Informatics in radiology: RADTF: a semantic search-enabled, natural language processor-generated radiology teaching file.
Storing and retrieving radiology cases is an important activity for education and clinical research, but this process can be time-consuming. In the process of structuring reports and images into organized teaching files, incidental pathologic conditions not pertinent to the primary teaching point can be omitted, as when a user saves images of an aortic dissection case but disregards the incidental osteoid osteoma. An alternate strategy for identifying teaching cases is text search of reports in radiology information systems (RIS), but retrieved reports are unstructured, teaching-related content is not highlighted, and patient identifying information is not removed. Furthermore, searching unstructured reports requires sophisticated retrieval methods to achieve useful results. An open-source, RadLex(®)-compatible teaching file solution called RADTF, which uses natural language processing (NLP) methods to process radiology reports, was developed to create a searchable teaching resource from the RIS and the picture archiving and communication system (PACS). The NLP system extracts and de-identifies teaching-relevant statements from full reports to generate a stand-alone database, thus converting existing RIS archives into an on-demand source of teaching material. Using RADTF, the authors generated a semantic search-enabled, Web-based radiology archive containing over 700,000 cases with millions of images. RADTF combines a compact representation of the teaching-relevant content in radiology reports and a versatile search engine with the scale of the entire RIS-PACS collection of case material.


Low coherence interferometry for central thickness measurement of rigid and soft contact lenses.
In this paper we propose contact lens central thickness measurement with a low coherence interferometry technique using either a SLED source or a broadband continuum generated in air-silica Microstructured Optical Fiber (MOF) pumped with a picosecond microchip laser. Each of these sources associated with the interferometer provides, at the same time, good measurement resolution and quick signal recording without moving any optical elements and without need of a Fourier Transform operation. Signal improvement is performed afterwards by a numerical treatment for optimal correlation peaks detection leading to central thickness value of several contact lenses.


A trade off between mlo resistance to powdery mildew and increased susceptibility of barley to a newly important disease, Ramularia leaf spot.
Ramularia leaf spot (RLS), caused by the fungus Ramularia collo-cygni, is a serious, recently emerged disease of barley in Europe and other temperate regions. This study investigated the trade off between strong resistance to powdery mildew conferred by mlo mutant alleles and increased susceptibility to RLS. In field trials and seedling tests, the presence of mlo alleles increased severity of RLS. Genetic analysis of a doubled-haploid population identified one quantitative trait locus for susceptibility to RLS, colocalizing with the mlo-11 allele for mildew resistance. The effect of mlo-11 on RLS severity was environmentally sensitive. Analysis of near-isogenic lines of different mlo mutations in various genetic backgrounds confirmed that mlo alleles increased RLS severity in seedlings and adult plants. For mlo resistance to mildew to be fully effective, the genes ROR1 and ROR2 are required. RLS symptoms were significantly reduced on mlo-5 ror double mutants but fungal DNA levels remained as high as in mlo-5 single mutants, implying that ror alleles modify the transition of the fungus from endophytism to necrotrophy. These results indicate that the widespread use of mlo resistance to control mildew may have inadvertently stimulated the emergence of RLS as a major disease of barley.


Characterization of EhaJ, a New Autotransporter Protein from Enterohemorrhagic and Enteropathogenic Escherichia coli.
Enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) are diarrheagenic pathotypes of E. coli that cause gastrointestinal disease with the potential for life-threatening sequelae. While certain EHEC and EPEC virulence mechanisms have been extensively studied, the factors that mediate host colonization remain to be properly defined. Previously, we identified four genes (ehaA, ehaB, ehaC, and ehaD) from the prototypic EHEC strain EDL933 that encode for proteins that belong to the autotransporter (AT) family. Here we have examined the prevalence of these genes, as well as several other AT-encoding genes, in a collection of EHEC and EPEC strains. We show that the complement of AT-encoding genes in EHEC and EPEC strains is variable, with some AT-encoding genes being highly prevalent. One previously uncharacterized AT-encoding gene, which we have termed ehaJ, was identified in 12/44 (27%) of EHEC and 2/20 (10%) of EPEC strains. The ehaJ gene lies immediately adjacent to a gene encoding a putative glycosyltransferase (referred to as egtA). Western blot analysis using an EhaJ-specific antibody indicated that EhaJ is glycosylated by EgtA. Expression of EhaJ in a recombinant E. coli strain, revealed EhaJ is located at the cell surface and in the presence of the egtA glycosyltransferase gene mediates strong biofilm formation in microtiter plate and flow cell assays. EhaJ also mediated adherence to a range of extracellular matrix proteins, however this occurred independent of glycosylation. We also demonstrate that EhaJ is expressed in a wild-type EPEC strain following in vitro growth. However, deletion of ehaJ did not significantly alter its adherence or biofilm properties. In summary, EhaJ is a new glycosylated AT protein from EPEC and EHEC. Further studies are required to elucidate the function of EhaJ in colonization and virulence.


Dynamics of a ratio-dependent population model for Green Sea Turtle with age structure.
The reproduction of the green sea turtles is characterized by the temperature dependent sex determination (TSD). Green sea turtle eggs are laid asexually. Temperature during hatching determines the sex of baby green sea turtles. In order to study the population dynamics of the green sea turtles and understand the dynamics of the sex ratio, in this paper we establish a stage-structured model by incorporating TSD and the ratio dependent Holling III functional response in the reproduction process of the green sea turtle population. The effects of incubation temperature and sex ratio deviation on persistence of the population are captured by the sole basic reproduction number. The persistent mode can be either a stable equilibrium or periodic oscillations. Numerical simulations and sensitive analysis help us to identify vital parameters in our model. Our research in the paper is in favor of elevating sexual encounter rates, reducing the searching time for males and increasing survival odds from baby state into adult in order to maintain sustainability of the green sea turtles.


Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure.
We studied the phenotype of late kidney graft failure in a prospective study of unselected kidney transplant biopsies taken for clinical indications. We analyzed histopathology, HLA antibodies and death-censored graft survival in 234 consecutive biopsies from 173 patients, taken 6 days to 31 years posttransplant. Patients with late biopsies (>1 year) frequently displayed donor-specific HLA antibody (particularly class II) and microcirculation changes, including glomerulitis, glomerulopathy, capillaritis, capillary multilayering and C4d staining. Grafts biopsied early rarely failed (1/68), whereas grafts biopsied late often progressed to failure (27/105) within 3 years. T-cell-mediated rejection and its lesions were not associated with an increased risk of failure after biopsy. In multivariable analysis, graft failure correlated with microcirculation inflammation and scarring, but C4d staining was not significant. When microcirculation changes and HLA antibody were used to define antibody-mediated rejection, 17/27 (63%) of late kidney failures after biopsy were attributable to antibody-mediated rejection, but many were C4d negative and missed by current diagnostic criteria. Glomerulonephritis accounted for 6/27 late losses, whereas T-cell-mediated rejection, drug toxicity and unexplained scarring were uncommon. The major cause of late kidney transplant failure is antibody-mediated microcirculation injury, but detection of this phenotype requires new diagnostic criteria.


Results of microsurgical treatment of large and giant ICA aneurysms using the retrograde suction decompression (RSD) technique: series of 92 patients.
Microsurgical treatment of large and giant paraclinoid internal carotid artery (ICA) aneurysms often requires the use of the retrograde suction decompression (RSD) technique to facilitate clipping. Surgical results, functional outcomes at discharge, and technique limitations based on single institution series are presented. Between 1996 and 2009, eighty-three consecutive patients (19 to 68 years, mean 45.5 ± 9.9 years), predominantly women (69 women and 14 men) with large (23 patients, 27.7%) or giant (60 patients, 72.3%) paraclinoid aneurysms were surgically treated with the RSD technique performed by the neck route (62 patients, 74.4%) or later on, by endovascular means (21 patients, 25.3%). Patients were admitted after hemorrhage (48 patients, 57.9%), pseudotumor course (28 patients, 33.7%), mixed symptoms (5 patients, 6%), or asymptomatic (2 patients, 2.4%). In most RSD surgeries (90.4%) aneurysms were successfully excluded: neck was clipped in 57 patients (68.7%) or clipping with ICA reconstruction was achieved in 18 patients (21.7%). In six patients aneurysms were wrapped with glue (7.2%), trapped in one patient (1.2%), and in one patient, ICA balloon deconstruction was performed (1.2%). Good or excellent results (Glasgow Outcome Scale scores 4-5) at discharge were achieved in 69 patients (83.1%), 11 patients (13.3%) remained severely disabled (Glasgow Outcome Scale 3), and 3 patients died (3.6%). Surgical clipping with the RSD method remains a treatment of choice with acceptable outcomes for patients not amenable for endovascular treatment.


Novel electrodynamic oscillation technique enables enhanced mass transfer and mixing for cultivation in micro-bioreactor.
Micro-bioreactors (MBRs) have become an indispensable part for modern bioprocess development enabling automated experiments in parallel while reducing material cost. Novel developments aim to further intensify the advantages as dimensions are being reduced. However, one factor hindering the scale-down of cultivation systems is to provide adequate mixing and mass transfer. Here, vertical oscillation is demonstrated as an effective method for mixing of MBRs with a reaction volume of 20 μL providing adequate mass transfer. Electrodynamic exciters are used to transduce kinetic energy onto the cultivation broth avoiding additional moving parts inside the applied model MBR. The induced vertical vibration leads to oscillation of the liquid surface corresponding to the frequency and displacement. On this basis, the resonance frequency of the fluid was identified as the most decisive factor for mixing performance. Applying this vertical oscillation method outstanding mixing times below 1 s and exceptionally high oxygen transport with volumetric mass transfer coefficients (kL a) above 1,000/hr can be successfully achieved and controlled. To evaluate the applicability of this vertical oscillation mixing for low volume MBR systems, cultivations of Escherichia coli BL21 as proof-of-concept were performed. The dissolved oxygen was successfully online monitored to assure any avoidance of oxygen limitations during the cultivation. The here presented data illustrate the high potential of the vertical oscillation technique as a flexible measure to adapt mixing times and oxygen transfer according to experimental demands. Thus, the mixing technique is a promising tool for various biological and chemical micro-scale applications still enabling adequate mass transfer.


