Cardiovascular, endocrine, and body fluid-electrolyte responses to salt loading in mRen-2 transgenic rats.
We previously demonstrated that mRen-2 transgenic [Tg(+)] rats are sensitive to chronic high NaCl intake, showing increased arterial pressure and vasopressin (VP) secretion. In this study, we determined the effect of a chronic osmotic challenge, 4 days of drinking 2% NaCl, on direct arterial blood pressure, heart rate, fluid-electrolyte balance, circadian rhythm of mean arterial pressure (MAP), and changes in plasma VP and catecholamines. Under baseline conditions, male Tg(+) rats showed a significant shift in the peak in circadian MAP into the light portion of the day-night cycle. Substitution of 2% NaCl for drinking water caused a rapid increase in MAP, 20 +/- 5 mmHg in Tg(+) rats within 6 h. Whereas the amplitude of circadian MAP fluctuations increased in salt-loaded Tg(+) rats, there was no significant change in the circadian timing of peak MAP with salt loading. Tg(+) rats showed exaggerated osmotic-induced increases in plasma VP, norepinephrine (NE), and epinephrine (Epi) compared with Tg(-) rats. Plasma NE and Epi were increased two- and fourfold, respectively, in the hypertensive rats with no significant change in the Tg(-) rats. Intravenous administration of a VP antagonist did not alter arterial pressure in either Tg(+) or Tg(-) rats. Tg(+) and Tg(-) rats showed a positive sodium balance with no significant difference observed between the groups. Tg(+) rats showed a significant increase in salt consumption, plasma sodium, osmolality, and hematocrit, accompanied by a negative water balance. We conclude that Tg(+) rats are sensitive to acute and chronic osmotic stimuli in terms of blood pressure, fluid-electrolyte balance, and plasma VP and catecholamines. Whereas elevated plasma VP does not contribute to the hypertensive response, increased sympathetic drive may mediate the salt-induced blood pressure changes in this model.


A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain.
The mammalian brain is composed of millions to billions of cells that are organized into numerous cell types with specific spatial distribution patterns and structural and functional properties. An essential step towards understanding brain function is to obtain a parts list, i.e., a catalog of cell types, of the brain. Here, we report a comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain. The cell type atlas was created based on the combination of two single-cell-level, whole-brain-scale datasets: a single-cell RNA-sequencing (scRNA-seq) dataset of ~7 million cells profiled, and a spatially resolved transcriptomic dataset of ~4.3 million cells using MERFISH. The atlas is hierarchically organized into five nested levels of classification: 7 divisions, 32 classes, 306 subclasses, 1,045 supertypes and 5,200 clusters. We systematically analyzed the neuronal, non-neuronal, and immature neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain: the dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. We also systematically characterized cell-type specific expression of neurotransmitters, neuropeptides, and transcription factors. The study uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types across the brain, suggesting they mediate a myriad of modes of intercellular communications. Finally, we found that transcription factors are major determinants of cell type classification in the adult mouse brain and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole-mouse-brain transcriptomic and spatial cell type atlas establishes a benchmark reference atlas and a foundational resource for deep and integrative investigations of cell type and circuit function, development, and evolution of the mammalian brain.


The Endocranial Cavity of Oviraptorosaur Dinosaurs and the Increasingly Complex, Deep History of the Avian Brain.
Unraveling the origins of the character complexes diagnosing major crown clades is one of the greatest challenges in evolutionary biology. These origination events tend to optimize along extraordinarily long stem lineages where the comparative biology of extant lineages is relatively weak in its heuristic power. Here we add to a growing paleontological literature on the evolutionary origins of the modern avi an brain by describing the endocranial casts of two oviraptorosaur dinosaurs, Citipati osmolskae and Khaan mckennai. These fossil data confirm the antiquity of several avian features, including the expanded cerebrum. They also extend our appreciation of both the inherent variability in the brain-skull relationship along the avian stem and the dynamic nature of these crown characters in the earliest history of their expression.


First insights into the genetic diversity of Mycobacterium tuberculosis isolates from HIV-infected Mexican patients and mutations causing multidrug resistance.
The prevalence of infections with Mycobacterium tuberculosis (MTb) and nontuberculous mycobacteria (NTM) species in HIV-infected patients in Mexico is unknown. The aims of this study were to determine the frequency of MTb and NTM species in HIV-infected patients from Mexico City, to evaluate the genotypic diversity of the Mycobacterium tuberculosis complex strains, to determine their drug resistance profiles by colorimetric microplate Alamar Blue assay (MABA), and finally, to detect mutations present in katG, rpoB and inhA genes, resulting in isoniazid (INH) and rifampin (RIF) resistance. Of the 67 mycobacterial strains isolated, 48 were identified as MTb, 9 as M. bovis, 9 as M. avium and 1 as M. intracellulare. IS6110-RFLP of 48 MTb strains showed 27 profiles. Spoligotyping of the 48 MTb strains yielded 21 patterns, and 9 M. bovis strains produced 7 patterns. Eleven new spoligotypes patterns were found. A total of 40 patterns were produced from the 48 MTb strains when MIRU-VNTR was performed. Nineteen (39.6%) MTb strains were resistant to one or more drugs. One (2.1%) multidrug-resistant (MDR) strain was identified. A novel mutation was identified in a RIF-resistant strain, GAG --> TCG (Glu --> Ser) at codon 469 of rpoB gene. This is the first molecular analysis of mycobacteria isolated from HIV-infected patients in Mexico, which describe the prevalence of different mycobacterial species in this population. A high genetic diversity of MTb strains was identified. New spoligotypes and MIRU-VNTR patterns as well as a novel mutation associated to RIF-resistance were found. This information will facilitate the tracking of different mycobacterial species in HIV-infected individuals, and monitoring the spread of these microorganisms, leading to more appropriate measures for tuberculosis control.


Alcohol-involved maxillofacial fractures.
Alcohol-related facial trauma is an increasingly prominent social problem and health hazard. Interpersonal violence (IPV) is often implicated in these trauma presentations and the facial skeleton frequently targeted. This paper examines the characteristics of admitted patients with alcohol-related facial fractures. Electronic data of patients assessed or treated for facial fractures from January 2012 to December 2014 at Western Health was obtained through the Clinical Record Department. Variables analysed include patient age and gender, fracture site(s), alcohol involvement, country of birth, injury mechanism and surgical intervention. Of 659 patient records analysed, 18% presentations had alcohol involvement. In the alcohol group, 88% were male, 44% in the 20-34 year age group, 41% suffered nasal fractures, 65% presented following IPV and 60% required surgery. Thirty-seven per cent of patients were non-Australians. Alcohol involvement was significantly correlated with gender, age group and fracture sites but not with surgical intervention or ethnic origin. A binge drinking culture has contributed to prevalence of alcohol-related trauma. This study reports alcohol involvement in facial fractures to have high predilection for gender, age group of patients and fracture location. Facial trauma frequently necessitates surgical intervention. Educational programmes should be implemented to raise awareness of this potentially preventable health burden among health providers.


Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-retinoic acid.
All-trans-retinoic acid (ATRA) induces complete remission (CR) in up to 90% of acute promyelocytic leukemia (APL) patients with rapid amelioration of the bleeding syndrome. Previous studies indicate that ATRA treatment in vitro of the APL NB4 cell line can affect their procoagulant activity (PCA). To assess whether ATRA has this effect also in vivo, we prospectively studied the PCA of bone marrow blasts from APL patients on therapy with ATRA alone or associated with chemotherapy. Samples were obtained before, during, and after ATRA. To characterize the coagulopathy, we measured a series of plasma hemostatic variables before and during the first two weeks of therapy, as follows: (1) markers of hypercoagulability; (2) natural anticoagulants; (3) fibrinolysis proteins; and (4) elastase. The results by enzymatic and immunologic methods show that both total (tissue factor-like) and factor VII-independent (cancer procoagulant-like) blast cell PCAs, present before therapy, were reduced during (69% and 65% decrement, respectively) and virtually undetectable after ATRA. The plasma hemostatic assessment of patients before treatment was elevated hypercoagulability markers, low mean protein C, normal fibrinolysis proteins, and increased elastase. After starting ATRA, hypercoagulability markers were reduced within 4 to 8 days, protein C augmented, the overall fibrinolytic balance was unmodified, and elastase remained elevated. These results were not different either with or without chemotherapy and are consistent with the clinical findings of rapid improvement of the coagulopathy.


GSK3β is involved in promoting Alzheimer's disease pathologies following chronic systemic exposure to Porphyromonas gingivalis lipopolysaccharide in amyloid precursor proteinNL-F/NL-F knock-in mice.
In line with the strong association between periodontitis and Alzheimer's disease (AD) clinically, preclinical studies have shown that systemic exposure to Porphyromonas gingivalis (Pg) initiates AD pathologies. However, the involvement of periodontitis in promoting AD pathologies is unclear. In the present study, we provided evidence that chronic systemic exposure to lipopolysaccharide derived from Pg (PgLPS, 1 mg/kg, daily, intraperitoneally) prompted neuroinflammation and tau hyperphosphorylation in 10-month-old of amyloid precursor protein (APP) knock-in mice, a model of AD, carrying the Swedish and Beyreuther/Iberian mutation (APPNL-F/NL-F). The learning and memory function were assessed using the passive avoidance test. The production of APP, Amyloid (A)β1-42, cytokines, synaptic proteins and the activation of glycogen synthase kinase (GSK)-3β as well as phosphorylation of tau were analyzed by immunohistochemistry, Western blotting or an enzyme-linked immunosorbent assay (ELISA) in the cortex of APPNL-F/NL-F mice. We found that systemic exposure of PgLPS for three consecutive weeks induced learning and memory deficits with significantly reduced postsynaptic density protein (PSD95). Increased hyperphosphorylation of tau in multiple residues, including Ser202, Thr231 and Ser396, but not the accumulation of Aβ1-42 was detected in the neurons of APPNL-F/NL-F mice. Furthermore, PgLPS increased the GSK3β activity by reducing its phosphorylation of the serine residue at position 9 (Ser9) and promoted neuroinflammation by increasing the expression of interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) while decreasing that of interleukin-10 (IL-10) and transforming growth factor (TGFβ) in the cortex of APPNL-F/NL-F mice. Moreover, the PgLPS-increased GSK3β activity was detected in both microglia and neurons, while the PgLPS-increased TNF-α expression was mainly detected in the microglia in the cortex of APPNL-F/NL-F mice. In in vitro studies, PgLPS (1 µg/ml) stimulation increased the mRNA and protein level of TNF-α in MG6 microglia, which were significantly inhibited by the GSK3β-specific inhibitor TWS119. In contrast, the tau hyperphosphorylation and activation of GSK3β in N2a neurons were enhanced after treatment with conditioned medium from PgLPS-stimulated microglia, which was attenuated after pre-treatment with TNF-α inhibitor. Taken together, these findings indicate that GSK3β is involved in prompting microglia (TNF-α)-dependent tau hyperphosphorylation in neurons, resulting in learning and memory deficits in APPNL-F/NL-F mice without changes in the Aβ expression during chronic systemic exposure to PgLPS. We propose that dampening GSK3β activation may help delay the periodontitis-promoted pathological progression of AD.


