GermOnline, a cross-species community knowledgebase on germ cell differentiation.
GermOnline provides information and microarray expression data for genes involved in mitosis and meiosis, gamete formation and germ line development across species. The database has been developed, and is being curated and updated, by life scientists in cooperation with bioinformaticists. Information is contributed through an online form using free text, images and the controlled vocabulary developed by the GeneOntology Consortium. Authors provide up to three references in support of their contribution. The database is governed by an international board of scientists to ensure a standardized data format and the highest quality of GermOnline's information content. Release 2.0 provides exclusive access to microarray expression data from Saccharomyces cerevisiae and Rattus norvegicus, as well as curated information on approximately 700 genes from various organisms. The locus report pages include links to external databases that contain relevant annotation, microarray expression and proteome data. Conversely, the Saccharomyces Genome Database (SGD), S.cerevisiae GeneDB and Swiss-Prot link to the budding yeast section of GermOnline from their respective locus pages. GermOnline, a fully operational prototype subject-oriented knowledgebase designed for community annotation and array data visualization, is accessible at http://www.germonline.org. The target audience includes researchers who work on mitotic cell division, meiosis, gametogenesis, germ line development, human reproductive health and comparative genomics.


A novel defined risk signature of cuproptosis-related long non-coding RNA for predicting prognosis, immune infiltration, and immunotherapy response in lung adenocarcinoma.
Background: Cuproptosis is a newly discovered non-apoptotic form of cell death that may be related to the development of tumors. Nonetheless, the potential role of cuproptosis-related lncRNAs in tumor immunity formation and patient-tailored treatment optimization of lung adenocarcinoma (LUAD) is still unclear. Methods: RNA sequencing and survival data of LUAD patients were downloaded from The Cancer Genome Atlas (TCGA) database for model training. The patients with LUAD in GSE29013, GSE30219, GSE31210, GSE37745, and GSE50081 were used for validation. The proofed cuproptosis-related genes were extracted from the previous studies. The Pearson correlation was applied to select cuproptosis-related lncRNAs. We chose differentially expressed cuproptosis-related lncRNAs in the tumor and normal tissues and allowed them to go to a Cox regression and a LASSO regression for a lncRNA signature that predicts the LUAD prognosis. Kaplan-Meier estimator, Cox model, ROC, tAUC, PCA, nomogram predictor, decision curve analysis, and real-time PCR were further deployed to confirm the model's accuracy. We examined this model's link to other regulated cell death forms. Applying TMB, immune-related signatures, and TIDE demonstrated the immunotherapeutic capabilities of signatures. We evaluated the relationship of our signature to anticancer drug sensitivity. GSEA, immune infiltration analysis, and function experiments further investigated the functional mechanisms of the signature and the role of immune cells in the prognostic power of the signature. Results: An eight-lncRNA signature (TSPOAP1-AS1, AC107464.3, AC006449.7, LINC00324, COLCA1, HAGLR, MIR4435-2HG, and NKILA) was built and demonstrated owning prognostic power by applied to the validation cohort. Each signature gene was confirmed differentially expressed in the real world by real-time PCR. The eight-lncRNA signature correlated with 2321/3681 (63.05%) apoptosis-related genes, 11/20 (55.00%) necroptosis-related genes, 34/50 (68.00%) pyroptosis-related genes, and 222/380 (58.42%) ferroptosis-related genes. Immunotherapy analysis suggested that our signature may have utility in predicting immunotherapy efficacy in patients with LUAD. Mast cells were identified as key players that support the predicting capacity of the eight-lncRNA signature through the immune infiltrating analysis. Conclusion: In this study, an eight-lncRNA signature linked to cuproptosis was identified, which may improve LUAD management strategies. This signature may possess the ability to predict the effect of LUAD immunotherapy. In addition, infiltrating mast cells may affect the signature's prognostic power.


A Key Motif in the Cholesterol-Dependent Cytolysins Reveals a Large Family of Related Proteins.
The cholesterol-dependent cytolysins (CDCs) are bacterial, β-barrel, pore-forming toxins. A central enigma of the pore-forming mechanism is how completion of the prepore is sensed to initiate its conversion to the pore. We identified a motif that is conserved between the CDCs and a diverse family of nearly 300 uncharacterized proteins present in over 220 species that span at least 10 bacterial and 2 eukaryotic phyla. Except for this motif, these proteins exhibit little similarity to the CDCs at the primary structure level. Studies herein show this motif is a critical component of the sensor that initiates the prepore-to-pore transition in the CDCs. We further show by crystallography, single particle analysis, and biochemical studies of one of these CDC-like (CDCL) proteins from Elizabethkingia anophelis, a commensal of the malarial mosquito midgut, that a high degree of structural similarity exists between the CDC and CDCL monomer structures and both form large oligomeric pore complexes. Furthermore, the conserved motif in the E. anophelis CDCL crystal structure occupies a nearly identical position and makes similar contacts to those observed in the structure of the archetype CDC, perfringolysin O (PFO). This suggests a common function in the CDCs and CDCLs and may explain why only this motif is conserved in the CDCLs. Hence, these studies identify a critical component of the sensor involved in initiating the prepore-to-pore transition in the CDCs, which is conserved in a large and diverse group of distant relatives of the CDCs.IMPORTANCE The cholesterol-dependent cytolysins' pore-forming mechanism relies on the ability to sense the completion of the oligomeric prepore structure and initiate the insertion of the β-barrel pore from the assembled prepore structure. These studies show that a conserved motif is an important component of the sensor that triggers the prepore-to-pore transition and that it is conserved in a large family of previously unidentified CDC-like proteins, the genes for which are present in a vast array of microbial species that span most terrestrial environments, as well as most animal and human microbiomes. These studies establish the foundation for future investigations that will probe the contribution of this large family of CDC-like proteins to microbial survival and human disease.


Could the 3D Printing Technology be a Useful Strategy to Obtain Customized Nutrition?
Within the concept of personalized nutrition we want to introduce the terms of "customized food formula" which refers to the preparation (at home) or the production (at industrial level) of new food formulations having nutrients and functional compounds necessary to prevent diseases or to reduce the risk for each subject (or subjects category) who exhibit a susceptibility to diseases. Three-dimensional (3D) printing is a group of technologies of growing interest able to produce, slice by slice, materials with any desired shape, dimension, and structure properties. The application of 3D printing in food science, as called "3D food printing," is a pioneering technology that could allow to build personalized foods by depositing nutrients and functional compounds or soft-materials obtained by their mixture. Also by 3D food printing it is expected to obtain personalized food formula having desired shape, dimension, and microstructure. This would be useful for people having swallowing problems. In this paper we analyzed the first examples of 3D food printing available in literature as well as we reported our results focused on the production of 3D printed wheat-based snacks enriched with insect powder (Tenebrio molitor) with the aim to improve the quality and the content of proteins.


Immunosuppression of canine renal allograft recipients by CD4 and CD8 monoclonal antibodies.
A state of tolerance to MHC mismatched allografts can be generated in rodents by treatment with CD4 and CD8 monoclonal antibodies (mAb). In order to transpose this type of therapy to large animals and ultimately to the clinic, a suitable model is required. To this end we have generated a series of mAb to the canine CD4, CD8, and Thy-1 antigens and have tested their ability to prevent rejection of renal allografts. Donor-recipient pairs were selected from a colony of mongrel dogs in which untreated rejection of two haplotype-mismatched kidneys occurred by day 7 (defined as a serum creatinine > 300 mumol/l). Therapy with either the CD4 or the CD8 mAb, using no other immunosuppression, did not prolong graft survival. Depletion of T cells by a Thy-1 mAb prior to surgery only extended graft survival to day 9. However, treating with combinations of mAb up to day 10 (CD4 plus Thy-1; CD4 plus CD8; or CD4 plus CD8 plus Thy-1) prolonged renal allograft function up to 25 days. Combination of the triple mAb therapy with a sub-therapeutic immunosuppressive drug regimen (cyclosporin A plus azathioprine that alone gave a median survival of 15 days) favored survival to a median of 38 days. This protocol also inhibited the antiglobulin response that had curtailed the effects of mAb treatment, opening the way to more extended, and potentially tolerizing, mAb plus drug regimens.