Occurrence of two different glutamate dehydrogenase activities in the halophilic bacterium Salinibacter ruber.
Salinibacter ruber, an extremely halophilic member of the domain Bacteria, has two different cytoplasmic glutamate dehydrogenase activities, marked as GDHI and GDHII. GDHI showed a strong dependence on high salt concentrations for stability, but not for activity, displaying maximal activity in the absence of salts. GDHII depended on high salt concentrations for both activity and stability. It catalyzed amination of 2-oxoglutarate with optimal activity in 3 M KCl at pH 8. No activating effect was found when NaCl was replaced by KCl. Only GDHII displayed activity in the deamination reaction of glutamate with an optimal pH of 9.5. Both enzymes were activated by certain amino acids (L-leucine, L-histidine, L-phenylalanine) and by nucleotides such as ADP or ATP. A low-molecular-mass cytoplasmic fraction was found to be a highly effective activator of GDHII in the presence of high NaCl concentrations.


Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis.
Anti-neutrophil cytoplasmic autoantibodies (ANCA) cause vasculitis and necrotizing crescentic glomerulonephritis (NCGN). Steroids and cytotoxic drugs reduce mortality but can cause significant adverse events. The proteasome inhibitor bortezomib (BTZ) prevents glomerulonephritis in mouse models of lupus but its efficacy in ANCA-associated glomerulonephritis is unknown. We induced anti-MPO IgG-mediated NCGN by transplanting wild-type bone marrow (BM) into irradiated MPO-deficient mice immunized with MPO. Four weeks after BM transplantation, we treated mice with steroid/cyclophosphamide (S/CYC) or BTZ. Compared with untreated control mice, both S/CYC and BTZ significantly reduced urine abnormalities, NCGN, and infiltration of neutrophils and macrophages. Response to BTZ depended on timing of administration: BTZ abrogated NCGN if begun 3 weeks, but not 5 weeks, after BM transplantation. BTZ treatment significantly reduced total and MPO-specific plasma cells in both the spleen and bone marrow, resulting in significantly reduced anti-MPO titers. Furthermore, BTZ affected neither B cells nor total CD4 and CD8 T cells, including their naive and effector subsets. In contrast, S/CYC reduced the total number of cells in the spleen, including total and MPO-specific plasma cells and B cells. In contrast to BTZ, S/CYC did not affect total and MPO-specific plasma cells in the bone marrow. Three of 23 BTZ-treated mice died within 36 hours after BTZ administration. In summary, BTZ depletes MPO-specific plasma cells, reduces anti-MPO titers, and prevents NCGN in mice.


Postoperative adverse outcomes in surgical patients with epilepsy: a population-based study.
People with epilepsy are more likely than healthy people to experience comorbidities and complications in various medical situations. However, the prevalence of postoperative complications, mortality, and use of medical resources in surgical patients with epilepsy has not been studied. The purpose of this study is to examine whether epilepsy is an independent risk factor for postoperative adverse outcomes of patients receiving major surgery. Retrospective cohort study using the National Health Insurance Research Database to identify patients with epilepsy who underwent major surgery in Taiwan between the years 2004 and 2007. For each case, four age- and sex-matched participants without epilepsy were included. Preoperative comorbidities in the 24 months before surgery were identified. Eight major postoperative complications, overall 30-day mortality, and in-hospital utilization of medical resources (including length of hospital stay, percentage of postoperative intensive care unit admissions, and in-hospital medical expenditures) served as the major outcome measurements. Comorbidities, status of receiving renal dialysis, teaching hospital status, types of surgery, and patients living in urban or rural areas were adjusted by multivariate logistic regression. A total of 13,103 participants with epilepsy and 52,412 without were included. Patients with epilepsy have significantly more preoperative comorbidities and demonstrated more risks of any postoperative complications (odds ratio 2.02, 95% confidence interval 1.90-2.14). Consumption of in-hospital medical resources was also significantly higher in patients with epilepsy, but no significant differences in postoperative mortality rates between the two groups were noted. Stroke was identified as the most significant postoperative complication for surgical patients with epilepsy. Patients, especially those with previous hospitalization or emergency visits due to the disease, confronted significantly higher postoperative complication rates, and consumed more in-hospital medical resources without differences in overall mortality rates. Further revision of health care standards to provide early recognition of postoperative complications and better management for surgical patients with epilepsy is needed.


Protein markers of ischemic insult in brain endothelial cells identified using 2D gel electrophoresis and ICAT-based quantitative proteomics.
The blood-brain barrier (BBB) is formed by endothelial cells of cerebral microvessels sealed by tight junctions. Ischemic brain injury is known to initiate a series of biochemical and molecular processes that lead to the disruption of the BBB, development of vascular inflammation, and subsequent neurovascular remodeling including angiogenesis. Molecular effectors of these changes are multiple and are regulated in a dynamic fashion. The current study was designed to analyze changes in cellular and secreted proteins in rat brain endothelial cells (BEC) exposed to ischemic insult in vitro using two complementary quantitative proteomic approaches: two-dimensional gel electrophoresis (2DE) and isotope-coded affinity tag (ICAT)-based proteomics. We show a comprehensive qualitative and quantitative comparison between the two proteomic methods applied to the same experimental system with respect to their reproducibility, specificity, and the type of proteins identified. In total, >160 proteins showed differential expression in response to the ischemic insult, with 38 identified by 2DE and 138 by ICAT. Only 15 proteins were commonly identified. ICAT showed superior reproducibility over 2DE and was more suitable for detecting small, large, basic, hydrophobic, and secreted proteins than 2DE. However, positive identification of proteins by MS/MS was more reliably done using a 2DE-based method compared to ICAT. Changes in proteins involved in nucleic acid, protein, and carbohydrate metabolism, signal transduction, cell structure, adhesion and motility, immunity and defense, cell cycle, and apoptosis were observed. The functional significance of observed protein changes was evaluated through a multifaceted protein classification and validation process, which included literature mining and comparative evaluation of protein changes in analogous in vitro and in vivo ischemia models. The comparative analyses of protein changes between the in vitro and in vivo models demonstrated a significant correlative relationship, emphasizing the 'translational' value of in vitro endothelial models in neurovascular research.


Se-methylselenocysteine alters collagen gene and protein expression in human prostate cells.
The anti-cancer activity of selenium is dose-dependent and species-specific but the mechanism is unclear. Se-methylselenocysteine (MSC), found in selenium-enriched alliums, is one of the most potent forms. We exposed two human prostate cell lines (LNCaP clone FGC and PNT1A) to nutritionally relevant doses of MSC and selenite, ranging from deficient to the equivalent of selenium supplementation in humans. The cells were adapted for one month to attain steady-state selenium status. Two microarray platforms, an in-house printed microarray (14,000 genes) and the Affymetrix U133A array (22,000 genes) were used to probe the molecular effects of selenium dose and form and several selenium-responsive genes were identified, many of which have been ascribed to cancer cell growth and progression. In response to MSC supplementation, the expression of 23 genes changed significantly, including several collagen genes. Quantitative RT-PCR assays were designed and optimized for four of the collagen genes to validate array data. Significant decreases in expression of collagen type I alpha 1 (COL1A1), COL1A2 and COL7A1 genes were observed in cells adapted to MSC supplementation compared to the control and selenite exposed cells. There were significant increases in genes encoding other types of collagen, including significant increases in COL6A1 and COL4A5 in response to MSC dose. Functional changes in collagen type I protein expression in response to MSC were confirmed by ELISA. This study reveals for the first time that MSC can alter the expression of several types of collagen and thus potentially modulate the extracellular matrix and stroma, which may at least partially explain the anti-cancer activity of MSC.


Triggered activity in cardiac muscle fibers of the simian mitral valve.
The action potential of cardiac fibers in the anterior mitral valve leaflet of the monkey heart is followed by an after-hyperpolarization. The addition of catecholamines causes a delayed after-depolarization to follow the after-hyperpolarization. The amplitude of the after-depolarization increases as the stimulus cycle length is decreased, or after premature stimulation, and as a result can reach threshold to yield nondriven, sustained rhythmic activity which we term triggered activity. This sustained rhythmic activity can be terminated by a single, appropriately timed, premature stimulus. The amplitude of the action potentials of mitral valve fibers is increased by catecholamines; the amplitude and rate of depolarization are depressed by verapamil. The amplitude of the action potentials is little affected by tetrodotoxin (TTX) but the maximum rate of depolarization is reduced by TTX. The delayed after-depolarization induced by catecholamines is abolished by verapamil, as is triggered activity. These observations suggest that mitral valve fibers generate slow response action potentials, that triggerable sustained rhythmic activity may be a property of the slow response and that such activity may cause the types of cardiac arrhythmias that usually are attributed to reentry.


Intergenerational wealth transmission and homeownership in Europe-a comparative perspective.
The literature on social and wealth inequality has long acknowledged the importance of intergenerational wealth transmission (IWT) to inequality in homeownership tenure. However, it has paid insufficient attention to the institutional structures that moderate these inequalities. Therefore, in this study, we ask how institutional factors via differential housing finance systems and governmental housing policies, moderate the association between IWT and homeownership tenure. This is done by using the framework of housing regime configurations and mortgage market financialization. To do so, we pooled data for 20 European countries from the European Central Bank's Household Finance and Consumption Survey (HFCS) for 2010-2017, for household heads aged 25-40. Our main findings show consistent contradiction to the welfare state-homeownership "trade-off" hypothesis: that is, when the rental market is more heavily regulated, it is actually young adults who benefited from IWT or who received higher value of IWT have a higher probability of mortgaged homeownership. Paradoxically, when housing finance institutions are more active and generous, the wealthiest young adults hold an advantage in mortgaged homeownership. Therefore, liberal mortgage markets actually serve to enable wealthier young adults to reproduce and preserve their parental wealth status. Further, when housing prices are less affordable (median mortgage-to-income ratio), those who have received a higher amount of IWT hold an advantage in mortgaged homeownership. We discuss the implications of our findings, which cut across the socioeconomic, spatial, and demographical arenas.