Environmental influences on the longitudinal covariance of expressive vocabulary: measuring the home literacy environment in a genetically sensitive design.
Despite the well-replicated relationship between the home literacy environment and expressive vocabulary, few studies have examined the extent to which the home literacy environment is associated with the development of early vocabulary ability in the context of genetic influences. This study examined the influence of the home literacy environment on the longitudinal covariance of expressive vocabulary within a genetically sensitive design. Participants were drawn from the Western Reserve Reading Project, a longitudinal twin project of 314 twin pairs based in Ohio. Twins were assessed via three annual home visits during early elementary school; expressive vocabulary was measured via the Boston Naming Test (BNT), and the Home Literacy Environment (HLE) was assessed using mothers' report. The heritability of the BNT was moderate and significant at each measurement occasion, h(2) = .29-.49, as were the estimates of the shared environment, c(2) = .27-.39. HLE accounted for between 6-10% of the total variance in each year of vocabulary assessment. Furthermore, 7-9% of the total variance of the stability over time in BNT was accounted for by covariance in the home literacy environment. These results indicate that aspects of the home literacy environment, as reported by mothers, account for some of the shared environmental variance associated with expressive vocabulary in school aged children.


Analysis of insecticide exposure in California hummingbirds using liquid chromatography-mass spectrometry.
External feather rinses and homogenized whole-carcass tissue matrix from two hummingbird species found in California (Calypte anna and Archilochus alexandri) were analyzed for the presence of nine insecticides commonly used in urban settings. Using a liquid chromatography-high-resolution mass spectrometry (LC-HRMS) analytical method, samples were quantitatively tested for the following neonicotinoids: dinotefuran, nitenpyram, thiamethoxam, acetamiprid, thiacloprid, clothianidin, imidacloprid, and sulfoxaflor. This analytical method was also used to qualitatively screen for the presence of approximately 150 other pesticides, drugs, and natural products. Feather rinsates from both hummingbird species had detectable concentrations of carbamate and neonicotinoid classes of insecticides. Combined results of the rinsate and homogenized samples (n = 64 individual hummingbirds) showed that 44 individuals (68.75%) were positive for one to four target compounds. This study documented that hummingbirds found in California are exposed to insecticides. Furthermore, feather rinsates and carcass homogenates are matrices that can be used for assessing pesticide exposure in small bird species. The small body size of hummingbirds limits traditional sampling methods for tissues and whole blood to evaluate for pesticide exposure. Thus, utilization of this analytical method may facilitate future research on small-sized avian species, provide insight into pesticide exposure, and ultimately lead to improved conservation of hummingbirds.


Asp271 is critical for substrate interaction with the surface binding site in β-agarase a from Zobellia galactanivorans.
In the marine environment agar degradation is assured by bacteria that contain large agarolytic systems with enzymes acting in various endo- and exo-modes. Agarase A (AgaA) is an endo-glycoside hydrolase of family 16 considered to initiate degradation of agarose. Agaro-oligosaccharide binding at a unique surface binding site (SBS) in AgaA from Zobellia galactanivorans was investigated by computational methods in conjunction with a structure/sequence guided approach of site-directed mutagenesis probed by surface plasmon resonance binding analysis of agaro-oligosaccharides of DP 4-10. The crystal structure has shown that agaro-octaose interacts via H-bonds and aromatic stacking along 7 subsites (L through R) of the SBS in the inactive catalytic nucleophile mutant AgaA-E147S. D271 is centrally located in the extended SBS where it forms H-bonds to galactose and 3,6-anhydrogalactose residues of agaro-octaose at subsites O and P. We propose D271 is a key residue in ligand binding to the SBS. Thus AgaA-E147S/D271A gave slightly decreasing KD values from 625 ± 118 to 468 ± 13 μM for agaro-hexaose, -octaose, and -decaose, which represent 3- to 4-fold reduced affinity compared with AgaA-E147S. Molecular dynamics simulations and interaction analyses of AgaA-E147S/D271A indicated disruption of an extended H-bond network supporting that D271 is critical for the functional SBS. Notably, neither AgaA-E147S/W87A nor AgaA-E147S/W277A, designed to eliminate stacking with galactose residues at subsites O and Q, respectively, were produced in soluble form. W87 and W277 may thus control correct folding and structural integrity of AgaA.


High levels of plasma dengue viral load during defervescence in patients with dengue hemorrhagic fever: implications for pathogenesis.
Studies of the pathogenesis of dengue hemorrhagic fever (DHF), a potentially life-threatening disease, have revealed the importance of initial high levels of virus replication. However, the possible involvement of virus during the transition from fever to defervescence, a critical stage in determining the severity of disease, has not been appreciated. Using quantitative reverse transcription-polymerase chain reaction, we examined the levels of plasma dengue viral load during both fever and defervescence periods in patients from a DEN-3 outbreak in southern Taiwan in 1998. Higher levels of plasma dengue viral RNA were found in DHF patients than in DF patients. During defervescence, while the level of plasma dengue viral RNA was undetectable in most DF patients, it remains high in all DHF patients. Using a modified immunoprecipitation assay, we demonstrated for the first time that the plasma dengue viruses persisting during defervescence were in the immune complexes for most DHF patients. These findings suggest that continued active viral replication or delay in the clearance of viremia contributes to the pathogenesis of DHF. Moreover, high levels of plasma dengue viral RNA during defervescence may serve as a disease marker for DHF.


Treatment cost and access to care: experiences of young women diagnosed with breast cancer.
Breast cancer is the leading cause of cancer-related deaths in women younger than 40 years. We aim to evaluate cost as a barrier to care among female breast cancer patients diagnosed between 18 to 39 years. In early 2017, we distributed a survey to women diagnosed with breast cancer between the ages of 18 and 39 years, as identified by the central cancer registries of California, Georgia, North Carolina, and Florida. We used multivariable statistics to explore cost-related barriers to receiving breast cancer care for the 830 women that completed the survey. About half of the women (47.4%) reported spending more on breast cancer care than expected, and almost two-thirds (65.3%) had not discussed costs with their care team. A third of the patients (31.8%) indicated forgoing care due to cost. Factors associated with not receiving anticipated care due to cost included age less than35 years at diagnosis, self-insurance, comorbid conditions, and late-stage diagnosis. Previous studies using breast cancer registry data have not included detailed insurance information and care received by young women. Young women with breast cancer frequently forgo breast cancer care due to cost. Our results highlight the potential for policies that facilitate optimal care for young breast cancer patients which could include the provision of comprehensive insurance coverage.


Outcomes of knee arthrodesis following infected total knee arthroplasty: a retrospective analysis of 8 cases.
There is insufficient information regarding patient-based outcomes after knee arthrodesis following infected total knee arthroplasty (TKA). The purpose of this study was to analyze outcomes in patients who underwent knee arthrodesis following infected TKA using clinical and radiographic measurements including a patient-based outcome measuring system. We evaluated 8 patients (mean age 72.9 years) who were followed for more than 3 years after arthrodesis. Clinical and radiographic evaluation was performed, including examination of the patient's function and use of supportive equipment for walking. The Japanese knee osteoarthritis measurement (JKOM) was used for measuring patient-based outcomes and health-related quality of life. Knee fusion was achieved in 7 patients. The mean limb-length discrepancy was 5.4 cm. All patients could walk at least inside the house, and activity of daily living (ADL) independence was achieved by the patients with successful knee fusion, although walking aids, including a shoe lift causing little discomfort, were required. The results of JKOM for the patients with successful fusion were comparable to the data for patients who underwent TKA. When knee arthrodesis was performed for infected TKA cases, pain was reduced and ADL independence was established when knee fusion was achieved. This study demonstrated that information from subjective and functional evaluations of knee arthrodesis patients is useful in understanding postoperative activity and situations, and revealed the importance of supportive elements for walking.


Stable biomimetic super-hydrophobic engineering materials.
We describe a simple and inexpensive method to produce super-hydrophobic surfaces on aluminum and its alloy by oxidation and chemical modification. Water or aqueous solutions (pH = 1-14) have contact angles of 168 +/- 2 and 161 +/- 2 degrees on the treated surfaces of Al and Al alloy, respectively. The super-hydrophobic surfaces are produced by the cooperation of binary structures at micro- and nanometer scales, thus reducing the energies of the surfaces. Such super-hydrophobic properties will greatly extend the applications of aluminum and its alloy as lubricating materials.


The findings--diagnosis continuum: implications for image descriptions and clinical databases.
As part of the Unified Medical Language System (UMLS) project, we have been exploring the use of semantic net representation to build a medical ontology that can adapt to the needs and perspective of differing kinds of users with varying purposes. A principal objective is to facilitate indexing and retrieval of objects in a variety of target databases, using their own source vocabularies, while maintaining the representation of concepts to which these source vocabularies refer in a single consistent form, so that retrievals that span resource types can be accommodated. In addition, a particular area of deficiency of the existing UMLS Metathesaurus is that of clinical findings, a part of the problem being the multiple alternative views and granularity levels at which clinical findings are described in different target databases. The problem is particularly obvious when one examines the way in which image findings are described, which may be at a purely perceptual level, or at varying levels of aggregation into higher level observations or interpretations. We have developed a recursive model for representing observations and interpretations in a semantic net along a continuum of degree of aggregation, that appears to lend itself well to adaptation to varying perspectives.


