Comparison of survival outcome of patients with primary peritoneal and fallopian tube carcinoma treated with neoadjuvant chemotherapy versus primary debulking surgery.
This study examines the overall survival of primary peritoneal cancer (PPC), in those patients who had primary debulking surgery (PDS) followed by six cycles of chemotherapy versus those who had neoadjuvant chemotherapy (NACT). This was a prospective observational study performed at Oxford Gynaecological Cancer Centre, over a 5-year period. Eighty-seven patients were clinically suspected of having PPC. Histology confirmed that 64 of these were PPC, with the balance being tubal in origin. PDS was performed in 31 cases. Although NACT was planned in 56 patients, 4 patients didn't receive NACT and therefore excluded from the survival analysis. The overall median survival was 34 months. However, the 5-year survival was 12%. Survival in the PDS group was 46 months versus 24 months in the NACT (p = .011). The conclusion drawn from this study is that patients affected by PPC, selected for PDS have a greater survival advantage than those who had NACT.


Aberrant X chromosome skewing and acquired clonal hematopoiesis in adult-onset common variable immunodeficiency.
Advances in genomic medicine have elucidated an increasing number of genetic etiologies for patients with common variable immunodeficiency (CVID). However, there is heterogeneity in clinical and immunophenotypic presentations and a limited understanding of the underlying pathophysiology of many cases. The primary defects in CVID may extend beyond the adaptive immune system, and the combined defect in both the myeloid and lymphoid compartments suggests the mechanism may involve bone marrow output and earlier progenitors. Using the methylation profile of the human androgen receptor (AR) gene as a surrogate epigenetic marker for bone marrow clonality, we examined the hematopoietic compartments of patients with CVID. Our data show that clonal hematopoiesis is common among patients with adult-onset CVID who do not have associated noninfectious complications. Nonblood tissues did not show a skewed AR methylation status, supporting a model of an acquired clonal hematopoietic event. Attenuation of memory B cell differentiation into long-lived plasma cells (CD20-CD27+CD38+CD138+) was associated with marked changes in the postdifferentiation methylation profile, demonstrating the functional consequence of clonal hematopoiesis on humoral immunity in these patients. This study sheds light on a potential etiology of a subset of patients with CVID, and the findings suggest that it is a stage of an acquired lymphocyte maturation disorder.


Phosphorylation/dephosphorylation of the beta-adrenergic receptor regulates its functional coupling to adenylate cyclase and subcellular distribution.
Prolonged exposure of cells or tissues to drugs or hormones such as catecholamines leads to a state of refractoriness to further stimulation by that agent, known as homologous desensitization. In the case of the beta-adrenergic receptor coupled to adenylate cyclase, this process has been shown to be intimately associated with the sequestration of the receptors from the cell surface through a cAMP-independent process. Recently, we have shown that homologous desensitization in the frog erythrocyte model system is also associated with increased phosphorylation of the beta-adrenergic receptor. We now provide evidence that the phosphorylation state of the beta-adrenergic receptor regulates its functional coupling to adenylate cyclase, subcellular translocation, and recycling to the cell surface during the process of agonist-induced homologous desensitization. Moreover, we show that the receptor phosphorylation is reversed by a phosphatase specifically associated with the sequestered subcellular compartment. At 23 degrees C, the time courses of beta-adrenergic receptor phosphorylation, sequestration, and adenylate cyclase desensitization are identical, occurring without a lag, exhibiting a t1/2 of 30 min, and reaching a maximum at approximately 3 hr. Upon cell lysis, the sequestered beta-adrenergic receptors can be partially recovered in a light membrane vesicle fraction that is separable from the plasma membranes by differential centrifugation. The increased beta-adrenergic receptor phosphorylation is apparently reversed in the sequestered vesicle fraction as the sequestered receptors exhibit a phosphate/receptor stoichiometry that is similar to that observed under basal conditions. High levels of a beta-adrenergic receptor phosphatase activity appear to be associated with the sequestered vesicle membranes. The functional activity of the phosphorylated beta-adrenergic receptor was examined by reconstituting purified receptor with its biochemical effector the guanine nucleotide regulatory protein (Ns) in phospholipid vesicles and assessing the receptor-stimulated GTPase activity of Ns. Compared to controls, phosphorylated beta-adrenergic receptors, purified from desensitized cells, were less efficacious in activating the Ns GTPase activity. These results suggest that phosphorylation of the beta-adrenergic receptor leads to its functional uncoupling and physical translocation away from the cell surface into a sequestered membrane domain. In the sequestered compartment, the phosphorylation is reversed thus enabling the receptor to recycle back to the cell surface and recouple with adenylate cyclase.


Use of the photoaffinity cross-linking agent N-hydroxysuccinimidyl-4-azidosalicylic acid to characterize salivary-glycoprotein-bacterial interactions.
The present study has utilized the iodinatable cross-linking agent N-hydroxysuccinimidyl-4-azidosalicylic acid (ASA) to examine the specific interaction between the proline-rich glycoprotein (PRG) of human parotid saliva and Streptococcus sanguis G9B. The binding of 125I-ASA-PRG to Streptococcus sanguis G9B displayed saturation kinetics, reversibility and was inhibited by unlabelled PRG. Inhibition studies with other glycoproteins and saccharides indicated that binding was mediated by a bacterial adhesin with specificity towards N-acetylneuraminic acid, galactose, and N-acetylgalactosamine. After cross-linking, the 125I-ASA-PRG-adhesin complex could be extracted with SDS and separated from uncoupled 125I-ASA-PRG by gel filtration on Sepharose CL-6B. Approx. 1% of the 125I-ASA-PRG was cross-linked to the bacterial surface. Examination of the 125I-ASA-PRG-adhesin complex by SDS/polyacrylamide-gel electrophoresis/fluorography on 5% -(w/v)-polyacrylamide gels revealed that PRG was bound to two bacterial components. These findings support our previous suggestion that human salivary glycoproteins can specifically interact with oral streptococci and that these interactions occur between the glycoprotein's carbohydrate units and lectin(s) on the bacterial cell surface.


HLA-DRB1-associated rheumatoid arthritis risk at multiple levels in African Americans: hierarchical classification systems, amino acid positions, and residues.
To evaluate HLA-DRB1 genetic risk of rheumatoid arthritis (RA) in African Americans by 3 validated allele classification systems and by amino acid position and residue, and to compare genetic risk between African American and European ancestries. Four-digit HLA-DRB1 genotyping was performed on 561 autoantibody-positive African American cases and 776 African American controls. Association analysis was performed on Tezenas du Montcel (TdM), de Vries (DV), and Mattey classification system alleles and separately by amino acid position and individual residues. TdM S2 and S3P alleles were associated with RA (odds ratio [95% confidence interval] 2.8 [2.0-3.9] and 2.1 [1.7-2.7], respectively). The DV (P = 3.2 × 10(-12)) and Mattey (P = 6.5 × 10(-13)) system alleles were both protective in African Americans. Amino acid position 11 (permutation P < 0.00001) accounted for nearly all variability explained by HLA-DRB1, although conditional analysis demonstrated that position 57 was also significant (0.01 ≤ permutation P ≤ 0.05). The valine and aspartic acid residues at position 11 conferred the highest risk of RA in African Americans. With some exceptions, the genetic risk conferred by HLA-DRB1 in African Americans is similar to that in individuals of European ancestry at multiple levels: classification system (e.g., TdM), amino acid position (e.g., 11), and residue (Val11). Unlike that reported for individuals of European ancestry, amino acid position 57 was associated with RA in African Americans, but positions 71 and 74 were not. Asp11 (odds ratio 1 in European ancestry) corresponds to the 4-digit classical allele *09:01, which is also a risk allele for RA in Koreans.


Synthesis, structure, and opto-electronic properties of organic-based nanoscale heterojunctions.
Enormous research effort has been put into optimizing organic-based opto-electronic systems for efficient generation of free charge carriers. This optimization is mainly due to typically high dissociation energy (0.1-1 eV) and short diffusion length (10 nm) of excitons in organic materials. Inherently, interplay of microscopic structural, chemical, and opto-electronic properties plays crucial role. We show that employing and combining advanced scanning probe techniques can provide us significant insight into the correlation of these properties. By adjusting parameters of contact- and tapping-mode atomic force microscopy (AFM), we perform morphologic and mechanical characterizations (nanoshaving) of organic layers, measure their electrical conductivity by current-sensing AFM, and deduce work functions and surface photovoltage (SPV) effects by Kelvin force microscopy using high spatial resolution. These data are further correlated with local material composition detected using micro-Raman spectroscopy and with other electronic transport data. We demonstrate benefits of this multi-dimensional characterizations on (i) bulk heterojunction of fully organic composite films, indicating differences in blend quality and component segregation leading to local shunts of photovoltaic cell, and (ii) thin-film heterojunction of polypyrrole (PPy) electropolymerized on hydrogen-terminated diamond, indicating covalent bonding and transfer of charge carriers from PPy to diamond.


Breast cancer clinicopathological presentation, gravity and challenges in Eritrea, East Africa: management practice in a resource-poor setting.
In Africa, breast cancer closely compares with cervical cancer as the most common malignancy affecting women and the incidence rates appear to be rising. Early detection of breast cancer is a key strategy for a good treatment outcome. However, there is no established protocol or guideline for management of breast cancer in Eritrea, East Africa. To assess the clinicopathological presentation, gravity and management challenges presented in breast cancer treatment in Eritrea. Methods. Our investigation was a retrospective, descriptive study to assess the clinical features and severity of breast cancer at time of presentation. We reviewed the medical records of all patients who presented with breast malignancies over the 2-year period from 1 January 2007 to 31 December 2008. Eighty-two patients ranging in age from 26 - 80 years (mean 48 years) were included in the study. Of these 51% were premenopausal women; 61% of the patients presented with breast mass only and the remainder with manifestations of local (mass plus discharge, breast pain or breast ulceration) or distant metastatic disease. More than 60% of the patients presented after >2 years following onset of symptoms. Two-thirds of patients had late stage (III or IV) disease. All except one case was managed surgically. Most cases presented at younger age and advanced stage. These findings call for strengthening health education to promote early health-seeking behaviour and advocacy for the introduction of national screening, implementation of a management protocol and establishment of a radio-chemotherapy centre.


