Interactome mapping of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway identifies deformed epidermal autoregulatory factor-1 as a new glycogen synthase kinase-3 interactor.
The phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR) pathway plays pivotal roles in cell survival, growth, and proliferation downstream of growth factors. Its perturbations are associated with cancer progression, type 2 diabetes, and neurological disorders. To better understand the mechanisms of action and regulation of this pathway, we initiated a large scale yeast two-hybrid screen for 33 components of the PI3K-mTOR pathway. Identification of 67 new interactions was followed by validation by co-affinity purification and exhaustive literature curation of existing information. We provide a nearly complete, functionally annotated interactome of 802 interactions for the PI3K-mTOR pathway. Our screen revealed a predominant place for glycogen synthase kinase-3 (GSK3) A and B and the AMP-activated protein kinase. In particular, we identified the deformed epidermal autoregulatory factor-1 (DEAF1) transcription factor as an interactor and in vitro substrate of GSK3A and GSK3B. Moreover, GSK3 inhibitors increased DEAF1 transcriptional activity on the 5-HT1A serotonin receptor promoter. We propose that DEAF1 may represent a therapeutic target of lithium and other GSK3 inhibitors used in bipolar disease and depression.


Conjunctivochalasis. A cause of tearing and its management.
Conjunctivochalasis is an isolated bilateral condition in which redundant conjunctival tissue overlies the lower eyelid margin or covers the lower punctum. It causes tearing by mechanically disrupting the normal flow of tears. Unlike the boggy conjunctiva seen in an allergic reaction, the extent of this redundant tissue is small, well-localized, and unresponsive to antihistamine drops. During the 40-month period from May 1981 through September 1984, 15 patients complaining of epiphora were found to have this problem. Simple local surgical excision relieved their symptoms. Follow-up period ranged from 10 to 40 months, with an average of 27 months. Conjunctivochalasis can be recognized by a thorough ocular examination and managed by simple excision of the redundant tissue. Consequently, before extensive surgery such as dacryocystorhinostomy, eyelid surgery, or silicone intubation of the lacrimal system is contemplated, conjunctivochalasis should be ruled out and corrected.


Disruption to the development of maternal responsiveness? The impact of prenatal depression on mother-infant interactions.
Both prenatal and postnatal maternal depression are independently associated with an increased risk of adverse infant development. The impact of postnatal depression on infants may be mediated through the effect of depression in reducing maternal responsiveness. However, the mechanisms underlying the effect of prenatal depression are unclear. Using longitudinal data from over 900 mother-infant pairs in a UK birth cohort (ALSPAC), we found that women with high depressive symptom scores during mid pregnancy, but NOT when their infants were 8 months, had a 30% increased risk of low maternal responsiveness when the infant was 12 months compared to women with consistently low depression. This may provide a mechanism to explain the independent association between prenatal depression and poorer infant development.


Growth hormone overexpression generates an unfavorable phenotype in juvenile transgenic zebrafish under hypoxic conditions.
Growth hormone (GH) has numerous functions in different organisms. A recently described function for GH is its role in protecting against damage caused by a decrease in oxygen levels. To evaluate the effects of GH-transgenesis on hypoxia tolerance, we used a GH-transgenic zebrafish model. We found that the transgenic fish have higher mortality rates when exposed to low oxygen levels (1.5 mg O₂L(-1)) for 24 h. The lower capacity of GH-transgenic fish to manage a hypoxic environment was investigated by analyzing different metabolic and molecular factors. The transgenic fish showed increased oxygen consumption, which confirms the larger oxygen demand imposed by transgenesis. At the gene expression level, transgenesis increased lactate dehydrogenase (LDH) and creatine kinase muscle (CKM) expression in fish under normoxic conditions. This result suggests that excessive GH expression stimulates the synthesis of enzymes involved in anaerobic metabolism. Conversely, the interaction between transgenesis and hypoxia caused an increased expression of hemoglobin (Hb), hypoxia-inducible factor (HIF1a) and prolyl-4-hydroxylase (PHD) genes. Additionally, GH-transgenesis increased LDH activity and increased lactate content. Taken together, these findings indicate that GH-transgenesis impaired the ability of juvenile zebrafish to sustain an aerobic metabolism and induced anaerobic metabolism when the fish were challenged with low oxygen levels.


Magainin 2 and PGLa in Bacterial Membrane Mimics II: Membrane Fusion and Sponge Phase Formation.
We studied the synergistic mechanism of equimolar mixtures of magainin 2 (MG2a) and PGLa in phosphatidylethanolamine/phosphatidylglycerol mimics of Gram-negative cytoplasmic membranes. In a preceding article of this series, we reported on the early onset of parallel heterodimer formation of the two antimicrobial peptides already at low concentrations and the resulting defect formation in the membranes. Here, we focus on the structures of the peptide-lipid aggregates occurring in the synergistic regime at elevated peptide concentrations. Using a combination of calorimetric, scattering, electron microscopic, and in silico techniques, we demonstrate that the two peptides, even if applied individually, transform originally large unilamellar vesicles into multilamellar vesicles with a collapsed interbilayer spacing resulting from peptide-induced adhesion. Interestingly, the adhesion does not lead to a peptide-induced lipid separation of charged and charge-neutral species. In addition to this behavior, equimolar mixtures of MG2a and PGLa formed surface-aligned fibril-like structures, which induced adhesion zones between the membranes and the formation of transient fusion stalks in molecular dynamics simulations and a coexisting sponge phase observed by small-angle x-ray scattering. The previously reported increased leakage of lipid vesicles of identical composition in the presence of MG2a/PGLa mixtures is therefore related to a peptide-induced cross-linking of bilayers.


Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians.
Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, including diabetic nephropathy. Endothelial-derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with endothelial dysfunction. We evaluated the association of the constitutive endothelial nitric oxide synthase gene (eNOS) polymorphisms with type 2 diabetic nephropathy. We genotyped three polymorphisms of eNOS (Two SNPs: -786T > C, 894G > T and one 27-bp repeat polymorphism in Intron 4 (27VNTR)) in type 2 diabetic nephropathy patients (cases: n = 195) and type 2 diabetic without nephropathy (controls: n = 255), using validated PCR-RFLP assays. We measured serum NO levels in these subjects and examined its correlation with diabetic nephropathy and eNOS genotypes. The frequency of CC (-786T > C), TT (894G > T) and aa genotypes (27VNTR) were significantly higher in diabetic nephropathy patients as compared to the diabetes without nephropathy group (CC: P = 0.003, TT: P = 0.03, aa: P < 0.0001). These mutant genotypes were found to be associated with higher risk of nephropathy (-786T > C: OR: 5.5, 95%CI: 1.53-19.79; 894G > T: OR: 1.8, 95%CI: 1.03-3.16; Intron 4: OR: 6.23, 95%CI: 2.23-16.31). Haplotype with all the wild alleles (T-b-G) was found to be associated with a decreased risk of nephropathy (OR: 0.68, P = 0.005) and haplotype with all mutant alleles (C-a-T) was associated with higher risk of diabetic nephropathy as compared to diabetes without nephropathy group (OR: 2.6, P = 0.14). No significant linkage disequilibria were observed among the variants in this case-control study. The serum NO levels were observed to be significantly (P < 0.05) lower in mutant allele carriers ('C' allele of T-786C SNP and/or 'T' allele of G894T SNP) as compared with the wild-type allele carriers (-786T and/or 894G) within each of the subject groups (with and without nephropathy). These results suggest that the eNOS gene locus is associated with diabetic nephropathy and the functional polymorphisms (-786T > C & 894G > T) might lead to a decreased expression of eNOS gene.


Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum?
Diabetes and related complications are associated with long-term damage and failure of various organ systems. The line of demarcation between the pathogenic mechanisms of microvascular and macrovascular complications of diabetes and differing responses to therapeutic interventions is blurred. Diabetes induces changes in the microvasculature, causing extracellular matrix protein synthesis, and capillary basement membrane thickening which are the pathognomic features of diabetic microangiopathy. These changes in conjunction with advanced glycation end products, oxidative stress, low grade inflammation, and neovascularization of vasa vasorum can lead to macrovascular complications. Hyperglycemia is the principal cause of microvasculopathy but also appears to play an important role in causation of macrovasculopathy. There is thought to be an intersection between micro and macro vascular complications, but the two disorders seem to be strongly interconnected, with micro vascular diseases promoting atherosclerosis through processes such as hypoxia and changes in vasa vasorum. It is thus imperative to understand whether microvascular complications distinctly precede macrovascular complications or do both of them progress simultaneously as a continuum. This will allow re-focusing on the clinical issues with a unifying perspective which can improve type 2 diabetes mellitus outcomes.


A 100 year sedimentary record of heavy metal pollution in a shallow eutrophic lake, Lake Chaohu, China.
This study has worked on the evaluation of the temporal and spatial evolution of heavy metal contamination in sediment taken from a shallow eutrophic lake, Lake Chaohu, China, over the last 100 years, and thereby used (137)Cs and (210)Pb dating, a PIRLA procedure, statistical analysis, geochemical normalization and a enrichment factor calculation (EF). Concentrations of 5174, 29 325, 10.7, 36.4, 20.4, 386.0, 21.1 and 38.4 mg kg(-1) for Ti, Fe, Co, Cr, Cu, Mn, Pb and Zn, respectively, are proposed as natural background values for the Lake Chaohu based on a PIRLA procedure. The contamination history from the last 100 years can be divided into two periods. Before the 1960s, heavy metal contamination did not occur and there was no spatial difference for heavy metal distribution. Since the 1960s, heavy metal enrichment and contamination has occurred, and the west half of the lake region showed a higher degree of contamination than the east half to various intensified anthropogenic activities. In the east half of the lake region, the anthropogenic source of heavy metals mainly originated from agricultural intensification, whereas in the west half of the lake it originated from city runoff and industry as well as agriculture. In all anthropogenic heavy metals, Co is only from industry.