Use and uptake of technology by people with dementia and their supporters during the COVID-19 pandemic.
This rapid review aims to identify the types of technologies used by people with dementia and their supporters during the COVID-19 pandemic, and the issues which influenced technology adoption within their usual care routines. PubMed, PsychInfo, Scopus, and Cochrane COVID reviews were searched to identify peer-review studies published since 2020. A total of 18 studies were included and synthesised thematically. Of these, most were conducted in the community (n = 15) with people with dementia only (n = 11) and involved qualitative methods (n = 11). The majority (n = 12) focused on digital off-the-shelf and low-cost solutions, such as free video conferencing platforms, to access care, socialise or take part in interventions. Whilst often well-accepted and associated with positive outcomes (such as improved social connectedness), lack of digital literacy or support to use technologies, limited access to appropriate technology, individuals' physical, cognitive, or sensory difficulties, were highlighted and likely to threaten the adoption of these solutions. The quality of the evidence was mixed, neither very robust nor easily generalisable which may be attributed to the challenges of conducting research during the pandemic or the need to rapidly adapt to a new reality. While COVID-19 has fast-tracked the adoption of technology, its use is likely to continue beyond the pandemic. We need to ensure this technology can leverage dementia support and care and that people with dementia are enabled and empowered to use it.


Enhanced spatiotemporal laser-beam smoothing in gas-jet plasmas.
Spatiotemporal smoothing of large-scale laser intensity fluctuations is observed for a laser beam focused into underdense helium plasmas. This smoothing is found to be severely enhanced when focusing the laser beam into a helium gas jet. In contrast to other experiments with preformed plasmas, the average and the peak laser intensities are well below the threshold for ponderomotive self-focusing. The coherence characteristics of the transmitted light are measured for various electron densities, and the smoothing effect is explained by multiple scattering of laser light on self-induced density perturbations.


Ligatin: a peripheral membrane protein with covalently bound palmitic acid.
The ligatin monomer is a polypeptide of Mr = 10,000 which is soluble in acidified chloroform:methanol, a characteristic similar to that of Folch-Lee proteolipid. The hydrophobicity of ligatin is also reflected by its ability to interpolate into the phosphatidylcholine bilayer as shown by a concentration-dependent change in membrane conductance. However, unlike other proteolipids the amino acid composition of ligatin is not enriched in hydrophobic amino acids (isoleucine, leucine, valine, methionine, phenylalanine, tryptophan). Instead, the hydrophobic character of ligatin could be explained, at least in part, by the covalent association of fatty acids, 1.4-1.7 mol of palmitate/10,000 g of protein, as revealed by gas chromatography mass spectrographic analyses. The post-translational addition of fatty acid may therefore be the means by which ligatin acquires an affinity for membranes.


One-Pot Regioselective Diacylation of Pyranoside 1,2-cis Diols.
A one-pot strategy for functionalizing pyranoside 1,2-cis-diols with two different ester protecting groups is reported. The approach employs regioselective acylation via orthoester hydrolysis promoted by a carboxylic acid, e.g., levulinic acid, acetic acid, benzoic acid, or chloroacetic acid. Upon removal of water and introduction of a coupling agent, the carboxylic acid is esterified to the hydroxyl group liberated during hydrolysis. Although applied to 1,2-cis-diols on pyranoside scaffolds, the method should be applicable to such motifs on any six-membered ring.


Higher incidence of persistent chronic infection of Chlamydia pneumoniae among coronary artery disease patients in India is a cause of concern.
There is growing evidence that Chlamydia pneumoniae may be involved in the pathogenesis of atherosclerosis, as several studies have demonstrated the presence of the organism in atherosclerotic lesions. C. pneumoniae infections, which are especially persistent infections, have been difficult to diagnose either by serological methods or isolation of the organism from the tissue. Nucleic Acid Amplification tests (NAATs) has emerged as an important method for detecting C. pneumoniae. Inspite of high prevalence of C. pneumoniae specific antibodies in coronary heart disease patients, direct detection of C. pneumoniae in circulating blood of coronary artery disease (CAD) patients by sensitive nucleic acid amplification tests nested PCR (nPCR), multiplex PCR (mPCR) has not been carried out is required. Further correlation of the presence of C. pneumoniae in blood of CAD patients with C. pneumoniae specific IgA and IgG antibodies, which may indicative of the status of infection with the progression of atherosclerosis. This will help in order to prepare strategies for the antibiotic intervention to avoid the progression towards CAD. Venous blood was obtained from 91 CAD patients and 46 healthy controls. Nucleic acid amplification tests viz. nested-, semi-nested- and multiplex PCR were used for detection of C. pneumoniae. ELISA carried out prevalence of C. pneumoniae specific IgG and IgA antibodies. 29.67% (27/91) patients were positive for C. pneumoniae using nested PCR. The sensitivity and specificity of semi-nested and multiplex PCR were 37.03%, 96.96% and 22.22%, 100% with respect to nested PCR. Positive nPCR patients were compared with presence of C. pneumoniae specific IgA, IgA+IgG and IgG antibodies. Among 27 (29.67%) nPCR C. pneumoniae positive CAD patients, 11(12%) were IgA positive, 13(14.2%) were IgA+IgG positive and only1 (1.1%) was IgG positive. A significant presence of C. pneumoniae was detected in heavy smokers, non-alcoholics and with family histories of diabetes and blood pressure group of CAD patients by nPCR. The results indicate synergistic association of C. pneumoniae infection and development of CAD with other risk factors. We also detected increased positivity for C. pneumoniae IgA than IgG in nPCR positive CAD patients. Positive nPCR findings in conjunction with persisting high C. pneumoniae specific antibody strongly suggest an ongoing infection.


Chromokinesin Kif4 promotes proper anaphase in mouse oocyte meiosis.
Oocytes of many species lack centrioles and therefore form acentriolar spindles. Despite the necessity of oocyte meiosis for successful reproduction, how these spindles mediate accurate chromosome segregation is poorly understood. We have gained insight into this process through studies of the kinesin-4 family member Kif4 in mouse oocytes. We found that Kif4 localizes to chromosomes through metaphase and then largely redistributes to the spindle midzone during anaphase, transitioning from stretches along microtubules to distinct ring-like structures; these structures then appear to fuse together by telophase. Kif4's binding partner PRC1 and MgcRacGAP, a component of the centralspindlin complex, have a similar localization pattern, demonstrating dynamic spindle midzone organization in oocytes. Kif4 knockdown results in defective midzone formation and longer spindles, revealing new anaphase roles for Kif4 in mouse oocytes. Moreover, inhibition of Aurora B/C kinases results in Kif4 mislocalization and causes anaphase defects. Taken together, our work reveals essential roles for Kif4 during the meiotic divisions, furthering our understanding of mechanisms promoting accurate chromosome segregation in acentriolar oocytes.


Primary Cilium-Regulated EG-VEGF Signaling Facilitates Trophoblast Invasion.
Trophoblast invasion is an important event in embryo implantation and placental development. During these processes, endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is the key regulator mediating the crosstalk at the feto-maternal interface. The primary cilium is a cellular antenna receiving environmental signals and is crucial for proper development. However, little is known regarding the role of the primary cilium in early human pregnancy. Here, we demonstrate that EG-VEGF regulates trophoblast cell invasion via primary cilia. We found that EG-VEGF activated ERK1/2 signaling and subsequent upregulation of MMP2 and MMP9, thereby facilitating cell invasion in human trophoblast HTR-8/SVneo cells. Inhibition of ERK1/2 alleviated the expression of MMPs and trophoblast cell invasion after EG-VEGF treatment. In addition, primary cilia were observed in all the trophoblast cell lines tested and, more importantly, in human first-trimester placental tissue. The receptor of EG-VEGF, PROKR1, was detected in primary cilia. Depletion of IFT88, the intraflagellar transporter required for ciliogenesis, inhibited primary cilium growth, thereby ameliorating ERK1/2 activation, MMP upregulation, and trophoblast cell invasion promoted by EG-VEGF. These findings demonstrate a novel function of primary cilia in controlling EG-VEGF-regulated trophoblast invasion and reveal the underlying molecular mechanism. J. Cell. Physiol. 232: 1467-1477, 2017. © 2016 Wiley Periodicals, Inc.


The Dubowitz syndrome: a retrospective.
The purpose of the article is to update information concerning Dubowitz syndrome. A review of the literature since the disorder was originally described in 1965 is presented. In addition, case reports are presented for two siblings described in 1971 describing speech and dental development and current clinical findings. Analysis of approximately 30 cases reveals prevalence of growth failure and delayed bone age, mild microcephaly, broad forehead with sparse frontal hair, telecanthus, blepharophimosis, abnormal pinnae, broad nose, and micrognathia. Overt cleft palate or submucous cleft palate is not a prevalent finding (16%). High-pitched and hoarse voice quality appears to be a constant feature. There is the suggestion of an association with leukemia, lymphoma, and neuroblastoma. Inheritance appears clearly autosomal recessive.


Ogilvie's syndrome: management and outcomes.
Ogilvie's syndrome, also known as acute colonic pseudo-obstruction, refers to pathologic dilation of the colon without underlying mechanical obstruction, occurring primarily in patients with serious comorbidities. Diagnosis of Ogilvie's syndrome is based on clinical and radiologic grounds, and can be treated conservatively or with interventions such as acetylcholinesterase inhibitors (such as neostigmine), decompressive procedures including colonoscopy, and even surgery. Based on our clinical experience we hypothesized that conservative management yields similar, if not superior, results to interventional management. Therefore, we retrospectively examined all patients over the age of 18 with Ogilvie's syndrome who presented to the Medical University of South Carolina (MUSC). The diagnosis of Ogilvie's syndrome was confirmed by clinical criteria, including imaging evidence of colonic dilation ≥9 cm. Patients were divided and analyzed in 2 groups based on management: conservative (observation, rectal tube, nasogastric tube, fluid resuscitation, and correction of electrolytes) and interventional (neostigmine, colonoscopy, and surgery). Use of narcotics in relation to maximal bowel size was also analyzed. Over the 11-year study period (2005-2015), 37 patients with Ogilvie's syndrome were identified. The average age was 67 years and the average maximal bowel diameter was 12.5 cm. Overall, 19 patients (51%) were managed conservatively and 18 (49%) underwent interventional management. There was no significant difference in bowel dilation (12.0 cm vs 13.0 cm; P = .21), comorbidities (based on the Charlson Comorbidity Index (CCI), 3.2 vs 3.4; P = .74), or narcotic use (P = .79) between the conservative and interventional management groups, respectively. Of the 18 patients undergoing interventional management, 11 (61%) had Ogilvie's-syndrome-related complications compared to 4 (21%) of the 19 patients in the conservative management group (P < .01). There was no difference in overall length of stay in the 2 groups. Two patients, one in each group, died from complications unrelated to their Ogilvie's syndrome. We conclude that Ogilvie's syndrome, although uncommon, and typically associated with severe underlying disease, is currently associated with a low inpatient mortality. While interventional management is often alluded to in the literature, we found no evidence that aggressive measures lead to improved outcomes.