A dataset of publication records for Nobel laureates.
A central question in the science of science concerns how to develop a quantitative understanding of the evolution and impact of individual careers. Over the course of history, a relatively small fraction of individuals have made disproportionate, profound, and lasting impacts on science and society. Despite a long-standing interest in the careers of scientific elites across diverse disciplines, it remains difficult to collect large-scale career histories that could serve as training sets for systematic empirical and theoretical studies. Here, by combining unstructured data collected from CVs, university websites, and Wikipedia, together with the publication and citation database from Microsoft Academic Graph (MAG), we reconstructed publication histories of nearly all Nobel prize winners from the past century, through both manual curation and algorithmic disambiguation procedures. Data validation shows that the collected dataset presents among the most comprehensive collection of publication records for Nobel laureates currently available. As our quantitative understanding of science deepens, this dataset is expected to have increasing value. It will not only allow us to quantitatively probe novel patterns of productivity, collaboration, and impact governing successful scientific careers, it may also help us unearth the fundamental principles underlying creativity and the genesis of scientific breakthroughs.


Identification of an endosomal antigen specific to absorptive cells of suckling rat ileum.
A membrane fraction enriched in apical endosomal tubules was isolated from absorptive cells of suckling rat ileum and used as an immunogen to generate anti-endosome monoclonal antibodies. By immunofluorescence, one of these antibodies bound exclusively to the region of the apical endocytic complex in ileal absorptive cells, but not to other cell types. Immunoblot analysis showed the antigen as a diffuse 55-61-kD band which was highly enriched in the endosome fraction over whole-cell homogenate. The antigen appears to be an intramembrane glycoprotein: it partitioned primarily in the detergent phase after TX-114 extraction, and shifted to 44 kD after chemical deglycosylation. EM immunocytochemistry showed that the antibody bound to the luminal side of endosomal tubule membranes, a portion of endosomal vesicle membranes, and in endocytic pits of apical plasma membranes. However, it did not bind to multivesicular bodies, the giant lysosome, or other organelles. Immunocytochemistry after uptake with adsorbed or soluble tracer proteins showed that the antigen labeled portions of both prelysosomal pathways previously described in these cells (Gonnella, P.A., and M. R. Neutra, 1984, J. Cell Biol., 99:909-917). The function of this glycoprotein is not known, but inasmuch as it has been detected only in absorptive cells of suckling rat ileum, it may serve a function specific to these cells. Nevertheless, this endosomal antigen, designated glycoprotein (gp) 55-61, will serve as a useful marker for exploring membrane dynamics in early stages of the endocytic pathway.


Exploring stress and coping among urban African American adolescents: the Shifting the Lens study.
Stress can have a significant effect on an adolescent's long-term physical and mental well-being. An understanding of the role of unmanaged stress during early adolescence is critical for the prevention of chronic diseases such as depression. The purpose of the Shifting the Lens study was to explore perceptions of stress, sources of social support, and use of coping strategies among urban African American ninth graders. A youth-driven, mixed-method approach was used to assess teens' perceptions of stress. During the 2001-2002 school year, teen participants (N = 26) from East Baltimore, Md, completed questionnaires, audio journals, pile-sort activities, and personal social support network maps. In contrast with existing literature that emphasizes the influence of violence and neighborhood factors on stress among teens, teens prioritized other sources of stress, particularly from school, friends, and family. For support, they relied on different individuals, depending on the source of the stress--friends for romantic relationship stress and family for job, school, and family stress. Sex differences in the coping styles of the participating teens were found. Girls reported more frequent use of support-seeking and active coping strategies than boys. The use of multiple data collection strategies to explore stress uniquely contributes to our understanding of how one group of teens perceives and copes with stress. Future research should explore stress from the youth perspective in communities that are similar to East Baltimore, Md. In addition, programmatic recommendations include the need for sex-specific stress management activities and education about youth stress for adults. Community participatory translation interventions based on study findings, such as a youth-produced video and a resource guide for youth service providers, were implemented.


Aloe vera for prevention of radiation-induced dermatitis: a self-controlled clinical trial.
To evaluate an Aloe vera lotion for prevention of radiation-induced dermatitis, all patients with a prescription of radiotherapy to a minimum dose of 40 Gy were eligible provided that their treatment area could be divided into two symmetrical halves. Patients were given a lotion of Aloe vera to use on one half of the irradiated area, with no medication to be used on the other half. The grade of dermatitis in each half was recorded weekly until 4 weeks after the end of radiotherapy. The trial enrolled 60 patients (mean age: 52 years; 67% women). Most patients had breast cancer (38%), followed by pelvic (32%), head-and-neck (22%), and other cancers (8%). Field size was 80-320 cm(2) (mean: 177 cm(2)), and the dose of radiotherapy was 40-70 Gy (mean: 54 Gy). Concurrent chemotherapy was administered in 20 patients. From week 4 to week 6 of radiotherapy and then at weeks 2 and 4 after radiotherapy, the mean grade of dermatitis with and without Aloe vera was 0.81 and 1.10 (p < 0.001), 0.96 and 1.28 (p < 0.001), 1.00 and 1.57 (p = 0.006), 0.59 and 0.79 (p = 0.003), and 0.05 and 0.21 (p = 0.002) respectively. Age and radiation field size had a significant effect on the grade of dermatitis. Based on these results, we conclude that the prophylactic use of Aloe vera reduces the intensity of radiationinduced dermatitis.


The Pak1 kinase: an important regulator of neuronal morphology and function in the developing forebrain.
The mammalian central nervous system (CNS) represents a highly complex unit, the correct function of which relies on the appropriate differentiation and survival of its neurones. It is becoming apparent that the Rho family of small GTPases and their downstream targets have a major function in regulating CNS development. Among the effectors, the role of the Pak family of kinases, especially Pak1, is becoming increasingly evident. Although highest levels of Pak1 expression and activation are detected in the developing nervous system, much remains undiscovered concerning its function in neurones. This review summarises what is currently known regarding the biological and molecular role of Pak1 in the mammalian forebrain. It emphasises the importance of Pak1 in regulating neuronal polarity, morphology, migration and synaptic function. Consequently, there are also strong indications that Pak1 is required for normal cognitive function. Furthermore, loss of Pak1 has been associated with the progression of neurodegenerative disorders, particularly Alzheimer's disease, while up-regulation and de-regulation may be responsible for oncogenic transformation of support cells within the CNS, especially astrocyte progenitors. Together, these new and exciting findings encourage the future exploration into the function of Pak1 in the nervous system, thus, paving the way for novel strategies towards improved diagnosis and therapeutic treatment of diseases that affect the CNS.


RCT of web-based personalized normative feedback for college drinking prevention: are typical student norms good enough?
Personalized normative feedback (PNF) interventions are generally effective at correcting normative misperceptions and reducing risky alcohol consumption among college students. However, research has yet to establish what level of reference group specificity is most efficacious in delivering PNF. This study compared the efficacy of a web-based PNF intervention using 8 increasingly specific reference groups against a Web-BASICS intervention and a repeated-assessment control in reducing risky drinking and associated consequences. Participants were 1,663 heavy-drinking Caucasian and Asian undergraduates at 2 universities. The referent for web-based PNF was either the typical same-campus student or a same-campus student at 1 (either gender, race, or Greek affiliation), or a combination of 2 (e.g., gender and race), or all 3 levels of specificity (i.e., gender, race, and Greek affiliation). Hypotheses were tested using quasi-Poisson generalized linear models fit by generalized estimating equations. The PNF intervention participants showed modest reductions in all 4 outcomes (average total drinks, peak drinking, drinking days, and drinking consequences) compared with control participants. No significant differences in drinking outcomes were found between the PNF group as a whole and the Web-BASICS group. Among the 8 PNF conditions, participants receiving typical student PNF demonstrated greater reductions in all 4 outcomes compared with those receiving PNF for more specific reference groups. Perceived drinking norms and discrepancies between individual behavior and actual norms mediated the efficacy of the intervention. Findings suggest a web-based PNF intervention using the typical student referent offers a parsimonious approach to reducing problematic alcohol use outcomes among college students.


Rare-earth-containing perovskite nanomaterials: design, synthesis, properties and applications.
As star material, perovskites have been widely used in the fields of optics, photovoltaics, electronics, magnetics, catalysis, sensing, etc. However, some inherent shortcomings, such as low efficiency (power conversion efficiency, external quantum efficiency, etc.) and poor stability (against water, oxygen, ultraviolet light, etc.), limit their practical applications. Downsizing the materials into nanostructures and incorporating rare earth (RE) ions are effective means to improve their properties and broaden their applications. This review will systematically summarize the key points in the design, synthesis, property improvements and application expansion of RE-containing (including both RE-based and RE-doped) halide and oxide perovskite nanomaterials (PNMs). The critical factors of incorporating RE elements into different perovskite structures and the rational design of functional materials will be discussed in detail. The advantages and disadvantages of different synthesis methods for PNMs will be reviewed. This paper will also summarize some practical experiences in selecting suitable RE elements and designing multi-functional materials according to the mechanisms and principles of REs promoting the properties of perovskites. At the end of this review, we will provide an outlook on the opportunities and challenges of RE-containing PNMs in various fields.


Balloonborne lidar for cloud physics studies.
An innovative balloonborne microjoule lidar (MULID) has been developed within the framework of the HIBISCUS project to provide nighttime measurements of visible and subvisible cirrus and aerosols. MULID has been designed to be a low-cost and an ultralow consumption instrument, due to the remote possibilities of payload recovery and the necessity of a low-weight battery power supply. Ground tests have been performed at the Observatory of Haute Provence (France), and the first technical flight has been made from Trapani, Italy, on a stratospheric balloon; finally, the instrument has been scientifically deployed during the pre-HIBISCUS and HIBISCUS tropical campaigns in Bauru, Brazil, in February 2003 and February 2004, respectively. A description of the instrument is provided together with the results of the ground-based and flight tests as well as an overview and discussion of the first results.