Genome sequencing and CRISPR/Cas9 gene editing of an early flowering Mini-Citrus (Fortunella hindsii).
Hongkong kumquat (Fortunella hindsii) is a wild citrus species characterized by dwarf plant height and early flowering. Here, we identified the monoembryonic F. hindsii (designated as 'Mini-Citrus') for the first time and constructed its selfing lines. This germplasm constitutes an ideal model for the genetic and functional genomics studies of citrus, which have been severely hindered by the long juvenility and inherent apomixes of citrus. F. hindsii showed a very short juvenile period (~8 months) and stable monoembryonic phenotype under cultivation. We report the first de novo assembled 373.6 Mb genome sequences (Contig-N50 2.2 Mb and Scaffold-N50 5.2 Mb) for F. hindsii. In total, 32 257 protein-coding genes were annotated, 96.9% of which had homologues in other eight Citrinae species. The phylogenomic analysis revealed a close relationship of F. hindsii with cultivated citrus varieties, especially with mandarin. Furthermore, the CRISPR/Cas9 system was demonstrated to be an efficient strategy to generate target mutagenesis on F. hindsii. The modifications of target genes in the CRISPR-modified F. hindsii were predominantly 1-bp insertions or small deletions. This genetic transformation system based on F. hindsii could shorten the whole process from explant to T1 mutant to about 15 months. Overall, due to its short juvenility, monoembryony, close genetic background to cultivated citrus and applicability of CRISPR, F. hindsii shows unprecedented potentials to be used as a model species for citrus research.


A preliminary investigation into the relationship between functional movement screen scores and athletic physical performance in female team sport athletes.
There is little research investigating relationships between the Functional Movement Screen (FMS) and athletic performance in female athletes. This study analyzed the relationships between FMS (deep squat; hurdle step [HS]; in-line lunge [ILL]; shoulder mobility; active straight-leg raise [ASLR]; trunk stability push-up; rotary stability) scores, and performance tests (bilateral and unilateral sit-and-reach [flexibility]; 20-m sprint [linear speed]; 505 with turns from each leg; modified T-test with movement to left and right [change-of-direction speed]; bilateral and unilateral vertical and standing broad jumps; lateral jumps [leg power]). Nine healthy female recreational team sport athletes (age = 22.67 ± 5.12 years; height = 1.66 ± 0.05 m; body mass = 64.22 ± 4.44 kilograms) were screened in the FMS and completed the afore-mentioned tests. Percentage between-leg differences in unilateral sit-and-reach, 505 turns and the jumps, and difference between the T-test conditions, were also calculated. Spearman's correlations (p ≤ 0.05) examined relationships between the FMS and performance tests. Stepwise multiple regressions (p ≤ 0.05) were conducted for the performance tests to determine FMS predictors. Unilateral sit-and-reach positive correlated with the left-leg ASLR (r = 0.704-0.725). However, higher-scoring HS, ILL, and ASLR related to poorer 505 and T-test performance (r = 0.722-0.829). A higher-scored left-leg ASLR related to a poorer unilateral vertical and standing broad jump, which were the only significant relationships for jump performance. Predictive data tended to confirm the correlations. The results suggest limitations in using the FMS to identify movement deficiencies that could negatively impact athletic performance in female team sport athletes.


Methyl- and acetyltransferases are stable epigenetic markers postmortem.
Postmortem brain tissue has been reported to be suitable to delineate regional pattern of possible disturbances underlying epigenetic functionality. However, from many parameters that have been detected in postmortem brain regions it is noteworthy that an effect of postmortem interval (PMI), storage time and premortem parameters should not be underestimated. Our previous investigation revealed that tryptophan (TRP) levels in postmortem brain tissue is affected by PMI and storage time. Since, alteration in TRP levels are assumed to be due to protein degradation, we further investigated whether TRP correlates to variables such as RNA, proteins and DNA modulators. In addition, we aimed to elucidate whether established postmortem variables may influence epigenetic parameters. These were investigated in well characterized postmortem human brain tissue originating from the European Brain Bank consortium II (BNEII). We could confirm previous findings, in which some protein levels alter because of prolonged PMI. Similarly, we demonstrated an influence of increased storage period on TRP levels, which might indicate degradation of proteins. Still not all proteins degrade in a similar manner, therefore a specific analysis for the protein of interest would be recommended. We found that methyltransferase- and acetyltransferase-activities were relatively preserved with PMI and storage duration. In conclusion, preservation of acetyltransferase- and methyltransferase-activities provides possible evidence of stability for epigenetic studies using postmortem tissue.


Non-electrocardiogram-gated multidetector-row computed tomography findings of cardiac pathology in oncologic patients.
Multidetector-row computed tomography (MDCT) plays an essential role in oncologic imaging as the modality of mapping out the treatment strategy at staging, assessing response to the treatment, and following up patient outcome after the treatment. Even without electrocardiogram gating, MDCT provides accurate information about the heart. In the group of oncologic patients, different tumoral and non-tumoral-related heart disorders can be found, for example, metastatic cardiac involvement (approximately 10% of patients with lung or breast cancer will develop metastases to the heart), paraneoplastic cardiac disorders, non-tumor-related heart disorders, and chemotherapy- and radiotherapy-related cardiac side effects. MDCT plays a role in the detection of these entities. We show the non-electrocardiogram-gated MDCT findings of oncology-related cardiac disorders to encourage radiologists to recognize and report cardiac findings in oncologic patients. Appropriate knowledge of tumoral and non-tumoral-related MDCT features allows a complete evaluation of oncologic patients with ancillary cardiac findings. An adequate knowledge of the patient's medical history, previous treatments, and concomitant illnesses is essential to interpret heart findings in oncologic patients who undergo MDCT.


Treatment of Morton's neuroma using percutaneous electrocoagulation.
A new modality for treating Morton's neuroma was introduced and performed by the authors, using a nerve lesion generator. Seventy-nine lesions were evaluated by obtaining the patients' responses to three questions. By rating their symptoms on a 0-5 scale both before and after the neurectomy, the patients showed a 56% reduction in symptoms. With a gone-improved-same-worse rating, the patients responded with 25%, 46%, 24%, and 5% in each respective category. The overall assessment of the procedure by the patients yielded 68% pleased and 32% not pleased. An average of 4 hr was missed from work following the neurectomy, and only 20% of the patients required mild analgesics.


The evidence for efficacy of omega-3 fatty acids in preventing or slowing the progression of retinitis pigmentosa: a systematic review.
Studies in preterm and term human infants have suggested that a dietary supply of omega-3 fatty acids is essential for optimal visual development. Several basic science studies support the hypothesis that omega-3 fatty acids may be useful therapeutic agents for pathologies of the retina and lens. As part of a systematic review of the effect of omega-3 fatty acids on eye health, the purpose of this study was to conduct a systematic review of the scientific-medical literature to appraise and synthesize the evidence for the effects of omega-3 fatty acids in preventing the development or progression of retinitis pigmentosa. A comprehensive search was undertaken in MEDLINE, PREMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Global Health, and Dissertation Abstracts. Unpublished literature was sought through manual searches of reference lists of included studies and key review articles and from the files of content experts. Searches were not restricted by language of publication, publication type, or study design. Eligibility criteria were applied to screen eligible studies on two levels. Data extraction and quality assessment were performed. Six studies published between 1995 and 2004 met eligibility criteria in investigating the question of the possible value of omega-3 fatty acids in slowing the progression of retinitis pigmentosa. Meta-analysis was not performed because there was not enough available information for formal quantitative analysis. There are trends in improvement of some retinitis pigmentosa outcomes with omega-3 fatty acids in the higher quality studies. Clinical research is preliminary in this field, however. Accordingly, definitive answers will require significantly more observational and interventional clinical research.


[Hyphessobrycon taphorni and H. eschwartzae (Teleostei: Characidae) two new species of fish in the basin of Madre de Dios river, Peru].
Hyphessobrycon with 129 valid species, is a genus of fish that has a great diversity of species in the Neotropical ichthyofauna, reaches its greatest diversity in the Amazon basin with about 70% of these species, is highly desired by hobbyists because of their beauty and color, and are still meeting new species. We analyzed specimens from the Departamento de Ictiología, Museo de Historia Natural de la Universidad Mayor de San Marcos, Lima, Perú (MUSM); and measurements of the specimens were taken point to point with digital calipers. Observations of bone and cartilage structures were made on cleared and stained (C&S) samples. The morphometric relationships between species using 21 variables were explored using a principal component analysis (PCA). Here we describe two new species, Hyphessobrycon taphorni and H. eschwartzae from the Madre de Dios River drainage, Peru. Hyphessobrycon taphorni sp. n. can be distinguished by the number of dorsal-fin rays (iii, 8), by the number of: pored lateral-line scales (4-5), teeth in the outer premaxillary row (1-2), teeth in the inner premaxillary row (7-8), by: the caudal-peduncle length (11.4-16.4% SL), number of lateral scales (28-29, except from H. loretoensis which has 29-30) and absence of a humeral spot (vs. present), it differs from H. loretoensis by the number of: scales between the lateral line and the anal fin origin (4 vs. 3) and maxillary teeth (2 vs. 3-4), and it differs from H. agulha by the number of branched pectoral-fin rays (11-12 vs. 9-10). Hyphessobrycon eschwartzae sp. n. is distinguished by the number of: simple anal-fin rays (iv), teeth on the dentary (13-15), teeth in the inner premaxillary row (6), teeth in the outer premaxillary row (3, except from H. heterorhabdus and H. loretoensis which have 3-4); it differs from H. loretoensis by the number of: pored lateral-line scales (7 vs. 9-10), scales between the lateral line and the dorsal-fin origin (5 vs. 3-4); it differs from H. agulha in the number of lateral scales (30-31 vs. 33-34), by the number of: predorsal scales (9 vs. 10), maxillary teeth (4 vs. 0-1); in having in life a red lateral stripe above the dark lateral stripe that extends from the posterior part of the opercle to the caudal peduncle (vs. absent) and by the presence of bony hooks in mature males only on the anal fin (vs. hooks on all fins, including the caudal).


Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes.
Skeletal muscle insulin resistance (IR) is considered a critical component of type II diabetes, yet to date IR has evaded characterization at the global gene expression level in humans. MicroRNAs (miRNAs) are considered fine-scale rheostats of protein-coding gene product abundance. The relative importance and mode of action of miRNAs in human complex diseases remains to be fully elucidated. We produce a global map of coding and non-coding RNAs in human muscle IR with the aim of identifying novel disease biomarkers. We profiled >47,000 mRNA sequences and >500 human miRNAs using gene-chips and 118 subjects (n = 71 patients versus n = 47 controls). A tissue-specific gene-ranking system was developed to stratify thousands of miRNA target-genes, removing false positives, yielding a weighted inhibitor score, which integrated the net impact of both up- and down-regulated miRNAs. Both informatic and protein detection validation was used to verify the predictions of in vivo changes. The muscle mRNA transcriptome is invariant with respect to insulin or glucose homeostasis. In contrast, a third of miRNAs detected in muscle were altered in disease (n = 62), many changing prior to the onset of clinical diabetes. The novel ranking metric identified six canonical pathways with proven links to metabolic disease while the control data demonstrated no enrichment. The Benjamini-Hochberg adjusted Gene Ontology profile of the highest ranked targets was metabolic (P < 7.4 x 10-8), post-translational modification (P < 9.7 x 10-5) and developmental (P < 1.3 x 10-6) processes. Protein profiling of six development-related genes validated the predictions. Brain-derived neurotrophic factor protein was detectable only in muscle satellite cells and was increased in diabetes patients compared with controls, consistent with the observation that global miRNA changes were opposite from those found during myogenic differentiation. We provide evidence that IR in humans may be related to coordinated changes in multiple microRNAs, which act to target relevant signaling pathways. It would appear that miRNAs can produce marked changes in target protein abundance in vivo by working in a combinatorial manner. Thus, miRNA detection represents a new molecular biomarker strategy for insulin resistance, where micrograms of patient material is needed to monitor efficacy during drug or life-style interventions.


Clinical evaluation of the cartridge-based GeneXpert human papillomavirus assay in women referred for colposcopy.
High-risk human papillomavirus (hrHPV) testing is now being introduced as a potential primary screening test for improved detection of cervical precancer and cancer. Current U.S. Food and Drug Administration-approved tests are batch tests that take several hours to complete. A rapid, non-batch test might permit point-of-care (POC) testing, which can facilitate same-day screen and management strategies. For a non-batch, random-access platform (GeneXpert; Cepheid, Sunnyvale, CA), a prototype hrHPV assay (Xpert) has been developed where testing for 14 hrHPV types can be completed in 1 h. In the first clinical evaluation, Xpert was compared to two validated hrHPV tests, the cobas HPV test (cobas, Roche Molecular Systems) and Hybrid Capture 2 (hc2, Qiagen), and to histologic outcomes using specimens from colposcopy referral populations at 7 clinical sites in the United States (n = 697). The sensitivity of Xpert for cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) (n = 141) was equal to that of cobas (90.8% versus 90.8%, P = 1) and greater than that of hc2 (90.8% versus 81.6%, P = 0.004). Xpert was more specific than cobas (42.6% versus 39.6%, P = 0.02) and less specific than hc2 (42.6% versus 47.7%, P < 0.001). Similar results were observed for cervical intraepithelial neoplasia grade 3 or higher (CIN3+) (n = 91). HPV16 detection by Xpert identified 41.8% of the CIN2+ specimens with a positive predictive value (PPV) of 54.6%. By comparison, HPV16 detection by cobas identified 42.6% of the CIN2+ specimens with a PPV of 55.0%. hrHPV detection by the Xpert demonstrated excellent clinical performance for identifying women with CIN2+ and CIN3+ that was comparable to that of currently available clinically validated tests.


Weight loss to treat urinary incontinence in overweight and obese women.
Obesity is an established and modifiable risk factor for urinary incontinence, but conclusive evidence for a beneficial effect of weight loss on urinary incontinence is lacking. We randomly assigned 338 overweight and obese women with at least 10 urinary-incontinence episodes per week to an intensive 6-month weight-loss program that included diet, exercise, and behavior modification (226 patients) or to a structured education program (112 patients). The mean (+/-SD) age of the participants was 53+/-11 years. The body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) and the weekly number of incontinence episodes as recorded in a 7-day diary of voiding were similar in the intervention group and the control group at baseline (BMI, 36+/-6 and 36+/-5, respectively; incontinence episodes, 24+/-18 and 24+/-16, respectively). The women in the intervention group had a mean weight loss of 8.0% (7.8 kg), as compared with 1.6% (1.5 kg) in the control group (P<0.001). After 6 months, the mean weekly number of incontinence episodes decreased by 47% in the intervention group, as compared with 28% in the control group (P=0.01). As compared with the control group, the intervention group had a greater decrease in the frequency of stress-incontinence episodes (P=0.02), but not of urge-incontinence episodes (P=0.14). A higher proportion of the intervention group than of the control group had a clinically relevant reduction of 70% or more in the frequency of all incontinence episodes (P<0.001), stress-incontinence episodes (P=0.009), and urge-incontinence episodes (P=0.04). A 6-month behavioral intervention targeting weight loss reduced the frequency of self-reported urinary-incontinence episodes among overweight and obese women as compared with a control group. A decrease in urinary incontinence may be another benefit among the extensive health improvements associated with moderate weight reduction. (ClinicalTrials.gov number, NCT00091988.)


Role of Nods in bacterial infection.
Research into intracellular sensing of microbial products is an up and coming field in innate immunity. Nod1 and Nod2 are members of the rapidly expanding family of NACHT domain-containing proteins involved in intracellular recognition of bacterial products. Nods proteins are involved in the cytosolic detection of peptidoglycan motifs of bacteria, recognized through the LRR domain. The role of the NACHT-LRR system of detection in innate immune responses is highlighted at the mucosal barrier, where most of the membranous Toll like receptors (TLRs) are not expressed, or with pathogens that have devised ways to escape TLR sensing. For a given pathogen, the sum of the pathways induced by the recognition of the different "pathogen associated molecular patterns" (PAMPs) by the different pattern recognition receptors (PRRs) trigger and shape the subsequent innate and adaptive immune responses. Knowledge gathered during the last decade on PRR and their agonists, and recent studies on bacterial infections provide new insights into the immune response and the pathogenesis of human infectious diseases.


Best Practices in Modified Barium Swallow Studies.
Purpose The modified barium swallow study (MBSS) is a widely used videofluoroscopic evaluation of the functional anatomy and physiology of swallowing that permits visualization of bolus flow throughout the upper aerodigestive tract in real time. The information gained from the examination is critical for identifying and distinguishing the type and severity of swallowing impairment, determining the safety of oral intake, testing the effect of evidence-based frontline interventions, and formulating oral intake recommendations and treatment planning. The goal of this review article is to provide the state of the science and best practices related to MBSS. Method State of the science and best practices for MBSS are reviewed from the perspectives of speech-language pathologists (SLPs) and radiologists who clinically practice and conduct research in this area. Current quandaries and emerging clinical and research trends are also considered. Results This document provides an overview of the MBSS and standards for conducting, interpreting, and reporting the exam; the SLPs' and radiologist's perspectives on standardization of the exam; radiation exposure; technical parameters for recording and reviewing the exam; the importance of an interdisciplinary approach with engaged radiologists and SLPs; and special considerations for examinations in children. Conclusions The MBSS is the primary swallowing examination that permits visualization of bolus flow and swallowing movement throughout the upper aerodigestive tract in real time. The clinical validity of the study has been established when conducted using reproducible and validated protocols and metrics applied according to best practices to provide accurate and reliable information necessary to direct treatment planning and limit radiation exposure. Standards and quandaries discussed in this review article, as well as references, provide a basis for understanding the current best practices for MBSS.


Genomic and Transcriptomic Evidence for Carbohydrate Consumption among Microorganisms in a Cold Seep Brine Pool.
The detailed lifestyle of microorganisms in deep-sea brine environments remains largely unexplored. Using a carefully calibrated genome binning approach, we reconstructed partial to nearly-complete genomes of 51 microorganisms in biofilms from the Thuwal cold seep brine pool of the Red Sea. The recovered metagenome-assembled genomes (MAGs) belong to six different phyla: Actinobacteria, Proteobacteria, Candidatus Cloacimonetes, Candidatus Marinimicrobia, Bathyarchaeota, and Thaumarchaeota. By comparison with close relatives of these microorganisms, we identified a number of unique genes associated with organic carbon metabolism and energy generation. These genes included various glycoside hydrolases, nitrate and sulfate reductases, putative bacterial microcompartment biosynthetic clusters (BMC), and F420H2 dehydrogenases. Phylogenetic analysis suggested that the acquisition of these genes probably occurred through horizontal gene transfer (HGT). Metatranscriptomics illustrated that glycoside hydrolases are among the most highly expressed genes. Our results suggest that the microbial inhabitants are well adapted to this brine environment, and anaerobic carbohydrate consumption mediated by glycoside hydrolases and electron transport systems (ETSs) is a dominant process performed by microorganisms from various phyla within this ecosystem.


[The development of an instrument to assess nursing care responsiveness at a university hospital].
Responsiveness is a quality indicator presented by the World Health Organization in the field of health evaluation. Therefore, the objective of this study was to develop an instrument to evaluate the clients' opinions regarding the responsiveness of the nursing service of a public university hospital. The research was developed in the following stages: developing the instrument based on a literature review, apparent validation, applicability test and pilot test. The instrument allows the identification of the clients' expectations and perceptions, subdivided into aspects related to the Structure Process and Outcomes, measured using a 7-point Likert scale. Based on the results of the pilot test it was possible to establish a numerical indication of the Relative Satisfaction Rate and its interval. The study promoted the development of an acceptability percentage scale for the interval, which indicates the extent to which the nursing service meets the clients' expectations.