[Results of application of synthetic antioxidants in treatment of patients with destructive pancreatitis].
Results of examination and treatment of 103 patients with pancreonecrosis are presented. Influence of antioxidant mexidol on acute pancreatitis (AP) was studied. It is demonstrated that mexidol in AP permits to slow down destructive processes in the pancreas, promotes localization of inflammation and normalization of clinical and laboratory picture of the disease that permits to decrease significantly number of severe complications of AP and reduce lethality.


A Curriculum for Genomic Education of Molecular Genetic Pathology Fellows: A Report of the Association for Molecular Pathology Training and Education Committee.
Molecular genetic pathology (MGP) is a subspecialty of pathology and medical genetics and genomics. Genomic testing, which is defined as that which generates large data sets and interrogates large segments of the genome in a single assay, is increasingly recognized as essential for optimal patient care through precision medicine. The most common genomic testing technologies in clinical laboratories are next-generation sequencing and microarray. It is essential to train in these methods and to consider the data generated in the context of the diagnosis, medical history, and other clinical findings of individual patients. Accordingly, updating the MGP fellowship curriculum to include genomics is timely, important, and challenging. At the completion of training, an MGP fellow should be capable of independently interpreting and signing out results of a wide range of genomic assays and, given the appropriate context and institutional support, of developing and validating new assays in compliance with applicable regulations. The Genomics Task Force of the MGP Program Directors, a working group of the Association for Molecular Pathology Training and Education Committee, has developed a genomics curriculum framework and recommendations specific to the MGP fellowship. These recommendations are presented for consideration and implementation by MGP fellowship programs with the understanding that MGP programs exist in a diversity of clinical practice environments with a spectrum of available resources.


Bicuspid aortic valve aortopathies: An hemodynamics characterization in dilated aortas.
Bicuspid aortic valve (BAV) aortopathy remains of difficult clinical management due to its heterogeneity and further assessment of related aortic hemodynamics is necessary. The aim of this study was to assess systolic hemodynamic indexes and wall stresses in patients with diverse BAV phenotypes and dilated ascending aortas. The aortic geometry was reconstructed from patient-specific images while the aortic valve was generated based on patient-specific measurements. Physiologic material properties and boundary conditions were applied and fully coupled fluid-structure interaction (FSI) analysis were conducted. Our dilated aortic models were characterized by the presence of abnormal hemodynamics with elevated degrees of flow skewness and eccentricity, regardless of BAV morphotype. Retrograde flow was also present. Both features, predicted by flow angle and flow reversal ratios, were consistently higher than those reported for non-dilated aortas. Right-handed helical flow was present, as well as elevated wall shear stress (WSS) on the outer ascending aortic wall. Our results suggest that the abnormal flow associated with BAV may play a role in aortic enlargement and progress it further on already dilated aortas.


[Structural Deterioration of a Bovine Pericardial Valve in a Tricuspid Position 14 Years Postoperatively;Report of a Case].
Although nonstructural dysfunction of a bioprosthesis caused by pannus formation or native valve attachment has been well described, structural valve deterioration( SVD) caused by calcification or tear of a bioprosthesis, especially a bovine pericardial valve, is very rare in the tricuspid position. We report a case of redo tricuspid valve surgery for SVD 14 years after tricuspid valve replacement( TVR) using a Carpentier-Edwards Perimount (CEP) pericardial valve. A 71-year-old woman was referred to our hospital because of exertional dyspnea and pre-syncope. She had undergone mitral valve replacement with a St. Jude Medical mechanical valve and TVR with a CEP pericardial valve 14 years previously. Transthoracic echocardiography revealed tricuspid valve stenosis with a mean trans-tricuspid valve pressure gradient (TVPG) of 7.3 mmHg. Redo TVR using a CEP Magna Mitral Ease valve was performed under cardiac arrest. Severe calcification was observed on the ventricular side of the leaflets of the explanted valve. The mean TVPG decreased to 3.2 mmHg after surgery, and the patient's postoperative course was uneventful.


Physical structure and inversion charge at a semiconductor interface with a crystalline oxide.
We show that the physical and electrical structure and hence the inversion charge for crystalline oxides on semiconductors can be understood and systematically manipulated at the atomic level. Heterojunction band offset and alignment are adjusted by atomic-level structural and chemical changes, resulting in the demonstration of an electrical interface between a polar oxide and a semiconductor free of interface charge. In a broader sense, we take the metal oxide semiconductor device to a new and prominent position in the solid-state electronics timeline. It can now be extensively developed using an entirely new physical system: the crystalline oxides-on-semiconductors interface.


Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled phase IIIb study of patients with moderate-to-severe genital psoriasis.
Genital psoriasis (GenPs) is a common, debilitating and difficult-to-treat manifestation of plaque psoriasis. However, few controlled, interventional studies of GenPs exist. To determine the efficacy of ixekizumab vs. placebo in patients with moderate-to-severe GenPs with ≥ 1% involved body surface area (BSA). Patients with moderate-to-severe GenPs, defined as a baseline static Physician's Global Assessment of Genitalia (sPGA-G) score of ≥ 3, with BSA ≥ 1% were randomized 1 : 1 to receive placebo (n = 74) or the recommended dosing of ixekizumab (n = 75). Major outcomes included the percentage of patients achieving 0 or 1 scores on the sPGA-G (primary end point), overall sPGA, GenPs Sexual Frequency Questionnaire (GenPs-SFQ) item 2, and ≥ 3-point improvement from baseline on the GenPs itch numerical rating scale. At week 12, ixekizumab was superior to placebo for sPGA-G 0/1 (73% vs. 8%, P < 0·001), overall sPGA 0/1 (73% vs. 3%, P < 0·001), GenPs-SFQ item 2 score of 0 or 1 (78% vs. 21%, P < 0·001) and genital itch (60% vs. 8%, P < 0·001). No candidiasis was reported, no deaths occurred and one (1%) serious adverse event was reported in a patient receiving placebo. Ixekizumab was superior to placebo for the treatment of moderate-to-severe GenPs with BSA ≥ 1%. The safety profile of ixekizumab was consistent with previous studies in moderate-to-severe plaque psoriasis.


The Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer.
The cardiovascular toxicity related to abiraterone and enzalutamide has been previously studied by our group. In this analysis, we aim to update our previous findings related to abiraterone and enzalutamide, including the new available evidence, both in castration-resistant and hormone-sensitive prostate cancer. PATIENTS AND METHODS: Prospective studies were identified by searching the MEDLINE/PubMed, Cochrane Library, and ASCO Meeting abstracts. Combined relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects methods. We included 7 articles in this meta-analysis, covering a total of 8660 patients who were used to evaluate cardiovascular toxicity. The use of new hormonal agents was associated with an increased risk of all-grade (RR, 1.36; 95% CI, 1.13-1.64; P = .001) and high-grade (RR, 1.84; 95% CI, 1.21-2.80; P = .004) cardiac toxicity. The use of new hormonal agents was also associated with an increased risk of all-grade (RR, 1.98; 95% CI, 1.62-2.43; P = .001) and high-grade (RR, 2.26; 95% CI, 1.84-2.77; P = .004) hypertension compared with the controls. Abiraterone was found to significantly increase the risk of both cardiac toxicity and hypertension, whereas enzalutamide significantly increases only the risk of hypertension. No differences were found based on the dose of prednisone used with abiraterone. The major limitation of this study is that data are available only as aggregate, and no single-patient information could be analyzed. Abiraterone and enzalutamide significantly increase the incidence and RR of cardiovascular toxicity in patients affected by metastatic prostate cancer. Follow-up for the onset of treatment-related cardiovascular events should therefore be considered in these patients.


Bioaccumulation of Organophosphorus (OPs) and Carbamate (CBs) Residues in Cultured Pangas Catfish (Pangasius pangasius) and Health Risk Assessment.
In the present study, the presence of organophosphorus (OPs) and carbamates (CBs) residues in the pond water and cultured Pangas catfish (Pangasius pangasius) samples collected from Comilla and Mymensingh areas were detected and assessed for their potential health risks. A total of 100 samples from each category were analysed among which 17% of the pond water samples and 9% of the fish samples were detected contaminated with OP and CB residues. The pond water and fish samples were extracted by liquid-liquid extraction (LLE), quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction, and ultrasonic extraction, respectively, and analysed through gas chromatography tandem mass spectrometry (GC-MS/MS). Among the detected OPs, Dursban (chlorpyrifos) and dichlorvos were detected, while among CB pesticides, carbofuran and sevin (Carbaryl) were detected in fish muscle samples. The detected OP and CB residual levels were below than the maximum residue limits (MRLs). The risk assessment study indicated no potential health risks. However, the level of compliance should be maintained through proper monitoring and controlling the overuse of pesticides in agricultural fields for public health safety.


Mechanisms of nicotinamide and thymidine protection from alloxan and streptozocin toxicity.
A common mechanism has been proposed for the beta-cell toxins alloxan (ALX) and streptozocin (STZ) involving the formation of single-strand breaks in DNA that lead to the overactivation of the enzyme poly(ADP-ribose) synthetase and the critical depletion of its substrate NAD. If the toxins act via this common mechanism, the poly(ADP-ribose) synthetase inhibitors nicotinamide and thymidine would be expected to affect the formation of DNA single-strand breaks in a similar fashion. To test the effects of these inhibitors, the formation of single-strand breaks in the DNA of insulin-secreting RINr cells was monitored by assessing changes in the supercoiling of nucleoids after exposure to STZ, ALX, or methylnitrosourea (MNU). With the inclusion of nicotinamide or thymidine and STZ or MNU, more single-strand breaks in RINr cell DNA were detected. These results would be expected if nicotinamide and thymidine acted through inhibition of poly(ADP-ribose) synthetase. However, when the inhibitors were used in combination with ALX, fewer single-strand breaks were present. This suggests a reduction in ALX-induced hydroxyl radicals available to interact with DNA. Because nicotinamide has been demonstrated to be a hydroxyl-radical scavenger, the ability of thymidine to scavenge hydroxyl radicals was investigated. Thymidine, like nicotinamide, was found to be a potent scavenger of hydroxyl radicals. Thus, the mechanisms by which nicotinamide and thymidine protect against the toxic effects of STZ or ALX appear different. These findings suggest that the actions of beta-cell toxins are more complex than simply the overactivation of a single enzyme.