Anthocyanin-Rich Extract from Red Chinese Cabbage Alleviates Vascular Inflammation in Endothelial Cells and Apo E-/- Mice.
Anthocyanins, the most prevalent flavonoids in red/purple fruits and vegetables, are known to improve immune responses and reduce chronic disease risks. In this study, the anti-inflammatory activities of an anthocyanin-rich extract from red Chinese cabbage (ArCC) were shown based on its inhibitory effects in cultured endothelial cells and hyperlipidemic apolipoprotein E-deficient mice. ArCC treatment suppressed monocyte adhesion to tumor necrosis factor-α-stimulated endothelial cells. This was validated by ArCC's ability to downregulate the expression and transcription of endothelial adhesion molecules, determined by immunoblot and luciferase promoter assays, respectively. The regulation of adhesion molecules was accompanied by transcriptional inhibition of nuclear factor-κB, which restricted cytoplasmic localization as shown by immunocytochemistry. Administration of ArCC (150 or 300 mg/kg/day) inhibited aortic inflammation in hyperlipidemic apolipoprotein E-deficient mice, as shown by in vivo imaging. Immunohistochemistry and plasma analysis showed that the aortas from these mice exhibited markedly lower leukocyte infiltration, reduced plaque formation, and lower concentrations of blood inflammatory cytokines than those observed in the control mice. The results suggest that the consumption of anthocyanin-rich red Chinese cabbage is closely correlated with lowering the risk of vascular inflammatory diseases.


Complicated vascular access port removals: incidence, antecedents and avoidance.
Port removal is usually a straightforward procedure delegated to trainees. However, some port removals are complicated by central venous catheter (CVC) fragmentation, a challenge for even experienced surgeons. This study aimed to determine the incidence of, and risk factors for, complicated port removal in children. A single-centre study assessed the outcome of removal for all paediatric ports inserted from 1996 to 2012. Data were recorded detailing patient, insertion, device and removal characteristics. Risk factors for complicated removals were scrutinised using Chi-square tests; p < 0.05 significant. Of 628 ports inserted from 1996 to 2012, 443 were subsequently removed at the same centre. 8/443 (1.8%) removals were complicated by CVC fragmentation, a median of 3.3 (2.4-3.9) years after insertion. Of complicated cases, 8/8 underwent formal neck dissection, 3/8 intravascular dissection, and 1/8 endovascular retrieval. 2/8 cases have retained intravascular CVC fragments. Risk factors for complication were CVC caliber <6Fr (p < 0.001) and use duration >2 years (p < 0.001). Greatest care and senior supervision should be ensured when removing ports with CVC caliber <6Fr and/or >2 years since insertion. However, complications also occur with larger CVCs or after shorter durations. Therefore, the key to avoiding complicated port removal may simply be: preparation, preparation, neck preparation.


Quality of life and anxiety in a phase II cardiac rehabilitation program.
Cardiac rehabilitation programs increasingly attempt to improve both quantity and quality of life (QOL). Documenting QOL changes requires appropriate instruments, and interpreting QOL data requires an understanding of the factors that influence such reports. To address both issues, we assessed QOL among 77 patients before and after participation in a 12-wk phase II cardiac rehabilitation program. Individual psychological differences in trait anxiety and defensiveness were also assessed. The sample was 76.6% male, 70.1% married, and had a mean age of 58.8 yr. The QOL scales detected changes which occurred over the 12-wk testing period. QOL reports were strongly and differentially influenced by individual differences in trait anxiety, such that patients reporting high trait anxiety displayed poorer QOL than those low in trait anxiety. More specifically, trait anxiety influenced affect reports most strongly, functional aspects moderately, and physical aspects of QOL reports the least. Defensiveness was unrelated to QOL reports. The 17% of participants who voluntarily left the rehabilitation program prematurely were characterized as younger, having better self-perceived health, having a less severe cardiac history, and being high in both trait anxiety and defensiveness. Study benefits and limitations are discussed.


Mozambican grass seed consumption during the Middle Stone Age.
The role of starchy plants in early hominin diets and when the culinary processing of starches began have been difficult to track archaeologically. Seed collecting is conventionally perceived to have been an irrelevant activity among the Pleistocene foragers of southern Africa, on the grounds of both technological difficulty in the processing of grains and the belief that roots, fruits, and nuts, not cereals, were the basis for subsistence for the past 100,000 years and further back in time. A large assemblage of starch granules has been retrieved from the surfaces of Middle Stone Age stone tools from Mozambique, showing that early Homo sapiens relied on grass seeds starting at least 105,000 years ago, including those of sorghum grasses.


The impact of electronic health records on people with diabetes in three different emergency departments.
To evaluate if electronic health records (EHR) with prior clinical information have observable effects for patients with diabetes presenting to emergency departments (ED), we examined measures of quality and resource utilization. Retrospective observational studies of patients in three ED (A=5510; B=4393; C=3324) were conducted comparing patients with prior information in the EHR to those without such information. Differences with respect to hospitalization, mortality, length of stay (LOS), and numbers of ED orders for tests, procedures and medications were examined after adjusting for age, gender, race, marital status, comorbidities and for acuity level within each ED. There were 7% fewer laboratory test orders at one ED and 3% fewer at another; fewer diagnostic procedures were performed at two of the sites. At one site 36% fewer medications were ordered. The odds of being hospitalized were lower for EHR patients at one site and hospital LOS was shorter at two of the sites. EHR patient ED LOS was 18% longer at one site. There was no demonstrable impact of an EHR on mortality. Results varied in magnitude and direction by site. The pattern of significant results varied by ED but tended to reveal reduced utilization and better outcomes for patients although EHR patients' ED LOS was longer at one site. The presence of prior information in an EHR may be a valuable adjunct in the care of diabetes patients in ED settings but the pattern of impact may vary from ED to ED.


GATA4, 5 and 6 mediate TGFbeta maintenance of endodermal gene expression in Xenopus embryos.
The individual contributions of the three vertebrate GATA factors to endoderm formation have been unclear. Here we detail the early expression of GATA4, 5 and 6 in presumptive endoderm in Xenopus embryos and their induction of endodermal markers in presumptive ectoderm. Induction of HNF3beta by all three GATA factors was abolished when protein synthesis was inhibited, showing that these inductions are indirect. In contrast, whereas induction of Sox17alpha and HNF1beta by GATA4 and 5 was substantially reduced when protein synthesis was inhibited, induction by GATA6 was minimally affected, suggesting that GATA6 is a direct activator of these early endodermal genes. GATA4 induced GATA6 expression in the same assay and antisense morpholino oligonucleotides (MOs), designed to knock down translation of GATA6, blocked induction of Sox17alpha and HNF1beta by GATA4, suggesting that GATA4 induces these genes via GATA6 in this assay. All three GATA factors were induced by activin, although GATA4 and 6 required lower concentrations. GATA MOs inhibited Sox17alpha and HNF1beta induction by activin at low and high concentrations in the order: GATA6>GATA4>GATA5. Together with the timing of their expression and the effects of GATA MOs in vivo, these observations identify GATA6 as the predominant GATA factor in the maintenance of endodermal gene expression by TGFbeta signaling in gastrulating embryos. In addition, examination of gene expression and morphology in later embryos, revealed GATA5 and 6 as the most critical for the development of the gut and the liver.


Palisade endings in human extraocular muscles.
The presence of nerve terminals in the tendinous insertions of human eye muscles was investigated histologically in adult human eye muscles obtained from donor eyes and in muscle pieces resected from juvenile patients undergoing surgical correction for strabismus. Lateral and medial recti, superior and inferior oblique muscles from adults, were stained "en bloc" using a silver impregnation method. Numbers of nerve terminals were isolated that resembled "palisade endings" previously described in other species. A single palisade ending usually appeared as an interwoven network of fine neural filaments that cupped the inserting tip of a single extrafusal fiber. A collection of palisade endings on several neighboring muscle fibers were supplied by a single myelinated axon that branched from a nerve bundle in the muscle mass. The presence of nerve terminals at the distal musculotendinous interface of juvenile muscle also was observed when some resected specimens of lateral and medial recti were sectioned and stained using Holmes' silver method with a picrofuschin counterstain. No conventional Golgi tendon organs were seen.


Chronic pain impairs cognitive flexibility and engages novel learning strategies in rats.
Cognitive flexibility, the ability to adapt behavior to changing outcomes, is critical to survival. The prefrontal cortex is a key site of cognitive control, and chronic pain is known to lead to significant morphological changes to this brain region. Nevertheless, the effects of chronic pain on cognitive flexibility and learning remain uncertain. We used an instrumental paradigm to assess adaptive learning in an experimental model of chronic pain induced by tight ligation of the spinal nerves L5/6 (spinal nerve ligation model). Naive, sham-operated, and spinal nerve ligation (SNL) rats were trained to perform fixed-ratio, variable-ratio, and contingency-shift behaviors for food reward. Although all groups learned an initial lever-reward contingency, learning was slower in SNL animals in a subsequent choice task that reversed reinforcement contingencies. Temporal analysis of lever-press responses across sessions indicated no apparent deficits in memory consolidation or retrieval. However, analysis of learning within sessions revealed that the lever presses of SNL animals occurred in bursts, followed by delays. Unexpectedly, the degree of bursting correlated positively with learning. Under a variable-ratio probabilistic task, SNL rats chose a less profitable behavioral strategy compared with naive and sham-operated animals. After extinction of behavior for learned preferences, SNL animals reverted to their initially preferred (ie, less profitable) behavioral choice. Our data suggest that in the face of uncertainty, chronic pain drives a preference for familiar associations, consistent with reduced cognitive flexibility. The observed burst-like responding may represent a novel learning strategy in animals with chronic pain.