Optimized angle scanning method for array sample detection in surface plasmon resonance biosensor.
An optimized angle scanning method is presented for array sample detection in a surface plasmon resonance biosensor. It provides a way to find the optimal rotation axis in the prism to resolve the drifting problem of the light incidence point on samples in the plane prism-coupling mode. The detection of array samples can be achieved by the translation of the prism along a particular direction. The validity of this method is theoretically analyzed and demonstrated by experiments.


Sac1p plays a crucial role in microsomal ATP transport, which is distinct from its function in Golgi phospholipid metabolism.
Analysis of microsomal ATP transport in yeast resulted in the identification of Sac1p as an important factor in efficient ATP uptake into the endoplasmic reticulum (ER) lumen. Yet it remained unclear whether Sac1p is the authentic transporter in this reaction. Sac1p shows no homology to other known solute transporters but displays similarity to the N-terminal non-catalytic domain of a subset of inositol 5'-phosphatases. Furthermore, Sac1p was demonstrated to be involved in inositol phospholipid metabolism, an activity whose absence contributes to the bypass Sec14p phenotype in sac1 mutants. We now show that purified recombinant Sac1p can complement ATP transport defects when reconstituted together with sac1Delta microsomal extracts, but is unable to catalyze ATP transport itself. In addition, we demonstrate that sac1Delta strains are defective in ER protein translocation and folding, which is a direct consequence of impaired ATP transport function and not related to the role of Sac1p in Golgi inositol phospholipid metabolism. These data suggest that Sac1p is an important regulator of microsomal ATP transport providing a possible link between inositol phospholipid signaling and ATP-dependent processes in the yeast ER.


Comparison of measurement methods with a mixed effects procedure accounting for replicated evaluations (COM3PARE): method comparison algorithm implementation for head and neck IGRT positional verification.
Comparison of imaging measurement devices in the absence of a gold-standard comparator remains a vexing problem; especially in scenarios where multiple, non-paired, replicated measurements occur, as in image-guided radiotherapy (IGRT). As the number of commercially available IGRT presents a challenge to determine whether different IGRT methods may be used interchangeably, an unmet need conceptually parsimonious and statistically robust method to evaluate the agreement between two methods with replicated observations. Consequently, we sought to determine, using an previously reported head and neck positional verification dataset, the feasibility and utility of a Comparison of Measurement Methods with the Mixed Effects Procedure Accounting for Replicated Evaluations (COM3PARE), a unified conceptual schema and analytic algorithm based upon Roy's linear mixed effects (LME) model with Kronecker product covariance structure in a doubly multivariate set-up, for IGRT method comparison. An anonymized dataset consisting of 100 paired coordinate (X/ measurements from a sequential series of head and neck cancer patients imaged near-simultaneously with cone beam CT (CBCT) and kilovoltage X-ray (KVX) imaging was used for model implementation. Software-suggested CBCT and KVX shifts for the lateral (X), vertical (Y) and longitudinal (Z) dimensions were evaluated for bias, inter-method (between-subject variation), intra-method (within-subject variation), and overall agreement using with a script implementing COM3PARE with the MIXED procedure of the statistical software package SAS (SAS Institute, Cary, NC, USA). COM3PARE showed statistically significant bias agreement and difference in inter-method between CBCT and KVX was observed in the Z-axis (both p - value<0.01). Intra-method and overall agreement differences were noted as statistically significant for both the X- and Z-axes (all p - value<0.01). Using pre-specified criteria, based on intra-method agreement, CBCT was deemed preferable for X-axis positional verification, with KVX preferred for superoinferior alignment. The COM3PARE methodology was validated as feasible and useful in this pilot head and neck cancer positional verification dataset. COM3PARE represents a flexible and robust standardized analytic methodology for IGRT comparison. The implemented SAS script is included to encourage other groups to implement COM3PARE in other anatomic sites or IGRT platforms.


Agriculture and groundwater nitrate contamination in the Seine basin. The STICS-MODCOU modelling chain.
A software package is presented here to predict the fate of nitrogen fertilizers and the transport of nitrate from the rooting zone of agricultural areas to surface water and groundwater in the Seine basin, taking into account the long residence times of water and nitrate in the unsaturated and aquifer systems. Information on pedological characteristics, land use and farming practices is used to determine the spatial units to be considered. These data are converted into input data for the crop model STICS which simulates the water and nitrogen balances in the soil-plant system with a daily time-step. A spatial application of STICS has been derived at the catchment scale which computes the water and nitrate fluxes at the bottom of the rooting zone. These fluxes are integrated into a surface and groundwater coupled model MODCOU which calculates the daily water balance in the hydrological system, the flow in the rivers and the piezometric variations in the aquifers, using standard climatic data (rainfall, PET). The transport of nitrate and the evolution of nitrate contamination in groundwater and to rivers is computed by the model NEWSAM. This modelling chain is a valuable tool to predict the evolution of crop productivity and nitrate contamination according to various scenarios modifying farming practices and/or climatic changes. Data for the period 1970-2000 are used to simulate the past evolution of nitrogen contamination. The method has been validated using available data bases of nitrate concentrations in the three main aquifers of the Paris basin (Oligocene, Eocene and chalk). The approach has then been used to predict the future evolution of nitrogen contamination up to 2015. A statistical approach allowed estimating the probability of transgression of different concentration thresholds in various areas in the basin. The model is also used to evaluate the cost of the damage resulting of the treatment of drinking water at the scale of a groundwater management unit in the Seine river basin.


Visual function in Rett syndrome.
The authors examined refractive error, pattern onset visual evoked potentials, ocular posture and they performed internal and external eye examinations in 11 subjects with Rett syndrome (aged between four and 24 years) and 18 normal controls (aged between six and 20 years). Substantial refractive errors were common in the Rett syndrome group. Spectacle correction had never previously been worn and glasses were provided where appropriate. No subjects had nystagmus or optic nerve pallor and only one was strabismic. All subjects had recognisable and reproducible pattern-onset VEPs and latencies and amplitudes did not differ significantly from those of the controls. All demonstrated VEP thresholds of at least 24'. In contrast to other populations with profound disabilities, people with Rett syndrome have good function of the afferent visual pathways and, in view of their substantial refractive errors, are likely to benefit from spectacle correction.


Coronary Aneurysm Formation After Bioresorbable Vascular Scaffold Implantation Resulting in Acute Myocardial Infarction.
BACKGROUND Development of a true coronary aneurysm after percutaneous coronary intervention is a rare event, and a coronary aneurysm resulting in acute myocardial infarction is even rarer. Coronary aneurysm formation after bioresorbable vascular scaffold (BVS) implantation, eventually leading to thrombosis, embolization, and myocardial infarction, has never been reported before in the literature. CASE REPORT A 62-year-old man received an elective BVS for a proximal left anterior descending lesion. Two months later, he suffered from a non-ST-segment myocardial infarction. Coronary angiography showed a non-significant distal stent edge restenosis over the left anterior descending artery and a small aneurysm after the first diagonal branch. A XIENCE Xpedition stent was used to cover both lesions and final angiography showed shrinkage of the aneurysm and resolution of the restenosis. CONCLUSIONS Since a consensus or an established treatment guideline for treating coronary aneurysms is currently lacking, each case should be treated with caution and should be guided by the accompanying circumstances presented during the procedure. Although size, rapidity of growth, and the presence of high-risk features are the main determinants of whether to treat the lesion, the inherent risk of restenosis or reocclusion after use of drug-eluting stents and the coronary intervention procedure itself should also be taken into consideration. However, one must not take lightly a small coronary aneurysm when discovered, as the abnormal fluid dynamics inside may result in thrombus formation and embolization. The fundamental technical aspects of stent deployment, such as avoiding overstretching during lesion preparation, use of balloons shorter than the implanted device, and normal-to-normal or healthy "landing zone" of the device, should be followed.


The dog genome: survey sequencing and comparative analysis.
A survey of the dog genome sequence (6.22 million sequence reads; 1.5x coverage) demonstrates the power of sample sequencing for comparative analysis of mammalian genomes and the generation of species-specific resources. More than 650 million base pairs (>25%) of dog sequence align uniquely to the human genome, including fragments of putative orthologs for 18,473 of 24,567 annotated human genes. Mutation rates, conserved synteny, repeat content, and phylogeny can be compared among human, mouse, and dog. A variety of polymorphic elements are identified that will be valuable for mapping the genetic basis of diseases and traits in the dog.


Systematic study of human alpha beta T cell receptor V segments shows allelic variations resulting in a large number of distinct T cell receptor haplotypes.
The variation of the alpha beta T cell receptor (TCR) results mainly from rearrangements of germ-line V, D and J elements combined with the processes of N- and P-region addition. In addition to this extensive diversity, diallelic polymorphism is also recognized in V regions of beta loci. Four such polymorphisms have previously been defined, but the full extent of such variation has not yet been established. To investigate allelic polymorphism, we used a strategy based V locus-specific polymerase chain reaction and single-strand conformation polymorphisms. Studying the two V beta 2 loci and the V alpha 8.1 locus, we found that all exhibited a coding polymorphism. One of the V beta 2 loci proved to be the first multiallele segment to be recognized, with three common variants. The second V beta 2 locus, for which none of the two alleles has been identified in cDNA, appeared in fact to be a V beta orphon, in abnormal location on the chromosome 9. A yeast artificial chromosome containing part of the TCRB locus allowed us to place the first V beta 2 segment on the known map to define haplotypes with two other polymorphic segments: V beta 1 and V beta 6.7. Multiple distinct haplotypes result from combinations between these polymorphic loci, showing that V beta regions are highly variable between individuals. Two alleles exist at the V alpha 8.1 segment and both are expressed. This represents the first example of a frequent coding polymorphism for TCRA gene. The distribution of allele frequencies for these segments suggest the action of balancing selection. These data add a further dimension to TCR polymorphism and suggest new candidates to explore TCR-encoded susceptibility to autoimmune diseases.