[Prevalence of intestinal helminths in dogs from Quindío Province].
Intestinal helminths are pathogens for domestic animals and provide a source of potential infection for humans. The prevalence of intestinal helminths in domestic dogs was determined in a province-wide survey in Quindío Province, Colombia. The sample size was calculated based upon the data of the 2003 antirabies vaccination program in Quindio. Information in the form of an epidemiological questionnaire was provided by dog owners. Fecal samples from dogs were analyzed by Ritchie's concentration method. Of 324 samples, 67.6% were from purebred dog races and 32.4% were mongrels. A 22.2% prevalence for intestinal helminthes was found. Ancylostoma caninum was the most prevalent parasite (13.9%), followed by Trichuris vulpis (4.3%), Toxocara canis (2.5%), and Strongyloides stercoralis (4.0%). Multiparasite infestations were observed in 2.46% of the dogs. Presence of parasites was strongly correlated with age and degree of association with the open streets. Control programs are recommended for helminth surveillance in human and canine populations.


Septic bursitis of the foot: diagnosis, management and end-result.
Septic bursitis of the foot is a disorder infrequently reported in the medical literature. This infrequent reporting may represent a true low incidence of occurrence or may be a reflection of failure to recognize and diagnose this condition. This paper retrospectively reviews the presentation, clinical course, and outcome of patients presenting with septic bursitis of the foot. The authors have reviewed those features of this disorder that may aid the clinician in diagnosis and management of this infrequent, but disabling entity. They describe a brief case history of 10 patients with septic bursitis of the foot, provide radiographic and microbacterial evaluation, and give an outcome determination. They make recommendations for diagnosis and treatment based upon this review of patients and review of the literature.


In vivo antineoplastic activity of ascorbic acid for human mammary tumor.
The effect of ascorbic acid on the growth of human mammary tumor xenografts was investigated using the 6-day subrenal capsule assay method. The results showed that ascorbic acid (1 or 5 g/liter) administered in the drinking water significantly inhibited the growth of tumor fragments implanted beneath the renal capsule of immunocompetent mice. The results agree with other work carried out in animal experiments with animal tumors. Administration of ascorbic acid in the mouse diet did not affect the growth of the human mammary tumor fragments within the 6-day experimental period. Tumor growth was inhibited when mice were fed a diet containing ascorbic acid (50g/kg diet) together with cupric sulfate (18 or 90 mg/liter) in the drinking water. The results support the hypothesis that certain oxidation and degradation products of ascorbic acid are active antineoplastic agents for the human mammary carcinoma studied.


Developing a national database for higher education student counselling services: the importance of collaborations.
Student counselling services are at the forefront of providing mental health support to Irish Higher Education students. Since 1996, the Psychological Counsellors in Higher Education in Ireland (PCHEI) association, through their annual survey collection, has collected aggregate data for the sector. However, to identify national trends and effective interventions, a standardised non-aggregate sectoral approach to data collection is required. The Higher Education Authority funded project, 3SET, builds on the PCHEI survey through the development of a national database. In this paper, we outline the steps followed in developing the database, identify the parties involved at each stage and contrast the approach taken to the development of similar databases. Important factors shaping the development have been the autonomy of counselling services, compliance with General Data Protection Regulation, and the involvement of practitioners. This is an ongoing project with the long-term sustainability of the database being a primary objective.


Neurotrauma and plasticity a conference of the German BMBF-research initiative.
A conference was held in Magdeburg, Germany on March 4–6 where experts discussed current research in neurotraumatology and neurop-sychological rehabilitation. A total of about 60 research projects of a nationwide program project funded by the German Ministry of Education and Research (BMBF) were presented in conjunction with projects from the BMBF-initiative program "Neuropathology" of the Otto-v.-Guericke University of Magdeburg and the Graduate Program in Neuroscience which were funded by the German Research Society (DFG) and the State of Sachsen-Anhalt. The scientific program ranges from molecular, cell biological, anatomical, physiological and behavioral analyses of secondary cell death, regeneration and plasticity to clinical outcome studies and epidemiological evaluations. As such, the conference provides a broad overview of German neuroscience in the areas of neurotrauma, rehabilitation and brain plasticity. The abstracts are part of a special issue of Restorative Neurology and Neuroscience on "Neurotrauma and Neuropsychological Rehabilitation" which was published on the occasion of the conference.


Transcriptomic profiling of citrus fruit peel tissues reveals fundamental effects of phenylpropanoids and ethylene on induced resistance.
Penicillium spp. are the major postharvest pathogens of citrus fruit in Mediterranean climatic regions. The induction of natural resistance constitutes one of the most promising alternatives to avoid the environmental contamination and health problems caused by chemical fungicides. To understand the bases of the induction of resistance in citrus fruit against Penicillium digitatum, we have used a 12k citrus cDNA microarray to study transcriptional changes in the outer and inner parts of the peel (flavedo and albedo, respectively) of elicited fruits. The elicitor treatment led to an over-representation of biological processes associated with secondary metabolism, mainly phenylpropanoids and cellular amino acid biosynthesis and methionine metabolism, and the down-regulation of genes related to biotic and abiotic stresses. Among phenylpropanoids, we detected the over-expression of a large subset of genes important for the synthesis of flavonoids, coumarins and lignin, especially in the internal tissue. Furthermore, these genes and those of ethylene biosynthesis showed the highest induction. The involvement of both phenylpropanoid and ethylene pathways was confirmed by examining changes in gene expression and ethylene production in elicited citrus fruit. Therefore, global results indicate that secondary metabolism, mainly phenylpropanoids, and ethylene play important roles in the induction of resistance in citrus fruit.


Gaps in the evidence base of opioids for refractory breathlessness. A future work plan?
Breathlessness or "shortness of breath," medically termed dyspnea, remains a devastating problem for many people and those who care for them. As a treatment intervention, administration of opioids to relieve breathlessness is an area where progress has been made with the development of an evidence base. As evidence in support of opioids has accumulated, so has our collective understanding about trial methodology, research collaboration, and infrastructure that is crucial to generate reliable research results for palliative care clinical settings. Analysis of achievements to date and what it takes to accomplish these studies provides important insights into knowledge gaps needing further research and practical insight into design of pharmacological and nonpharmacological intervention trials in breathlessness and palliative care. This article presents the current understanding of opioids for treating breathlessness, what is still unknown as priorities for future research, and highlights methodological issues for consideration in planned studies.


Types of Cancers Diagnosed and the Preference of Families of Adult Patients with Cancer about Disclosing Diagnosis to the Patients.
Cancer has become one of the top causes of death in developing nations killing more people than the common infectious diseases do. For several reasons, disclosing cancer diagnosis to the patient is a challenging job for physicians and family members. A cross-sectional study was done to determine the common cancer diagnosis and the preference about disclosing cancer diagnosis to the patients among attendants of adult cancer patients seen at the regular surgical OPD of St. Paul's Hospital Millennium Medical college (SPHMMC) in June 1-31st 2015. Medical records of the patients and face-to-face interview with attendants were used to generate the data and analysis was done with SPSS version 19.0. A total 112(7.3%) patients were diagnosed to have cancer and 104 attendants (93%) were interviewed. The mean age of the patients was 48.2 years, Females made up 59% of the patients. The commonest cancer diagnosed was breast cancer. Male (62.7%) and children (36.1%) were the main attendants. Only 56.6% of the attendants agreed that patients should be the first to know diagnosis results. When possible, 84.3% preferred to hide diagnosis. Although 81.3% attendants did not like diagnosis disclosure to the patient, all of them wanted to know the diagnosis if they develop cancer. Nearly all, 98.8%, of the attendants preferred to hear the diagnosis from their doctors. Cancer is a relatively common diagnosis occurring at a younger age. The rate of cancer diagnosis disclosure acceptance and practice by attendants was low. Population-based and multicentre study with a larger sample size is recommended to define the condition better.


A self-assembled nanoscale robotic arm controlled by electric fields.
The use of dynamic, self-assembled DNA nanostructures in the context of nanorobotics requires fast and reliable actuation mechanisms. We therefore created a 55-nanometer-by-55-nanometer DNA-based molecular platform with an integrated robotic arm of length 25 nanometers, which can be extended to more than 400 nanometers and actuated with externally applied electrical fields. Precise, computer-controlled switching of the arm between arbitrary positions on the platform can be achieved within milliseconds, as demonstrated with single-pair Förster resonance energy transfer experiments and fluorescence microscopy. The arm can be used for electrically driven transport of molecules or nanoparticles over tens of nanometers, which is useful for the control of photonic and plasmonic processes. Application of piconewton forces by the robot arm is demonstrated in force-induced DNA duplex melting experiments.


Coeliac disease and risk of sarcoidosis.
Several case reports indicate a link between coeliac disease (CD) and sarcoidosis. Our main objective was to investigate the risk of subsequent sarcoidosis in individuals with CD in a general population cohort study. A second aim was to estimate the risk of CD in individuals with prior sarcoidosis. We used Cox proportional hazards method to calculate the risk of subsequent sarcoidosis in 14,349 individuals who had received a diagnosis of CD (1964-2003) and 69,998 age- and sex-matched individuals without a diagnosis of CD. Subjects were identified through the Swedish national Inpatient Register. Conditional logistic regression was used to study the risk of CD associated with prior sarcoidosis. CD was associated with an increased risk of sarcoidosis (Hazard ratio (HR) = 4.03; 95% CI = 2.32-7.00; p < 0.001), and was not notably affected by adjustment for socioeconomic index. In individuals with CD listed as the main diagnosis, the HR was 3.66 (95% CI HR = 1.80-7.45; p < 0.001). Prior sarcoidosis was associated with an increased risk of CD (Odds ratio = 3.58; 95% CI = 1.98-6.45; p < 0.001). Immune characteristics of CD may be linked to an increased risk of sarcoidosis.