Identity and resistance: why spiritual care needs 'enemies'.
This paper explores certain key critiques of spirituality-in-nursing as they have been offered by people outside of the discipline. It argues that nurses have not taken seriously enough the recent criticism of the nature and role of spirituality in nursing. Not to listen to the 'enemies' of spirituality-in-nursing is to risk stagnation and a drift into obscurity. The area of spirituality has become a growing field of interest for nurses and has produced a burgeoning body of research literature. Yet, whilst much has been written about the positive aspects of spirituality, nurses have offered almost no critique of the ways in which spirituality and spiritual care are understood, despite the fact that there are clearly certain key issues that require robust critique and thoughtful reflection. Almost all of the major criticisms of spirituality-in-nursing have come from people outside of the discipline of nursing. The paper argues that nurses need to listen carefully to the criticisms of spirituality and spiritual care offered by the 'enemies' of spiritual care in nursing. When listened to constructively, they highlight issues that are vital for the development and forward movement of this important area of nursing practice. Literature review and critical reflection on current critiques of spirituality in nursing practice. The paper concludes that nurses need to begin to develop spirituality as a specific field of enquiry with its own bodies of knowledge, methodologies, assumptions and core disciplines. In listening to and taking seriously its 'enemies', nursing has the opportunity to establish spirituality as an important, creative and vibrant aspect of nursing practice that has the capacity to grow and respond constructively to its 'enemies', in ways that make whole-person-care a real possibility.


Beyond Primates: Research Protections and Animal Moral Value.
Should monkeys be used in painful and often deadly infectious disease research that may save many human lives? This is the challenging question that Anne Barnhill, Steven Joffe, and Franklin G. Miller take on in their carefully argued and compelling article "The Ethics of Infection Challenges in Primates." The authors offer a nuanced and even-handed position that takes philosophical worries about nonhuman primate moral status seriously and still appreciates the very real value of such research for human welfare. Overall, they argue for an extension and revision of the recommendations regarding chimpanzee research offered by the Institute of Medicine in 2011; the practical upshot of their argument would allow for infection challenge research for promising interventions for Ebola and Marburg virus diseases but not for smallpox or the common cold. The IOM recommendations regarding chimpanzee research put in motion an exceptionalist policy for this great ape population. Barnhill and colleagues' proposal would enlarge the scope of that exceptionalism to embrace NHPs other than great apes. But is such exceptionalism warranted? It is not obvious to me either that the more sophisticated capacities of a species as a whole give it greater ethical protections or that less intellectually or socially sophisticated animals ought to therefore receive less protection when it comes to painful experimental interventions.


Leading a Horse to Water: Facilitating Registration and Use of a Prescription Drug Monitoring Program.
Prescription Drug Monitoring Programs (PDMPs) can help inform patient management, coordinate care, and identify drug safety risks, abuse, or diversion. However, many clinicians are not registered to use these systems, and use may be suboptimal. We sought to describe outreach efforts in 1 state (Oregon); quantify uptake of system use; identify barriers; and identify potential system improvements. Program reports of outreach efforts and operational metrics provided rates of registration and use. A statewide survey identified perceived barriers and potential improvements from users and nonusers of the system. Even with extensive registration efforts, <25% of clinicians and pharmacists acquired PDMP accounts over 2 years of operation. Rapid increases in registration and use in 2013 corresponded to new requirements among large pharmacy chains that pharmacists register for and use the PDMP. Among surveyed PDMP nonusers, nearly half were unaware that they could register. Among users and nonusers, over two thirds indicated that time constraints were a major barrier and over half thought that inability to delegate access was a major barrier. Desired improvements included linking state systems, faster entry of pharmacy data, and use of unique patient identifiers. Users also wanted better insurance coverage for mental health and addiction referrals. Increasing registration and use of PDMPs remains important. Clinician feedback indicates that program enhancements and health care system changes would facilitate using and responding to PDMP information. It appears premature to judge the efficacy of PDMPs until best practices for their use are identified and impacts are assessed.


Knowledge and attitudes of oncology nurses regarding pharmacogenomic testing.
More than 20 different pharmacogenomic tests are being used in the oncology field. The current descriptive study was conducted with 368 oncology nurses in North Carolina to identify and test key elements of Rogers' Diffusion of Innovation Theory that play a role in the adoption of pharmacogenomic testing. Oncology nurses who participated in this study had limited knowledge of genomics and pharmacogenomic testing. Attitudes toward pharmacogenomic testing were positive overall, and the study revealed that oncology nurses in this study routinely use pharmacogenomic testing information. Variable selection methods revealed that total genomic knowledge was more accurately predicted by prior experience and personality variables, pharmacogenomic knowledge was more accurately predicted by personality variables, and attitude was more accurately predicted by prior experience and perceived need of innovation. Based on these findings, several factors play key roles in the diffusion of pharmacogenomic testing within the oncology nursing field. Therefore, assessment of these variables may benefit the widespread adoption of pharmacogenomic testing. Further research should be conducted with these variables to assess the adoption of the innovation.


Mixed-methods investigation of women's experiences with second-trimester abortion care in the Midwest and Northeast United States.
We studied women's experiences seeking and receiving second-trimester abortion care in two geographically and legislatively different settings to inform ways to improve abortion care access and services. We conducted in-depth interviews with women who obtained second-trimester abortion care. Themes from the interviews were then used to inform a self-administered survey, which was completed by 108 women who received second-trimester abortion care in the Northeast and Midwest. We calculated descriptive statistics and used chi-squared and t-tests to compare responses. We interviewed eight women and surveyed 108 women. Most interviewees and 65.2% of survey respondents reported difficulties accessing care. Although most interview and survey respondents had insurance, a slight majority reported difficulty funding care. All interviewees and 57.9% of survey respondents reported positive experiences with providers, with many interviewees and 62.0% of survey respondents saying their abortion care was better than their usual health care. Most interviewees and 75.8% of survey respondents reported pain as low to moderate, and the majority of participants reported it was the same or less than expected. Knowledge about abortion restrictions was low. Most interviewees and 68.4% survey respondents disagreed with restrictions on insurance coverage of abortion. Common recommendations to improve experiences were to ensure travel and financial support and to decrease wait times at clinics. There were few regional differences among outcomes. Women seeking second-trimester abortion in these locations reported positive abortion experiences. However, they had to overcome significant obstacles to obtain care. This is the first study to systematically research women's second-trimester care experiences in two different regions of the United States. Regardless of location, women experienced barriers due to policies that impose gestational age restrictions, limit provider availability (consequently increasing wait times), and increase costs. Policy change to reduce these barriers is critical to improve access to and experiences with second trimester abortion care.


Modelling challenges in context: lessons from malaria, HIV, and tuberculosis.
Malaria, HIV, and tuberculosis (TB) collectively account for several million deaths each year, with all three ranking among the top ten killers in low-income countries. Despite being caused by very different organisms, malaria, HIV, and TB present a suite of challenges for mathematical modellers that are particularly pronounced in these infections, but represent general problems in infectious disease modelling, and highlight many of the challenges described throughout this issue. Here, we describe some of the unifying challenges that arise in modelling malaria, HIV, and TB, including variation in dynamics within the host, diversity in the pathogen, and heterogeneity in human contact networks and behaviour. Through the lens of these three pathogens, we provide specific examples of the other challenges in this issue and discuss their implications for informing public health efforts.


White-nose syndrome initiates a cascade of physiologic disturbances in the hibernating bat host.
The physiological effects of white-nose syndrome (WNS) in hibernating bats and ultimate causes of mortality from infection with Pseudogymnoascus (formerly Geomyces) destructans are not fully understood. Increased frequency of arousal from torpor described among hibernating bats with late-stage WNS is thought to accelerate depletion of fat reserves, but the physiological mechanisms that lead to these alterations in hibernation behavior have not been elucidated. We used the doubly labeled water (DLW) method and clinical chemistry to evaluate energy use, body composition changes, and blood chemistry perturbations in hibernating little brown bats (Myotis lucifugus) experimentally infected with P. destructans to better understand the physiological processes that underlie mortality from WNS. These data indicated that fat energy utilization, as demonstrated by changes in body composition, was two-fold higher for bats with WNS compared to negative controls. These differences were apparent in early stages of infection when torpor-arousal patterns were equivalent between infected and non-infected animals, suggesting that P. destructans has complex physiological impacts on its host prior to onset of clinical signs indicative of late-stage infections. Additionally, bats with mild to moderate skin lesions associated with early-stage WNS demonstrated a chronic respiratory acidosis characterized by significantly elevated dissolved carbon dioxide, acidemia, and elevated bicarbonate. Potassium concentrations were also significantly higher among infected bats, but sodium, chloride, and other hydration parameters were equivalent to controls. Integrating these novel findings on the physiological changes that occur in early-stage WNS with those previously documented in late-stage infections, we propose a multi-stage disease progression model that mechanistically describes the pathologic and physiologic effects underlying mortality of WNS in hibernating bats. This model identifies testable hypotheses for better understanding this disease, knowledge that will be critical for defining effective disease mitigation strategies aimed at reducing morbidity and mortality that results from WNS.


Processing of O6-methylguanine by mismatch correction in human cell extracts.
Human cell extracts perform an aberrant form of DNA synthesis on methylated plasmids [1], which represents processing of O6-methylguanine (O6-meG). Here, we show that extracts of colorectal carcinoma cells with defects in the mismatch repair proteins that normally correct replication errors do not carry out this synthesis. hMSH2-defective LoVo cell extracts (hMSH for human MutS homologue) performed O6-meG-dependent DNA synthesis only after the addition of the purified hMutS alpha mismatch recognition complex. Processing of O6-meG by mismatch correction requires PCNA and therefore probably DNA polymerase delta and/or epsilon. Mismatch repair-defective cells withstand O6-meG in their DNA [2], making them tolerant to methylating agents. Methylation-tolerant HeLaMR clones, with a mutator phenotype and a defect in either mismatch recognition or correction in vitro, also performed little O6-meG-dependent DNA synthesis. Assays of pairwise combinations of tolerant and colorectal carcinoma cell extracts identified hMLH1 as the missing mismatch repair function in a group of tolerant clones. The absence of processing by extracts of methylation-tolerant cells provides the first biochemical evidence that lethality of DNA O6-meG derives from its interaction with mismatch repair.