How complete is AIDS surveillance in Europe? An eagle eye comparison with mortality data.
Preliminary assessment of the adequacy of AIDS surveillance efforts in Europe by comparing data from two official sources-AIDS surveillance and mortality statistics. The study used ENAADS (European Non-Aggregate AIDS Data Set) data compiled by the European Centre for the Epidemiological Monitoring of AIDS in St Maurice, France, and mortality statistics from WHO. As ENAADS provides information about AIDS incidence as well as AIDS mortality, both series were compared with WHO mortality data. Western European countries with more than 1000 adult AIDS cases as of July 1997 were included in the cross country comparative analyses. AIDS surveillance and mortality statistics in Europe depict four different patterns: (1) high overall concordance (Austria, Italy, Switzerland); (2) concordance between incidence by ENAADS and mortality by WHO, but a delay in mortality reporting in ENAADS (France, Spain); (3) more cases in WHO mortality data than in ENAADS data (Germany, Portugal); (4) more cases in ENAADS data than in WHO mortality data (Sweden, United Kingdom, Greece, Belgium). National AIDS surveillance systems in Europe exhibit important differences in terms of completeness and functionality. New challenges such as the introduction of effective but expensive and complex treatments will exert demands on surveillance efforts. Countries with discrepant AIDS and mortality data should try to improve and update their surveillance systems.


antiSMASH 3.0-a comprehensive resource for the genome mining of biosynthetic gene clusters.
Microbial secondary metabolism constitutes a rich source of antibiotics, chemotherapeutics, insecticides and other high-value chemicals. Genome mining of gene clusters that encode the biosynthetic pathways for these metabolites has become a key methodology for novel compound discovery. In 2011, we introduced antiSMASH, a web server and stand-alone tool for the automatic genomic identification and analysis of biosynthetic gene clusters, available at http://antismash.secondarymetabolites.org. Here, we present version 3.0 of antiSMASH, which has undergone major improvements. A full integration of the recently published ClusterFinder algorithm now allows using this probabilistic algorithm to detect putative gene clusters of unknown types. Also, a new dereplication variant of the ClusterBlast module now identifies similarities of identified clusters to any of 1172 clusters with known end products. At the enzyme level, active sites of key biosynthetic enzymes are now pinpointed through a curated pattern-matching procedure and Enzyme Commission numbers are assigned to functionally classify all enzyme-coding genes. Additionally, chemical structure prediction has been improved by incorporating polyketide reduction states. Finally, in order for users to be able to organize and analyze multiple antiSMASH outputs in a private setting, a new XML output module allows offline editing of antiSMASH annotations within the Geneious software.


Far-infrared protects vascular endothelial cells from advanced glycation end products-induced injury via PLZF-mediated autophagy in diabetic mice.
The accumulation of advanced glycation end products (AGEs) in diabetic patients induces vascular endothelial injury. Promyelocytic leukemia zinc finger protein (PLZF) is a transcription factor that can be activated by low-temperature far-infrared (FIR) irradiation to exert beneficial effects on the vascular endothelium. In the present study, we investigated the influence of FIR-induced PLZF activation on AGE-induced endothelial injury both in vitro and in vivo. FIR irradiation inhibited AGE-induced apoptosis in human umbilical vein endothelial cells (HUVECs). PLZF activation increased the expression of phosphatidylinositol-3 kinases (PI3K), which are important kinases in the autophagic signaling pathway. FIR-induced PLZF activation led to autophagy in HUVEC, which was mediated through the upregulation of PI3K. Immunofluorescence staining showed that AGEs were engulfed by HUVECs and localized to lysosomes. FIR-induced autophagy promoted AGEs degradation in HUVECs. In nicotinamide/streptozotocin-induced diabetic mice, FIR therapy reduced serum AGEs and AGEs deposition at the vascular endothelium. FIR therapy also reduced diabetes-induced inflammatory markers in the vascular endothelium and improved vascular endothelial function. These protective effects of FIR therapy were not found in PLZF-knockout mice. Our data suggest that FIR-induced PLZF activation in vascular endothelial cells protects the vascular endothelium in diabetic mice from AGE-induced injury.


The First Organ-Based Ontology for Arthropods (Ontology of Arthropod Circulatory Systems - OArCS) and its Integration into a Novel Formalization Scheme for Morphological Descriptions.
Morphology, the oldest discipline in the biosciences, is currently experiencing a renaissance in the field of comparative phenomics. However, morphological/phenotypic research still suffers on various levels from a lack of standards. This shortcoming, first highlighted as the "linguistic problem of morphology", concerns the usage of terminology and also the need for formalization of morphological descriptions themselves, something of paramount importance not only to the field of morphology but also when it comes to the use of phenotypic data in systematics and evolutionary biology. We therefore argue, that for morphological descriptions, the basis of all systematic and evolutionary interpretations, ontologies need to be utilized which are based exclusively on structural qualities/properties and which in no case include statements about homology and/or function. Statements about homology and function constitute interpretations on a different or higher level. Based on these "anatomy ontologies", further ontological dimensions (e.g., referring to functional properties or homology) may be exerted for a broad use in evolutionary phenomics. To this end we present the first organ-based ontology for the most species-rich animal group, the Arthropoda. Our Ontology of Arthropod Circulatory Systems (OArCS) contains a comprehensive collection of 383 terms (i.e., labels) tied to 296 concepts (i.e., definitions) collected from the literature on phenotypic aspects of circulatory organ features in arthropods. All of the concepts used in OArCS are based exclusively on structural features, and in the context of the ontology are independent of homology and functional assumptions. We cannot rule out that in some cases, terms are used which in traditional usage and previous accounts might have implied homology and/or function (e.g. heart, sternal artery). Concepts are composed of descriptive elements that are used to classify observed instances into the organizational framework of the ontology. That is, descriptions in ontologies are only descriptions of individuals if they are necessary/and or sufficient representations of attributes (independently) observed and recorded for an individual. In addition, we here present for the first time an entirely new approach to formalizing phenotypic research, a semantic model for the description of a complex organ system in a highly disparate taxon, the arthropods. We demonstrate this with a formalized morphological description of the hemolymph vascular system in one specimen of the European garden spider Araneus diadematus. Our description targets five categories of descriptive statement: "position", "spatial relationships", "shape", "constituents", and "connections", as the corresponding formalizations constitute exemplary patterns useful not only when talking about the circulatory system, but also in descriptions in general. The downstream applications of computer-parsable morphological descriptions are widespread, with their core utility being the fact that they make it possible to compare collective description sets in computational time, that is, very quickly. Among other things, this facilitates the identification of phenotypic plasticity and variation when single individuals are compared, the identification of those traits which correlate between and within taxa, and the identification of links between morphological traits and genetic (using GO, Gene Ontology) or environmental (using ENVO, Environmental Ontology) factors. [Arthropoda; concept; function; hemolymph vascular system; homology; terminology.].


Estimating effective population size changes from preferentially sampled genetic sequences.
Coalescent theory combined with statistical modeling allows us to estimate effective population size fluctuations from molecular sequences of individuals sampled from a population of interest. When sequences are sampled serially through time and the distribution of the sampling times depends on the effective population size, explicit statistical modeling of sampling times improves population size estimation. Previous work assumed that the genealogy relating sampled sequences is known and modeled sampling times as an inhomogeneous Poisson process with log-intensity equal to a linear function of the log-transformed effective population size. We improve this approach in two ways. First, we extend the method to allow for joint Bayesian estimation of the genealogy, effective population size trajectory, and other model parameters. Next, we improve the sampling time model by incorporating additional sources of information in the form of time-varying covariates. We validate our new modeling framework using a simulation study and apply our new methodology to analyses of population dynamics of seasonal influenza and to the recent Ebola virus outbreak in West Africa.


Morphological and physiological changes in esterase and lipid peroxidation of two bean cultivars pre-soaked with potassium nitrate under salt stress.
Two broad bean cultivars (Vicia faba CV Nobaria3 and Vicia faba CV Sakha3) were obtained from Mallwi Agriculture Research Center, El Minia Governorate, Egypt. The seeds were divided into two groups, the first group soaked with distilled water, while the second group were soaked with 3 mM KNO₃, respectively, for 4 hours. Seeds were sown and left to grow for 3 weeks then treated with different concentrations of NaCl (0.0, 40, 80, 120 and 160 mM) by top irrigation, then they left to grow further for 65 days from sowing. Plant samples were collected for some measurements: leaf area, plant height, root length, fresh and dry weight, photosynthetic pigments, carotenoids, soluble sugars, soluble proteins, total free amino acids, esterase enzyme, as well as MDA (malondialdehyde) content. Salinity reduced both fresh and dry weight in two broad bean cultivars, this reduction were more pronounced in Sakha3 than Nobaria3. Seed pre-soaking with KNO₃resulted in enhancement of fresh and dry weight production in both cultivars especially at 40 mM NaCl. Photosynthetic pigments were substantially affected by salt treatment while the carotenoids were increased, seed pre-soaking with KNO₃improved these components. The soluble sugars, amino acids as well as soluble proteins showed various responses with increasing salinity in the cultivars, seed pre-soaking with KNO₃has improved these parameters to some extent. The shoots of two cultivars exhibited significant accumulation of MDA, compared to roots exposed to the highest salinity levels. Pre-soaking seeds with KNO₃did not improve MDA in shoots but enhanced it in roots, however, in most cases still lower than the absolute control. The assessment of the esterase isozyme profiles on 7.5% native polyacrylamide gel revealed the presence of 13 isoforms in two faba bean plants in response to KNO₃pre-soaking and treatments with different concentrations of NaCl.


Prevalence and risk factors for chronic bronchitis and farmer's lung in French dairy farmers.
The prevalence of chronic bronchitis and of clinical farmer's lung was studied in 30 districts of the French Doubs province in relation to individual (age, sex, smoking) and geographical (altitude) factors. 5703 exclusively dairy farmers (response rate 83%) participated in the study by answering a medical questionnaire. Prevalences of chronic bronchitis and clinical farmer's lung were 9.3% and 1.4% respectively. A logistic regression model was used to evaluate risk factors for chronic bronchitis and clinical farmer's lung. A risk of chronic bronchitis was associated with male sex (p < 10(-4)), age (p < 10(-4)), smoker category (p < 10(-4)), and altitude (p < 10(-4)). A risk of clinical farmer's lung was associated with non-smokers (p < 0.05), and linearly with altitude (p < 10(-4)). Also there was a strong positive relation between chronic bronchitis and clinical farmer's lung (odds ratio 19.5 (95% confidence interval 12.1-31.4) after adjustment for confounding variables. The main finding of this study is the highly significant increase of prevalence of the diseases in relation to altitude.


Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice.
The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aβ42/Aβ40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.


Behavioral treatment of insomnia: treatment outcome and the relevance of medical and psychiatric morbidity.
Recently, we undertook a case series study and found that behavior therapy for insomnia was effective as plied in the clinic setting and that the findings were similar to those in the "clinical trial" literature. In the present study, we evaluate a second set of case series data to assess (1) the replicability of our original findings, (2) if our treatment outcomes are statistically comparable to those in the literature, and (3) if medical and psychiatric morbidity influence treatment outcome. It was found that patients who completed four or more sessions of cognitive behavioral therapy for insomnia (CBT) were, on average, 33% improved. This average corresponded to a 56% reduction in wake time after sleep onset, a 34% reduction in sleep latency, a 29% increase in total sleep time, and a 13% decrease in number of awakenings per night. These findings are not significantly different from those reported in literature for both CBT and pharmacotherapy interventions. Medical and psychiatric comorbidity did not influence treatment outcome.


Disentangling serology to elucidate henipa- and filovirus transmission in Madagascar fruit bats.
Bats are reservoirs for emerging human pathogens, including Hendra and Nipah henipaviruses and Ebola and Marburg filoviruses. These viruses demonstrate predictable patterns in seasonality and age structure across multiple systems; previous work suggests that they may circulate in Madagascar's endemic fruit bats, which are widely consumed as human food. We aimed to (a) document the extent of henipa- and filovirus exposure among Malagasy fruit bats, (b) explore seasonality in seroprevalence and serostatus in these bat populations and (c) compare mechanistic hypotheses for possible transmission dynamics underlying these data. To this end, we amassed and analysed a unique dataset documenting longitudinal serological henipa- and filovirus dynamics in three Madagascar fruit bat species. We uncovered serological evidence of exposure to Hendra-/Nipah-related henipaviruses in Eidolon dupreanum, Pteropus rufus and Rousettus madagascariensis, to Cedar-related henipaviruses in E. dupreanum and R. madagascariensis and to Ebola-related filoviruses in P. rufus and R. madagascariensis. We demonstrated significant seasonality in population-level seroprevalence and individual serostatus for multiple viruses across these species, linked to the female reproductive calendar. An age-structured subset of the data highlighted evidence of waning maternal antibodies in neonates, increasing seroprevalence in young and decreasing seroprevalence late in life. Comparison of mechanistic epidemiological models fit to these data offered support for transmission hypotheses permitting waning antibodies but retained immunity in adult-age bats. Our findings suggest that bats may seasonally modulate mechanisms of pathogen control, with consequences for population-level transmission. Additionally, we narrow the field of candidate transmission hypotheses by which bats are presumed to host and transmit potentially zoonotic viruses globally.


Location specific sleep spindle activity in the early visual areas and perceptual learning.
Visual perceptual learning (VPL) is consolidated during sleep. However, the underlying neuronal mechanisms of consolidation are not yet fully understood. It has been suggested that the spontaneous brain oscillations that characterize sleep stages are indicative of the consolidation of learning and memory. We investigated whether sleep spindles and/or slow-waves are associated with consolidation of VPL during non-rapid eye movement (NREM) sleep during the first sleep cycle, using magnetoencephalography (MEG), magnetic resonance imaging (MRI), and polysomnography (PSG). We hypothesized that after training, early visual areas will show an increase in slow sigma, fast sigma and/or delta activity, corresponding to slow/fast sleep spindles and slow-waves, respectively. We found that during sleep stage 2, but not during slow-wave sleep, the slow sigma power within the trained region of early visual areas was larger after training compared to baseline, and that the increase was larger in the trained region than in the untrained region. However, neither fast sigma nor delta band power increased significantly after training in either sleep stage. Importantly, performance gains for the trained task were correlated with the difference of power increases in slow sigma activity between the trained and untrained regions. This finding suggests that slow sigma activity plays a critical role in the consolidation of VPL, at least in sleep stage 2 during the first sleep cycle.


Human vaccination against Plasmodium vivax Duffy-binding protein induces strain-transcending antibodies.
Plasmodium vivax is the most widespread human malaria geographically; however, no effective vaccine exists. Red blood cell invasion by the P. vivax merozoite depends on an interaction between the Duffy antigen receptor for chemokines (DARC) and region II of the parasite's Duffy-binding protein (PvDBP_RII). Naturally acquired binding-inhibitory antibodies against this interaction associate with clinical immunity, but it is unknown whether these responses can be induced by human vaccination. Safety and immunogenicity of replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and modified vaccinia virus Ankara (MVA) viral vectored vaccines targeting PvDBP_RII (Salvador I strain) were assessed in an open-label dose-escalation phase Ia study in 24 healthy UK adults. Vaccines were delivered by the intramuscular route in a ChAd63-MVA heterologous prime-boost regimen using an 8-week interval. Both vaccines were well tolerated and demonstrated a favorable safety profile in malaria-naive adults. PvDBP_RII-specific ex-vivo IFN-γ T cell, antibody-secreting cell, memory B cell, and serum IgG responses were observed after the MVA boost immunization. Vaccine-induced antibodies inhibited the binding of vaccine homologous and heterologous variants of recombinant PvDBP_RII to the DARC receptor, with median 50% binding-inhibition titers greater than 1:100. We have demonstrated for the first time to our knowledge that strain-transcending antibodies can be induced against the PvDBP_RII antigen by vaccination in humans. These vaccine candidates warrant further clinical evaluation of efficacy against the blood-stage P. vivax parasite. Clinicaltrials.gov NCT01816113. Support was provided by the UK Medical Research Council, UK National Institute of Health Research Oxford Biomedical Research Centre, and the Wellcome Trust.


Concerning CT features used to select patients for treatment of peritoneal metastases, a pictoral essay.
During the Fifth International Workshop on Peritoneal Surface Malignancy in Milan in 2008, a consensus was reached that contrast-enhanced CT (ceCT) was the principal imaging modality for patients being evaluated for treatment of peritoneal metastases. This fact being accepted, the radiologic criteria for that may exclude patients from a high value cytoreductive surgery (CRS) plus hyperthermic perioperative chemotherapy (HIPEC) have not been reliably determined. From a consensus of surgeons and radiologists, radiologic images were selected and their determinant radiologic characteristics described. The anatomic pathology causing the abnormal images were identified and characterised. The cytoreductive surgical procedures that may, in selected patients, result in a complete resection of the pathology identified were presented. Radiographs of 15 CT images that cause concern when a patient is being evaluated for CRS were listed. The anatomic pathology these images define and possible surgical resections they require were reviewed. The surgical implications of the absence or presence of a single, or of multiple concerning CT features was extracted from the surgical and radiologic literature. There is a definite need to identify new pre-operative imaging parameters to define optimal indication of CRS with HIPEC. The presence of a single concerning radiologic feature is associated with the possibility of an adverse outcome or technically more complex resections associated with increased morbidity and mortality. If two or more of the concerning radiologic features are described from the CT, suboptimal cytoreduction will usually occur.


Cyberbullying and adolescent mental health: systematic review.
Cyberbullying is a new form of violence that is expressed through electronic media and has given rise to concern for parents, educators and researchers. In this paper, an association between cyberbullying and adolescent mental health will be assessed through a systematic review of two databases: PubMed and Virtual Health Library (BVS). The prevalence of cyberbullying ranged from 6.5% to 35.4%. Previous or current experiences of traditional bullying were associated with victims and perpetrators of cyberbullying. Daily use of three or more hours of Internet, web camera, text messages, posting personal information and harassing others online were associated with cyberbullying. Cybervictims and cyberbullies had more emotional and psychosomatic problems, social difficulties and did not feel safe and cared for in school. Cyberbullying was associated with moderate to severe depressive symptoms, substance use, ideation and suicide attempts. Health professionals should be aware of the violent nature of interactions occurring in the virtual environment and its harm to the mental health of adolescents.


Forest type influences transmission of Phytophthora ramorum in California oak woodlands.
The transmission ecology of Phytophthora ramorum from bay laurel (Umbellularia californica) leaves was compared between mixed-evergreen and redwood forest types throughout winter and summer disease cycles in central, coastal California. In a preliminary multisite study, we found that abscission rates of infected leaves were higher at mixed-evergreen sites. In addition, final infection counts were slightly higher at mixed-evergreen sites or not significantly different than at redwood sites, in part due to competition from other foliar pathogens at redwood sites. In a subsequent, detailed study of paired sites where P. ramorum was the main foliar pathogen, summer survival of P. ramorum in bay laurel leaves was lower in mixed-evergreen forest due to lower recovery from infected attached leaves and higher abscission rates of infected leaves. Onset of inoculum production and new infections of bay laurel leaves occurred later in mixed-evergreen forest. Mean inoculum levels in rainwater and final infection counts on leaves were higher in redwood forest. Based on these two studies, lower summer survival of reservoir inoculum in bay laurel leaves in mixed-evergreen forest may result in delayed onset of both inoculum production and new infections, leading to slower disease progress in the early rainy season compared with redwood forest. Although final infection counts also will depend on other foliar pathogens and disease history, in sites where P. ramorum is the main foliar pathogen, these transmission patterns suggest higher rates of disease spread in redwood forests during rainy seasons of short or average length.