4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes.
Liver injury due to acetaminophen (APAP) overdose is the major cause of acute liver failure in the United States. While treatment with N-acetylcysteine is the current standard of care for APAP overdose, anecdotal evidence suggests that administration of 4-methylpyrazole (4MP) may be beneficial in the clinic. The objective of the current study was to examine the protective effect of 4MP and its mechanism of action. Male C57BL/6J mice were co-treated with 300 mg/kg of APAP and 50 mg/kg of 4MP. The severe liver injury induced by APAP at 6 h as indicated by elevated plasma alanine aminotransferase activities, centrilobular necrosis, and nuclear DNA fragmentation was almost completely eliminated by 4MP. In addition, 4MP largely prevented APAP-induced activation of c-Jun N-terminal kinase (JNK), mitochondrial translocation of phospho-JNK and Bax, and the release of mitochondrial intermembrane proteins. Importantly, 4MP inhibited the generation of APAP protein adducts and formation of APAP-glutathione (GSH) conjugates and attenuated the depletion of the hepatic GSH content. These findings are relevant to humans because 4MP also prevented APAP-induced cell death in primary human hepatocytes. In conclusion, early treatment with 4MP can completely prevent liver injury after APAP overdose by inhibiting cytochrome P450 and preventing generation of the reactive metabolite.


Efficient hydrogen bonding recognition in water using aryl-extended calix[4]pyrrole receptors.
We describe the synthesis of four water-soluble aryl-extended calix[4]pyrrole receptors and report their binding properties with multiple neutral polar guests in water. The prepared receptors present different functionalization at their upper rims and have in common the placement of water solubilizing pyridinium groups at their lower rims. We investigate the interaction of the receptors with a guest series in water solution using 1H NMR titrations and ITC experiments. Despite the known competitive nature of water for hydrogen-bonding interactions, we demonstrate the formation of thermodynamically highly stable 1 : 1 inclusion complexes stabilized by hydrogen-bonding interactions. We show that increasing the hydrogen-bond acceptor character of the guest has a positive impact on binding affinity. This result suggests that the receptor's cavity is indeed a better hydrogen-bond donor to interact with the guests than water molecules. We also assess the important contribution of the hydrophobic effect to binding by comparing the binding affinities of analogous inclusion complexes in water and chloroform solutions. The more polar guests are bound with similar affinities in the two solvents. We compare the binding properties of the different complexes in order to derive general trends.


Postnatal changes in dolichol-pathway enzyme activities in rat liver.
The activity of hepatic protein N-glycosylation was compared in rats of different ages by incubating UDP-[14C]glucose with liver microsomes. Dolichyl-phosphate [14C]glucose, [14C]glucosyl-oligosaccharide-lipid and [14C]glycoproteins formed were increased after birth to maximal levels at 2 weeks; thereafter dolichylphosphate [14C]glucose remained constant, while [14C]glucosyl-oligosaccharide-lipid and [14C]glycoproteins were decreased to constant levels at 4 weeks. The postnatal change in the formation of [14C]glycoproteins was similar to the change in the hexosamine content of N-glycans in liver microsomes and plasma, suggesting that the N-glycosylation of proteins in rat liver increases after birth to a maximum at 2 weeks, and thereafter decreases to a constant level at 4 weeks. The possibility of a regulatory role for dolichyl phosphate in glycoprotein synthesis in rat liver during postnatal development was eliminated by demonstrating the inefficiency of exogenous dolichyl phosphate on the postnatal changes in [14C]glycoprotein formation. The transfer of [14C]glucose from UDP-[14C]glucose to denatured alpha-lactalbumin in liver microsomes increased to a maximum at 2 weeks and then decreased to a constant level, as with transfer to endogenous proteins (i.e. the formation of [14C]glycoproteins). On the other hand, the transfer of oligosaccharide from exogenous [14C]glucosyl-oligosaccharide-lipid to denatured alpha-lactalbumin reached a maximum at 2 weeks and then remained constant. These results strongly suggest that oligosaccharide-lipid available for N-glycosylation is limiting in rat liver after 2 weeks post partum. The activities of dolichyl-phosphate glucose, dolichyl-phosphate mannose and dolichyl-pyrophosphate N-acetylglucosamine synthases increased until 2 weeks post partum. Thereafter, the activity of dolichyl-pyrophosphate N-acetylglucosamine synthase decreased to a constant level at 4 weeks, while the activities of dolichyl-phosphate glucose and dolichyl-phosphate mannose synthases remained constant. These results suggest that N-glycosylation of proteins in rat liver increases until 2 weeks post partum, and that this depends on the activities of dolichol-pathway enzymes as a whole rather than on the activity of specific enzymes. N-Glycosylation then decreases to a constant level at 4 weeks due to decreases in the activities of enzymes responsible for oligosaccharide assembly on lipids, including dolichyl-pyrophosphate N-acetylglucosamine synthase.


The effectiveness of a rational-emotive intervention on teachers' unconditional self-acceptance, perfectionism, and pupil control ideology.
The present research aimed to investigate the effectiveness of a Rational Emotive Behavior Therapy (REBT) intervention on in-service teachers. A quasi-experimental 2-group (intervention vs. control) × 3-time (pre, post-test, follow-up) design was applied to explore to what extent the REBT interventions help teachers increase their level of unconditional self-acceptance as the primary outcome and decrease their perfectionism tendencies and pupil control ideology as secondary outcomes. The sample consisted of 100 in-service teachers assigned to either the intervention group (n = 50) or the control group (n = 50). The experimental group received a 6-week intervention program. Every session was held weekly and lasted 90-120 min. The Unconditional Self-Acceptance Questionnaire (USAQ), Pupil Control Ideology Scale (PCI), and Perfectionism Inventory Scale (PI) were used to collect data. This study used a mixed model ANOVA 2 × 3 for data analysis. The results indicated that in the experimental group, there was a statistically significant increase in unconditional self-acceptance level from pre-test to post-test, which remains significant at the 6-month follow-up. Likewise, there were no statistically significant differences in unconditional self-acceptance levels between the post-test and 6-month follow-up in the intervention group. These findings prove that REBT interventions are effective in increasing teachers' unconditional self-acceptance.


[Use of a diagnostic prospective algorithm for patients with recurrent miscarriage].
The application of a diagnostic algorithm to couples with recurrent pregnancy loss, was evaluated in this descriptive, prospective, clinical trial, at Infertility Clinic and Assisted Reproduction Unit, Instituto Nacional de Perinatología (INPer), México City. Fifty couples with primary or secondary recurrent pregnancy loss, were studied. A study protocol was applied to evaluate the following factors of miscarriage: anatomic, endocrine, infectious, genetic and immunologic. The frequency of altered factors was determined in the couples including in this trial. There were no cases of diabetes mellitus or impaired glucose tolerance in the studied group. The most common abnormal findings were: luteal phase defects; genital infections (Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum) and; an elevated frequency of chromosomal abnormalities. In addition, in 16% of the couples there was not an identified cause of their problem. The applied algorithm find the etiology of the recurrent pregnancy loss in the 84% of the couples studies. The method included new technologies (detection of anti-immunity, allo-immunity and infectious diseases), however, need corrections to increase its diagnostic and prognosis accuracy.


Sex differences in brain response to anticipated and experienced visceral pain in healthy subjects.
Women demonstrate higher pain sensitivity and prevalence of chronic visceral pain conditions such as functional gastrointestinal disorders than men. The role of sex differences in the brain processing of visceral pain is still unclear. In 16 male and 16 female healthy subjects we compared personality, anxiety levels, skin conductance response (SCR), and brain processing using functional MRI during anticipation and pain induced by esophageal distension at pain toleration level. There was no significant difference in personality scores, anxiety levels, SCR, and subjective ratings of pain between sexes. In group analysis, both men and women demonstrated a similar pattern of brain activation and deactivation during anticipation and pain consistent with previous reports. However, during anticipation women showed significantly greater activation in the cuneus, precuneus, and supplementary motor area (SMA) and stronger deactivation in the right amygdala and left parahippocampal gyrus, whereas men demonstrated greater activation in the cerebellum. During pain, women demonstrated greater activation in the midcingulate cortex, anterior insula, premotor cortex, and cerebellum and stronger deactivation in the caudate, whereas men showed increased activity in the SMA. The pattern of brain activity suggests that, during anticipation, women may demonstrate stronger limbic inhibition, which is considered to be a cognitive modulation strategy for impending painful stimulation. During pain, women significantly activate brain areas associated with the affective and motivation components of pain. These responses may underlie the sex differences that exist in pain conditions, whereby women may attribute more emotional importance to painful stimuli compared with men.


A 90-kDa protein serum marker for the prediction of progression to AIDS in a cohort of HIV-1+ homosexual men.
Levels of a 90-kDa protein (90K), recently reported as a possible marker of HIV-1 infection, were serially examined in a group of HIV-1-infected (HIV-1+) and uninfected (HIV-1-) subjects drawn from the same cohort of homosexual men. The first phase of the study included 61 HIV-1+ AIDS-free subjects 4 years (+/- 6 months) postseroconversion and 75 contemporaneous unifected subjects. Two years later, a subset of 35 HIV-1+ AIDS-free subjects and 72 HIV-1- controls was examined. Mean 90K levels for HIV-1+ subjects were significantly higher than for contemporaneous HIV-1- subjects both 4 and 6 years postseroconversion (p < 0.0001). A significantly more rapid progression to AIDS was seen in HIV-1+ subjects with high 90K levels both 4 years (p = 0.01) and 6 years (p = 0.003) postseroconversion. Four years postseroconversion, 90K was significantly correlated with CD8 cell percent, interferon, neopterin, and beta 2-microglobulin (p < 0.05). Two years later, significant correlations were seen between 90K levels and CD4 cell percent, CD4 cell number, and beta 2-microglobulin (p < 0.05). Stepwise-stepdown regression modeling using 90K, CD4 cell percent, interferon, and beta 2-microglobulin levels 4 years postseroconversion showed that the predictive value of a trivariate model of 90K-interferon-CD4 percent was better than any univariate or bivariate model. We conclude that the 90K protein may be a useful predictor of progression to AIDS in HIV-1+ patients, particularly in combination with the established markers of CD4 cell percent and interferon.