Mixed Gangliocytoma-Pituitary Adenoma: Insights on the Pathogenesis of a Rare Sellar Tumor.
Gangliocytomas originating in the sellar region are rare; most are tumors composed of gangliocytic and pituitary adenomatous elements, forming the so-called mixed gangliocytoma-pituitary adenoma. The majority of mixed gangliocytoma adenomas are associated with endocrinopathies, mainly acromegaly and less often Cushing disease and hyperprolactinemia. In the present study, 10 cases of mixed gangliocytoma and somatotroph adenomas were evaluated for patterns of cellular differentiation and expression of lineage-specific transcription factors. The tumors were characterized by immunohistochemistry for pituitary hormones, cytokeratins, Pit-1, and the neuronal markers NeuN, neurofilaments (NFP), and MAP2. Double-labeling immunohistochemistry for Pit-1/GH, Pit-1/NFP, Pit-1/MAP2, and NeuN/GH was performed in 9/10 tumors. Our data demonstrate that both adenomatous and ganglionic cells express the acidophilic lineage transcription factor Pit-1. Although mixed gangliocytomas and somatotroph adenomas show histologically distinct cellular populations, there is at least a small population of cells that coexpress the Pit-1 transcription factor and neuronal-associated cytoskeletal proteins favoring the theory of transdifferentiation of neuroendocrine cells into neuronal elements of these mixed tumors.


Anaplasma phagocytophilum delay of neutrophil apoptosis through the p38 mitogen-activated protein kinase signal pathway.
Human granulocytic anaplasmosis is caused by the obligate intracellular bacterium Anaplasma phagocytophilum. The bacterium avoids host innate defenses in part by infecting, surviving in, and propagating in neutrophils, as well as by inhibiting neutrophil apoptosis. However, the mechanisms of A. phagocytophilum survival in neutrophils and the inhibition of spontaneous apoptosis are not well understood. In this study, we demonstrated that antiapoptotic Mcl-1 protein (Bcl-2 family) expression is maintained and that inhibition of procaspase-3 processing occurs in A. phagocytophilum-infected human neutrophils. An evaluation of p38 mitogen-activated protein kinase (MAPK) showed evidence of increased phosphorylation with infection. Moreover, antagonism of p38 MAPK by the inhibitor SB203580 reversed apoptosis inhibition in live or heat-killed A. phagocytophilum-infected neutrophils. A role for the autocrine or paracrine production of antiapoptotic interleukin 8 (IL-8) expressed with A. phagocytophilum infection was excluded by the use of IL-8-, IL-8R1 (CXCR1)-, and IL-8R2 (CXCR2)-blocking antibodies. As previously demonstrated, the antiapoptotic effect was initially mediated by exposure to A. phagocytophilum components in heat-killed bacteria. However, an important role for active infection is demonstrated by the additional delay in apoptosis with intracellular growth and the refractory abrogation of this response by the p38 MAPK inhibitor 3 to 6 h after neutrophil infection. These results suggest that the initial activation of the p38 MAPK pathway leading to A. phagocytophilum-delayed neutrophil apoptosis is bypassed with active intracellular infection. Moreover, active intracellular infection contributes more to the overall delay in apoptosis than do components of heat-killed A. phagocytophilum alone.


Treg cell-based therapies: challenges and perspectives.
Cellular therapies using regulatory T (Treg) cells are currently undergoing clinical trials for the treatment of autoimmune diseases, transplant rejection and graft-versus-host disease. In this Review, we discuss the biology of Treg cells and describe new efforts in Treg cell engineering to enhance specificity, stability, functional activity and delivery. Finally, we envision that the success of Treg cell therapy in autoimmunity and transplantation will encourage the clinical use of adoptive Treg cell therapy for non-immune diseases, such as neurological disorders and tissue repair.


Balo's Concentric Sclerosis with Acute Presentation and Co-Existing Multiple Sclerosis-Typical Lesions on MRI.
Balo's disease also known as Balo's concentric sclerosis (BCS) is a rare demyelinating disorder which is characterized pathologically and radiologically by concentric rings of demyelinated and relatively myelin-preserved white matter. We describe the case of a 25-year-old female presenting with stroke-like symptoms who was diagnosed with BCS on MRI. At clinical onset, she also showed co-existing multiple sclerosis (MS)-typical lesions in the brain. This report extends the recent concept that BCS may share similar pathogenesis and radiological progression as MS lesions, that they may occur simultaneously in the same patient and that they may represent different manifestations of the same disease process. Also, BCS needs not be a fulminant disease and may often show a benign self-limiting course as in our case.


Anti-S100A4 Antibody Therapy Is Efficient in Treating Aggressive Prostate Cancer and Reversing Immunosuppression: Serum and Biopsy S100A4 as a Clinical Predictor.
S100A4 oncoprotein plays a critical role during prostate cancer progression and induces immunosuppression in host tissues. We hypothesized that S100A4-regulated oncogenic activity in immunosuppressed prostate tumors promotes growth of neoplastic cells, which are likely to become aggressive. In the current study, we investigated whether biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive prostate cancer. Aided by DECIPHER-genomic test, we show biopsy-S100A4 overexpression as predictive of (i) poor ADT response and (ii) high risk of mortality in 228 radical prostatectomy-treated patients. Furthermore, analysis of tumor genome data of more than 1,000 patients with prostate cancer (PRAD/SU2C/FHCRC studies) validated the association of S100A4-alteration to poor survival and metastasis. We show that increased serum-S100A4 levels are associated to the prostate cancer progression in patients. The prerequisite for metastasis is the escape of tumor cells via vascular system. We show that extracellular-S100A4 protein as a growth factor induces vascular transmigration of prostate cancer cells and bone demineralization thus forms an ideal target for therapies for treating prostate cancer. By employing surface plasmon resonance and isothermal titration calorimetry, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 therapy reduced the (i) osteoblastic demineralization of bone-derived MSCs, (ii) S100A4-target (NFκB/MMP9/VEGF) levels in prostate cancer cells, and (iii) tumor growth in a TRAMPC2 syngeneic mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased Stat4+/T-bet+ and decreased GATA2+/CD68+/CD45+/CD206+ cells); (ii) modulated cytokine levels in CD4+ T cells; and (iii) decreased levels of IL5/6/12/13, sTNFR1, and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive prostate cancer in patients.


Paneth cell-like change of the prostate gland. A histological, immunohistochemical, and electron microscopic study.
Paneth cell-like change (PCLC) of the prostatic glandular epithelium was focally observed in one case of normal glandular epithelium, two cases of glandular and stromal hyperplasia, one case of prostatic intraepithelial neoplasia, and four cases of prostatic adenocarcinoma. The distinctive cells were characterized by bright, eosinophilic cytoplasmic granules on routine hematoxylin and eosin-stained material. The cytoplasmic granules in the benign prostatic epithelium were periodate-Schiff's procedure (PAS)-positive and diastase resistant and immunohistochemically negative for lysozyme, neuron-specific enolase, chromogranin, and serotonin. The eosinophilic granules in the prostatic intraepithelial neoplasia and adenocarcinoma cases were immunohistochemically positive for chromogranin, serotonin, and neuron-specific enolase, and negative for lysozyme. By electron microscopy the eosinophilic granules represented exocrine-like or lysosomal-like vesicles in the benign epithelium and neuro-endocrine granules in the malignant epithelium. The lesion represents a prostatic epithelial PCLC rather than a Paneth cell metaplasia. PCLC is the common histological manifestation of two different phenomena: (a) a PAS-positive and diastase-resistant eosinophilic cytoplasmic granular change in benign prostatic epithelium, and (b) endocrine differentiation with neuroendocrine granules in dysplastic and malignant prostatic epithelia. The importance of recognizing PCLC lies in its differentiation from other possible prostatic cytoplasmic inclusions.


The Macrophage Response Is Driven by Mesenchymal Stem Cell-Mediated Metabolic Reprogramming.
Mesenchymal stem cells (MSCs) are multipotent adult stromal cells widely studied for their regenerative and immunomodulatory properties. They are capable of modulating macrophage plasticity depending on various microenvironmental signals. Current studies have shown that metabolic changes can also affect macrophage fate and function. Indeed, changes in the environment prompt phenotype change. Therefore, in this review, we will discuss how MSCs orchestrate macrophage's metabolic plasticity and the impact on their function. An improved understanding of the crosstalk between macrophages and MSCs will improve our knowledge of MSC's therapeutic potential in the context of inflammatory diseases, cancer, and tissue repair processes in which macrophages are pivotal.


Ciguatera fish poisoning: impact for the military health care provider.
Ciguatera toxin is a marine neurotoxin produced by microorganisms that becomes concentrated in predatory fish. Toxicity in humans results from the ingestion of contaminated fish harvested in tropical waters. Clinical manifestations of illness include the rapid onset of gastrointestinal symptoms and neurological abnormalities. Because of the rapid onset of symptoms and the potential for case clusters from a common source ingestion of contaminated fish, there is the potential that ciguatera poisoning may initially mimic illnesses caused by antipersonnel biological and chemical agents. We present data on an active duty soldier who presented to sick call for evaluation of new onset paresthesias and was diagnosed with ciguatera toxin poisoning. We also present a review of ciguatera poisoning literature with emphasis on the distinguishing features between ciguatoxin and other neurotoxins of military significance.


