in vitro. Dentin fluid flow was measured before and after treatment of dentin with patent dentinal tubules using 1 or 3 applications of the dicalcium and tetracalcium phosphate containing agent TeethmateTM (TM) and comparing the results with two sodium fluoride varnishes VellaTM (VLA) and VanishTM (VAN), after storage in artificial saliva for 24 h, 48 h and 7 days. Significant differences were observed among the 4 methods employed for reducing dentin permeability (p < 0.001) and the 3 post-treatment times (p < 0.001). VLA and VAN never achieved 50% permeability reductions consistently in any of the 3 time periods. Only the calcium phosphate-based desensitizer applied for 3 times consistently reduced dentin permeability by 50% after 24 h. When applied once, the permeability reduction of TM increased progressively over the 3 time periods. After 7 days, only one and three applications of the calcium phosphate-based desensitizer consistently reduced dentin permeability by more than 50%. Permeability reductions corresponded well with scanning electron microscopy examination of dentinal tubule orifice occlusion in dentin specimens treated with the agents. Overall, the dicalcium and tetracalcium phosphate-based desensitizer is effective in reducing dentin permeability via a tubule occlusion mechanism. The ability of the agent to reduce dentin permeability renders it to be potentially useful as a clinical dentin desensitizing agent, which has to be confirmed in future clinical studies. By contrast, the two sodium fluoride varnishes are not effective in dentin permeability reduction and should be considered as topical fluoride delivering agents rather than tubular orifice-blocking agents.


Assessment of mandibular advancement surgery with 3D CBCT models superimposition.
OBJECTIVES: To assess surgery and short-term post-surgery changes in the position of the condyles, rami and chin after mandibular advancement. METHODOLOGY: Pre-surgery (T1), 1 week post-surgery (T2), and 6 week post-surgery (T3) CBCT scans were acquired for 20 retrognathic patients with short or normal face height. 3D models were built and superimposed through a fully automated voxel-wise method using the cranial base of the pre-surgery scan as reference. Anatomic regions of interest were selected and analyzed separately. Within-subject surface distances between T1-T2, T2-T3, and T1-T3 were computed. Color-coded maps and semi-transparent display of overlaid structures allowed the evaluation of displacement directions. RESULTS: After an antero-inferior chin displacement with surgery in all cases (>4 mm in 87.5%), 25% of the patients showed some kind of posterior movement (< 3 mm), and 69% showed an antero-superior movement after splint removal. Comparing T1-T3, an antero-inferior (87.5% of the cases) or only inferior (12.5%) displacement was observed (>4 mm in 80%). Considering all directions of displacement, the surface distance differences for the condyles and rami were small: 77.5% of the condyles moved <2 mm with surgery (T1-T2), and 90% moved <2 mm in the short-term (T2-T3) and in the total evaluation (T1-T3), while the rami showed a <3 mm change with surgery in 72.5% of the cases, and a <2 mm change in 87.5% (T2-T3) and in 82% (T1-T3). CONCLUSIONS: Expected displacements with surgery were observed and post-surgery changes suggested a short-term adaptive response toward recovery of condyle and ramus displacements. The changes on the chin following splint removal suggested an acceptable adaptation, but with considerable individual variability.


An encapsulation system for the immunoisolation of pancreatic islets.
Over a thousand combinations of polyanions and polycations were tested to search for new polymer candidates that would be suitable for encapsulation of living cells. The combination of sodium alginate, cellulose sulfate, poly (methylene-co-guanidine) hydrochloride, calcium chloride, and sodium chloride was most promising. In parallel, a novel multiloop chamber reactor was developed to control the time of complex formation and to negate gravitational effects such as pancreatic islet sedimentation and droplet deformation during the encapsulation process. Encapsulated rat islets demonstrated glucose-stimulated insulin secretion in vitro, and reversed diabetes in mice. This new capsule formulation and encapsulation system allows independent adjustments of capsule size, wall thickness, mechanical strength, and permeability, which may offer distinct advantages for immunoisolating cells.


Mechanism of inactivation of the beta 2 subunit of Escherichia coli tryptophan synthase by monoclonal antibodies.
Monoclonal antibodies directed against the native form of the beta 2 subunit of Escherichia coli tryptophan synthase strongly inhibit both its tryptophan synthase and its serine deaminase activities. The mechanism of this inactivation is studied here, by monitoring quantitatively the absorption and fluorescence properties of different well-characterized successive intermediates in the catalytic cycle of tryptophan synthase. It is shown that the antibodies interfere specifically with the formation of one or the other of these intermediates. It is concluded that the antibodies either modify or block the molecular flexibility of the protein, thus preventing conformational changes that the protein has to undergo during the catalysis. At least two different stages of the catalytic process, each one sensitive to a different class of antibodies, are shown to involve molecular movements of the polypeptide chain. Indications are given on the regions of the molecule involved in these movements.