A long-term, multitrophic level study to assess pulp and paper mill effluent effects on aquatic communities in four US receiving waters: background and status.
An industry-funded, long-term, receiving water study was initiated in 1998/1999 to adress questions about the potential effects of pulp and paper mill effluent discharges on US receiving waters. Although the study continues, the knowledge gained to date provides an opportunity to reflect on the study development process, its progress, and its outcomes. As a backdrop to a series of articles in this special issue describing study results, this article describes the process by which study information objectives were identified as well as the process by which the experimental design was developed. A review of past literature and research identified gaps in long-term population/community data about effluent effects and that, consequently, emerged as a primary information objective. The selected streams for study included 1) Codorus Creek (Pennsylvania, USA), 2) Leaf River (Mississippi, USA), 3) McKenzie River (Oregon, USA), and 4) Willamette River (Oregon) represent a blend of mill process types, coldwater and warmwater stream types, and a range of effluent concentrations. Measurements included numbers of periphyton, macroinvertebrate, and fish communities; the assessment of water and effluent quality; laboratory bioassays; and fish full-life-cycle assays. Information objectives included addressing natural variability and, consequently, the study included long-term temporal (>10 y) and watershed-scale spatial frameworks. Regional-scale ecological risk assessments were performed for each site that aided in placing each site in an ecological and regulatory context. An adaptive-management process is described that allowed for modifications over time as a result of lessons learned as the study progressed. Results from the initial 7 to 8 y of monitoring, as described in the series of articles in this special issue, provide a unique data set with respect to addressing point-source pulp and paper mill effluent discharge concerns and may serve as a template for others to use in developing monitoring or management programs to assess or address water quality conditions or concerns.


Treatment of Borrelia burgdorferi-Infected Mice with Apoptotic Cells Attenuates Lyme Arthritis via PPAR-γ.
Infection of mice with Borrelia burgdorferi causes an inflammatory arthritis that peaks 3-4 wk postinfection and then spontaneously resolves. Although the recruitment of neutrophils is known to drive the development of arthritis, mechanisms of disease resolution remain unclear. Efficient clearance of apoptotic cells (AC) is likely an important component of arthritis resolution. In this article, we show the number of AC increases in the joints of B. burgdorferi-infected mice around day 21 postinfection and peaks around day 28. Injection of AC directly into the ankles of B. burgdorferi-infected mice limited ankle swelling but had no effect on spirochete clearance or arthritis severity scores. In vitro, addition of AC to bone marrow macrophage cultures decreased B. burgdorferi-induced TNF-α and KC and increased IL-10. In addition, phagocytosis of B. burgdorferi and neutrophil migration to LTB4 were inhibited by AC. Exogenous AC caused an increase in peroxisome proliferator-activated receptor-γ (PPAR-γ) expression both in vitro and in vivo during B. burgdorferi infection. The PPAR-γ agonist rosiglitazone elicited similar changes in macrophage cytokine production and neutrophil migration as exogenous AC. Addition of the PPAR-γ antagonist GW 9662 abrogated the effects of AC in vitro. Injection of rosiglitazone directly into the tibiotarsal joints of B. burgdorferi-infected mice decreased ankle swelling and immune cell recruitment, similar to the injection of AC. These results suggest that clearance of AC plays a role in the resolution of inflammation during experimental Lyme arthritis through the activation of PPAR-γ. PPAR-γ agonists, such as rosiglitazone, may therefore be effective treatments for inducing arthritis resolution.


Nonsteroidal antiinflammatory drugs and articular cartilage.
Salicylates and some other nonsteroidal antiinflammatory drugs (NSAID) suppress proteoglycan biosynthesis in normal articular cartilage in vitro. Their effect on osteoarthritic cartilage in vitro is even greater than their effect on normal cartilage. Aspirin has a similar effect in vivo on both atrophic cartilage and osteoarthritic cartilage in the dog, although no in vivo effect of salicylate on normal joint cartilage has been observed. While the magnitude of the effects of NSAID on proteoglycan metabolism in cartilage appeared to be inversely related to the proteoglycan content of the matrix, it is possible that some drugs are selectively bound to cartilage matrix components, which could affect their action on the chondrocyte. If NSAID have similar effects in patients with arthritis, this could have implications with respect to articular cartilage lesions.


Unusual fluorescent photoswitching of imidazole derivatives: the role of molecular conformation and twist angle controlled organic solid state fluorescence.
Molecular photoswitching, light induced reversible color/fluorescence modulation, has mostly been realized in organic molecules via E/Z isomerization of azobenzenes and stilbenes and ring opening/closing reactions of spiropyrans and diarylethenes. We report here new fluorescent molecular photoswitches based on triphenylamine (TPA)-imidazole derivatives, N-phenyl-N-(4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenyl)benzenamine (NTPB) and N-phenyl-N-(4-(1-phenyl-1H-phenanthro[9,10-d]imidazol-2-yl)phenyl)benzenamine (NPPB), that exhibited light induced reversible fluorescence switching via conformational change from a twisted molecular structure to more planar. NTPB and NPPB in CHCl3 showed red shift of absorption and fluorescence upon UV light irradiation whereas white light exposure reversed both absorption as well as fluorescence. The role of the TPA-imidazole twisted molecular structure in photoswitching was established based on structure property, computational and photophysical studies. The isobestic point observed in time dependent fluorescence change under UV light irradiation clearly demonstrated the presence of two different conformational isomers. Interestingly, polymorphism and torsion angle (τ) dependent fluorescence of NTPB and NPPB in the solid state also supported the role of the twisted molecular structure of TPA-imidazole in fluorescence switching/tuning. Interestingly, NTPB showed fluorescence photoswitching in the solid state also whereas rigid phenanthrene based NPPB did not show fluorescence photoswitching. Thus the present studies provide structural insight for designing a new type of fluorescent organic molecular photoswitches based on conformational modulation that could be of potential interest in optoelectronic devices.


An ictidosaur fossil from north america.
Teeth of a North American ictidosaur, Pachygenelus milleri, n. sp., found in the Upper Triassic Dockum Group of Texas, indicate that it is very similar to Pachygenelus monus of South Africa and Chaliminia musteloides of South America. The presence of a Gondwana element in the Northern Hemisphere attests to the ease of dispersal of the Late Triassic vertebrates through Pangea. Ictidosaurs are small, highly advanced, carnivorous cynodonts that display a mosaic of reptilian and mammalian features in the masticatory apparatus. They were contemporaneous with early mammals and probably closely related to them.


Cysteines in the transmembrane region of major histocompatibility complex antigens are fatty acylated via thioester bonds.
Exogenous radioactive palmitic acid is incorporated post-translationally into the HLA-B and -DR heavy chains, but not HLA-A heavy chains or -DR light chains of the human B lymphoblastoid cells JY and T51 . Protease digestions localize the label to the transmembrane region of the B7 heavy chain. Both B7 and DR heavy chains have a cysteine in the transmembrane hydrophobic region, while the A2 heavy chain and DR light chains have none. Palmitic acid is covalently linked to these transmembrane cysteines via a thioester bond since: 1) the label is not removed by organic extraction or boiling in sodium dodecyl sulfate and dithiothreitol, but is released at room temperature by methanolic KOH as methyl palmitate, and by hydroxylamine as palmitohydroxamate . 2) The pH sensitivity and kinetics of release by hydroxylamine and Tris are similar to those of palmitoyl-CoA (thioester linkage) and unlike those of methyl palmitate and palmitoyllysophosphatidylcholine ( hydroxyester linkages). 3) Neutral hydroxylamine treatment (but not neutral Tris treatment) generates sites that can be reduced and alkylated in the transmembrane region of B7 heavy chain and to a lesser extent in DR heavy chain. 4) Organic extraction of pronase digests of labeled B7 yields peptides containing palmitate and cysteine (but not serine or threonine) which co-migrate by thin layer chromatography. A population of beta 2-microglobulin molecules not associated with heavy chains is palmitylated , but not via a thioester linkage.


Paternal Uniparental Isodisomy of Chromosome 2 in a Patient with CNGA3-Associated Autosomal Recessive Achromatopsia.
Achromatopsia (ACHM) is a rare autosomal recessively inherited retinal disease characterized by congenital photophobia, nystagmus, low visual acuity, and absence of color vision. ACHM is genetically heterogeneous and can be caused by biallelic mutations in the genes CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, or ATF6. We undertook molecular genetic analysis in a single female patient with a clinical diagnosis of ACHM and identified the homozygous variant c.778G>C;p.(D260H) in the CNGA3 gene. While segregation analysis in the father, as expected, identified the CNGA3 variant in a heterozygous state, it could not be displayed in the mother. Microsatellite marker analysis provided evidence that the homozygosity of the CNGA3 variant is due to partial or complete paternal uniparental isodisomy (UPD) of chromosome 2 in the patient. Apart from the ACHM phenotype, the patient was clinically unsuspicious and healthy. This is one of few examples proving UPD as the underlying mechanism for the clinical manifestation of a recessive mutation in a patient with inherited retinal disease. It also highlights the importance of segregation analysis in both parents of a given patient or especially in cases of homozygous recessive mutations, as UPD has significant implications for genetic counseling with a very low recurrence risk assessment in such families.


[Effect of malting and thermoplastic extrusion on the technologic quality of soybean-derived products].
Seeds of soybean cultivar BR 16 were submitted to malting for 24 and 48 hours and to extrusion originating flakes used as ingredient to make biscuits which were chemically and sensorially evaluated. Macronutrient composition did not show any relevant modification presenting only a small decrease in carbohydrates and increase in the relative lipid composition. Some anti-nutritional factors were affected by the processes. Trypsin inhibitors decreased about 50% after 24 h of malting and disappeared after extrusion. Phytic acid was resistant to the processes while alfa-galactosides presented about 80% of loss as a result of the combination of malting and extrusion.