Empowering human anatomy education through gamification and artificial intelligence: An innovative approach to knowledge appropriation.
Gamification has appeared as an alternative educational methodology to traditional tools. Specifically, in anatomy teaching, multiple technological applications have emerged in response to the difficulties of accessing cadaveric material; however, there is insufficient information about the effects of these applications on the performance achieved by students, or about to the best way to adapt learning to meet their educational needs. In this study, we investigated how teaching human anatomy through a mobile gamified technological tool containing recommendation systems can be combined with a virtual assistant to improve the learning and academic performance of medical students in the Anatomy Department at the Universidad de La Frontera in Temuco, Chile and the Anatomy Department at the Pontificia Universidad Católica de Chile. In total, 131 students participated in the experiment, which was divided into two case studies. The main findings led to the conclusion that gamified components support students in learning anatomy. In addition, the predictions and recommendations provided by the virtual assistant enabled the academic aspects that the students needed to improve to be extracted adequately. Future work is expected to support adaptive learning by incorporating new artificial intelligence in education elements that can generate personalized scenarios for studying anatomy based on the application.


A randomized controlled trial of antibiotics on symptom resolution in patients presenting to their general practitioner with a sore throat.
Sore throat is a common symptom presented to general practitioners (GPs), and there remains controversy about the appropriate use of antibiotics. To compare, in a randomized controlled trial, the effectiveness of penicillin, cefixime and placebo on symptom resolution in patients presenting with a sore throat in general practice. Twenty-two GPs in Avon recruited 154 patients, aged 16-60 years, presenting to their GP with a sore throat, and for whom the GP would normally prescribe an antibiotic. Patients were randomized to one of three groups: penicillin V 250 mg four times a day; cefixime 200 mg daily; and placebo. Each was prescribed for five days. The main outcome measures were a diary of symptom resolution over seven days and eradication of group A beta-haemolytic streptococcus (GABHS). Of the 103 (67%) patients who completed symptom diaries, 40 were allocated to receive penicillin, 29 cefixime and 34 placebo. In the analysis including all patients, symptom resolution was greater by day 3 in the cefixime group than in the placebo group. Penicillin did not improve symptom resolution by day 3 compared with placebo, and cefixime was not statistically significantly different from penicillin. There were significant differences in the proportion of patients using analgesia at day 3, with the proportion being lowest in the cefixime group. The results for the subgroup of patients without GABHS were similar to those for all patients; in particular, the only statistically significant difference was between cefixime and placebo. Although numbers were too small for statistical significance, among patients with GABHS the effects of penicillin and cefixime were similarly raised in relation to placebo. Compared with placebo, cefixime can improve the rate of resolution of symptoms in patients with a sore throat who are selected for antibiotic treatment by their GP. The unexpected finding that cefixime was of benefit compared with placebo for patients without GABHS suggests that bacteria other than GABHS may be important in the pathogenesis of sore throat.


Nusinersen: A Treatment for Spinal Muscular Atrophy.
To review the efficacy and safety of nusinersen (Spinraza) in the treatment of spinal muscular atrophy (SMA). An English-language literature search of PubMed and MEDLINE (1946 to June 2018) was performed using the terms nusinersen, ISIS-SMN (Rx), and spinal muscular atrophy. Manufacturer prescribing information, abstracts, article bibliographies, and clinicaltrials.gov data were incorporated for additional materials. All clinical trials of nusinersen were identified and analyzed in the review. Nusinersen is the first drug therapy approved for the treatment of SMA. It is a novel modified antisense oligonucleotide designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron protein deficiency. Nusinersen has been studied for safety, pharmacokinetics, and efficacy in both open-label and randomized controlled trials. The studies show improvement in motor function across SMA of all types. The most common adverse effects were respiratory tract infections, headache, back pain, constipation, and post-lumbar puncture syndrome. Relevance to Patient Care and Clinical Practice: Based on phase III trial data, nusinersen produced positive changes in the clinical course of patients with SMA. The acquisition and administration of nusinersen present a number of challenges in clinical practice. Its intrathecal delivery and costly price tag must be recognized. Nusinersen is safe and effective in patients with SMA. It was well tolerated across all studied age groups.


Ustekinumab in Real-Life Practice: Experience in 116 Patients with Moderate-To-Severe Psoriasis.
Ustekinumab is a monoclonal antibody directed against the p40 subunit common to both IL-12 and IL-23 cytokines. Although the evidence of ustekinumab efficacy and safety in clinical trials is extensively recognized, data on its use in clinical practice is limited. Our objective is to report on the real-life experience of two Portuguese dermatology departments with ustekinumab in patients with moderate to severe psoriasis, and to identify the clinical characteristics associated with a weaker clinical response. Clinical, demographic, and therapeutic response data was retrospectively collected in 116 patients with moderate to severe psoriasis treated with ustekinumab between November 2009 and December 2015. A PASI75 therapeutic response was observed in 67.2%, 85.3%, 89.6% and 88.7% of patients at weeks 4, 12, 24 and 52, respectively. Ustekinumab was discontinued in seven patients (three due to primary failure, three due to secondary treatment failure, and one due to adverse events). Neither cardiovascular events nor cases of reactivation of previous infections (tuberculosis, hepatitis B) were observed during follow-up. In nine patients methotrexate was used as adjuvant therapy, and fourteen patients required ustekinumab dosage optimization. No side effects were observed in the two latter groups. The therapeutic response was higher in patients naïve to biologic therapies as compared to non-naïve patients. A trend towards lower clinical response was observed in patients weighing between 90-100 kg, and dosage optimization in this group of patients may be of value prior to considering biologic switch.


A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics.
In complex biological systems, small molecules often mediate microbe-microbe and microbe-host interactions. Using a systematic approach, we identified 3,118 small-molecule biosynthetic gene clusters (BGCs) in genomes of human-associated bacteria and studied their representation in 752 metagenomic samples from the NIH Human Microbiome Project. Remarkably, we discovered that BGCs for a class of antibiotics in clinical trials, thiopeptides, are widely distributed in genomes and metagenomes of the human microbiota. We purified and solved the structure of a thiopeptide antibiotic, lactocillin, from a prominent member of the vaginal microbiota. We demonstrate that lactocillin has potent antibacterial activity against a range of Gram-positive vaginal pathogens, and we show that lactocillin and other thiopeptide BGCs are expressed in vivo by analyzing human metatranscriptomic sequencing data. Our findings illustrate the widespread distribution of small-molecule-encoding BGCs in the human microbiome, and they demonstrate the bacterial production of drug-like molecules in humans. PAPERCLIP:


Counting on Numbers-Numerical Abilities in Grey Bamboo Sharks and Ocellate River Stingrays.
Over the last decade, studies examining the cognitive abilities of fish have increased, using a broad range of approaches. One of the foci has been to test the ability of fish to discriminate quantities of items and to determine whether fish can solve tasks solely on the basis of numerical information. This study is the first to investigate this ability in two elasmobranch species. All animals were trained in two-alternative forced-choice visual experiments and then examined in transfer tests, to determine if previously gained knowledge could be applied to new tasks. Results show that the grey bamboo shark (Chiloscyllium griseum) and the ocellate river stingray (Potamotrygon motoro) can discriminate quantities based on numerical information alone, while continuous variables were controlled for. Furthermore, the data indicates that similar magnitudes and limits for quantity discrimination exist as in other animals. However, the high degree of intraspecific variation that was observed as well as the low rate of animals proving to be successful suggest that the ability to discriminate quantities may not be as important to these species as to some other vertebrate and invertebrate species tested so far.


Recombinant Human Lysyl Oxidase-like 2 Secreted from Human Embryonic Kidney Cells Displays Complex and Acidic Glycans at All Three N-Linked Glycosylation Sites.
Human lysyl oxidase-like 2 (hLOXL2), a glycoprotein implicated in tumor progression and organ fibrosis, is a molecular target for anticancer and antifibrosis treatment. This glycoprotein contains three predicted N-linked glycosylation sites; one is near the protein's active site, and at least one more is known to facilitate the protein's secretion. Because the glycosylation impacts the protein's biology, we sought to characterize the native, mammalian glycosylation profile and to determine how closely this profile is recapitulated when the protein is expressed in insect cells. All three glycosylation sites on the protein, expressed in human embryonic kidney (HEK) cells, were characterized individually using a mass spectrometry-based glycopeptide analysis workflow. These data were compared to the glycosylation profile of the same protein expressed in insect cells. We found that the producer cell type imparts a substantial influence on the glycosylation of this important protein. The more-relevant version, expressed in HEK cells, contains large, acidic glycoforms; these glycans are not generated in insect cells. The glycosylation differences likely have structural and functional consequences, and these data should be considered when generating protein for functional studies or for high-throughput screening campaigns.