Anterolateral thigh flap for abdominal wall reconstruction.
The free or pedicled anterolateral thigh flap was introduced for the reconstruction of large abdominal wall defects. This flap is superior to the tensor fasciae latae musculocutaneous flap in several respects. These include the wide, reliable skin territory (which can reach the level of the knee) and the long pedicle. Therefore, a pedicled anterolateral thigh flap with reliable blood circulation can easily be positioned above the umbilicus. In addition, the free anterolateral thigh flap has greater freedom of orientation and can be used to repair larger abdominal wall defects than can the tensor fasciae latae flap. Seven patients in whom abdominal wall defects had been reconstructed with pedicled or free anterolateral thigh flaps were reviewed. Their average age was 47.1 years (range, 21 to 74 years), and the average follow-up period was 10.7 months (range, 2 to 21 months). The size of the abdominal wall defects ranged from 12 x 12 cm to 18 x 24 cm, and the size of the transferred flap ranged from 10 x 20 cm to 20 x 20 cm. Three flaps were pedicled and four were free, of which three incorporated the tensor fasciae latae flap. All flaps survived completely, and no postoperative abdominal hernias developed. Despite some variations in vascular anatomy and technical difficulties in elevating the anterolateral thigh flap, the authors conclude that the pedicled or free anterolateral thigh flap is superior to the tensor fasciae latae flap for reconstruction of large abdominal wall defects.


Assessment of factors influencing morale in the elderly.
We examined the relationship between morale measured by the Philadelphia Geriatric Morale Scale (PGC) and disability, social support, religiosity, and personality traits. Instruments predicting morale were then tested against PGC domains. The study utilized a cross-sectional survey with a multistage cluster sampling design. Instruments used were disability (disease burden; WHO Disability Score-II, WHODAS-II), social support (Duke Social Support Scale, DUSOCS; Lubben Social Network Scale, LSNS-6; Medical Outcomes Study Social Support Survey, MOS-SSS), religiosity (Revised Intrinsic-Extrinsic Religious Orientation Scale, I/E-R), and personality (Ten-Item Personality Inventory, TIPI). These were plotted as bar charts against PGC, resolved with one-way ANOVA and Kruskal-Wallis tests, then corrected for multiple comparisons. This process was repeated with PGC domains. Contribution of factors was modeled using population attributable risk (PAR) and odds ratios. Effect of confounders such as gender, age, and ethnicity were checked using binary logistic regression. All instruments showed clear relationships with PGC, with WHODAS-II and DUSOCS performing well (ANOVA p<0.001). For PGC domains, attitude toward aging and lonely dissatisfaction trended together, while agitation did not. PAR, odds ratios, and Exp(β) were disability (WHODAS-II: 28.5%, 3.8, 2.8), social support (DUSOCS: 28.0%, 3.4, 2.2), religiosity (I/E-R: 21.6%, 3.2, 2.1), and personality (TIPI: 27.9%, 3.6, 2.4). Combined PAR was 70.9%. Disability, social support, religiosity, and personality strongly influence morale in the elderly. WHODAS-II and DUSOCS perform best in measuring disability and social support respectively.


Harnessing the potential of dystrophin-related proteins for ameliorating Duchenne's muscular dystrophy.
Duchenne's muscular dystrophy (DMD) is a fatal disease caused by mutations in the DMD gene that lead to quantitative and qualitative disturbances in dystrophin expression. Dystrophin is a member of the spectrin superfamily of proteins. Dystrophin itself is closely related to three proteins that constitute a family of dystrophin-related proteins (DRPs): the chromosome 6-encoded DRP or utrophin, the chromosome-X encoded, DRP2 and the chromosome-18 encoded, dystrobrevin. These proteins share sequence similarity and functional motifs with dystrophin. Current attempts at somatic gene therapy of DMD face numerous technical problems. An alternative strategy for DMD therapy, that circumvents many of these problems, has arisen from the demonstration that the DRP utrophin can functionally substitute for the missing dystrophin and its overexpression can rescue dystrophin-deficient muscle. Currently, a promising avenue of research consists of identifying molecules that would increase the expression of utrophin and the delivery of these molecules to dystrophin-deficient tissues as a means of DMD therapy. In this review, we will focus on DRPs from the perspective of strategies and issues related to upregulating utrophin expression for DMD therapy. Additionally, we will address the techniques used for anatomical, biochemical and physiological evaluation of the potential benefits of this and other forms of DMD therapy in dystrophin-deficient animal models.


Study of required clerkships in internal medicine in U.S. and Canadian medical schools.
The authors studied teaching of clinical skills and the supervision of clinical education of undergraduate medical students by reviewing students' patient-related experiences in required internal medicine clerkships in the United States and Canada during the 1979-1982 accreditation cycle of the Liaison Committee on Medical Education. The reported patient-related experiences of 180 medical students from 42 medical schools who took histories and performed physical examinations on 2,891 patients formed the basis of this paper. Variability in clerkship length, time worked, supervision, and patient mix suggests that additional quantitative data should be sought on medical students' experiences during the clerkship.


A circular economy approach to green energy: Wind turbine, waste, and material recovery.
Wind energy has been considered as one of the greenest renewable energy sources over the last two decades. However, attention is turning to reducing the possible environmental impacts from this sector. We argue that wind energy would not be effectively "green" if anthropogenic materials are not given attention in a responsible manner. Using the concept of the circular economy, this paper considers how anthropogenic materials in the form of carbon fibers can reenter the circular economy system at the highest possible quality. This paper first investigates the viability of a carbon-fiber-reinforced polymer extraction process using thermal pyrolysis to recalibrate the maximum carbon fiber value by examining the effect of (a) heating rate, (b) temperature, and (c) inert gas flow rate on char yield. With cleaner and higher quality recovered carbon fibers, this paper discusses the economic preconditions for the takeoff and growth of the industry and recommends the reuse of extracted carbon fibers to close the circular economy loop.


Cultural adaptation of Hap-pas-Hapi, an internet and mobile-based intervention for the treatment of psychological distress among Albanian migrants in Switzerland and Germany.
Internet- and mobile-based mental health interventions have the potential to narrow the treatment gap in ethnic groups. Little evidence exists on the cultural adaptation of such interventions. Cultural adaptation of evidence-based interventions distinguishes between surface and deep structure adaptation. Surface refers to matching materials (e.g., illustrations, language) or methods of treatment delivery to the target population, whereas deep structure adaptation considers cultural concepts of distress (CCD). So far, CCD have only been considered to a limited extent in cultural adaptation of psychological interventions, and there is a lack of well documented adaptation procedures. With a cross-disciplinary and mixed-method approach, following a new conceptual framework for cultural adaptation of scalable psychological interventions, this study aimed to develop both surface and deep structure adaptations of an internet- and mobile-based intervention called Hap-pas-Hapi for the treatment of psychological distress among Albanian migrants in Switzerland and Germany. A qualitative ethnopsychological study was conducted to examine the target group's CCD. Focus group discussions, an online survey, and individual key informant interviews were utilised to evaluate the original intervention, adaptation drafts and the final adapted intervention. A reporting system was developed to support the decision-making process and to report all adaptations in a transparent and replicable way. The ongoing involvement of target population key informants provided valuable feedback for the development of a more person-centred intervention, which might enhance treatment acceptance, motivation and adherence. This study provides empirical and theory-based considerations and suggestions for future implementation that may foster acceptability and effectiveness of culturally adapted evidence-based interventions.


Terminal transferase-dependent PCR (TDPCR) for in vivo UV photofootprinting of vertebrate cells.
Terminal transferase-dependent PCR (TDPCR) is a versatile, sensitive method for detecting DNA lesions such as those generated by the footprinting agents commonly used to detect in vivo protein-DNA interactions. Data similar to those obtained by ligation-mediated PCR (LMPCR) are obtained, but one advantage of TDPCR is that no special enzymes are needed other than terminal deoxynucleotide transferase, T4 DNA ligase, and thermostable DNA polymerases. A detailed TDPCR protocol is given for using UV photofootprinting to detect in vivo footprints and chromatin fine structure in vertebrate cells. One version of the protocol makes use of nonradioactive labeling by near-infrared fluorochromes and detection by a LI-COR DNA sequencing instrument. Sensitivity similar to that of (32)P-labeling is obtained, but with superior band resolution and quantitation.


An insight into the mechanism of protein separation by colloidal gas aphrons (CGA) generated from ionic surfactants.
Colloidal gas aphrons (CGA), which are surfactant stabilised microbubbles, have been previously applied for the recovery of proteins from model mixtures and a few studies have demonstrated the potential of these dispersions for the selective recovery of proteins from complex mixtures. However there is a lack of understanding of the mechanism of separation and forces governing the selectivity of the separation. In this paper a mechanistic study is carried out to determine the main factors and forces influencing the selectivity of separation of whey proteins with CGA generated from ionic surfactants. Two different separation strategies were followed: (i) separation of lactoferrin and lactoperoxidase by anionic CGA generated from a solution of sodium bis-(2-ethyl hexyl) sulfosuccinate (AOT); (ii) separation of beta-lactoglobulin by cationic CGA generated from a solution of cetyltrimethylammonium bromide (CTAB). Separation results indicate that electrostatic interactions are the main forces determining the selectivity however these could not completely explain the selectivities obtained following both strategies. Protein-surfactant interactions were studied by measuring the zeta potential changes on individual proteins upon addition of surfactant and at varying pH. Interestingly strongest electrostatic interactions were measured at those pH and surfactant to protein mass ratios which were optimum for protein separation. Effect of surfactant on protein conformation was determined by measuring the change in fluorescence intensity upon addition of surfactant at varying pH. Differences in the fluorescence patterns were detected among proteins which were correlated to differences in their conformational features which could in turn explain their different separation behaviour. The effect of conformation on selectivity was further proven by experiments in which conformational changes were induced by pre-treatment of whey (heating) and by storage at 4 degrees C. Overall it can be concluded that separation of proteins by ionic CGA is driven mainly by electrostatic interactions however conformational features will finally determine the selectivity of the separation with competitive adsorption having also an effect.