NK cell activity differs between patients with localized and diffuse cutaneous leishmaniasis infected with Leishmania mexicana: a comparative study of TLRs and cytokines.
Leishmania mexicana causes localized (LCL) or diffuse cutaneous leishmaniasis (DCL). The cause of dissemination in DCL remains unknown, yet NK cells possibly play a role in activating leishmanicidal mechanisms during innate and adaptive immune responses. We had previously shown that Leishmania lipophosphoglycan (LPG) is a ligand for TLR2, activating human NK cells. We have now analyzed NK cells in LCL and DCL patients. NK numbers and effector mechanisms differed drastically between both groups of patients: DCL patients showed reduced NK cell numbers; diminished IFN-γ and TNF-α production; and lower TLR2, TLR1, and TLR6 expression as compared to LCL patients. The altered protein expression found in NK cells of DCL patients correlated with their down-regulation of IFN-γ gene expression in LPG-stimulated and non-stimulated cells as compared to LCL patients. NK cell response was further analyzed according to gender, age, and disease evolution in LCL patients showing that female patients produced higher IFN-γ levels throughout the disease progression, whereas TLR2 expression diminished in both genders with prolonged disease evolution and age. We furthermore show the activation pathway of LPG binding to TLR2 and demonstrated that TLR2 forms immunocomplexes with TLR1 and TLR6. In addition to the reduced NK cell numbers in peripheral blood, DCL patients also showed reduced NK cell numbers in the lesions. They were randomly scattered within the lesions, showing diminished cytokine production, which contrasts with those of LCL lesions, where NK cells produced IFN-γ and TNF-α and were found within organized granulomas. We conclude that in DCL patients the reduced NK-cell numbers and their diminished activity, evidenced by low TLR expression and low cytokine production, are possibly involved in the severity of the disease. Our results provide new information on the contribution of NK cells in Leishmania infections of the human host.


Cortical afferents of visual area MT in the Cebus monkey: possible homologies between New and Old World monkeys.
Cortical projections to the middle temporal (MT) visual area were studied by injecting the retrogradely transported fluorescent tracer Fast Blue into MT in adult New World monkeys (Cebus apella). Injection sites were selected based on electrophysiological recordings, and covered eccentricities from 2-70 deg, in both the upper and lower visual fields. The position and laminar distribution of labeled cell bodies were correlated with myeloarchitectonic boundaries and displayed in flat reconstructions of the neocortex. Topographically organized projections were found to arise mainly from the primary, second, third, and fourth visual areas (V1, V2, V3, and V4). Coarsely topographic patterns were observed in transitional V4 (V4t), in the parieto-occipital and parieto-occipital medial areas (PO and POm), and in the temporal ventral posterior area (TVP). In addition, widespread or nontopographic label was found in visual areas of the superior temporal sulcus (medial superior temporal, MST, and fundus of superior temporal, FST), annectent gyrus (dorsointermediate area, DI; and dorsomedial area, DM), intraparietal sulcus (lateral intraparietal, LIP; posterior intraparietal, PIP; and ventral intraparietal, VIP), and in the frontal eye field (FEF). Label in PO, POm, and PIP was found only after injections in the representation of the peripheral visual field (> 10 deg), and label in V4 and FST was more extensive after injections in the central representation. The projections from V1 and V2 originated predominantly from neurons in supragranular layers, whereas those from V3, V4t, DM, DI, POm, and FEF consisted of intermixed patches with either supragranular or infragranular predominance. All of the other projections were predominantly infragranular. Invasion of area MST by the injection site led to the labeling of further pathways, including substantial projections from the dorsal prelunate area (DP) and from an ensemble of areas located along the medial wall of the hemisphere. In addition, weaker projections were observed from the parieto-occipital dorsal area (POd), area 7a, area prostriata, the posterior bank of the arcuate sulcus, and areas in the anterior part of the lateral sulcus. Despite the different nomenclatures and areal boundaries recognized by different models of simian cortical organization, the pattern of projections to area MT is remarkably similar among primates. Our results provide evidence for the existence of many homologous areas in the extrastriate visual cortex of New and Old World monkeys.


Virtual practicums within an MPH program: a career development case study.
This article focuses on an innovative "virtual" practicum arrangement and provides insight for public health professionals seeking a meaningful practicum experience. The traditional practicum model where a student physically reports to work at the field site with a near full-time commitment has become increasingly challenging and often limiting in terms of field site choices and experiences available to a student depending on the location of a school and the student's area of interest. This is particularly true with students who are enrolled in a distance learning program. The experience obtained from a practicum is more important than ever before as rapid changes occur in health service delivery models as a result of the Patient Protection and Affordable Care Act. Career development through a practicum can be vitally important to a mid-career student seeking to remain relevant and in demand within a changing job market. To fulfill these needs, while still obtaining the benefits of a practicum, a virtual practicum arrangement could provide a solution. This case study provides practical tips based on the successful experience of a recent MPH graduate.


Agreement between two large pan-cancer CRISPR-Cas9 gene dependency data sets.
Genome-scale CRISPR-Cas9 viability screens performed in cancer cell lines provide a systematic approach to identify cancer dependencies and new therapeutic targets. As multiple large-scale screens become available, a formal assessment of the reproducibility of these experiments becomes necessary. We analyze data from recently published pan-cancer CRISPR-Cas9 screens performed at the Broad and Sanger Institutes. Despite significant differences in experimental protocols and reagents, we find that the screen results are highly concordant across multiple metrics with both common and specific dependencies jointly identified across the two studies. Furthermore, robust biomarkers of gene dependency found in one data set are recovered in the other. Through further analysis and replication experiments at each institute, we show that batch effects are driven principally by two key experimental parameters: the reagent library and the assay length. These results indicate that the Broad and Sanger CRISPR-Cas9 viability screens yield robust and reproducible findings.


Australian midwives' knowledge of antenatal and postpartum depression: a national survey.
Emotional care provided by midwives may improve health and well-being; reduce stress, trauma, and depressive symptoms; and enhance maternal outcomes in childbearing women. The provision of intrapartum and postpartum emotional care can be challenging and requires a good knowledge base for the provider to screen and assist distressed women. This study assessed Australian midwives' levels of knowledge and learning needs regarding antenatal depression and postpartum depression. Eight hundred and fifteen members of the Australian College of Midwives completed a postal survey, which consisted of 20 items drawn from the literature and the National Baseline Survey-Health Professional Knowledge Questionnaire. On average, respondents correctly answered 62.9% of items related to antenatal depression and 70.7% of questions about postpartum depression. Many midwives were unable to identify the risk factors (70.6%) or prevalence of antenatal depression (49.6%). Nearly all (98.3%) respondents underestimated the percentage of antenatally depressed women that attempts suicide. Significant percentages of midwives did not correctly identify the incidence (44.4%), onset period (71%), and treatment options (32%) associated with postpartum depression. About half did not understand the use of antidepressant medications (48.6%) and incorrectly reported that the Edinburgh Postnatal Depression Scale was a suitable instrument to assess symptoms of psychotic depression (43.8%). There are key knowledge deficits relating to onset of, assessment of, and treatment for depressive symptoms during the antenatal and postpartum periods. There is a need for continuing professional education to improve midwives' knowledge and competency in the assessment and care of women suffering depression.


The diversity of reproductive parasites among arthropods: Wolbachia do not walk alone.
Inherited bacteria have come to be recognised as important components of arthropod biology. In addition to mutualistic symbioses, a range of other inherited bacteria are known to act either as reproductive parasites or as secondary symbionts. Whilst the incidence of the alpha-proteobacterium Wolbachia is relatively well established, the current knowledge of other inherited bacteria is much weaker. Here, we tested 136 arthropod species for a range of inherited bacteria known to demonstrate reproductive parasitism, sampling each species more intensively than in past surveys. The inclusion of inherited bacteria other than Wolbachia increased the number of infections recorded in our sample from 33 to 57, and the proportion of species infected from 22.8% to 32.4%. Thus, whilst Wolbachia remained the dominant inherited bacterium, it alone was responsible for around half of all inherited infections of the bacteria sampled, with members of the Cardinium, Arsenophonus and Spiroplasma ixodetis clades each occurring in 4% to 7% of all species. The observation that infection was sometimes rare within host populations, and that there was variation in presence of symbionts between populations indicates that our survey will itself underscore incidence. This extensive survey demonstrates that at least a third of arthropod species are infected by a diverse assemblage of maternally inherited bacteria that are likely to strongly influence their hosts' biology, and indicates an urgent need to establish the nature of the interaction between non-Wolbachia bacteria and their hosts.


Low Charge and Reduced Mobility of Membrane Protein Complexes Has Implications for Calibration of Collision Cross Section Measurements.
Ion mobility mass spectrometry of integral membrane proteins provides valuable insights into their architecture and stability. Here we show that, due to their lower charge, the average mobility of native-like membrane protein ions is approximately 30% lower than that of soluble proteins of similar mass. This has implications for drift time measurements, made on traveling wave ion mobility mass spectrometers, which have to be calibrated to extract collision cross sections (Ω). Common calibration strategies employ unfolded or native-like soluble protein standards with masses and mobilities comparable to the protein of interest. We compare Ω values for membrane proteins, derived from standard calibration protocols using soluble proteins, to values measured using an RF-confined drift tube. Our results demonstrate that, while common calibration methods underestimate Ω for native-like or unfolded membrane protein complexes, higher mass soluble calibration standards consistently yield more accurate Ω values. These findings enable us to obtain directly structural information for highly charge-reduced complexes by traveling wave ion mobility mass spectrometry.


Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma.
Malignant Pleural Mesothelioma (MPM) is a heterogeneous disease. Morphologically, three different phenotypes are distinguishable: epithelioid (e-), sarcomatoid (s-) and biphasic (biph-) MPM, the latest, being a mixture of e- and s-MPM cells. Being an intermediate entity, management of biph-MPM, remains debatable and controversial, with different guidelines recommending distinct approaches. Identification of biph-MPM associated genetic alterations, through deep sequencing analysis, may provide useful tools to understand these lesions. A retrospective cohort of 69 surgically resected MPMs, 39 biph-MPMs (56.5%) and 30 e-MPMs (43.5%) was selected. A separate set of 16 biph-MPM was used as validation set. Deep sequencing analysis on an MPM-specific custom panel (MPM_geneset) comprising 1041 amplicons spanning 34 genes was performed. A total of 588 variants and 5309 mutational events were detected. In total, 91.3% of MPMs showed at least one mutation and 76.8% showed co-occurrence of more than one alteration. Mutations in MXRA5 (p = 0.05) and NOD2 (p = 0.018) were significantly associated with biph-MPM both in the training and validation cohort and correlated with the extent of the sarcomatoid component. Mutations in NOD2 and XRCC6 correlated with patients' survival. We demonstrated that biph-MPM are associated with a specific mutation set, and that genetic analysis at diagnosis may improve patients' risk stratification.


Open-Label, Multicenter, Phase II Study of Ceritinib in Patients With Non-Small-Cell Lung Cancer Harboring ROS1 Rearrangement.
Purpose ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC. Patients and Methods We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization. Ceritinib 750 mg was administered once daily. The primary end point was objective response rate. The secondary end points were disease control rate; duration of response; progression-free survival; overall survival; toxicity; and concordance among fluorescent in situ hybridization, immunohistochemistry, and next-generation sequencing. Results Between June 7, 2013, and February 1, 2016, 404 patients underwent ROS1 prescreening, and 32 patients with ROS1 rearrangement were enrolled. All patients except two were crizotinib-naïve. At the time of data cutoff, the median follow-up was 14.0 months, and 18 patients (56%) had discontinued treatment. Of the 32 patients enrolled, 28 were evaluable for response by independent radiologic review. Objective response rate was 62% (95% CI, 45% to 77%), with one complete response and 19 partial responses; duration of response was 21.0 months (95% CI, 17 to 25 months); and disease control rate was 81% (95% CI, 65% to 91%). The median progression-free survival was 9.3 months (95% CI, 0 to 22 months) for all patients and 19.3 months (95% CI, 1 to 37 months) for crizotinib-naïve patients. The median overall survival was 24 months (95% CI, 5 to 43 months). Of the eight patients with brain metastases, intracranial disease control was reported in five (63%; 95% CI, 31% to 86%). The most common adverse events (majority, grade 1 or 2) for all treated patients were diarrhea (78%), nausea (59%), and anorexia (56%). Conclusion Ceritinib demonstrated potent clinical activity in patients with ROS1-rearranged NSCLC who were heavily treated previously with multiple lines of chemotherapy.


Coping strategies and mood profiles in patients with multiple sclerosis.
The aim of the present study was to investigate the coping strategies, mood characteristics and the association between these aspects in patients diagnosed with multiple sclerosis and healthy subjects. Fifty consecutive patients who were diagnosed with multiple sclerosis according to McDonald criteria and thirty-one healthy subjects were included in the study. In addition to the sociodemographic form, Expanded Disability Status Scale (EDSS), Coping Orientation for Problem Experiences Scale (COPE), and Profile of Mood States (POMS) tests were applied to the participants. Non-functional coping strategies were significantly higher in the secondary-progressive type (p≤0.05). Depression-dejection, fatigue-inertia and total POMS scores were significantly higher in the secondary-progressive type (p≤0.05). The results of our study demonstrate the importance of rehabilitation programs that encourage exercise among patients with multiple sclerosis to increase vigor-activity levels.


Type 2 diabetes and the vegetarian diet.
Based on what is known of the components of plant-based diets and their effects from cohort studies, there is reason to believe that vegetarian diets would have advantages in the treatment of type 2 diabetes. At present there are few data on vegetarian diets in diabetes that do not in addition have weight loss or exercise components. Nevertheless, the use of whole-grain or traditionally processed cereals and legumes has been associated with improved glycemic control in both diabetic and insulin-resistant individuals. Long-term cohort studies have indicated that whole-grain consumption reduces the risk of both type 2 diabetes and cardiovascular disease. In addition, nuts (eg, almonds), viscous fibers (eg, fibers from oats and barley), soy proteins, and plant sterols, which may be part of the vegetarian diet, reduce serum lipids. In combination, these plant food components may have a very significant impact on cardiovascular disease, one of the major complications of diabetes. Furthermore, substituting soy or other vegetable proteins for animal protein may also decrease renal hyperfiltration, proteinuria, and renal acid load and in the long term reduce the risk of developing renal disease in type 2 diabetes. The vegetarian diet, therefore, contains a portfolio of natural products and food forms of benefit for both the carbohydrate and lipid abnormalities in diabetes. It is anticipated that their combined use in vegetarian diets will produce very significant metabolic advantages for the prevention and treatment of diabetes and its complications.


Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics.
The Philadelphia chromosome translocation (t(9;22)) results in the molecular juxtaposition of two genes, BCR and ABL, to form an aberrant BCR-ABL gene on chromosome 22. BCR-ABL is critical to the pathogenesis of chronic myelogenous leukemia and a subset of acute leukemias. The chimeric Bcr-Abl protein has constitutively elevated tyrosine phosphokinase activity. This abnormal enzymatic activation is critical to the oncogenic potential of Bcr-Abl. Initially, protein kinases were thought to be poor therapeutic targets because of their ubiquitous nature and crucial role in many normal physiologic processes. However, the advent of imatinib mesylate (Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), formerly known as STI571 and CGP57148B, demonstrated that designer kinase inhibitors could be specific. This agent has shown striking activity in chronic myelogenous leukemia. It also inhibits phosphorylation of Kit (stem-cell factor receptor) and platelet-derived growth factor receptor. In addition, it has shown similar impressive responses, with little host toxicity, in gastrointestinal stromal tumors, which harbor activating Kit mutations, and in tumors with activated platelet-derived growth factor receptor. The studies of imatinib mesylate provide proof-of-principle for using aberrant kinases as a therapeutic target and are a model for the promise of molecular therapeutics. This paper reviews the current knowledge on the function of Bcr-Abl and its normal counterparts (Bcr and Abl), as well as the impact of this knowledge on the development of a remarkably successful targeted therapy approach.


The Effects of Repetitive Information Communication through Multiple Channels on Prevention Behavior during the 2015 MERS Outbreak in South Korea.
Although people nowadays engage in information communication repetitively through multiple channels during a public health crisis, the impacts of this communication on behavioral outcomes have not been fully examined. The present study empirically tests the effects of repetitive information communication through multiple channels (RICMC) on risk-prevention behavior. Additionally, the mediating roles of knowledge, perceived susceptibility, severity, response efficacy, and self-efficacy in the association between RICMC and risk-prevention behavior are examined. Analyses of online survey data (N = 1,036) collected during the 2015 Middle East respiratory syndrome (MERS) outbreak in South Korea revealed that RICMC was positively associated with MERS-prevention behavior. Furthermore, this association was mediated by perceived susceptibility, severity, and self-efficacy. Although response efficacy and knowledge were not significant mediators, RICMC was positively associated with all mediating variables. The implications, theoretical contributions, and limitations of this study are discussed.


Towards practical cognitive assessment for detection of early dementia: a 30-minute computerized battery discriminates as well as longer testing.
Early detection of cognitive decline may lead to more effective treatment. Clinical cognitive assessment is essential for early detection, but must be brief with easily interpretable results. The present study defines and evaluates a 30-minute cognitive battery consisting of a subset of tests that comprise a longer computerized battery recently validated in detecting mild cognitive impairment (MCI). Participants were from three tertiary care memory clinics and an assisted living facility (final group: N=161) with consensus diagnoses of cognitively healthy, MCI, or mild dementia. A comprehensive NeuroTrax battery evaluated memory, executive function, visual spatial perception, verbal function, information processing speed, and motor skills. Validity of a single summary measure ('MCI Score') designed for dementia detection and built exclusively from tests of memory, executive function, and visual spatial perception was evaluated with receiver operating characteristic (ROC) analysis. Discriminant validity (area under the curve: AUC) was at least as large for the 6-parameter MCI Score as for a 20-parameter score necessitating administration of the entire battery. Further, the MCI Score had a larger AUC with reduced variance relative to its constituent parameters. AUC for distinguishing dementia was 0.886; AUC for distinguishing cognitively healthy was 0.823. Finally, the MCI Score discriminated among all three diagnostic groups (ANOVA; F[2,150]=52.54, p<0.001). Hence a reduced NeuroTrax battery (30 minutes) with MCI Score is a useful clinical tool for summarizing cognitive data relevant to early dementia detection.


Revisiting the Structure of the Short Dark Triad.
In the past decade, extensive interest has been directed toward the Dark Triad (i.e., Machiavellianism, narcissism, and psychopathy), popularly assessed by the Short Dark Triad (SD3). Nevertheless, relatively little research has been conducted on the SD3's factor structure. We investigated the SD3's psychometric properties in three studies with three independent samples, using exploratory and confirmatory factor analyses ( N1 = 1,487; N2 = 17,740; N3 = 496). In all three studies, Machiavellianism and psychopathy items displayed large general factor loadings, and narcissism larger specific factor loadings. In subsequent studies, two- and three-factor models fitted the data similarly, with the best fitting model being a bifactor model with items from Machiavellianism and psychopathy modelled as one specific factor, and narcissism as a second specific factor. On this basis, we suggest that the SD3 does not seem to capture the different mental processes theorized to underlie the similar behaviors generated by Machiavellianism and psychopathy. Additionally, we recommend the use of a single SD3 composite score, and not subscale scores, as subscales contain small amounts of reliable variance beyond the general factor.