Catheter-obtained, Enterococcus and Proteus positive urine cultures may represent mostly contamination or asymptomatic bacteriuria in infants <90 days.
Urinary tract infection (UTI) diagnosis in infants is often made by a positive urine culture result, regardless of urine dipstick findings. To assess parameters that may affect positive urine culture results interpretation in infants, including dipstick performance, obtainment method, bacteria type, age and laboratory results. A retrospective, cohort study. Infants <90 days with urine dipstick and culture obtained through subrapubic aspiration (SPA) or catheter, 2015-2016, were included. Overall, 19% (129/678) of cultures were positive. The dipstick sensitivity was 51% for all cultures; 66%, 47%, 15% and 10% for Escherichia coli (n= 71), Klebsiella (n= 19), Enterococcus (n= 34) and Proteus (n= 10), respectively (p<.001). Sensitivity was higher in SPA vs. catheter for all cultures (67% vs. 43%); E. coli (78% vs. 59%); and Klebsiella (88% vs. 18%). For Enterococcus, dipstick sensitivity was low in both SPA and catheter (0-16%). All Proteus episodes were catheter obtained. Positive culture with negative dipstick and Enterococcus episodes had lower C-reactive protein levels, and higher proportion of mixed infection compared with positive dipstick and E. coli episodes. Urine cultures in infants should be obtained by SPA, since catheter-obtained, Enterococcus and Proteus positive cultures may represent contamination or asymptomatic bacteriuria, rather than true UTI.


Engineering rotor ring stoichiometries in the ATP synthase.
ATP synthase membrane rotors consist of a ring of c-subunits whose stoichiometry is constant for a given species but variable across different ones. We investigated the importance of c/c-subunit contacts by site-directed mutagenesis of a conserved stretch of glycines (GxGxGxGxG) in a bacterial c(11) ring. Structural and biochemical studies show a direct, specific influence on the c-subunit stoichiometry, revealing c(<11), c(12), c(13), c(14), and c(>14) rings. Molecular dynamics simulations rationalize this effect in terms of the energetics and geometry of the c-subunit interfaces. Quantitative data from a spectroscopic interaction study demonstrate that the complex assembly is independent of the c-ring size. Real-time ATP synthesis experiments in proteoliposomes show the mutant enzyme, harboring the larger c(12) instead of c(11), is functional at lower ion motive force. The high degree of compliance in the architecture of the ATP synthase rotor offers a rationale for the natural diversity of c-ring stoichiometries, which likely reflect adaptations to specific bioenergetic demands. These results provide the basis for bioengineering ATP synthases with customized ion-to-ATP ratios, by sequence modifications.


Transcriptional effects of glucocorticoid receptors in the dentate gyrus increase anxiety-related behaviors.
The Glucocorticoid Receptor (GR) is a transcription factor ubiquitously expressed in the brain. Activation of brain GRs by high levels of glucocorticoid (GC) hormones modifies a large variety of physiological and pathological-related behaviors. Unfortunately the specific cellular targets of GR-mediated behavioral effects of GC are still largely unknown. To address this issue, we generated a mutated form of the GR called DeltaGR. DeltaGR is a constitutively transcriptionally active form of the GR that is localized in the nuclei and activates transcription without binding to glucocorticoids. Using the tetracycline-regulated system (Tet-OFF), we developed an inducible transgenic approach that allows the expression of the DeltaGR in specific brain areas. We focused our study on a mouse line that expressed DeltaGR almost selectively in the glutamatergic neurons of the dentate gyrus (DG) of the hippocampus. This restricted expression of the DeltaGR increased anxiety-related behaviors without affecting other behaviors that could indirectly influence performance in anxiety-related tests. This behavioral phenotype was also associated with an up-regulation of the MAPK signaling pathway and Egr-1 protein in the DG. These findings identify glutamatergic neurons in the DG as one of the cellular substrate of stress-related pathologies.


Analysis of GABAA Receptor Activation by Combinations of Agonists Acting at the Same or Distinct Binding Sites.
Under both physiologic and clinical conditions GABAA receptors are exposed to multiple agonists, including the transmitter GABA, endogenous or exogenous neuroactive steroids, and various GABAergic anesthetic and sedative drugs. The functional output of the receptor reflects the interplay among all active agents. We have investigated the activation of the concatemeric α1β2γ2L GABAA receptor by combinations of agonists. Simulations of receptor activity using the coagonist concerted transition model demonstrate that the response amplitude in the presence of agonist combinations is highly dependent on whether the paired agonists interact with the same or distinct sites. The experimental data for receptor activation by agonist combinations were in agreement with the established views of the overlap of binding sites for several pairs of orthosteric (GABA, β-alanine, and piperidine-4-sulfonic acid) and/or allosteric agents (propofol, pentobarbital, and several neuroactive steroids). Conversely, the degree of potentiation when two GABAergic agents are coapplied can be used to determine whether the compounds act by binding to the same or distinct sites. We show that common interaction sites mediate the actions of 5α- and 5β-reduced neuroactive steroids, and natural and enantiomeric steroids. Furthermore, the results indicate that the anesthetics propofol and pentobarbital interact with partially shared binding sites. We propose that the findings may be used to predict the efficacy of drug mixtures in combination therapy and thus have potential clinical relevance.


Transient outward current in opossum esophageal circular muscle.
The whole cell patch-clamp technique was used to record a transient outward K+ current (ITO) from single smooth muscle cells isolated from opossum esophageal circular muscle. The threshold for its activation was -50 mV from holding potentials negative to -70 mV. The current peaked within 10 ms and decayed completely in 200 ms between test depolarization of -40 and -10 mV. ITO was recorded at room temperature in the presence of 5 mM internal ethylene glycol-bis(beta-amino-ethyl ether)-N,N,N',N'-tetraacetic acid. Both activation and inactivation kinetics of ITO were markedly changed when recordings were made at higher temperatures (32 degrees C). 4-Amino-pyridine (4-AP, 3 mM) abolished the fast component of the outward current. Tetraethylammonium ion (TEA, 1-30 mM) reduced the sustained component but did not affect ITO. In the presence of TEA and nifedipine, the voltage dependence of the steady-state inactivation data was well fitted by a Boltzmann distribution with a half-inactivation potential of -57 mV. The half-inactivation potential was shifted to a more positive potential in the presence of Cd2+ (-35 mV). The steady-state inactivation and activation data overlap between -50 and -30 mV, suggesting the presence of a "window" current in this potential range. In current-clamp mode, 4-AP depolarized single esophageal cells by approximately 8 mV and shifted the upstroke of the action potential to the left. These results indicate that, in the esophageal circular muscle, ITO is involved in the resting membrane potential and modulation of the onset of action potential.


Highly poly(ethylene) glycolylated islets improve long-term islet allograft survival without immunosuppressive medication.
The surface modification of islets using poly(ethylene glycol) (PEG) is being studied as a means of preventing host immune responses against transplanted islets. In this study, to completely shield islets with PEG molecules, we increased the amount of PEG conjugated to islet surfaces, by multiple PEGylation or amplified PEGylation using poly-L-lysine, poly(allylamine), or poly(ethyleneimine), respectively. Amplified PEGylation was associated with islet cytotoxicity and functional impairment, but multiple PEGylation affected neither islet viability nor functionality. In addition, when triply PEGylated islets were allotransplanted into diabetic recipients, these islets survived in 3 of the 7 recipients for more than 100 days without any immunosuppressive treatment. Moreover, the blood glucose levels of these 3 recipients were stable and in the normal range. Immunohistochemical analysis showed that 3 of 7 triply PEGylated islets transplants survived for 100 days and that 4 that were rejected before day 20 were all immunologically protected from immune cells. However, unmodified islets were completely destroyed within 1 week. Consequently, we suggest that multiple PEGylation offers an effective means of reducing the immunogenicity of transplanted islets by increasing the amount of surface-bound PEG.