Reprogramming the chemodiversity of terpenoid cyclization by remolding the active site contour of epi-isozizaene synthase.
The class I terpenoid cyclase epi-isozizaene synthase (EIZS) utilizes the universal achiral isoprenoid substrate, farnesyl diphosphate, to generate epi-isozizaene as the predominant sesquiterpene cyclization product and at least five minor sesquiterpene products, making EIZS an ideal platform for the exploration of fidelity and promiscuity in a terpenoid cyclization reaction. The hydrophobic active site contour of EIZS serves as a template that enforces a single substrate conformation, and chaperones subsequently formed carbocation intermediates through a well-defined mechanistic sequence. Here, we have used the crystal structure of EIZS as a guide to systematically remold the hydrophobic active site contour in a library of 26 site-specific mutants. Remolded cyclization templates reprogram the reaction cascade not only by reproportioning products generated by the wild-type enzyme but also by generating completely new products of diverse structure. Specifically, we have tripled the overall number of characterized products generated by EIZS. Moreover, we have converted EIZS into six different sesquiterpene synthases: F96A EIZS is an (E)-β-farnesene synthase, F96W EIZS is a zizaene synthase, F95H EIZS is a β-curcumene synthase, F95M EIZS is a β-acoradiene synthase, F198L EIZS is a β-cedrene synthase, and F96V EIZS and W203F EIZS are (Z)-γ-bisabolene synthases. Active site aromatic residues appear to be hot spots for reprogramming the cyclization cascade by manipulating the stability and conformation of critical carbocation intermediates. A majority of mutant enzymes exhibit only relatively modest 2-100-fold losses of catalytic activity, suggesting that residues responsible for triggering substrate ionization readily tolerate mutations deeper in the active site cavity.


Learning to predict protein-protein interactions from protein sequences.
In order to understand the molecular machinery of the cell, we need to know about the multitude of protein-protein interactions that allow the cell to function. High-throughput technologies provide some data about these interactions, but so far that data is fairly noisy. Therefore, computational techniques for predicting protein-protein interactions could be of significant value. One approach to predicting interactions in silico is to produce from first principles a detailed model of a candidate interaction. We take an alternative approach, employing a relatively simple model that learns dynamically from a large collection of data. In this work, we describe an attraction-repulsion model, in which the interaction between a pair of proteins is represented as the sum of attractive and repulsive forces associated with small, domain- or motif-sized features along the length of each protein. The model is discriminative, learning simultaneously from known interactions and from pairs of proteins that are known (or suspected) not to interact. The model is efficient to compute and scales well to very large collections of data. In a cross-validated comparison using known yeast interactions, the attraction-repulsion method performs better than several competing techniques.


Diagnosis and Outcome of Oesophageal Crohn's Disease.
Crohn's disease [CD] can involve any part of the gastrointestinal tract. We aimed to characterize the clinical, endoscopic and histological features and treatment outcomes of CD patients with oesophageal involvement. We collected cases through a retrospective multicentre European Crohn's and Colitis Organisation CONFER [COllaborative Network For Exceptionally Rare case reports] project. Clinical data were recorded in a standardized case report form. A total of 40 patients were reported (22 males, mean [±SD, range] age at oesophageal CD diagnosis: 25 [±13.3, 10-71] years and mean time of follow-up: 67 [±68.1, 3-240] months). Oesophageal involvement was established at CD diagnosis in 26 patients [65%] and during follow-up in 14. CD was exclusively located in the oesophagus in two patients. Thirteen patients [32.2%] were asymptomatic at oesophageal disease diagnosis. Oesophageal strictures were present in five patients and fistulizing oesophageal disease in one. Eight patients exhibited granulomas on biopsies. Proton-pump inhibitors [PPIs] were administered in 37 patients [92.5%]. Three patients underwent endoscopic dilatation for symptomatic strictures but none underwent oesophageal-related surgery. Diagnosis in pre-established CD resulted in treatment modifications in 9/14 patients. Clinical remission of oesophageal disease was seen in 33/40 patients [82.5%] after a mean time of 7 [±5.6, 1-18] months. Follow-up endoscopy was performed in 29/40 patients and 26/29 [89.7%] achieved mucosal healing. In this case series the endoscopic and histological characteristics of isolated oesophageal CD were similar to those reported in other sites of involvement. Treatment was primarily conservative, with PPIs administered in the majority of patients and modifications in pre-existing inflammatory bowel disease-related therapy occurring in two-thirds of them. Clinical and endoscopic remission was achieved in more than 80% of the patients.


In vivo liver endocytosis followed by purification of liver cells by liver perfusion.
The liver is the metabolic center of the mammalian body and serves as a filter for the blood. The basic architecture of the liver is illustrated in figure 1 in which more than 85% of the liver mass is composed of hepatocytes and the remaining 15% of the cellular mass is composed of Kupffer cells (KCs), stellate cells (HSCs), and sinusoidal endothelial cells (SECs). SECs form the blood vessel walls within the liver and contain specialized morphology called fenestrae within in the cytoplasm. Fenestration of the cytoplasm is the appearance of holes (˜100 μm) within the cells so that the SECs act as a sieve in which most chylomicrons, chylomicron remnants and macromolecules, but not cells, pass through to the hepatocytes and HSCs (1) (Fig. 1). Due to the lack of a basement membrane, the gap between the SECs and hepatocytes form the Space of Disse. HSCs occupy this space and play a prominent role in regulation and response to injury, storage of retinoic acid and immunoregulation of the liver (2). SECs are among the most endocytically active cells of the body displaying an array of scavenger receptors on their cell surface (3). These include SR-A, Stabilin-1 and Stabilin-2. Generally, small colloidal particles less than 230 nm and macromolecules in buffer phase are taken up by SECs, whereas, large particles and cellular debris is endocytosed (phagocytosed) by KCs (4). Thus, the bulk clearance of extracellular material such as the glycosaminoglycans from blood is largely dependent on the health and endocytic functions of SECs (5,6). For example, an increase in blood hyaluronan levels is indicative of liver disease ranging from mild to more severe forms (7). With the exception of one report (8), there are no immortalized SEC cell lines in existence. Even this immortalized cell line is de-differentiated in that it does not express scavenger receptors that are present on primary SECs (our data, not shown). All cell biological studies must be performed on primary cells obtained freshly from the animal. Unfortunately, SECs dedifferentiate under standard culture conditions and must be used within 1 or 2 days upon isolation from the animal. Differentiation of SECs is marked by the expression of Stabilin-2 or HARE receptor (9) , CD31, and the presence of cytoplasmic fenestration (1). Differentiation of SECs can be extended by the addition of VEGF in culture media or by culturing cells in hepatocyte conditioned medium (10,11). In this report, we will demonstrate the endocytic activity of SECs in the intact organ using radio-labeled heparin for hyaluronan for the SEC-specific Stabilin-2 receptor. We will then purify hepatocytes and SECs from the perfused liver to measure endocytosis.


The "other diseases" of the Millennium Development Goals: rhetoric and reality of free drug distribution to cure the poor's parasites.
The sixth MDG aims 'to combat HIV/AIDS, TB, malaria and other diseases'. The residual category of 'other diseases' has become the focus of intense interest, partly because it has provided an opportunity to increase resources for the control of the mostly parasitic 'neglected tropical diseases' (NTDs). Intense lobbying has secured large amounts of funding from donors, as well as generous donations of medicines from the major drug companies. A massive programme is now underway to treat the parasites of the poor in Africa via integrated vertical interventions of mass drug administration in endemic areas. The approach has been hailed as remarkably effective, with claims that there is now a real prospect of complete control and, for some NTDs, even elimination. However, a closer look at evaluation and research data reveals that much less is known about what is being achieved than is suggested. Competition between implementing organisations is leading to potentially counterproductive exaggerations about treatment coverage. Detailed local-level research in Uganda and Tanzania shows that actual rates of drug take-up among target populations are often lower than is necessary to effectively control the diseases, and that methods of drug distribution may even lead to active resistance to treatment. If current trends are not corrected, declining rates of NTD infection will not be sustained. Much more rigorous and effective monitoring is essential.


A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood.
Recent studies have indicated that the proliferation of malignant gliomas is in part dependent on excessive activation of protein kinase C (PKC)-mediated pathways. Conversely, inhibiting PKC may provide a novel approach for blocking glioma growth. The antiestrogen tamoxifen, a moderately potent PKC inhibitor, has been shown in vitro to block the proliferation of malignant glioma cell lines at concentrations several-fold higher than those typically attained during the treatment of breast cancer; such serum concentrations may be achieved with doses > 40 mg/m2 b.i.d. The safety and efficacy of these high doses for producing disease control in patients with malignant gliomas has recently been noted anecdotally, although a rigorous study of this agent has been lacking. To address this issue, we examined the safety and efficacy of high-dose tamoxifen in a series of children with malignant gliomas that had progressed after conventional therapy. An initial group was treated with 60 mg/m2 p.o. b.i.d. and a second group with 100 mg/m2 b.i.d. Steady-state serum tamoxifen and metabolite levels were measured in most patients. Toxicity with the regimen was minimal; two patients treated at the higher dose required reduction to the lower dose because of asymptomatic prolongation of the QT interval on an electrocardiogram. Although none of the patients exhibited clear-cut tumor regression, 4 of 14 patients had stabilization of previously progressive disease for at least 3 months; the longest survivor lived for 17 months after beginning tamoxifen. The moderate efficacy of this agent in otherwise end-stage disease coupled with its low toxicity and the relative ease of oral administration provides a rationale for proceeding with larger studies of this agent in patients with malignant gliomas, possibly as a means for potentiating the effects of conventional chemotherapeutic agents, which to date have shown limited efficacy in the treatment of these tumors.