Comparison of clinical features and outcomes for asthma-COPD overlap syndrome vs. COPD patients: a systematic review and meta-analysis.
The aim of this study was to review evidence to determine whether "pure" chronic obstructive pulmonary disease (COPD) patients without a history of asthma differ in the clinical characteristics, severity of airflow limitation, and clinical outcomes compared to patients with Asthma-COPD Overlap Syndrome (ACOS). An electronic search was performed in the MEDLINE, EMBASE, SCOPUS and Web of Science databases to identify comparing the clinical characteristics and outcomes between ACOS and "pure" COPD. The included studies were subjected to meta-analysis and risk of bias assessment using ROBINS-E tool. Eleven observational studies were included. The results of the meta-analysis showed increased expression of lung function parameters like forced expiration volume (FEV) at 1 sec{mean difference (MD) 2.36; 95% CI [0.05,4.66] ; p=0.004; I2= 72%} and clinical symptoms in terms of fever {Relative Risk (RR) 0.34, p<0.0001}, wheezing {RR 0.39, p<0.0001} and dyspnea {RR 0.53, p<0.0001}. The comorbidities associated with ACOS patients were similar to that found in patients with "pure" COPD. Interestingly, higher body mass index (BMI) was found in patients with ACOS (MD -0.73 95% CI [-1.06, -0.41], p<0.0001. The result showed higher risk in onset of frequent acute exacerbations, severe exacerbations requiring hospitalization and higher number of exacerbations experienced per year in ACOS patients. Within the limitations of the review, ACOS can be regarded as separate entity of co-existence which is classically associated with higher BMI, worsened lung function parameters and exacerbations with a varying degree of clinical symptoms.


Alzheimer's disease: a clinical practice-oriented review.
Investigation in the field of Alzheimer's disease (AD), the commonest cause of dementia, has been very active in recent years and it may be difficult for the clinician to keep up with all the innovations and to be aware of the implications they have in clinical practice. The authors, thus, reviewed recent literature on the theme in order to provide the clinician with an updated overview, intended to support decision-making on aspects of diagnosis and management. This article begins to focus on the concept of AD and on its pathogenesis. Afterward, epidemiology and non-genetic risk factors are approached. Genetics, including genetic risk factors and guidelines for genetic testing, are mentioned next. Recommendations for diagnosis of AD, including recently proposed criteria, are then reviewed. Data on the variants of AD is presented. First approach to the patient is dealt with next, followed by neuropsychological evaluation. Biomarkers, namely magnetic resonance imaging, single photon emission tomography, FDG PET, PiB PET, CSF tau, and Aβ analysis, as well as available data on their diagnostic accuracy, are also discussed. Factors predicting rate of disease progression are briefly mentioned. Finally, non-pharmacological and pharmacological treatments, including established and emerging drugs, are addressed.


[High-dose ifosfamide in the treatment of patients with soft tissue sarcoma].
The increasing doses of 2.4-3.5 g/m2 ifosfamide, i/v, dropwise, were administered for 40 min, on days 1-5 each week, for 3 weeks, in 4 courses. Simultaneously, MESNA was given in a dose two-thirds of that of ifosfamide. The maximum single tolerable dose of ifosfamide was 3.2 g/m2. The dose of 3.5 g/m2 proved neurotoxic causing encephalopathy. The other toxic effects were stage III-IV neutropenia (47%), nausea and vomiting (91%) and weakness (33%). No clinical evidence of renal failure was attributed to the high dosage of the drug in the course of assays of biochemical components of the blood, blood- and urine-beta-2-microglobulins, N-acetyl-D-hexoaminidase (NAG) level in urine, creatinine clearance and complex renoscintigraphy data. On days 3-5, ifosfamide treatment was followed by increase in NAG and beta-2-microglobulin levels in urine which pointed to the toxic effect exerted on the epithelium of renal tubules. The antitumor effect was apparent in 5 (29%) patients for 6 months, which testifies to the high effectiveness of ifosfamide treatment for soft-tissue sarcoma.


First Report of Watermelon mosaic virus in Zucchini Squash in Bosnia and Herzegovina.
Aphid-borne Watermelon mosaic virus (WMV; genus Potyvirus, family Potyviridae) is widely distributed in the Mediterranean area and is one of the most prevalent cucurbit viruses in the region (4). In July 2012, approximately 20% of zucchini squash (Cucurbita pepo L.) plants showing virus-like symptoms were observed in one field in Kukulje locality (region of Banja Luka), Bosnia and Herzegovina. Infected plants exhibited mild to severe mosaic, chlorotic mottling, and dark green vein banding, as well as puckering and leaf deformation. Symptoms mostly developed on leaves, while fruits usually only failed to develop a normal coloration. Leaves from 15 symptomatic zucchini squash plants were sampled and analyzed utilizing double-antibody sandwich (DAS)-ELISA kits (Bioreba, AG, Reinach, Switzerland) with commercial antisera specific for five commonly occurring cucurbit-infecting viruses: WMV, Zucchini yellow mosaic virus (ZYMV), Papaya ringspot virus (PRSV), Cucumber mosaic virus (CMV), and Squash mosaic virus (SqMV) (1,3,4). Commercial positive and negative controls were included in each test. WMV was detected serologically in all tested zucchini squash samples, while no presence of other tested viruses were found. Crude sap extracted from leaves of a serologically positive sample (307-12) using 0.01 M phosphate buffer (pH 7) was mechanically inoculated onto five plants of C. pepo 'Ezra F1' and severe mosaic accompanied by bubbling and leaf malformation was observed 14 days post-inoculation. Viral identification in all naturally and mechanically infected plants was further confirmed by conventional reverse transcription (RT)-PCR. Total RNAs were extracted with the RNeasy Plant Mini Kit (Qiagen, Hilden, Germany) and RT-PCR was performed using the One-Step RT-PCR Kit (Qiagen) with specific primers WMV 5' and WMV 3' (4), yielding a 402- to 408-bp fragment corresponding to the N-terminal part of the coat protein (CP) gene (2). Total RNAs obtained from the Serbian WMV isolate from oil pumpkin (GenBank Accession No. JF325890) and healthy zucchini squash leaves were used as positive and negative controls, respectively. A product of the correct predicted size was obtained in all naturally and mechanically infected plants as well as positive control. No amplicon was recorded in healthy control. After purification (QIAquick PCR Purification Kit, Qiagen) the amplicon obtained from one selected isolate 307-12 was sequenced directly in both direction, aligned and compared by MEGA5 software with WMV sequences available in GenBank. Sequence comparisons revealed that the zucchini squash isolate from Bosnia and Herzegovina (KF517099) showed the highest nucleotide identity of 100% with one isolate from Serbia (FJ325891) and two Slovakian WMV isolates (GQ241712 to 13), all belonging to the classical group of WMV isolates (4). To our knowledge, this is the first report of WMV infecting zucchini squash in Bosnia and Herzegovina. Since squash and other cucurbit species represent valuable crops in Bosnia and Herzegovina, with annual production close to US$8.5 million ( http://faostat.fao.org ) and rising rapidly, the presence of a devastating pathogen like as WMV could be a serious constraint for their production. References: (1) A. Ali et al. Plant Dis. 96:243, 2012. (2) C. Desbiez et al. Arch. Virol. 152:775, 2007. (3) S. Jossey and M. Babadoost. Plant Dis. 92:61, 2008. (4) H. Lecoq and C. Desbiez. Adv. Virus Res. 84:67, 2012.


Long-read targeted sequencing uncovers clinicopathological associations for C9orf72-linked diseases.
To examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10-4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10- 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.


Length of residence and caesarean section in migrant women in Sweden: a population-based study.
Prior studies have reported substantial differences in caesarean rates between migrant and non-migrant women. In this study we investigate whether the association between maternal country of birth and caesarean section is modified by length of residence in Sweden. Population-based register study. A total of 106 760 migrant and 473 881 Swedish-born women having singleton, first births were studied using multinomial multiple regression models to estimate odds ratios (OR) and 95% confidence intervals for mode of birth. Random effect meta-analyses were conducted to assess true heterogeneity between categories of length of residence. Longer duration of residence was associated with an increased overall risk of both unplanned and planned caesarean section among migrant women. This pattern was more pronounced among countries grouped as having higher prevalence (compared to Swedes) of unplanned: OR≤1=1.41 (1.32-1.50); OR>1-<6=1.49 (1.42-1.57); OR6-<10=1.61 (1.50-1.72); OR≥10=1.71 (1.64-1.79) and planned caesarean section [OR≤1=1.14 (0.95-1.36); OR>1-<6=1.30 (1.13-1.51); OR6-<10=1.97 (1.64-2.37]; OR≥10=1.82 (1.67-1.98)]. The results were robust to social, obstetric and health adjustments. There were some country-of-origin-specific findings. The fact that the risk of unplanned and planned caesarean section tended to increase with length of residence, even with adjustment for social, obstetric and health factors, suggests that receiving country-specific factors are playing an important role in caesarean section.


Identification of hypoxic cells using an organotellurium tag compatible with mass cytometry.
Mass cytometry (MC) offers unparalleled potential for the development of highly parameterized assays for characterization of single cells within heterogeneous populations. Current reagents compatible with MC analysis employ antibody-metal-chelating polymer conjugates to report on the presence of biomarkers. Here, we expand the utility of MC by developing the first activity-based probe designed specifically for use with the technology. A compact MC-detectable telluroether is linked to a bioreductively sensitive 2-nitroimidazole scaffold, thereby generating a probe sensitive to cellular hypoxia. The probe exhibits low toxicity and is able to selectively label O2-deprived cells. A proof-of-concept experiment employing metal-bound DNA intercalators demonstrates that a heterogeneous mixture of cells with differential exposure to O2 can be effectively discriminated by the quantity of tellurium-labeling. The organotellurium reagents described herein provide a general approach to the development of a large toolkit of MC-compatible probes for activity-based profiling of single cells.


Two visual systems and two theories of perception: An attempt to reconcile the constructivist and ecological approaches.
The two contrasting theoretical approaches to visual perception, the constructivist and the ecological, are briefly presented and illustrated through their analyses of space and size perception. Earlier calls for their reconciliation and unification are reviewed. Neurophysiological, neuropsychological, and psychophysical evidence for the existence of two quite distinct visual systems, the ventral and the dorsal, is presented. These two perceptual systems differ in their functions; the ventral system's central function is that of identification, while the dorsal system is mainly engaged in the visual control of motor behavior. The strong parallels between the ecological approach and the functioning of the dorsal system, and between the constructivist approach and the functioning of the ventral system are noted. It is also shown that the experimental paradigms used by the proponents of these two approaches match the functions of the respective visual systems. A dual-process approach to visual perception emerges from this analysis, with the ecological-dorsal process transpiring mainly without conscious awareness, while the constructivist-ventral process is normally conscious. Some implications of this dual-process approach to visual-perceptual phenomena are presented, with emphasis on space perception.