Compacting a Single Flow Diverter versus Overlapping Flow Diverters for Intracranial Aneurysms: A Computational Study.
Locally compacting the mesh of a flow diverter by a dynamic push-pull technique can accelerate intracranial aneurysm healing. We asked how this deployment strategy compares with overlapping 2 flow diverters for aneurysmal flow reduction. Using a high-fidelity virtual stent placement method, we simulated 3 flow-diverter strategies (single noncompacted, 2 overlapped, and single compacted) in 3 aneurysms (fusiform, large saccular, and medium saccular). Computational fluid dynamics analysis provided posttreatment hemodynamic parameters, including time-averaged inflow rate, aneurysm-averaged velocity, wall shear stress, total absolute circulation, and turnover time. We examined the relationship between the achieved degree of compaction and aneurysm orifice area. Flow-diverter compaction resulted in a compaction coverage of 57%, 47%, and 22% over the orifice of the fusiform, large, and medium saccular aneurysm, respectively. Compaction coverage increased linearly with orifice area. In the fusiform aneurysm, the single compacted flow diverter accomplished more aneurysmal flow reduction than the other 2 strategies, as indicated by all 5 hemodynamic parameters. In the 2 saccular aneurysms, the overlapped flow diverters achieved the most flow reduction, followed by the single compacted and the noncompacted flow diverter. Compacting a single flow diverter can outperform overlapping 2 flow diverters in aneurysmal flow reduction, provided that the compaction produces a mesh denser than 2 overlapped flow diverters and this denser mesh covers a sufficient portion of the aneurysm orifice area, for which we suggest a minimum of 50%. This strategy is most effective for aneurysms with large orifices, especially fusiform aneurysms.


Undiscovered Bat Hosts of Filoviruses.
Ebola and other filoviruses pose significant public health and conservation threats by causing high mortality in primates, including humans. Preventing future outbreaks of ebolavirus depends on identifying wildlife reservoirs, but extraordinarily high biodiversity of potential hosts in temporally dynamic environments of equatorial Africa contributes to sporadic, unpredictable outbreaks that have hampered efforts to identify wild reservoirs for nearly 40 years. Using a machine learning algorithm, generalized boosted regression, we characterize potential filovirus-positive bat species with estimated 87% accuracy. Our model produces two specific outputs with immediate utility for guiding filovirus surveillance in the wild. First, we report a profile of intrinsic traits that discriminates hosts from non-hosts, providing a biological caricature of a filovirus-positive bat species. This profile emphasizes traits describing adult and neonate body sizes and rates of reproductive fitness, as well as species' geographic range overlap with regions of high mammalian diversity. Second, we identify several bat species ranked most likely to be filovirus-positive on the basis of intrinsic trait similarity with known filovirus-positive bats. New bat species predicted to be positive for filoviruses are widely distributed outside of equatorial Africa, with a majority of species overlapping in Southeast Asia. Taken together, these results spotlight several potential host species and geographical regions as high-probability targets for future filovirus surveillance.


Primary biliary cirrhosis with multinucleated hepatocellular giant cells: implications for pathogenesis of primary biliary cirrhosis.
Histological and clinical features of syncytial giant cell hepatitis (GCH) are rarely observed in adults, and the disease has been associated with several autoimmune disorders and drug reactions. We describe here the case of a 62-year-old woman who presented with evidence of severe acute hepatocellular injury and cholestasis. Serum work-up demonstrated antimitochondrial antibodies specific for primary biliary cirrhosis (PBC) autoantigens, whereas markers of viral infection including hepatitis viruses, paramyxovirus and measles virus were negative. Liver histology revealed the presence of multinucleated hepatocellular giant cells in the parenchymal areas surrounding bridging necrosis. Importantly, damaged interlobular bile ducts were also observed within the lymphocyte-infiltrated portal tracts. Further study using transmission electron microscopy demonstrated the presence of filamentous strands and particles resembling paramyxovirus nucleocapsids in the cytoplasm of syncytial giant cells. To our knowledge, this is the first case of PBC with histological and clinical evidence of syncytial GCH in an adult, and we submit that it might provide novel clues in the enigma of PBC pathogenesis.


ERCC4 (XPF) encodes a human nucleotide excision repair protein with eukaryotic recombination homologs.
ERCC4 is an essential human gene in the nucleotide excision repair (NER) pathway, which is responsible for removing UV-C photoproducts and bulky adducts from DNA. Among the NER genes, ERCC4 and ERCC1 are also uniquely involved in removing DNA interstrand cross-linking damage. The ERCC1-ERCC4 heterodimer, like the homologous Rad10-Rad1 complex, was recently found to possess an endonucleolytic activity that incises on the 5' side of damage. The ERCC4 gene, assigned to chromosome 16p13.1-p13.2, was previously isolated by using a chromosome 16 cosmid library. It corrects the defect in Chinese hamster ovary (CHO) mutants of NER complementation group 4 and is implicated in complementation group F of the human disorder xeroderma pigmentosum. We describe the ERCC4 gene structure and functional cDNA sequence encoding a 916-amino-acid protein (104 kDa), which has substantial homology with the eukaryotic DNA repair and recombination proteins MEI-9 (Drosophila melanogaster), Rad16 (Schizosaccharomyces pombe), and Rad1 (Saccharomyces cerevisiae). ERCC4 cDNA efficiently corrected mutants in rodent NER complementation groups 4 and 11, showing the equivalence of these groups, and ERCC4 protein levels were reduced in mutants of both groups. In cells of an XP-F patient, the ERCC4 protein level was reduced to less than 5%, consistent with XPF being the ERCC4 gene. The considerable identity (40%) between ERCC4 and MEI-9 suggests a possible involvement of ERCC4 in meiosis. In baboon tissues, ERCC4 was expressed weakly and was not significantly higher in testis than in nonmeiotic tissues.


Elliptical exercise improves fatigue ratings and quality of life in patients with multiple sclerosis.
Fatigue, reduced quality of life (QOL), and lower physical activity levels are commonly reported in patients with multiple sclerosis (MS). This study evaluated the effects of elliptical exercise on fatigue and QOL reports in patients with MS. Patients with MS (n = 26) completed the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) before and after completing 15 elliptical exercise training sessions. Changes in fatigue and QOL were assessed based on any changes in the fatigue and SF-36 questionnaires, and correlations between changes in each of the scales were made to determine whether a relationship was present between the fatigue and QOL measures. Results showed significant improvement in FSS, MFIS, and five SF-36 subscales as a result of elliptical exercise. The change in FSS correlated with change in two of the SF-36 subscales. Elliptical exercise for patients with MS results in significant improvements in both fatigue and QOL. These findings indicate that regular elliptical exercise could be a part of inpatient and outpatient MS rehabilitation programs.


Evaluating scenarios for the evolutionary assembly of the brachiopod body plan.
The fossil faunas of the Cambrian provide the only direct insight into the assembly of animal body plans. However, for many animal groups, their early fossil record is linked to disarticulated remains, interpretation of which is problematic since they possess few characters from which their affinity to phyla can be established and, indeed, few characters at all. One such group is the tommotiids, which has been interpreted, on the basis of skeletal anatomy, as a paraphyletic assemblage uniting brachiopods and phoronids, through the acquisition and subsequent modification, or loss, of an imbricated set of dorsal phosphatic sclerites. Here we present a reexamination of the fossil evidence uniting the tommotiids and brachiopods, supplemented with new anatomical data from synchrotron radiation X-ray tomographic microscopy of key tommotiid taxa. The characters used to support the complex hypothesis of character evolution in the brachiopod stem lineage relies on scleritome reconstructions and inferred mode of life which themselves rely on brachiopods being chosen as the interpretative model. We advocate a more conservative interpretation of the affinity of these fossils, based a priori on their intrinsic properties, rather than the modern analogue in whose light they have been interpreted.


Moral distress and the contemporary plight of health professionals.
Once a term used primarily by moral philosophers, "moral distress" is increasingly used by health professionals to name experiences of frustration and failure in fulfilling moral obligations inherent to their fiduciary relationship with the public. Although such challenges have always been present, as has discord regarding the right thing to do in particular situations, there is a radical change in the degree and intensity of moral distress being expressed. Has the plight of professionals in healthcare practice changed? "Plight" encompasses not only the act of pledging, but that of predicament and peril. The author claims that health professionals are increasingly put in peril by healthcare reform that undermines their efficacy and jeopardizes ethical engagement with those in their care. The re-engineering of healthcare to give precedence to corporate and commercial values and strategies of commodification, service rationing, streamlining, and measuring of "efficiency," is literally demoralizing health professionals. Healthcare practice needs to be grounded in a capacity for compassion and empathy, as is evident in standards of practice and codes of ethics, and in the understanding of what it means to be a professional. Such grounding allows for humane response to the availability of unprecedented advances in biotechnological treatments, for genuine dialogue and the raising of difficult, necessary ethical questions, and for the mutual support of health professionals themselves. If healthcare environments are not understood as moral communities but rather as simulated marketplaces, then health professionals' moral agency is diminished and their vulnerability to moral distress is exacerbated. Research in moral distress and relational ethics is used to support this claim.


The emotional Stroop task and emotionality rating of negative and neutral words in late Thai-English bilinguals.
The current study investigated how emotions are represented in the lexicon of late Thai-English bilinguals and a comparison group of native English speakers. Two tasks were used. In the emotional Stroop task, which taps into an automatic early lexical level of processing, the bilingual participants did not display the same automatic level of activation in their second language (L2) as in their first language (L1). In the emotionality-rating task, which involves a later, more in-depth conscious level of processing than the preceding task, similar results were found in both languages spoken by the bilinguals. These findings are interpreted as indicating that late bilinguals do not automatically respond to the emotional arousal associated with the meanings of L2 words to the same extent as in the L1, and this is likely to be mediated by language proficiency and the context in which the language is learned.