Impact of UVA on pruritus during UVA/B phototherapy of inflammatory skin diseases: a randomized double-blind study.
Narrowband (TL-01) UVB phototherapy (UVB nb) is effective in treating inflammatory skin disease. The addition of UVA is traditionally advocated to reduce pruritus, but lacks evidence for this recommendation. The aim of this study was to assess the effect of UVB nb and UVA phototherapy in combination compared against UVB nb monotherapy on pruritus, disease activity and quality of life. In this double-blind randomized clinical trial, 53 patients suffering from inflammatory skin diseases with pronounced itching (Visual Analogue Scale (VAS) for pruritus ≥5) were randomized into two treatment groups. One group received UVB nb (311 nm) phototherapy alone and another group received a combination of UVB nb and UVA (320-400 nm) phototherapy. UV therapy was performed three times per week over 16 weeks. Pruritus (VAS and 5-D itch score), disease activity and quality of life (Dermatology Life Quality Index, DLQI) were assessed at baseline and weeks 4, 8, 12 and 16. In both treatment groups, there was a reduction in pruritus scores, disease activity and DLQI. No difference in pruritus score, disease activity and quality of life could be detected between the group receiving UVB nb alone and those receiving UVB nb combined with UVA. Phototherapy with UVB nb alone, and UVB nb combined with UVA are equally effective in treating inflammatory skin disease and indifferent in reducing disease-associated pruritus. Given this non-inferiority for UVB nb monotherapy, the recommendation of adding UVA to UVB nb phototherapy for pruritic inflammatory skin disease should be abandoned.


Growing sensitivity of maize to water scarcity under climate change.
Climate change can reduce crop yields and thereby threaten food security. The current measures used to adapt to climate change involve avoiding crops yield decrease, however, the limitations of such measures due to water and other resources scarcity have not been well understood. Here, we quantify how the sensitivity of maize to water availability has increased because of the shift toward longer-maturing varieties during last three decades in the Chinese Maize Belt (CMB). We report that modern, longer-maturing varieties have extended the growing period by an average of 8 days and have significantly offset the negative impacts of climate change on yield. However, the sensitivity of maize production to water has increased: maize yield across the CMB was 5% lower with rainfed than with irrigated maize in the 1980s and was 10% lower (and even >20% lower in some areas) in the 2000s because of both warming and the increased requirement for water by the longer-maturing varieties. Of the maize area in China, 40% now fails to receive the precipitation required to attain the full yield potential. Opportunities for water saving in maize systems exist, but water scarcity in China remains a serious problem.


Organic Molecule-Driven Polymeric Actuators.
Inspired by the motions of plant tissues in response to external stimuli, significant attention has been devoted to the development of actuating polymeric materials. In particular, polymeric actuators driven by organic molecules have been designed due to their combined superiorities of tunable functional monomers, designable chemical structures, and variable structural anisotropy. Here, the recent progress is summarized in terms of material synthesis, structure design, polymer-solvent interaction, and actuating performance. In addition, various possibilities for practical applications, including the ability to sense chemical vapors and solvent isomers, and future directions to satisfy the requirement of sensing and smart systems are also highlighted.


Bone marrow adiposity and multiple myeloma.
Multiple Myeloma (MM) is an incurable haematological malignancy and is the second most common blood cancer in adults; it is caused by the clonal expansion of abnormal plasma cells within the bone marrow and characterized by osteolytic bone lesions, bone pain, renal disease, and immunodeficiency. MM cells infiltrate the bone marrow where they hijack the microenvironment to sustain growth and survival. The contribution to this process by resident bone cells is well defined. However, the role of bone marrow adipocytes is less clear. As one of the most abundant cell types in the bone marrow these cells are surprisingly understudied. However, in the last few decades they have been recognised as having endocrine function. Adipocytes are metabolically active cells that secrete adipokines, growth factors, and inflammatory mediators, they influence the behaviour and function of neighbouring cells; and have the potential to dysregulate normal bone homeostasis. This review discusses how adipocytes contribute to the metastatic niche in multiple myeloma and cancers that metastasise to the bone and how these new discoveries may contribute to further understanding the mechanisms driving the devastating bone disease associated with MM.


Classification of Alzheimer's Disease with Respect to Physiological Aging with Innovative EEG Biomarkers in a Machine Learning Implementation.
Several studies investigated clinical and instrumental differences to make diagnosis of dementia in general and in Alzheimer's disease (AD) in particular with the aim to classify, at the individual level, AD patients and healthy controls cooperating with neuropsychological tests for an early diagnosis. Advanced network analysis of electroencephalographic (EEG) rhythms provides information on dynamic brain connectivity and could be used in classification processes. If successfully reached, this goal would add a low-cost, easily accessible, and non-invasive technique with neuropsychological tests. To investigate the possibility to automatically classify physiological versus pathological aging from cortical sources' connectivity based on a support vector machine (SVM) applied to EEG small-world parameter. A total of 295 subjects were recruited: 120 healthy volunteers and 175 AD. Graph theory functions were applied to undirected and weighted networks obtained by lagged linear coherence evaluated by eLORETA. A machine-learning classifier (SVM) was applied. EEG frequency bands were: delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). The receiver operating characteristic curve showed AUC of 0.97±0.03 (indicating very high classification accuracy). The classifier showed 95% ±5% sensitivity, 96% ±3% specificity, and 95% ±3% accuracy for the classification. EEG connectivity analysis via a combination of source/connectivity biomarkers, highly correlating with neuropsychological AD diagnosis, could represent a promising tool in identification of AD patients. This approach represents a low-cost and non-invasive method, one that utilizes widely available techniques which, when combined, reach high sensitivity/specificity and optimal classification accuracy on an individual basis (0.97 of AUC).


Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus.
Cap'n'collar (CNC) family basic leucine zipper transcription factors play crucial roles in the regulation of mammalian gene expression and development. To determine the in vivo function of the CNC protein Nrf3 (NF-E2-related factor 3), we generated mice deficient in this transcription factor. We performed targeted disruption of two Nrf3 exons coding for CNC homology, basic DNA-binding, and leucine zipper dimerization domains. Nrf3 null mice developed normally and revealed no obvious phenotypic differences compared to wild-type animals. Nrf3(-/-) mice were fertile, and gross anatomy as well as behavior appeared normal. The mice showed normal age progression and did not show any apparent additional phenotype during their life span. We observed no differences in various blood parameters and chemistry values. We infected wild-type and Nrf3(-/-) mice with acute lymphocytic choriomeningitis virus and found no differences in these animals with respect to their number of virus-specific CD8 and CD4 T cells as well as their B-lymphocyte response. To determine whether the mild phenotype of Nrf3 null animals is due to functional redundancy, we generated mice deficient in multiple CNC factors. Contrary to our expectations, an absence of Nrf3 does not seem to cause additional lethality in compound Nrf3(-/-)/Nrf2(-/-) and Nrf3(-/-)/p45(-/-) mice. We hypothesize that the role of Nrf3 in vivo may become apparent only after appropriate challenge to the mice.


Nighttime light level co-distributes with breast cancer incidence worldwide.
Breast cancer incidence varies widely among countries of the world for largely unknown reasons. We investigated whether country-level light at night (LAN) is associated with incidence. We compared incidence rates of five common cancers in women (breast, lung, colorectal, larynx, and liver), observed in 164 countries of the world from the GLOBOCAN database, with population-weighted country-level LAN, and with several developmental and environmental indicators, including fertility rate, per capita income, percent of urban population, and electricity consumption. Two types of regression models were used in the analysis: Ordinary Least Squares and Spatial Errors. We found a significant positive association between population LAN level and incidence rates of breast cancer. There was no such an association between LAN level and colorectal, larynx, liver, and lung cancers. A sensitivity test, holding other variables at their average values, yielded a 30-50% higher risk of breast cancer in the highest LAN exposed countries compared to the lowest LAN exposed countries. The possibility that under-reporting from the registries in the low-resource, and also low-LAN, countries created a spurious association was evaluated in several ways and shown not to account for the results. These findings provide coherence of the previously reported case-control and cohort studies with the co-distribution of LAN and breast cancer in entire populations.


Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms.
The SARS-CoV-2-infected disease (COVID-19) outbreak is a major threat to human beings. Previous studies mainly focused on Wuhan and typical symptoms. We analysed 74 confirmed COVID-19 cases with GI symptoms in the Zhejiang province to determine epidemiological, clinical and virological characteristics. COVID-19 hospital patients were admitted in the Zhejiang province from 17 January 2020 to 8 February 2020. Epidemiological, demographic, clinical, laboratory, management and outcome data of patients with GI symptoms were analysed using multivariate analysis for risk of severe/critical type. Bioinformatics were used to analyse features of SARS-CoV-2 from Zhejiang province. Among enrolled 651 patients, 74 (11.4%) presented with at least one GI symptom (nausea, vomiting or diarrhoea), average age of 46.14 years, 4-day incubation period and 10.8% had pre-existing liver disease. Of patients with COVID-19 with GI symptoms, 17 (22.97%) and 23 (31.08%) had severe/critical types and family clustering, respectively, significantly higher than those without GI symptoms, 47 (8.14%) and 118 (20.45%). Of patients with COVID-19 with GI symptoms, 29 (39.19%), 23 (31.08%), 8 (10.81%) and 16 (21.62%) had significantly higher rates of fever >38.5°C, fatigue, shortness of breath and headache, respectively. Low-dose glucocorticoids and antibiotics were administered to 14.86% and 41.89% of patients, respectively. Sputum production and increased lactate dehydrogenase/glucose levels were risk factors for severe/critical type. Bioinformatics showed sequence mutation of SARS-CoV-2 with m6A methylation and changed binding capacity with ACE2. We report COVID-19 cases with GI symptoms with novel features outside Wuhan. Attention to patients with COVID-19 with non-classic symptoms should increase to protect health providers.