COVID-19: Perturbation dynamics resulting chaos to stable with seasonality transmission.
The outbreak of coronavirus is spreading at an unprecedented rate to the human populations and taking several thousands of life all over the globe. In this paper, an extension of the well-known susceptible-exposed-infected-recovered (SEIR) family of compartmental model has been introduced with seasonality transmission of SARS-CoV-2. The stability analysis of the coronavirus depends on changing of its basic reproductive ratio. The progress rate of the virus in critical infected cases and the recovery rate have major roles to control this epidemic. Selecting the appropriate critical parameter from the Turing domain, the stability properties of existing patterns is obtained. The outcomes of theoretical studies, which are illustrated via Hopf bifurcation and Turing instabilities, yield the result of numerical simulations around the critical parameter to forecast on controlling this fatal disease. Globally existing solutions of the model has been studied by introducing Tikhonov regularization. The impact of social distancing, lockdown of the country, self-isolation, home quarantine and the wariness of global public health system have significant influence on the parameters of the model system that can alter the effect of recovery rates, mortality rates and active contaminated cases with the progression of time in the real world.


Effect of heat-shock protein B7 on oxidative stress in adipocytes from preruminant calves.
Dairy cows with ketosis display excessive lipolysis in adipose tissue. Heat-shock protein B7 (HSPB7), a small heat-shock protein, plays important roles in mediating cytoprotective responses to oxidative stress in rodent adipose tissue. Accordingly, it is assumed that HSPB7 may also play important roles in the antioxidant response in adipose tissue of ketotic cows. Therefore, the aim of this study is to investigate (1) the redox state of adipose tissue in ketotic cows and (2) the role and mechanism of HSPB7 on the regulation of oxidative stress in adipocytes from preruminant calves. An in vivo study consisting of 15 healthy and 15 clinically ketotic cows was performed to harvest subcutaneous adipose tissue and blood samples. In addition, adipocytes isolated from calves were treated with different concentrations of H2O2 (0, 12.5, 25, 50, 100, or 200 μM) for 2 h, transfected with adenovirus-mediated overexpression of HSPB7 for 48 h, or transfected with small interfering RNA of HSPB7 for 48 h followed by exposure to H2O2 (200 μM) for 2 h. Serum concentrations of nonesterified fatty acids and β-hydroxybutyrate were greater in cows with clinical ketosis, whereas serum concentration of glucose was lower. Compared with healthy cows, the malondialdehyde content was greater but the activity of glutathione peroxidase and superoxide dismutase was lower in adipose tissue of clinically ketotic cows. The abundance of HSPB7 and nuclear factor, erythroid 2 like 2 (NFE2L2) was greater in adipose tissue of clinically ketotic cows. In vitro, H2O2 treatment induced the overproduction of reactive oxygen species and malondialdehyde, and inhibited the activity of antioxidant enzymes glutathione peroxidase and superoxide dismutase in adipocytes from preruminant calves. The low concentration of H2O2 (12.5, 25, and 50 μM) increased the abundance of HSPB7 and NFE2L2, but high concentrations of H2O2 (100 or 200 μM) reduced the abundance of HSPB7 and NFE2L2. The overexpression of HSPB7 improved the H2O2-induced oxidative stress in adipocytes via increasing the abundance of NFE2L2 and its downstream target genes heme oxygenase-1 (HMOX1) and NADH quinone oxidoreductase 1 (NQO1). Knockdown of HSPB7 markedly inhibited the expression of NFE2L2, HMOX1, and NQO1 and further exacerbated H2O2-induced oxidative stress. Overall, these results indicate that activation of the HSPB7-NFE2L2 pathway increases cellular antioxidant capacity, thereby alleviating oxidative stress in bovine adipocytes.


Ethical Challenges in School-Based Immunization Programs for Adolescents: A Qualitative Study.
We investigated ethical issues in school-based immunization programs for adolescents and how they are addressed. We used qualitative methods and an ethnographic approach to observe 9 secondary schools on immunization days in South Australia in 2011; concurrently, we conducted 9 focus groups with female secondary school students, 6 semistructured interviews with parents, and 10 interviews with nurses and teachers. We explored ethical challenges from the perspective of these groups. We identified ethical challenges for the delivery of adolescent immunization in a school-based setting in 3 main areas: informed consent, restrictions on privacy, and harm to students in the form of fear and anxiety. We found areas in which the design and delivery of school-based immunization programs can be improved. Information about immunization should be provided in ways that are appropriate to young people and their parents, and privacy protections should be enhanced when possible. Involving young people in the design and delivery of programs would assist with making these improvements.


A comparative review of the efficacy and safety of established phosphate binders: calcium, sevelamer, and lanthanum carbonate.
Obstacles to successful management of hyperphosphatemia in chronic kidney disease include inadequate control of dietary phosphate and non-compliance with phosphate-binder therapy. Three major classes of phosphate binders include calcium-based binders, sevelamer HCl, and lanthanum carbonate. A literature search was performed using MEDLINE and EMBASE databases to identify clinical trials from January 1966 to May 2007 comparing classes of phosphate binders with regard to efficacy, safety, compliance, or pharmacoeconomics. Search terms included lanthanum AND sevelamer, lanthanum AND calcium, and sevelamer AND calcium. A total of 1372 articles were identified in the search, with 125 review articles and clinical trials of interest identified. Calcium-based binders are effective, but their potential to contribute to total body calcium overload and vascular calcification is an important long-term clinical concern. Sevelamer HCl is effective in reducing serum phosphate, has no systemic absorption, and does not increase total body calcium load. However, sevelamer HCl binds bile acids, is not an efficient phosphate binder in an acidic environment, and contributes to metabolic acidosis. Lanthanum carbonate is a potent and selective phosphate binder that retains high affinity for phosphate over a wide pH range, does not bind bile acids or contribute to metabolic acidosis, and has the potential to reduce pill burden and increase patient compliance compared with other phosphate binders. All three classes of phosphate binders are effective at reducing serum phosphate levels. Lanthanum carbonate may result in increased adherence by decreasing the pill burden.


Lean and leadership practices: development of an initial realist program theory.
Lean as a management system has been increasingly adopted in health care settings in an effort to enhance quality, capacity and safety, while simultaneously containing or reducing costs. The Ministry of Health in the province of Saskatchewan, Canada has made a multi-million dollar investment in Lean initiatives to create "better health, better value, better care, and better teams", affording a unique opportunity to advance our understanding of the way in which Lean philosophy, principles and tools work in health care. In order to address the questions, "What changes in leadership practices are associated with the implementation of Lean?" and "When leadership practices change, how do the changed practices contribute to subsequent outcomes?", we used a qualitative, multi-stage approach to work towards developing an initial realist program theory. We describe the implications of realist assumptions for evaluation of this Lean initiative. Formal theories including Normalization Process Theory, Theories of Double Loop and Organization Leaning and the Theory of Cognitive Dissonance help understand this initial rough program theory. Data collection included: key informant consultation; a stakeholder workshop; documentary review; 26 audiotaped and transcribed interviews with health region personnel; and team discussions. A set of seven initial hypotheses regarding the manner in which Lean changes leadership practices were developed from our data. We hypothesized that Lean, as implemented in this particular setting, changes leadership practices in the following ways. Lean: a) aligns the aims and objectives of health regions; b) authorizes attention and resources to quality improvement and change management c) provides an integrated set of tools for particular tasks; d) changes leaders' attitudes or beliefs about appropriate leadership and management styles and behaviors; e) demands increased levels of expertise, accountability and commitment from leaders; f) measures and uses data effectively to identify actual and relevant local problems and the root causes of those problems; and g) creates or supports a 'learning organization' culture. This study has generated initial hypotheses and realist program theory that can form the basis for future evaluation of Lean initiatives. Developing leadership capacity and culture is theorized to be a necessary precursor to other systemic and observable changes arising from Lean initiatives.


[Mutagenic effect of the food-coloring agents tartrazine and indigo carmine].
The authors studied the mutagenic action of the food dyes, tartrazine (both Soviet and imported) and indigocarmine in a microbial model and in warm-blooded animals (linear mice). Determined the toxicity and mutagenic action of the dyes on E. coli, strain K-12, carried out chromosomal analysis of the bone marrow, examined the dominant lethals in CBA X C57BL/6 mice. The recommended daily dose amounts to 400 mg/kg for tartrazine and to 50 mg/kg for indigocarmine with regard to the safety factor equal to 100. The data derived as a result of studying the mutagenic activity of tartrazine manufactured in the USSR and CSSR and indigocarmine paste in 3 experimental models allow the conclusion to be made that the doses of these dyes applied in food industry are fairly safe.