Intake of total and added sugars and nutrient dilution in Australian children and adolescents.
This analysis aimed to examine the association between intake of sugars (total or added) and nutrient intake with data from a recent Australian national nutrition survey, the 2007 Australian National Children's Nutrition and Physical Activity Survey (2007ANCNPAS). Data from participants (n 4140; 51 % male) who provided 2×plausible 24-h recalls were included in the analysis. The values on added sugars for foods were estimated using a previously published ten-step systematic methodology. Reported intakes of nutrients and foods defined in the 2007ANCNPAS were analysed by age- and sex-specific quintiles of %energy from added sugars (%EAS) or %energy from total sugars (%ETS) using ANCOVA. Linear trends across the quintiles were examined using multiple linear regression. Logistic regression analysis was used to calculate the OR of not meeting a specified nutrient reference values for Australia and New Zealand per unit in %EAS or %ETS. Analyses were adjusted for age, sex, BMI z-score and total energy intake. Small but significant negative associations were seen between %EAS and the intakes of most nutrient intakes (all P<0·001). For %ETS the associations with nutrient intakes were inconsistent; even then they were smaller than that for %EAS. In general, higher intakes of added sugars were associated with lower intakes of most nutrient-rich, 'core' food groups and higher intakes of energy-dense, nutrient-poor 'extra' foods. In conclusion, assessing intakes of added sugars may be a better approach for addressing issues of diet quality compared with intakes of total sugars.


Perceived need for mental health care among non-western labour migrants.
There is a supposed higher prevalence of common mental disorders among many migrant groups. At the same time, problems are reported regarding underutilisation of mental health services by migrants. Since perceived need for care is a powerful predictor of actual care utilisation, we aimed to study the hypothesis that, given the same level of mental morbidity, non-Western migrants would perceive less need for mental health care than ethnic Dutch residents. Additionally, we studied the extent to which needs are met in both groups, as well as several possible barriers to care. A cross-sectional study with data from the 2004/2005 Amsterdam Health Monitor. Data were complete from 626 ethnic Dutch and non-Western (Turkish and Moroccan) labour migrants. Respondents participated in a structured interview in their own language, which included the perceived need for care questionnaire (PNCQ) and the composite international diagnostic interview (CIDI) version 2.1 for anxiety and depressive disorders. Perceived need was much higher among Turkish migrants. Among Moroccans the perceived need was comparable to ethnic Dutch. Turkish migrants also reported that needs were met less often than ethnic Dutch. Differences were explained by a higher prevalence of common mental disorders and higher symptom levels among Turkish. When differences in mental morbidity were taken into account, Moroccans perceived less need for information, drugs, referral to specialised mental health care, or for counselling. The most important barrier to care in all ethnic groups was the preference to solve the problem on one's own. In case of similar mental morbidity, perceived need for care was lower than among ethnic Dutch. The results did not support the hypothesis that in case of similar mental distress, needs of migrants were less often met than needs of ethnic Dutch.


Polar effects on the thermal conductivity of cubic boron nitride under pressure.
We report the lattice thermal conductivity (κ) of cubic boron nitride (c-BN) under pressure calculated using density functional theory. Pressure was used to manipulate the c-BN phonon dispersion and study its effect on thermal conductivity. These results were compared to c-BN's mass-equivalent, nonpolar counterpart, diamond, in order to isolate the effect of polar bonds on thermal conductivity. Unlike diamond, the variation of κ at room temperature (κ(RT)) with applied pressure in c-BN is nonlinear in the low-pressure regime followed by a transition to a linear regime with a distinct change in the slope at P>114 GPa. We find that the change in κ with pressure cannot be described with power law expressions commonly used for Earth mantle materials. The nonlinearity in the low-pressure regime can be related to the nonlinear change in LO-TO gap, group velocities, and specific heat with increasing pressure. In addition, we find that, although optical branch contributions to thermal conductivity are small (∼2% at RT), the rise in κ(RT) for P>114 GPa is due to (1) the decoupling of the longitudinal acoustic branch from the optical branches and (2) depopulation of the optical branches. These lead to a sharp reduction in acoustic-acoustic-optic (a-a-o) scattering and a discrete change in the acoustic phonon mean free paths. This study illustrates the importance of optical branches and their interactions with acoustic branches in determining the total thermal conductivity of polar materials. This finding is also relevant for current research in geologic minerals under pressure and the design of thermoelectrics.


Testing for haemoglobinopathies in Johannesburg, South Africa: a 30-year review.
Haemoglobinopathies are seen mostly in regions where malaria occurs or has occurred, but population migration has resulted in affected individuals being identified in many countries globally. The first molecular genetics services for diagnostic testing and prenatal diagnosis were established, both worldwide and in South Africa (SA), for haemoglobinopathies. To analyse the diagnostic service offered by the Division of Human Genetics, National Health Laboratory Service and University of the Witwatersrand, from 1983 to 2012. A retrospective file analysis (N=1 249) was performed for all individuals who had molecular genetic testing for α-thalassaemia, β-thalassaemia and sickle cell anaemia to examine indications for testing, population origins of patients and molecular genetics findings. The α-thalassaemia testing was requested predominantly to explain microcytic hypochromic haematological indices. Five α-globin deletions were identified, the most common being the -α3.7, in individuals of different ethnicities. For β-thalassaemia and sickle cell anaemia, most testing was performed for prenatal diagnosis purposes. For sickle cell anaemia, most prenatal tests were requested by African families. The β-thalassaemia families were mostly of Indian or Mediterranean origin. The most common mutation identified in all Indian groups was IVS1 nt5 (G>C) (c.92+5G>C) and in individuals from the Mediterranean, IVS1 nt110 (G>A) (c.93-21G>A). The molecular genetics service for haemoglobinopathies in SA is comprehensive and specific to the needs of local ethnic groups. Clinically significant haemoglobinopathies occur at significant frequencies in specific high-risk ethnic groups. Appropriate screening programmes should be initiated so that genetic counselling and reproductive options can be offered.


CIP2A influences survival in colon cancer and is critical for maintaining Myc expression.
The cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic factor that stabilises the c-Myc protein. CIP2A is overexpressed in several tumours, and expression levels are an independent marker for long-term outcome. To determine whether CIP2A expression is elevated in colon cancer and whether it might serve as a prognostic marker for survival, we analysed CIP2A mRNA expression by real-time PCR in 104 colon cancer samples. CIP2A mRNA was overexpressed in colon cancer samples and CIP2A expression levels correlated significantly with tumour stage. We found that CIP2A serves as an independent prognostic marker for disease-free and overall survival. Further, we investigated CIP2A-dependent effects on levels of c-Myc, Akt and on cell proliferation in three colon cancer cell lines by silencing CIP2A using small interfering (si) and short hairpin (sh) RNAs. Depletion of CIP2A substantially inhibited growth of colon cell lines and reduced c-Myc levels without affecting expression or function of the upstream regulatory kinase, Akt. Expression of CIP2A was found to be dependent on MAPK activity, linking elevated c-Myc expression to deregulated signal transduction in colon cancer.


Metagenomics of the deep Mediterranean, a warm bathypelagic habitat.
Metagenomics is emerging as a powerful method to study the function and physiology of the unexplored microbial biosphere, and is causing us to re-evaluate basic precepts of microbial ecology and evolution. Most marine metagenomic analyses have been nearly exclusively devoted to photic waters. We constructed a metagenomic fosmid library from 3,000 m-deep Mediterranean plankton, which is much warmer (approximately 14 degrees C) than waters of similar depth in open oceans (approximately 2 degrees C). We analyzed the library both by phylogenetic screening based on 16S rRNA gene amplification from clone pools and by sequencing both insert extremities of ca. 5,000 fosmids. Genome recruitment strategies showed that the majority of high scoring pairs corresponded to genomes from Rhizobiales within the Alphaproteobacteria, Cenarchaeum symbiosum, Planctomycetes, Acidobacteria, Chloroflexi and Gammaproteobacteria. We have found a community structure similar to that found in the aphotic zone of the Pacific. However, the similarities were significantly higher to the mesopelagic (500-700 m deep) in the Pacific than to the single 4000 m deep sample studied at this location. Metabolic genes were mostly related to catabolism, transport and degradation of complex organic molecules, in agreement with a prevalent heterotrophic lifestyle for deep-sea microbes. However, we observed a high percentage of genes encoding dehydrogenases and, among them, cox genes, suggesting that aerobic carbon monoxide oxidation may be important in the deep ocean as an additional energy source. The comparison of metagenomic libraries from the deep Mediterranean and the Pacific ALOHA water column showed that bathypelagic Mediterranean communities resemble more mesopelagic communities in the Pacific, and suggests that, in the absence of light, temperature is a major stratifying factor in the oceanic water column, overriding pressure at least over 4000 m deep. Several chemolithotrophic metabolic pathways could supplement organic matter degradation in this most depleted habitat.


Dual ultrastructural localization of mu-opioid receptors and NMDA-type glutamate receptors in the shell of the rat nucleus accumbens.
The effectiveness of NMDA antagonists in modulating the motor and motivational effects of opiates is attributed, in part, to functional associations involving NMDA receptors and micro-opioid receptors (MORs) in the shell of the nucleus accumbens (Acb). To determine the subcellular sites for potential functional interactions between opiate ligands and NMDA receptors in this region, we examined the ultrastructural localization of antipeptide antisera against MOR and the R1 subunit of the NMDA receptor in the Acb shell of the adult rat brain. MOR-like immunoreactivity (MOR-LI) was seen primarily in dendrites, whereas NMDAR1-like immunoreactivity (NMDAR1-LI) was detected more often in axon terminals forming asymmetric synapses. In these profiles, MOR labeling was localized mainly to extrasynaptic plasma membranes, whereas NMDAR1-LI was associated with both synaptic and extrasynaptic sites. Of 307 MOR-labeled processes, 17.9% of the dendrites and 9.4% of the axon terminals also contained NMDAR1-LI. In addition, 24.7% of the dendrites containing only MOR-LI were apposed to NMDAR1-labeled axons or terminals. We conclude that in the shell of the Acb, the output of single neurons can be dually modulated by (1) activation of MOR and NMDA receptors in the same dendrites or (2) combined activation of presynaptic NMDA receptors in afferents contacting dendrites containing MOR. In addition, the colocalization of MOR and NMDAR1 in certain axon terminals in the Acb suggests their dual involvement in the presynaptic release of neurotransmitters in this region.