Evaluation of Interactive Visualization on Mobile Computing Platforms for Selection of Deep Brain Stimulation Parameters.
In recent years, there has been significant growth in the use of patient-specific models to predict the effects of neuromodulation therapies such as deep brain stimulation (DBS). However, translating these models from a research environment to the everyday clinical workflow has been a challenge, primarily due to the complexity of the models and the expertise required in specialized visualization software. In this paper, we deploy the interactive visualization system ImageVis3D Mobile, which has been designed for mobile computing devices such as the iPhone or iPad, in an evaluation environment to visualize models of Parkinson's disease patients who received DBS therapy. Selection of DBS settings is a significant clinical challenge that requires repeated revisions to achieve optimal therapeutic response, and is often performed without any visual representation of the stimulation system in the patient. We used ImageVis3D Mobile to provide models to movement disorders clinicians and asked them to use the software to determine: 1) which of the four DBS electrode contacts they would select for therapy; and 2) what stimulation settings they would choose. We compared the stimulation protocol chosen from the software versus the stimulation protocol that was chosen via clinical practice (independent of the study). Lastly, we compared the amount of time required to reach these settings using the software versus the time required through standard practice. We found that the stimulation settings chosen using ImageVis3D Mobile were similar to those used in standard of care, but were selected in drastically less time. We show how our visualization system, available directly at the point of care on a device familiar to the clinician, can be used to guide clinical decision making for selection of DBS settings. In our view, the positive impact of the system could also translate to areas other than DBS.


Temozolomide-Induced RNA Interactome Uncovers Novel LncRNA Regulatory Loops in Glioblastoma.
Resistance to chemotherapy by temozolomide (TMZ) is a major cause of glioblastoma (GBM) recurrence. So far, attempts to characterize factors that contribute to TMZ sensitivity have largely focused on protein-coding genes, and failed to provide effective therapeutic targets. Long noncoding RNAs (lncRNAs) are essential regulators of epigenetic-driven cell diversification, yet, their contribution to the transcriptional response to drugs is less understood. Here, we performed RNA-seq and small RNA-seq to provide a comprehensive map of transcriptome regulation upon TMZ in patient-derived GBM stem-like cells displaying different drug sensitivity. In a search for regulatory mechanisms, we integrated thousands of molecular associations stored in public databases to generate a background "RNA interactome". Our systems-level analysis uncovered a coordinated program of TMZ response reflected by regulatory circuits that involve transcription factors, mRNAs, miRNAs, and lncRNAs. We discovered 22 lncRNAs involved in regulatory loops and/or with functional relevance in drug response and prognostic value in gliomas. Thus, the investigation of TMZ-induced gene networks highlights novel RNA-based predictors of chemosensitivity in GBM. The computational modeling used to identify regulatory circuits underlying drug response and prioritizing gene candidates for functional validation is applicable to other datasets.


Identifying Malnutrition in an Elderly Ambulatory Rehabilitation Population: Agreement between Mini Nutritional Assessment and Validated Screening Tools.
Malnutrition is common in older adults and often goes unrecognised and untreated. Australian evidence-based guidelines for the management of malnutrition indicate that only the Mini Nutritional Assessment short form (MNA-sf) and Rapid Screen are recommended for use as malnutrition screening tools in the rehabilitation setting. The aim of this secondary analysis was to assess the validity and reliability of two malnutrition screening tools, validated in other adult sub-groups, in a rehabilitation population aged ≥60 years. The Council on Nutrition Appetite Questionnaire (CNAQ) and the Simplified Nutritional Appetite Questionnaire (SNAQ), were completed by 185 ambulatory rehabilitation patients (48% male; median age 78 years) and results compared to the full MNA as a reference technique. Prevalence of risk of malnutrition was 63% according to the MNA. For identification of risk of malnutrition the CNAQ had sensitivity of 54%, specificity 81%, positive predictive value 83% and negative predictive value 51%, compared to 28%, 94%, 89% and 44%, respectively, using SNAQ. Assessment of reliability indicated significant slight to fair agreement between MNA with CNAQ (κ = 0.309, p < 0.001) and SNAQ (κ = 0.176, p < 0.001). Neither the CNAQ nor the SNAQ have a high level of validity or reliability in this elderly population and are therefore not recommended for use in the ambulatory rehabilitation setting. Further work is necessary to assess the validity and reliability of other malnutrition screening tools to establish their usefulness in this population.


Closure of gap junction channels by arylaminobenzoates.
We determined the effect of flufenamic acid (FFA) and related derivatives on gap junction channel currents, applying the dual whole-cell patch-clamp technique to pairs of N2A neuroblastoma cells transfected with various connexins. FFA reduced gap junction channel currents in a reversible and concentration-dependent manner. Half-maximal concentrations for FFA-induced reduction of junctional conductance in cell pairs coupled by different connexins were similar (20 to 60 microM), indicating that FFA does not greatly discriminate between connexin subtypes. Hill coefficients for blockade were approximately 3, indicating a high degree of cooperativity. Analogs of FFA also reduced junctional conductance with similar potencies, whereas other unrelated chloride channel blockers had no effect. Inhibition of gap junction channels by FFA (pKa approximately 3.8) was increased at low external pH, suggesting that the uncharged form of the drug is important for blockade. The effect of FFA did not seem to be mediated by direct binding of the drug to the pore of the gap junction channel. Internal application of high concentrations of FFA by addition to patch pipettes did not cause inhibition of channel currents. The magnitude of inhibition was neither voltage-dependent nor influenced by the nature of permeant ion. Single-channel recordings indicated that FFA reduced the channel-open probability without modifying the current amplitude and induced slow transitions between open and closed states. We propose that FFA inhibits gap junctions by inducing a conformational change in the protein upon binding to a site that is presumably located within the membrane.


The homeodomain protein defective proventriculus is essential for male accessory gland development to enhance fecundity in Drosophila.
The Drosophila male accessory gland has functions similar to those of the mammalian prostate gland and the seminal vesicle, and secretes accessory gland proteins into the seminal fluid. Each of the two lobes of the accessory gland is composed of two types of binucleate cell: about 1,000 main cells and 40 secondary cells. A well-known accessory gland protein, sex peptide, is secreted from the main cells and induces female postmating response to increase progeny production, whereas little is known about physiological significance of the secondary cells. The homeodomain transcriptional repressor Defective proventriculus (Dve) is strongly expressed in adult secondary cells, and its mutation resulted in loss of secondary cells, mononucleation of main cells, and reduced size of the accessory gland. dve mutant males had low fecundity despite the presence of sex peptide, and failed to induce the female postmating responses of increased egg laying and reduced sexual receptivity. RNAi-mediated dve knockdown males also had low fecundity with normally binucleate main cells. We provide the first evidence that secondary cells are crucial for male fecundity, and also that Dve activity is required for survival of the secondary cells. These findings provide new insights into a mechanism of fertility/fecundity.


Haptic perception.
Fueled by novel applications, interest in haptic perception is growing. This paper provides an overview of the state of the art of a number of important aspects of haptic perception. By means of touch we can not only perceive quite different material properties, such as roughness, compliance, friction, coldness and slipperiness, but we can also perceive spatial properties, such as shape, curvature, size and orientation. Moreover, the number of objects we have in our hand can be determined, either by counting or subitizing. All these aspects will be presented and discussed in this paper. Although our intuition tells us that touch provides us with veridical information about our environment, the existence of prominent haptic illusions will show otherwise. Knowledge about haptic perception is interesting from a fundamental viewpoint, but it also is of eminent importance in the technological development of haptic devices. At the end of this paper, a few recent applications will be presented. WIREs Cogn Sci 2013, 4:357-374. DOI: 10.1002/wcs.1238 CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.


Antimycoplasmal activity of dimethylphenols in a tracheal explant culture system.
Mycoplasma pneumoniae induces pneumonia-like symptoms in hamsters and causes ciliostasis and cytonecrosis in hamster tracheal explants. 2,4-Dimethylphenol and, to a lesser extent, its 2,3-, 2,5-, and 2,6-dimethylphenol isomers protected tracheal explants from these changes after exposure to virulent M. pneumoniae strain PI 1428. The effect was concentration, time, and isomer dependent. At concentrations of 10(-9) M or greater, 2,4-dimethylphenol completely prevented the morphological (loss of ciliated cells) and biochemical (decreased dehydrogenase activity) changes normally observed after exposure to M. pneumoniae. Apparently, 2,4-dimethylphenol interfered with an early event in the infection process. Complete protection required that it be present during the first 2 h of exposure of the explants to the infecting mycoplasmas. These xylenols may prove to be useful tools for helping to define the mechanisms of pathogenesis in certain respiratory infections.


Family Care Availability And Implications For Informal And Formal Care Used By Adults With Dementia In The US.
Despite the important role that family members can play in dementia care, little is known about the association between the availability of family members and the type of care, informal (unpaid) or formal (paid), that is actually delivered to older adults with dementia in the US. Using data about older adults with dementia from the Health and Retirement Study, we found significantly lower spousal availability but greater adult child availability among women versus men, non-Hispanic Blacks versus non-Hispanic Whites, and people with lower versus higher socioeconomic status. Adults with dementia and disability who have greater family availability were significantly more likely to receive informal care and less likely to use formal care. In particular, the predicted probability of a community-dwelling adult moving to a nursing home during the subsequent two years was substantially lower for those who had a co-resident adult child (11 percent) compared with those who did not have a co-resident adult child but had at least one adult child living close (20 percent) and with those who have all children living far (23 percent). Health care policies on dementia should consider potential family availability in predicting the type of care that people with dementia will use and the potential disparities in consequences for them and their families.


Drosophila morgue associates with SkpA and polyubiquitin in vivo.
Morgue is a unique ubiquitination protein that influences programmed cell death and circadian rhythms in Drosophila. We have found that over-expression of wild-type Morgue results in organismal lethality. This over-expression phenotype was used as the basis for an in vivo functional assay to investigate the importance of the Morgue zinc finger, F box, Ubiquitin E2 Conjugase Variant (UEV) domain, and active site Glycine residue. Removal of the zinc finger or UEV domain reduced Morgue's ability to induce lethality and enhance cell death. In contrast, lack of the F box as well as several different substitutions of the active site Glycine did not alter Morgue-induced lethality or cell death enhancement. To further characterize Morgue functions, a Flag:Morgue protein was used to isolate Morgue-associated proteins from whole adult Drosophila. Mass spectrometry analysis of the Morgue-associated proteins identified SkpA as well as a ubiquitin multimer. The identification of SkpA is consistent with previous in vitro studies and further suggests Morgue acts in an SCF-type ubiquitin E3 ligase complex. The identification of poly-ubiquitin was unexpected and this interaction had not been previously identified. The associated poly-ubiquitin was found to exhibit a Lys-48 topology, consistent with distinct functions of Morgue in proteasome-mediated protein turnover. Multiple regions of Morgue were subsequently shown to be required for poly-ubiquitin binding. Overall, Morgue is a novel multi-functional ubiquitin-binding protein.