High waste contributes to low food intake in hospitalized patients.
The prevalence of disease-related malnutrition in hospital inpatients is high; many patients do not meet individual nutrition requirements while hospitalized. To better understand the reasons for inadequate nutrition intake, this study describes patient satisfaction, food provision, food intake, and waste of hospital meals. Over 6 days, 150 hospital meals were weighed and nutrient composition was calculated. On return from the wards, waste was weighed. In addition, nutrition intake was compared to nutrition requirements in 42 patients. In a separate study, the authors studied patient satisfaction with the hospital food service using interviews (n = 112). The 3 main meals accounted for a mean of 1809 ± 143 kcal and 76 ± 13 g of protein per day. In total, 38% of the food provided by the kitchen was wasted. As a consequence, the main meals supplied an average of 1105 ± 594 kcal and 47 ± 27 g of protein to patients. Sixty-one percent of patients had an energy intake <90% and 75% had a protein intake <90% of requirements. Most patients were satisfied or fairly satisfied with the choices, taste, and presentation of the main meals. Satisfaction with snack meals and information was inadequate. The standard meals provided by the hospital kitchen provide adequate amounts of energy and protein. However, most patients do not consume complete meals. It may be concluded that food waste is largely attributed to the inadequate intake of many hospitalized patients. Patients who experienced the worst health status ate the least.


[Cholelithic intestinal obstruction].
Analysis of the treatment of 25 patients with cholelithic intestinal obstruction is given. Questions of etiology, variants of the development, clinical course, diagnosis, operative treatment of the cholelithic ileus, causes of lethal outcomes are discussed. The authors propose measures of prophylactics .


[The conditions of industrial lighting and the state of the visual work capacity of operators working with video terminals].
Operators constantly working with video display computer terminals present significant changes in visual efficiency as evidenced by unstable dynamics of professionally meaningful functions and augmentation of excitatory process in cortical portion of the visual analyzer. The examinees' complaints and decrement in working efficiency in the second half of the work shift suggest generalization of the process. Strain in the visual analyzer performance is referrable to high intensity and strain in work, as well as to irrational lighting and unfavourable conditions for visual work.


Carotid artery stenting: identification of risk factors for poor outcomes.
Age greater than 80 has been identified as a risk factor for complications, including stroke and death, in patients undergoing carotid artery angioplasty and stenting (CAS). This study evaluates other potential predictors of perioperative complications in patients undergoing CAS. All cerebrovascular endovascular procedures performed by the vascular surgery division at our university hospital between July 2003 and December 2005 were retrospectively examined. During the course of 212 admissions, 198 patients underwent 215 procedures. Patient age, comorbidities, and admission status were analyzed as independent (predictor) variables. Complication rate, discharge disposition, and length of hospital stay were considered dependent (outcome) variables. Logistic regression and Fisher exact test or Student t test were performed, as appropriate. Complications included major and minor stroke, myocardial infarction, femoral artery pseudoaneurysm, and death. The rates of perioperative major and minor stroke were 0.5% and 2.8%, respectively. Chronic renal insufficiency was a predictor of perioperative complications, including stroke: patients with serum creatinine greater than 1.3 mg/dL had a 37% complication rate and a 11.1% stroke rate, while those with normal renal function had a 13% complication rate (P = .003) and a 0.6% stroke rate (P =.001). Similar association was seen between creatinine clearance and both stroke and complications. Obesity was a risk factor for complications, but not stroke: obese patients had a complication rate of 28%, while others had a 16% complication rate (P = .024). Emergency admission predicted both extended hospital stay (P < .001) and requirement for further inpatient care in a rehabilitation or nursing facility (P = .007). There was no significant difference in complication rate or stroke rate between octogenarians and others. This experience demonstrates that chronic renal insufficiency, obesity, and emergent clinical setting are risk factors for patients undergoing CAS.


Brain neuronal chromatin responses in acute soman intoxicated rats.
Male Sprague-Dawley rats (200 g) were injected subcutaneously with soman, a potent neuronal acetylcholinesterase (AChE) inhibitor, at doses of 0.5, 0.8 and 1.0 LD50 (1 LD50 = 135 micrograms/kg) before decapitation at 1 and 24 h post-exposure. Correlative data were obtained on the severity of brain AChE inactivation and physicochemical changes in nuclear chromatin of cerebrocortical (layer V) and striatal neurons using Feulgen-DNA (F-DNA) cytophotometry and ocular filar micrometry. Decreased lability of neurons to F-DNA acid hydrolysis (reduced F-DNA yield), nuclear shrinkage and chromatin aggregation (decreased chromophore area) were used as indices of suppression of genomic template activity; conversely, increases in F-DNA yield and chromophore area signify enhanced neuroexcitation. At 1 hr post-soman there was a dose-dependent inactivation of AChE with a moderate increase in chromatin activation, i.e., nuclear hypertrophy and chromatin dispersion. At 24 hr post-soman there was a partial restoration of AChE activity, notably in striatal neurons, with a suppression in chromatin template activity. These data indicate that actions of soman on neuronal functioning are time-dependent. The absence of any dose-related neuronal chromatin changes may signify existence of non-cholinergic mediated events.


Effect of parental age at birth on the accumulation of deficits, frailty and survival in older adults.
parental age at conception may affect life expectancy. Adult daughters of older fathers seem to live shorter lives and, in one study, being born to a mother aged <25 was an important predictor of exceptional longevity. The effect of parental age on fitness/frailty in late life is unknown. We aimed to investigate the relationships between parental age and frailty and longevity in older adults. in the Canadian Study of Health and Aging (CSHA), data was collected on individuals aged >or=65 using a Self-Assessed Risk Factor Questionnaire and screening interview. In this secondary analysis, 5112 participants had complete data for parental age, frailty status and 10-year survival. Parental age was divided into three groups, with cut-offs at 25 and 45 for fathers and at 25 and 40 for mothers. Frailty was defined by an index of deficits. Survival was analysed using Kaplan-Meier curves and Cox regression with analyses adjusted for subject's age, sex and age of the other parent. mean maternal age at subject's birth was 29.2y (SD 6.8) and mean paternal age 33.3y (SD 7.8). There was no effect of maternal or paternal age on survival for either sons or daughters. Similarly, there was no association between parental age and subject frailty in old age. we did not identify an association between parental age and frailty or longevity in older adult participants in the CSHA.


Mutation of the Rb1 pathway leads to overexpression of mTor, constitutive phosphorylation of Akt on serine 473, resistance to anoikis, and a block in c-Raf activation.
Atk can be activated by two independent phosphorylation events. Growth factor-dependent phosphorylation of threonine 308 (Akt-308) by phosphatidylinositol 3-kinase-dependent PDK1 leads to activation of mammalian target of rapamycin (mTor) complex 1 (TORC1) and stimulation of protein synthesis. Phosphorylation on serine 473 (Akt-473) is catalyzed by mTor in a second complex (TORC2), and Akt-473 phosphorylates Foxo3a to inhibit apoptosis. Accumulation of both phosphorylated forms of Akt is frequent in cancer, and TORC2 activity is required for progression to prostate cancer with Pten mutation. Here, we link Akt-473 to the Rb1 pathway and show that mTor is overexpressed with loss of the Rb1 family pathway. This leads to constitutive Akt-473 and, in turn, phosphorylation of Foxo3a and resistance to cell adhesion-dependent apoptosis (anoikis). Additionally, Akt-473 accumulation blocks c-Raf activation, thereby preventing downstream Erk activation. This block cannot be overcome by constitutively active Ras, and it also prevents induction of the Arf tumor suppressor by Ras. These studies link inactivation of the Rb1 pathway, a hallmark of cancer, to accumulation of Akt-473, resistance to anoikis, and a block in c-Raf/Erk activation.


A program for increasing manual signing by autistic and profoundly retarded youth within the daily environment.
A program was implemented to increase the manual signing of five profoundly retarded and four autistic youth within their daily environment. Each participant was nonvocal or minimally vocal. The program was based on modified incidental teaching strategies and was implemented by direct care personnel under supervision in an institutional setting. Specific components included rearranging the physical environment to prompt signing, altering routine staff-resident interactions to prompt, manually guide and/or reinforce signing; and conducting mini-training sessions. Additionally, staff modeled signs intermittently throughout the day. The program was sequentially implemented during two staff work shifts on each of two resident living modules. Observations conducted at four separate time periods during the day indicated that significant increases in signing occurred for all participating youth and that the increases generally maintained during follow-up checks at 5 and 17 weeks. Differential effects of the increased signing on frequency of vocalizations were noted across residents. A staff acceptability survey indicated favorable staff reports on the usefulness of signing to communicate with the youth. Results are discussed regarding the significance of manual signing for seriously developmentally disabled persons and the importance of ensuring that signing skills are used in the daily environment and not exclusively in formal training sessions. Also, areas for continued research are noted in terms of more refined analyses of client skills and subsequent progress in manual communication programs.