Shared and distinct contributions of rostrolateral prefrontal cortex to analogical reasoning and episodic memory retrieval.
Rostrolateral prefrontal cortex (RLPFC) is widely appreciated to support higher cognitive functions, including analogical reasoning and episodic memory retrieval. However, these tasks have typically been studied in isolation, and thus it is unclear whether they involve common or distinct RLPFC mechanisms. Here, we introduce a novel functional magnetic resonance imaging (fMRI) task paradigm to compare brain activity during reasoning and memory tasks while holding bottom-up perceptual stimulation and response demands constant. Univariate analyses on fMRI data from twenty participants identified a large swath of left lateral prefrontal cortex, including RLPFC, that showed common engagement on reasoning trials with valid analogies and memory trials with accurately retrieved source details. Despite broadly overlapping recruitment, multi-voxel activity patterns within left RLPFC reliably differentiated these two trial types, highlighting the presence of at least partially distinct information processing modes. Functional connectivity analyses demonstrated that while left RLPFC showed consistent coupling with the fronto-parietal control network across tasks, its coupling with other cortical areas varied in a task-dependent manner. During the memory task, this region strengthened its connectivity with the default mode and memory retrieval networks, whereas during the reasoning task it coupled more strongly with a nearby left prefrontal region (BA 45) associated with semantic processing, as well as with a superior parietal region associated with visuospatial processing. Taken together, these data suggest a domain-general role for left RLPFC in monitoring and/or integrating task-relevant knowledge representations and showcase how its function cannot solely be attributed to episodic memory or analogical reasoning computations.


Enhanced resolution and throughput of Fresnel incoherent correlation holography (FINCH) using dual diffractive lenses on a spatial light modulator (SLM).
Fresnel incoherent correlation holography (FINCH) records holograms under incoherent illumination. FINCH was implemented with two focal length diffractive lenses on a spatial light modulator (SLM). Improved image resolution over previous single lens systems and at wider bandwidths was observed. For a given image magnification and light source bandwidth, FINCH with two lenses of close focal lengths yields a better hologram in comparison to a single diffractive lens FINCH. Three techniques of lens multiplexing on the SLM were tested and the best method was randomly and uniformly distributing the two lenses. The improved quality of the hologram results from a reduced optical path difference of the interfering beams and increased efficiency.


Strain C3H-A-vy-fB mice: ninety percent incidence of mammary tumors transmitted by either parent.
Mammary tumorigenesis in C3H-A(vy)fB female mice is not due to milk-borne mammary tumor virus but to factors transmitted at conception. Prominent among these is the A(vy) gene which may increase the virulence or transmissibility of a variant of mammary tumor virus vertically transmitted by either parent, or may increase the tumorigenic response of the mammary tissue. These factors together with the influence of hormones of pregnancy resulted in the high incidence observed.


A novel Chk inhibitor, XL-844, increases human cancer cell radiosensitivity through promotion of mitotic catastrophe.
Check point kinases (Chk) play a major role in facilitating DNA repair upon radiation exposure. We tested the potency of a novel inhibitor of Chk1 and Chk2, XL-844 (provided by Exelixis Inc., CA, USA), to radiosensitize human cancer cells grown in culture and investigated the underlying mechanisms. HT-29 cells (a human colon cancer line) were exposed to XL-844, radiation, or both, and assessed for clonogenic cell survival. Treatment-dependent effects on phosphorylated forms of Chk proteins were assessed by Western blots. Further mechanistic investigations in HT-29 cells included cell cycle analysis by flowcytometry and assessment of DNA repair kinetics by immuno-cytochemistry (ICC) for nuclear appearance of the phosphorylated form of histone 2AX protein (γ-H2AX) staining. Cells undergoing mitotic catastrophe were identified by irregular pattern of mitotic spindle markers α and γ-tubulin staining by ICC. XL-844 enhanced radiosensitivity in a dose and schedule-dependent manner and the enhancement factor was 1.42 at 0.5 survival fraction. Mechanistically XL-844 abrogated radiation-induced Chk2 phosphorylation, induced pan-nuclear γ-H2AX, and prolonged the presence of radiation-induced γ-H2AX foci, and promoted mitotic catastrophe. In conclusion, our data showed that inhibition of Chk2 activity by XL-844 enhanced cancer cell radiosensitivity that was associated with inhibition of DNA repair and induction of mitotic catastrophe.


Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma.
Children with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients. This study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered. There were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths. MIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.


A Ketogenic Diet Is Acceptable in Women with Ovarian and Endometrial Cancer and Has No Adverse Effects on Blood Lipids: A Randomized, Controlled Trial.
Ketogenic diets (KDs) are emerging as effective therapies for several chronic diseases, including cancer. However, concerns regarding safety and adherence may prevent clinicians from prescribing KDs. We hypothesized that a KD does not negatively affect blood lipid profile compared to a lower-fat diet in ovarian and endometrial cancer patients, and that KD subjects would demonstrate acceptable adherence. Subjects were randomized to either a KD (70% fat, 25% protein, 5% carbohydrate), or the American Cancer Society diet (ACS; high-fiber and lower-fat). Blood lipids and ketones were measured at baseline and after 12 weeks of the assigned intervention. Adherence measures included urinary ketones in the KD and 4 days' diet records. Diet records were also examined to identify general patterns of consumption. Differences between the diets on blood lipids and dietary intake were assessed with Analysis of covariance and independent t-tests. Correlation analyses were used to estimate associations between dietary intake and serum analytes. At 12 weeks, there were no significant differences between diet groups in blood lipids, after adjusting for baseline values and weight loss. Adherence among KD subjects ranged from 57% to 80%. These findings suggest that KDs may be a safe and achievable component of treatment for some cancer patients.


A Mini-Review of Virtual Reality-Based Interventions to Promote Well-Being for People Living with Dementia and Mild Cognitive Impairment.
Assistive technology including virtual reality and augmented reality has gained interest as a novel intervention in a range of clinical settings. This technology has the potential to provide mental stimulation, a connection to autobiographical memory through reminiscence, and enhanced quality of life (QoL) to people living with dementia (PLWD) and mild cognitive impairment (MCI). In this mini-review, we examine the available evidence from studies reporting on the potential benefits of virtual and augmented reality to provide enjoyable, leisurely activities that may promote QoL and psychological well-being and facilitate social interaction. In total, 10 studies of varying study designs and durations (5 min to 6 months) using virtual (n = 9) and augmented reality (n = 1) were examined in PLWD (n = 6) and MCI (n= 3), in addition to 1 study that included participants with both conditions. Overall, the virtual experiences were enjoyed by the participants, improved their mood and apathy, and were preferred when compared with nonvirtual experiences. However, small sample sizes and variations in study design limit the generalizability of the results. Nevertheless, the use of virtual and augmented reality technology for PLWD and MCI is a novel and emerging method which may provide cognitive stimulation and improve well-being. Future research should explore the potential application of this technology to promote social interaction in both the community and aged care settings. We suggest future studies in PLWD and MCI assess the effects of more sustained use of virtual and augmented reality technology on psychological outcomes including QoL, apathy, and depressive symptoms, with the incorporation of physiological biomarker outcomes.


A Recent Update on the Effects of Omega-3 Fatty Acids in Alzheimer's Disease.
Dietary long chain polyunsaturated fatty acids belong to omega (ω)-3, -6 or -9 series. Both experimental and clinical studies demonstrated the beneficial effect of ω -3 fatty acids of fish oil, Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) against human ailments including cardiovascular diseases and rheumatoid arthritis. They are metabolized in cyclooxygenase and lipooxygenase pathways and also by cytochrome P450 isozymes. Biological importance of DHA in the development of brain and retina are well established. Recent studies highlighted the beneficial effect of ω-3 fatty acids in Alzheimer's Disease (AD) which may be attributed to their antioxidant, anti-inflammatory, antiapoptotic and neurotrophic properties. The effect was obtained by the consumption of either individual or combination of ω -3 fatty acids. The anti-inflammatory effect can be ascribed to the decreased cytokines and monocytic chemotactic protein-1 level by suppressing the nuclear factor-kappa B. Further, they inhibit cyclooxygenase-2 and nitric oxide synthase-2 activities. The antiapoptotic activity is due to the lowered Bax/Bcl ratio or caspase 3 levels. They can induce the transcription factor, nuclear erythroid factor-2 mediated expression of superoxide dismutase- 2 in order to facilitate the antioxidant effect. Both DHA and EPA can enhance the nerve growth factor level. Overall, they are beneficial to improve the cognitive function in very mild AD and major depressive disorder. Despite the beneficial effects, ω-3 fatty acids are easily prone to peroxidation. This review article discusses the recent update on the roles of ω -3 fatty acids in AD.


Chondroinductive Alginate-Based Hydrogels Having Graphene Oxide for 3D Printed Scaffold Fabrication.
Scaffolds based on bioconjugated hydrogels are attractive for tissue engineering because they can partly mimic human tissue characteristics. For example, they can further increase their bioactivity with cells. However, most of the hydrogels present problems related to their processability, consequently limiting their use in 3D printing to produce tailor-made scaffolds. The goal of this work is to develop bioconjugated hydrogel nanocomposite inks for 3D printed scaffold fabrication through a micro-extrusion process having improved both biocompatibility and processability. The hydrogel is based on a photocrosslinkable alginate bioconjugated with both gelatin and chondroitin sulfate in order to mimic the cartilage extracellular matrix, while the nanofiller is based on graphene oxide to enhance the printability and cell proliferation. Our results show that the incorporation of graphene oxide into the hydrogel inks considerably improved the shape fidelity and resolution of 3D printed scaffolds because of a faster viscosity recovery post extrusion of the ink. Moreover, the nanocomposite inks produce anisotropic threads after the 3D printing process because of the templating of the graphene oxide liquid crystal. The in vitro proliferation assay of human adipose tissue-derived mesenchymal stem cells (hADMSCs) shows that bioconjugated scaffolds present higher cell proliferation than pure alginate, with the nanocomposites presenting the highest values at long times. Live/Dead assay otherwise displays full viability of hADMSCs adhered on the different scaffolds at day 7. Notably, the scaffolds produced with nanocomposite hydrogel inks were able to guide the cell proliferation following the direction of the 3D printed threads. In addition, the bioconjugated alginate hydrogel matrix induced chondrogenic differentiation without exogenous pro-chondrogenesis factors as concluded from immunostaining after 28 days of culture. This high cytocompatibility and chondroinductive effect toward hADMSCs, together with the improved printability and anisotropic structures, makes these nanocomposite hydrogel inks a promising candidate for cartilage tissue engineering based on 3D printing.