Greenhouse gas emissions from global cities.
The world's population is now over 50% urban, and cities make an important contribution to national greenhouse gas (GHG) emissions. Many cities are developing strategies to reduce their emissions. Here we ask how and why emissions differ between cities. Our study often global cities shows how a balance of geophysical factors (climate, access to resources, and gateway status) and technical factors (power generation, urban design, and waste processing) determine the GHGs attributable to cities. Within the overall trends, however, there are differences between cities with more or less public transit while personal income also impacts heating and industrial fuel use. By including upstream emissions from fuels, GHG emissions attributable to cities exceed those from direct end use by upto 25%. Our findings should help foster intercity learning on reducing GHG emissions.


In the kingdom of "tortelli" (ravioli-like pasta) plant poisoning is still a threat. A case report of near-fatal poisoning from Digitalis Purpurea accidentally confused with Borago Officinalis.
A 58 years healthy old woman was admitted to the Emergency Department (ED) with cardiac arrest due to ventricular fibrillation (VF). Appropriate cardiopulmonary resuscitation (CPR), multiple DC shocks and oro-tracheal intubation (OTI) were effective to induce recovery of spontaneous circulation (ROSC). After ROSC was achieved, the electrocardiogram (ECG) showed an idio-ventricular rhythm with atrioventricular dissociation. A transcutaneous pacing was hence applied and the patient was administered with isoproterenol. Simultaneously, her husband was evaluated in the ED for gastrointestinal symptoms occurred after assumption of home-made "tortelli" (ravioli-like pasta) stuffed with cheese and leaves of a plant which they supposed to be borage two days before admission. Borage, during the non-flowering seasons, can be easily confused with foxglove (Digitalis spp.), and this was the main clue to suspect poisoning. Both patients were given DigiFab®, a sheep antibody fragment with high affinity for digoxin. The woman was then admitted in intensive care unit (ICU), where a rapid clinical improvement occurred, thus allowing discharge in a few days. The husband was instead discharged from the ED after clinical observation and ECG monitoring. In both cases, a significant plasma concentration of digoxin could be measured.


A proposed conceptualization of therapeutic competence: the three level model.
A model of therapeutic competence that equally satisfies the requirements of practice and research is still lacking. The existing models are not widely accepted, at least partially because the postulated competences can often not be operationalized in a satisfactory manner. Yet, in order to be measurable, therapeutic competences need to be operationalized. We present the Three Level Model of Therapeutic Competence as a working model for studying therapeutic competence. The model proposes that therapeutic competence develops based on rather stable individual Dispositions, which promote the acquisition of therapeutic competences. We further distinguish between Basic Competences, which are mostly independent of the theoretical orientation of the therapeutic approach, and Specific Competences, which are defined based on the theoretical underpinnings of a therapeutic orientation (e.g. Cognitive Behavioral Therapy). We describe this model and outline how it can be used to operationalize and assess therapeutic competence.


Novel fluoropyrimidines: improving the efficacy and tolerability of cytotoxic therapy.
The fluoropyrimidines were first synthesised nearly 50 years ago as rationally designed anti-cancer agents. Their target was pyrimidine and hence DNA synthesis. 5-Fluorouracil has been the most extensively used in a wide variety of malignancies. In more recent years a fuller understanding of the pharmacokinetics of these agents has lead to their utilisation as more effective and versatile anti-cancer drugs than might have been initially envisaged. This in part has occurred due to recognition of the schedule dependency of efficacy of 5-FU and modulation of its activity by leucovorin. However the development of novel fluropyrimidines such as capcetabine, UFT, and eniluracil which can be administered orally, has offered equal if not superior efficacy with improved tolerability and patient acceptance. It is now recognised that enzyme polymorphism's and heterogeneity of expression of key molecules are important determinants of the pharmacokinetic handling and pharmacodynamic effects of these drugs in individual patients. Further characterisation of such inter-individual and inter-tumoral variability, for example in enzymes such as DPD and thymidine phosphorylase is ongoing. This work offers the promise of improvements in efficacy and tolerability by the process of individualisation of chemotherapy (for both patient and tumour). In contrast to the advances made in the understanding of the pharmacokinetics, less progress has been made in Fluropyrimidine pharmacodynamics. The inhibition of thymidylate synthetase by dFUMP and thereby dTMP and DNA synthesis is thought to be the critical mechanism. The incorporation of FUTP and dFUTP into RNA and DNA are also postulated to be of importance. While these events have been well defined, exactly how they lead to cell death is less clearly understood. Similarly, the mechanism of selective cancer cell cytotoxicity is not well understood. Pharmacokinetics and cell cycle kinetics provide a partial explanation. There is some evidence to suggest that the most important factor in determining cytotoxicity is the cellular response to fluoropyrimidine induced biochemical abnormalities rather than the lesions themselves. In this hypothesis the difference in response between normal and cancer cells is of critical importance. Further improvements in efficacy and tolerability could be made by elucidation of the molecular mechanisms behind this process. This knowledge in combination with the advances already made (and ongoing) in pharmacokinetics may allow the full potential of fluoropyrimidines as anti-cancer agents to be realised in the future.


Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders.
Toxoplasma gondii is not only implicated in schizophrenia and related disorders, but also in Alzheimer's or Parkinson's disease, cancer, cardiac myopathies, and autoimmune disorders. During its life cycle, the pathogen interacts with ~3000 host genes or proteins. Susceptibility genes for multiple sclerosis, Alzheimer's disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson's disease, attention deficit hyperactivity disorder (P from 8.01E - 05 (ADHD) to 1.22E - 71) (multiple sclerosis), and autism (P = 0.013), but not anorexia or chronic fatigue are highly enriched in the human arm of this interactome and 18 (ADHD) to 33% (MS) of the susceptibility genes relate to it. The signalling pathways involved in the susceptibility gene/interactome overlaps are relatively specific and relevant to each disease suggesting a means whereby susceptibility genes could orient the attentions of a single pathogen towards disruption of the specific pathways that together contribute (positively or negatively) to the endophenotypes of different diseases. Conditional protein knockdown, orchestrated by T. gondii proteins or antibodies binding to those of the host (pathogen derived autoimmunity) and metabolite exchange, may contribute to this disruption. Susceptibility genes may thus be related to the causes and influencers of disease, rather than (and as well as) to the disease itself.


Dietary strategies for the prevention of obesity.
The rising tide of obesity has led to a resurgence of interest in dietary strategies to prevent excess weight gain. Data from controlled intervention studies is sparse, but nonetheless evidence from other diverse sources has identified a number of specific dietary factors and aspects of eating behaviour that either promote or protect against obesity. The present paper reviews the evidence in relation to energy density, the macronutrient composition of the diet, including the nature of carbohydrate foods and sugar-rich drinks, portion size and snacking habits. It concludes that there is now sufficient evidence to develop clear dietary guidelines to prevent weight gain that are largely consistent with those for the prevention of CVD and cancer. However, coordinated action across multiple stakeholders is also required if these guidelines are to be translated into sustained changes in eating habits.


Ubiquitin COOH-terminal hydrolase 1: a biomarker of renal cell carcinoma associated with enhanced tumor cell proliferation and migration.
Renal cell carcinoma (RCC) accounts for 2% to 3% of all malignancies. It represents one of the most radiation- and chemotherapy-resistant tumors and surgical resections are only effective in organ-defined disease. However, RCC is an immunogenic tumor with response rates to immunotherapies between 10% and 20% of the treated patients. Due to the currently inefficient therapies and the low 5-year survival rates of RCC patients, novel diagnostic, prognostic, and therapeutic markers are urgently needed for this disease. Proteome-based approaches were used to identify (a) differentially expressed proteins in RCC compared with normal kidney epithelium and (b) proteins that are able to induce an antibody response in RCC patients. Based on these experiments, a promising candidate was subsequently validated by reverse transcription-PCR, Western blot analyses, and immunohistochemistry. In addition, functional assays were done in generated transfectants. The ubiquitin COOH-terminal hydrolase L1 (UCHL1) was found to be differentially expressed in both RCC lesions and RCC cell lines and immunoreactive using patients' sera. UCHL1 expression was often down-regulated in primary RCC when compared with normal kidney epithelium but dependent on the RCC subtype, the von Hippel-Lindau phenotype, and the tumor grading. Moreover, the frequency and the level of UCHL1 expression were higher in metastases when compared with primary RCC lesions. Gain-of-function transfectants exhibited a significant higher proliferation and migration rate than UCHL1-negative RCC cells. UCHL1 expression seems to be associated with the metastatic phenotype of RCC and therefore might serve as potential biomarker for the diagnosis and prognosis of RCC patients.