[The locked-in patient and the characteristics of the electrical activity of his brain].
"Locked-in" state differs from the known states characterized by the motor activity blockade, preservation of conscience of speech contact, despite the fact that connection with outer world during this state is limited only by vertical movements of eyes and eyelids in response to speech signals. Three "locked-in" men were studied at different stages of development of this state. Spectral-coherent analysis of the EEG was conducted. The most typical for the developed state of the "locked-in" man is a uniform change of the intercentral EEG relations. In the motor areas of the cortex alpha-activity and its links are not formed (coherence in alpha-range is zero) while high and low frequencies are coherent. In the visual areas, in contrast, the alpha-rhythm is coherent. Distinct interhemispheric asymmetry of coherent connections appears. In the right hemisphere a decrease of coherence level is sharp and even, in the left one--in occipito-temporal parts the level remains close to norm, while in the frontal parts of the cortex it decreases.


Are individual differences in fatigue vulnerability related to baseline differences in cortical activation?
Recent evidence suggests that underlying patterns of cortical activation may partially account for individual differences in susceptibility to the effects of sleep deprivation. Here, functional magnetic resonance imaging (fMRI) was used to examine the activation of military pilots whose sleep-deprivation vulnerability previously was quantified. A Sternberg Working Memory Task (SWMT; S. Sternberg, 1966) was completed alternately with a control task during a 13-min blood oxygen level-dependent fMRI scan. Examination of the activated voxels in response to SWMT indicated that, as a group, the pilots were more similar to fatigue-resistant nonpilots than to fatigue-vulnerable nonpilots. Within the pilots, cortical activation was significantly related to fatigue vulnerability on simulator-flight performance. These preliminary data suggest that baseline fMRI scan activation during a working memory task may correlate with fatigue susceptibility.


Structural complexity in Prussian blue analogues.
We survey the most important kinds of structural complexity in Prussian blue analogues, their implications for materials function, and how they might be controlled through judicious choice of composition. We focus on six particular aspects: octahedral tilts, A-site 'slides', Jahn-Teller distortions, A-site species and occupancy, hexacyanometallate vacancies, and framework hydration. The promising K-ion cathode material KxMn[Fe(CN)6]y serves as a recurrent example that illustrates many of these different types of complexity. Our article concludes with a discussion of how the interplay of various distortion mechanisms might be exploited to optimise the performance of this and other related systems, so as to aid in the design of next-generation PBA materials.


Two-dimensional electronic spectroscopy of molecular aggregates.
The properties of molecular aggregates, coupled clusters of small molecules, are often challenging to unravel because of their inherent complexity and disordered environments. Their structure-function relationships are often far from obvious. However, their ability to efficiently channel excitation energy over remarkable distances, as is the case in photosynthetic light harvesting, is a compelling motivation to investigate them. Understanding and subsequently mimicking the processes in photosynthesis, for example, will set the stage for considerable advances in using light harvesting to fuel renewable energy technologies. Two-dimensional (2D) electronic spectroscopy is emerging as a nonlinear optical technique that provides significant insight into the interactions and dynamics of complex molecular systems. In addition to spectrally resolving excitation and emission energies over significant bandwidths with femtosecond resolution, this technique has already enabled discoveries about the structure and dynamics of photosynthetic light-harvesting complexes and other aggregates. Multiple capabilities unique to 2D electronic spectroscopy enable such findings. For example, the spectral resolution of excitation and emission combined with the ability to eliminate the effects of static disorder can reveal the homogeneous line width of a transition and the different dynamic contributions to it. Two dimensional spectroscopy is also sensitive to electronic coherence and has been employed to identify and characterize coherent excitation energy transfer dynamics in photosynthetic systems and conjugated polymers. The presence of cross-peaks, signals for which excitation and emission occur at different wavelengths, provides multiple forms of information. First, it allows the identification of states in congested spectra and reveals correlations between them. Second, we can track excitation energy flow from origin to terminus through multiple channels simultaneously. Finally, 2D electronic spectroscopy is uniquely sensitive to intermolecular electronic coupling through the sign and amplitude of the cross-peaks. This feature makes it possible to reveal spatial molecular configurations by probing electronic transitions. Another means of "resolving" these angstrom-scale arrangements is to manipulate the probing laser pulse polarizations. In this way, we can isolate and modulate specific processes in order to retrieve structural information. In this Account, we demonstrate these capabilities through a close collaboration between experiments and modeling on isolated photosynthetic pigment-protein complexes and also on J-aggregates. Each of the probed systems we describe offers insights that have both increased the utility of 2D electronic spectroscopy and led to discoveries about the molecular aggregates' dynamics and underlying structure.


The chemistry of social regulation: multicomponent signals in ant societies.
Chemical signals mediating communication in ant societies are usually complex mixtures of substances with considerable variation in molecular composition and in relative proportions of components. Such multicomponent signals can be produced in single exocrine glands, but they can also be composed with secretions from several glands. This variation is often functional, identifying groups or specific actions on a variety of organizational levels. Chemical signals can be further combined with cues from other sensory modalities, such as vibrational or tactile stimuli. These kinds of accessory signals usually serve in modulatory communication, lowering the response threshold in the recipient for the actual releasing stimulus. Comparative studies suggest that modulatory signals evolved through ritualization from actions originally not related to the same behavioral context, and modulatory signals may further evolve to become independent releasing signals.


Developmental neurotoxicity following prenatal exposures to methylmercury and PCBs in humans from epidemiological studies.
Adverse health effects following prenatal exposures to methylmercury (MeHg) have been apparent from several prospective cohort studies conducted in a fish-eating population. A prospective study in a Faroese birth cohort documented subtle deficits of several functional domains at prenatal MeHg exposure levels previously thought to be safe. Recent additional studies also showed neurobehavioral deficits associated with exposures to polychlorinated biphenyls (PCBs) with concomitant MeHg poisoning. In contrast, a prospective study in the Seychelles did not detect a similar association between MeHg exposure and neurodevelopmental deficits; children of the highest MeHg exposure group showed better scores in some developmental tests than those of the lower exposure groups for both prenatal and postnatal MeHg exposures. This paradoxical difference between both studies is summarized herein. The primary source of human exposure to MeHg is fish. Since a considerable number of pollutants, including polychlorinated biphenyls (PCBs) and pesticides, are also present in fish, and since some organochemical substances including PCBs are also well documented to be neurotoxic to the developing brain from epidemiological studies, the combined effects of these pollutants should be considered in discussing the neurotoxicity of MeHg. In this article, therefore, major prospective cohort studies focusing on the exposures to PCBs were reviewed.


Nasal dermoid with intracranial extension.
Nasal dermoids are rare congenital anomalies, which usually present in early childhood as a midline nasal mass that requires surgical management. It is important to rule out any intracranial extension before subjecting the patient to surgery. We describe a case of nasal dermoid with intracranial extension. The embryology of the formation of the nasal dermoid, cyst and sinus, with the role of CT scan and MRI in diagnosing intracranial extension, and its management are discussed.


Comparison of three methods for the treatment of pterygium: amniotic membrane graft, conjunctival autograft and conjunctival autograft plus mitomycin C.
To compare three techniques combined with excision in the treatment of primary and recurrent pterygium: amniotic membrane transplantation, conjunctival autograft, and conjunctival autograft plus mitomycin C. Forty-nine eyes of 49 subjects (30 primary, 19 recurrent pterygium) were included in this study. Combined with excision, 25 eyes (18 primary, 7 recurrent pterygium) were treated with conjunctival autografts (Group 1), and 16 eyes (12 primary, 4 recurrent pterygium) were treated with amniotic membrane transplantation for the closure of the defect (Group 2). In 8 eyes (all recurrent pterygium) low-dose mitomycin C (0.02%) was applied topically to the defect area and a conjunctival autograft was applied thereafter (Group 3). The three groups were compared with regard to the recurrence of pterygium and the defect area requiring treatment. The number and percentages of recurrence seen in groups 1, 2 and 3 were as follows: 4 (16%), 4 (25%), and 0(-), respectively. For the treatment of primary pterygium cases, amniotic membrane closure and conjunctival autograft closure were comparable in effectiveness (p > 0.05). In the treatment of recurrent pterygium, there was no significant difference between the three techniques (p > 0.05). Amniotic membrane closure and conjunctival autografts were equally effective for the treatment of both primary and recurrent pterygium (p > 0.05). The graft size was significantly larger in the cases with recurrent pterygium (p = 0.016). Amniotic membrane closure and conjunctival autografts seem to be equally effective in the prevention of recurrence of primary pterygium. Conjunctival autografts combined with mitomycin C are as effective as the above two techniques to prevent recurrence in the treatment of recurrent pterygium. Due to the larger area of subconjunctival fibrosis, a larger defect area is created after the excision of pterygium tissue and a larger graft is needed to close this defect in recurrent pterygium. This factor can guide the surgeon during the planning of the surgery to choose the most appropriate technique for closure of the defect.