Empirical evidence of correlated biases in dietary assessment instruments and its implications.
Multiple-day food records or 24-hour recalls are currently used as "reference" instruments to calibrate food frequency questionnaires (FFQs) and to adjust findings from nutritional epidemiologic studies for measurement error. The common adjustment is based on the critical requirements that errors in the reference instrument be independent of those in the FFQ and of true intake. When data on urinary nitrogen level, a valid reference biomarker for nitrogen intake, are used, evidence suggests that a dietary report reference instrument does not meet these requirements. In this paper, the authors introduce a new model that includes, for both the FFQ and the dietary report reference instrument, group-specific biases related to true intake and correlated person-specific biases. Data were obtained from a dietary assessment validation study carried out among 160 women at the Dunn Clinical Nutrition Center, Cambridge, United Kingdom, in 1988-1990. Using the biomarker measurements and dietary report measurements from this study, the authors compare the new model with alternative measurement error models proposed in the literature and demonstrate that it provides the best fit to the data. The new model suggests that, for these data, measurement error in the FFQ could lead to a 51% greater attenuation of true nutrient effect and the need for a 2.3 times larger study than would be estimated by the standard approach. The implications of the results for the ability of FFQ-based epidemiologic studies to detect important diet-disease associations are discussed.


p53 shapes genome-wide and cell type-specific changes in microRNA expression during the human DNA damage response.
The human DNA damage response (DDR) triggers profound changes in gene expression, whose nature and regulation remain uncertain. Although certain micro-(mi)RNA species including miR34, miR-18, miR-16 and miR-143 have been implicated in the DDR, there is as yet no comprehensive description of genome-wide changes in the expression of miRNAs triggered by DNA breakage in human cells. We have used next-generation sequencing (NGS), combined with rigorous integrative computational analyses, to describe genome-wide changes in the expression of miRNAs during the human DDR. The changes affect 150 of 1523 miRNAs known in miRBase v18 from 4-24 h after the induction of DNA breakage, in cell-type dependent patterns. The regulatory regions of the most-highly regulated miRNA species are enriched in conserved binding sites for p53. Indeed, genome-wide changes in miRNA expression during the DDR are markedly altered in TP53-/- cells compared to otherwise isogenic controls. The expression levels of certain damage-induced, p53-regulated miRNAs in cancer samples correlate with patient survival. Our work reveals genome-wide and cell type-specific alterations in miRNA expression during the human DDR, which are regulated by the tumor suppressor protein p53. These findings provide a genomic resource to identify new molecules and mechanisms involved in the DDR, and to examine their role in tumor suppression and the clinical outcome of cancer patients.


Relevance of Assessment Methods for Fluid Intake.
Reliable data at population level are essential to firmly establish links between fluid intake, hydration and health, investigate dose-response relationships and develop meaningful public health strategies or reference intake values. However, limited research exists regarding the most appropriate methodology for assessing beverage or total fluid intake (TFI). To date, methodologies have been developed to assess food and nutrient intake without due consideration of water or fluid intake behavior. A recent crossover study showed that a 24-hour food recall significantly underestimated mean TFI by 382 ml (95% CI 299-465) compared with a fluid specific 7-day record. The authors postulated that this average difference was mainly the result of missed drinking acts between meals a 24-hour recall was used. Using a 7-day record administered in paper form or on-line has also been shown to lead to a significantly different mean TFI of 129 ml. Therefore, the choice of methodology might result in measurement errors that limit between-survey or between-country comparisons. Such errors may contribute to variations in estimates of TFI that cannot be explained by differences in climate, physical activity or cultural habits. A recent survey confirmed the variation in methodologies used in European national dietary surveys. Since these surveys form the basis for setting adequate intakes for total water intake, measurement error between surveys should be limited, highlighting the need for the development of a consistent methodology that is validated for water and TFI estimation.


Adaptive evolution of chloroplast genome structure inferred using a parametric bootstrap approach.
Genome rearrangements influence gene order and configuration of gene clusters in all genomes. Most land plant chloroplast DNAs (cpDNAs) share a highly conserved gene content and with notable exceptions, a largely co-linear gene order. Conserved gene orders may reflect a slow intrinsic rate of neutral chromosomal rearrangements, or selective constraint. It is unknown to what extent observed changes in gene order are random or adaptive. We investigate the influence of natural selection on gene order in association with increased rate of chromosomal rearrangement. We use a novel parametric bootstrap approach to test if directional selection is responsible for the clustering of functionally related genes observed in the highly rearranged chloroplast genome of the unicellular green alga Chlamydomonas reinhardtii, relative to ancestral chloroplast genomes. Ancestral gene orders were inferred and then subjected to simulated rearrangement events under the random breakage model with varying ratios of inversions and transpositions. We found that adjacent chloroplast genes in C. reinhardtii were located on the same strand much more frequently than in simulated genomes that were generated under a random rearrangement processes (increased sidedness; p < 0.0001). In addition, functionally related genes were found to be more clustered than those evolved under random rearrangements (p < 0.0001). We report evidence of co-transcription of neighboring genes, which may be responsible for the observed gene clusters in C. reinhardtii cpDNA. Simulations and experimental evidence suggest that both selective maintenance and directional selection for gene clusters are determinants of chloroplast gene order.


Psychological and Psychosocial Impairment in Preschoolers With Selective Eating.
We examined the clinical significance of moderate and severe selective eating (SE). Two levels of SE were examined in relation to concurrent psychiatric symptoms and as a risk factor for the emergence of later psychiatric symptoms. Findings are intended to guide health care providers to recognize when SE is a problem worthy of intervention. A population cohort sample of 917 children aged 24 to 71 months and designated caregivers were recruited via primary care practices at a major medical center in the Southeast as part of an epidemiologic study of preschool anxiety. Caregivers were administered structured diagnostic interviews (the Preschool Age Psychiatric Assessment) regarding the child's eating and related self-regulatory capacities, psychiatric symptoms, functioning, and home environment variables. A subset of 188 dyads were assessed a second time ∼24.7 months from the initial assessment. Both moderate and severe levels of SE were associated with psychopathological symptoms (anxiety, depression, attention-deficit/hyperactivity disorder) both concurrently and prospectively. However, the severity of psychopathological symptoms worsened as SE became more severe. Impairment in family functioning was reported at both levels of SE, as was sensory sensitivity in domains outside of food and the experience of food aversion. Findings suggest that health care providers should intervene at even moderate levels of SE. SE associated with impairment in function should now be diagnosed as avoidant/restrictive food intake disorder, an eating disorder that encapsulates maladaptive food restriction, which is new to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.


Simultaneous Electrophysiology and Fiber Photometry in Freely Behaving Mice.
In vivo electrophysiology is the gold standard technique used to investigate sub-second neural dynamics in freely behaving animals. However, monitoring cell-type-specific population activity is not a trivial task. Over the last decade, fiber photometry based on genetically encoded calcium indicators (GECIs) has been widely adopted as a versatile tool to monitor cell-type-specific population activity in vivo. However, this approach suffers from low temporal resolution. Here, we combine these two approaches to monitor both sub-second field potentials and cell-type-specific population activity in freely behaving mice. By developing an economical custom-made system and constructing a hybrid implant of an electrode and a fiber optic cannula, we simultaneously monitor artifact-free mesopontine field potentials and calcium transients in cholinergic neurons across the sleep-wake cycle. We find that mesopontine cholinergic activity co-occurs with sub-second pontine waves, called P-waves, during rapid eye movement sleep. Given the simplicity of our approach, simultaneous electrophysiological recording and cell-type-specific imaging provides a novel and valuable tool for interrogating state-dependent neural circuit dynamics in vivo.


B-Type Natriuretic Peptide as a Predictor of Short-Term Mortality in On-Pump Coronary Artery Bypass Grafting.
The present study refers to a determination of the preoperative B-type natriuretic peptide is a predictor of short-term all-cause mortality in patients undergoing on-pump coronary artery bypass graft surgeries. Two hundred and twenty-one patients undergoing on-pump coronary artery bypass graft surgeries were evaluated prospectively during a 30-day postoperative follow-up period. Serum B-type natriuretic peptide concentration was measured without a 24-hour period prior to the surgical procedure and the value obtained was correlated with a short-term all-cause mortality. Data analysis showed that all-cause mortality rates were equal to 9.5% in 30 days. Accuracy analysis by the receiver operating characteristic curve found an ideal cut-off value of B-type natriuretic peptide equal to 150 pg/mL in relation to mortality (AUC=0.82, 95% CI=0.71-0.87, P<0.001). Multivariate analysis showed that B-type natriuretic peptide value greater than or equal to 150 pg/mL (P=0.030, HR=3.99, 95% CI=1.14-13.98) was an independent predictor of all-cause mortality in a 30-day follow-up period. Preoperative serum B-type natriuretic peptide concentration is an independent predictor of short-term all-cause mortality in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.


Physical and mental decline and yet rather happy? A study of Danes aged 45 and older.
Little is known about whether the feeling of happiness follows the age-related decline in physical and mental functioning. The objective of this study was to analyze differences with age in physical and mental functions and in the feeling of happiness among Danes aged 45 years and older. Three Danish population-based surveys including 11,307 participants aged 45+ years, of whom 2411 were in the age group of 90+, were conducted in the period 1995-2001. The participation rate in the three surveys was between 63% and 82% and the same design and the same instrument were used. Self-reported mobility, a cognitive composite score, and a depression symptomatology score including a question about happiness were assessed. T-score metric was used to compare across domains and age groups. Overall, successively older age groups performed worse than the youngest age group (45-49 years), and the estimated linear decline was greater after age 70 than before age 70. For example, when comparing the oldest age group (90+ years) with the youngest, the T-score differences were found to be the largest for the mobility score (men: 40.2, women: 41.4), followed by the cognitive function (men: 22.0, women: 24.9), and the total depression symptomatology score (men: 15.5, women: 17.4). Conversely, the T-score difference in happiness was small (men: 5.6, women: 6.0). Despite markedly poorer physical and mental functions with increasing age, in this Danish sample age did not seem to affect happiness to a similarly notable extent, although, in this study, cohort and age effects cannot be disentangled.


Efficacy of a Brief Biofeedback Intervention on Mood, Arousal, Mental Workload, Movement Time, and Biofeedback Device Preference.
Biofeedback (BF) training has been utilized with performers for years. Previous literature highlights the effectiveness of multi-week intervention protocols, but there is a lack of evidence for abbreviated interventions using portable devices and the performer's preference of these devices. Therefore, we investigated the effects of a brief BF intervention on mental workload, mood, arousal, and movement time and BF device preference. Participants (N = 40) were randomly assigned to one of two heart rate variability (HRV) BF interventions or a control group. Although the brief intervention did not have a significant effect on mood, movement time, or mental workload, it did significantly and positively impact perceived arousal. Overall, 12 participants (48%) preferred the EmWave™ desktop device, eight (32%) preferred the Inner Balance™ device, and five (20%) preferred the EmWave2™ portable device. Results support limited effectiveness of a brief HRV BF protocol, although the dose-response effectiveness should continue to be explored.


Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase.
Response to genotoxic stress can be considered as a multistage process involving initiation of cell-cycle arrest and maintenance of arrest during DNA repair. Although maintenance of G2/M checkpoints is known to involve Chk1, Chk2/Rad53 and upstream components, the mechanisms involved in its initiation are less well defined. Here we report that p38 kinase has a critical role in the initiation of a G2 delay after ultraviolet radiation. Inhibition of p38 blocks the rapid initiation of this checkpoint in both human and murine cells after ultraviolet radiation. In vitro, p38 binds and phosphorylates Cdc25B at serines 309 and 361, and Cdc25C at serine 216; phosphorylation of these residues is required for binding to 14-3-3 proteins. In vivo, inhibition of p38 prevents both phosphorylation of Cdc25B at serine 309 and 14-3-3 binding after ultraviolet radiation, and mutation of this site is sufficient to inhibit the checkpoint initiation. In contrast, in vivo Cdc25C binding to 14-3-3 is not affected by p38 inhibition after ultraviolet radiation. We propose that regulation of Cdc25B phosphorylation by p38 is a critical event for initiating the G2/M checkpoint after ultraviolet radiation.


The Correlation of Meralgia Paresthetica and Spinal Surgery in Prone Position.
To investigate the incidence, risk factors, and recovery of patients with meralgia paresthetica (MP) following posterior spine surgery. Patients who underwent posterior spine surgeries in prone position at the authors' clinics were included in this study. Patients with preoperative MP were excluded. Among the 560 patients who underwent spine surgery in prone position, 117 (21%) had impaired sensation along the anterolateral aspect of the thigh. One hundred three of them were treated with conservative treatment, whereas 14 underwent surgery for MP. Conservative treatment is the first option for MP. Patients who do not recover with conservative treatment may undergo surgical treatment.


Differential microRNA response to a high-cholesterol, high-fat diet in livers of low and high LDL-C baboons.
Dysregulation of microRNA (miRNA) expression has been implicated in molecular genetic events leading to the progression and development of atherosclerosis. We hypothesized that miRNA expression profiles differ between baboons with low and high serum low-density lipoprotein cholesterol (LDL-C) concentrations in response to diet, and that a subset of these miRNAs regulate genes relevant to dyslipidemia and risk of atherosclerosis. Using Next Generation Illumina sequencing methods, we sequenced hepatic small RNA libraries from baboons differing in their LDL-C response to a high-cholesterol, high-fat (HCHF) challenge diet (low LDL-C, n = 3; high LDL-C, n = 3), resulting in 517 baboon miRNAs: 490 were identical to human miRNAs and 27 were novel. We compared miRNA expression profiles from liver biopsies collected before and after the challenge diet and observed that HCHF diet elicited expression of more miRNAs compared to baseline (chow) diet for both low and high LDL-C baboons. Eighteen miRNAs exhibited differential expression in response to HCHF diet in high LDL-C baboons compared to 10 miRNAs in low LDL-C baboons. We used TargetScan/Base tools to predict putative miRNA targets; miRNAs expressed in high LDL-C baboons had significantly more gene targets than miRNAs expressed in low LDL-C responders. Further, we identified miRNA isomers and other non-coding RNAs that were differentially expressed in response to the challenge diet in both high LDL-C and low LDL-C baboons. We sequenced and annotated baboon liver miRNAs from low LDL-C and high LDL-C responders using high coverage Next Gen sequencing methods, determined expression changes in response to a HCHF diet challenge, and predicted target genes regulated by the differentially expressed miRNAs. The identified miRNAs will enrich the database for non-coding small RNAs including the extent of variation in these sequences. Further, we identified other small non-coding RNAs differentially expressed in response to diet. Our discovery of differentially expressed baboon miRNAs in response to a HCHF diet challenge that differ by LDL-C phenotype is a fundamental step in understating the role of non-coding RNAs in dyslipidemia.


Pump Position Impacts HeartMate II Left Ventricular Assist Device Thrombosis.
The PREVENtion of HeartMate II pump Thrombosis through clinical management (PREVENT) study was a multicenter, prospective investigation to evaluate the rate of pump thrombosis (PT) with adoption of a uniform set of surgical and medical practices for left ventricular assist device implantation. We sought to quantify pump position at baseline and retrospectively define a pump position associated with poor clinical outcomes. Chest x-rays at baseline were prospectively obtained per protocol. Pump pocket depth, inflow cannula (IC) angle relative to the pump, and IC angle relative to the vertical were measured. Pumps falling in the tail-ends of the IC angle and pump pocket depth distributions were categorized as having an extreme pump position within the PREVENT study. Patients with extreme pump position had a significantly higher risk of confirmed and suspected PT, hemolysis, and elevated lactate dehydrogenase. In a multivariable analysis of survival free of confirmed PT, extreme pump position was an independent risk factor (hazard ratio = 3.6; 95% confidence interval = 1.5-8.9; p = 0.006) when adjusting for differences in pump speed and anticoagulation level. Our analysis shows that HeartMate II pump position at implant can significantly impact event-free survival and the incidence of adverse events at 6 months.


Phenotypic nutrient up-take differences in an alley cropping system in semi-arid Machakos, Kenya.
Alley cropping of Cassia siamea and maize was studied in semi-arid Kenya for soil fertility improvement. Katumani composite maize was planted except in the short rains of 1988 (SR88) when a hybrid variety was sown. Therefore the grain yield per row increased differently in the alley cropped maize (CM). Sole maize (SM) and CM yields were higher in SR88 than in the long rains of 1988 (LR88) by 62% and 38%, while yields from the same treatments in LR89 were only 21% and 45% of those in SR88. These differences in relative maize yields are attributed to differences between the two maize varieties in competition under nutrient stress conditions.


The structural biochemistry of Zucchini implicates it as a nuclease in piRNA biogenesis.
PIWI-family proteins and their associated small RNAs (piRNAs) act in an evolutionarily conserved innate immune mechanism to provide essential protection for germ-cell genomes against the activity of mobile genetic elements. piRNA populations comprise a molecular definition of transposons, which permits them to distinguish transposons from host genes and selectively silence them. piRNAs can be generated in two distinct ways, forming either primary or secondary piRNAs. Primary piRNAs come from discrete genomic loci, termed piRNA clusters, and seem to be derived from long, single-stranded precursors. The biogenesis of primary piRNAs involves at least two nucleolytic steps. An unknown enzyme cleaves piRNA cluster transcripts to generate monophosphorylated piRNA 5' ends. piRNA 3' ends are probably formed by exonucleolytic trimming, after a piRNA precursor is loaded into its PIWI partner. Secondary piRNAs arise during the adaptive 'ping-pong' cycle, with their 5' termini being formed by the activity of PIWIs themselves. A number of proteins have been implicated genetically in primary piRNA biogenesis. One of these, Drosophila melanogaster Zucchini, is a member of the phospholipase-D family of phosphodiesterases, which includes both phospholipases and nucleases. Here we produced a dimeric, soluble fragment of the mouse Zucchini homologue (mZuc; also known as PLD6) and show that it possesses single-strand-specific nuclease activity. A crystal structure of mZuc at 1.75 Å resolution indicates greater architectural similarity to phospholipase-D family nucleases than to phospholipases. Together, our data suggest that the Zucchini proteins act in primary piRNA biogenesis as nucleases, perhaps generating the 5' ends of primary piRNAs.


Experiences of Undergraduates Publishing Biomechanics Research.
The aim of this study was to investigate student experiences of publishing undergraduate research in biomechanics. A total of 29 former students with experience of publishing peer-reviewed undergraduate biomechanics research completed an online survey regarding their perceived benefits, level of involvement, and experiences in aspects of the research process. On average, students perceived their experiences to be "largely helpful" or greater in all aspects. Areas were identified corresponding to: the greatest perceived benefits (eg, understanding of the research process); the least perceived benefits (eg, statistical analysis skills); the greatest student involvement (eg, reading relevant literature); and the least student involvement (eg, developing hypotheses and/or methods). A thematic analysis of open question responses identified themes relating to: future career, skills, scientific process, intra- and interpersonal factors, and pedagogy. Common intended learning outcomes may be achieved through involvement in the research process independently of the level of staff involvement. Staff should be encouraged to involve students in publishable biomechanics research projects where this is possible without compromising research standards and should explore ways of recreating the publishing process internally for all students.


Cementing technique in femoral resurfacing.
The cementing technique is one of the various speculated factors that might contribute to the failures of resurfacing arthroplasty of the hip. The influence of bony preparation by jet lavage or lavage only in combination with different cementing techniques and cements of different viscosity in a study on fresh human femoral heads has not been evaluated so far. Sixty fresh human femoral heads were prepared for resurfacing following manufacturers' instructions and divided into 12 groups. The different groups received either syringe lavage or jet lavage and either a low-, medium- or high-viscosity cement with either packing or quarter filling of the implant with recess of the femoral stem in each case. Application of the implant was standardized. After polymerization, the femoral heads were cut into quarters and polished. Cement penetration was assessed using a square millimeter grid under optical zoom. Manual packing with high viscosity cement is a reproducible method in resurfacing arthroplasty. Syringe lavage and jet lavage mainly showed comparable cement penetration patterns when applied same cementing techniques. The penetration depth ranged from a mean of 0.6 to 3.2 mm with 0.4 being the lowest and 4.0 being the deepest. The mantle thickness ranged from 0.8 to 2.4 mm with statistically significant thicker mantles with filling, compared to packing. Our results showed distinct less penetration depth than previously reported and that just medium viscosity cement reached reliable results in the supposed range of penetration depth and cement mantle thickness. Jet lavage should be recommended for the low-viscosity cement but avoided in combination with a cement filling technique of lower viscosity cements. Filling of the implant caused the greatest penetration depth and a higher number of incomplete seatings and should therefore be avoided.