Controlling the counterintuitive optical repulsive thrust of nano dimers with counter propagating type waves and background medium.
This work focuses on the utilization of counter-propagating plane waves for optical manipulation, which provides a unique approach to control the behavior of Rayleigh and Dipolar nanoparticles immersed in a homogeneous or heterogeneous medium. Our study presents an interesting finding of a repulsive force between plasmonic-chiral heterodimers where the particles move away from each other in both near and far field regions. Interestingly, this repulsive thrust supports the wave like nature of light for the case of homogeneous background but particle type nature of light for heterogenous background. At first, we have investigated the theory underlying the optical trapping of the chiral particle and the impact of this phenomenon on the overall repulsive behavior of the heterodimers placed in air (homogeneous) background. After that, our proposed set-up has further been investigated putting in air-water interface (heterogenous background) and by varying light angle only a little bit. Our observation for this interface case is suggesting the transfer of Minkowski momentum of photon to each optically pulled Rayleigh or dipolar particle of the dimer set, which ultimately causes a broad-band giant repulsive thrust of the dimers. However, in absence of the other particle in the cluster, a single half-immersed particle does not experience the pulling force for the broad-band spectrum. The 'common' reason of the observed repulsive thrust of the dimers for both the aforementioned cases has been attributed to "modified" longitudinal Optical Binding Force (OBF). Technically, this work may open a new way to control the repulsion and attraction between the nanoparticles both in near and far field regions by utilizing the background and the counter-propagating waves. We also believe that this work manifests a possible simple set-up, which will support to observe a background dependent wave 'or' particle nature of light experimentally.


Percentiles and Reference Values for the Accelerometric Assessment of Static Balance in Women Aged 50-80 Years.
The identification of factors that alter postural stability is fundamental in the design of interventions to maintain independence and mobility. This is especially important for women because of their longer life expectancy and higher incidence of falls compared to men. The objective of this study was to construct the percentile box charts and determine the values of reference for the accelerometric assessment of the static balance in women. For this, an observational and cross-sectional study with a sample composed of 496 women (68.8 ± 10.4 years old) was conducted. The measurement of accelerations used a triaxial accelerometer during three tests: two tests on the ground in monopodal support and a test on a mat with monopodal support for 30 s each. In all of the variables, an increase in the magnitude of the accelerations was detected as the age advanced. The box charts of the percentiles of the tests show the amplitude of the interquartile ranges, which increased as the age advanced. The values obtained can be used to assess changes in static balance due to aging, trauma and orthopaedic and neurodegenerative alterations that may alter postural stability and increase the risk of falling.


Vegetation shapes aboveground invertebrate communities more than soil properties and pollution: a preliminary investigation on a metal-contaminated site.
Pollution with trace metals (TM) has been shown to affect diversity and/or composition of plant and animal communities. While ecotoxicological studies have estimated the impact of TM contamination on plant and animal communities separately, ecological studies have widely demonstrated that vegetation is an important factor shaping invertebrate communities. It is supposed that changes in invertebrate communities under TM contamination would be explained by both direct impact of TM on invertebrate organisms and indirect effects due to changes in plant communities. However, no study has clearly investigated which would more importantly shape invertebrate communities under TM contamination. Here, we hypothesized that invertebrate communities under TM contamination would be affected more importantly by plant communities which constitute their habitat and/or food than by direct impact of TM. Our analysis showed that diversity and community identity of flying invertebrates were explained only by plant diversity which was not affected by TM contamination. Diversity of ground-dwelling (GD) invertebrates in spring was explained more importantly by plant diversity (27% of variation) than by soil characteristics including TM concentrations (8%), whereas their community identity was evenly explained by plant diversity and soil characteristics (2-7%). In autumn, diversity of GD invertebrates was only explained by plant diversity (12%), and their identity was only explained by soil characteristics (8%). We conclude that vegetation shapes invertebrate communities more importantly than direct effects of TM on invertebrates. Vegetation should be taken into account when addressing the impacts of environmental contamination on animal communities.


Contagious Bovine Pleuropneumonia: Challenges and Prospects Regarding Diagnosis and Control Strategies in Africa.
Contagious bovine pleuropneumonia (CBPP) is an infectious and contagious respiratory disease of cattle, caused by Mycoplasma mycoides subsp. mycoides (Mmm). In this review, basic epidemiological features of CBPP, complicated by existing different strains of Mycoplasmas with similar biochemical characteristics, with preference to Sub-Saharan Africa are discussed. Many sub-Saharan African countries are challenged by variable gaps that include diagnostic tools and control strategies. Science-based issues on diagnostic procedures, vaccination, treatment, and other control strategies are discussed. Participatory epidemiology (PE), a diagnostic technique used in the identification and solving of animal health problems in rural communities, was also discussed. PE application, in conjunction with conventional diagnostic tools, will improve CBPP identification in pastoral rural communities and promote control of the disease in Africa. Furthermore, adequate CBPP control can be achieved through stronger political commitments from governments by prioritizing the disease among major diseases of high economic importance to the livestock industry for surveillance and control. Investment in CBPP control in endemic African countries will assure food security, livelihoods and the general well-being of people, and international trade.


Metacognitive planning: development and validation of an online measure.
Planning is the critical first stage of metacognition. Although it has long been emphasized theoretically, it has not been the subject of much empirical study due to the lack of a valid assessment tool. Because planning is a metacognitive process, online methods that collect data during task performance would much better capture it. The present study was conducted to develop an online measure of metacognitive planning. Researchers designed a puzzle task that took the form of the popular game Sokoban, and the ratio between planning time and total time of each item was chosen as the metacognitive planning index. The task was administered to a heterogeneous sample of 440 participants composed of college students as well as 5th-, 7th-, and 10th-grade students. The results showed that valid inference could be made from the time ratio score. Cronbach's alpha and test-retest correlation provided robust evidence of reliability of the time ratio score. Confirmatory factor analysis further confirmed its unidimensionality. Validity evidence also supported the use of the time ratio score. After controlling for demographic variables, intelligence, and motivation, the time ratio score still accounted for a significant proportion of variance of Sokoban performance, the Tower of London performance, and academic achievement. The time ratio score was also found to increase with age. Taken together, the results of the study revealed that the time ratio is a psychometrically sound online measure of metacognitive planning.


Long-range magnetic interactions and proximity effects in an amorphous exchange-spring magnet.
Low-dimensional magnetic heterostructures are a key element of spintronics, where magnetic interactions between different materials often define the functionality of devices. Although some interlayer exchange coupling mechanisms are by now well established, the possibility of direct exchange coupling via proximity-induced magnetization through non-magnetic layers is typically ignored due to the presumed short range of such proximity effects. Here we show that magnetic order can be induced throughout a 40-nm-thick amorphous paramagnetic layer through proximity to ferromagnets, mediating both exchange-spring magnet behaviour and exchange bias. Furthermore, Monte Carlo simulations show that nearest-neighbour magnetic interactions fall short in describing the observed effects and long-range magnetic interactions are needed to capture the extent of the induced magnetization. The results highlight the importance of considering the range of interactions in low-dimensional heterostructures and how magnetic proximity effects can be used to obtain new functionality.


Hemophagocytic lymphohistiocytosis secondary to Varicella zoster infection in a child with Henoch-Schönlein purpura.
Hemophagocytic lymphohistiocytosis (HLH) is a fatal, hyper-inflammatory syndrome that is characterized by untimely activation of macrophages, and manifests as cytopenia, organ dysfunction, and coagulopathy. Secondary HLH can be associated with infection, drugs, malignancy, and transplantation, and is mostly triggered by infection. Herein, we report the case of a patient with Henoch-Schönlein purpura (HSP) who developed severe HLH secondary to Varicella zoster infection.


POLIOVIRUS: GROWTH IN NON-NUCLEATE CYTOPLASM.
Cytoplasmic fragments were produced by micromanipulation of cells from a human amnion cell line cultured on coverslips. The cultures were infected with type 1 (Mahoney) poliovirus, and incubated for 7 hours with tritiated uridine (H3U). Fluorescent antibody to the poliovirus indicated antigenic sites in a number of non-nucleate fragments. By autoradiography the incorporation of H3U was demonstrated at some of the same sites. The occurrence of poliovirus antigen at the same site as induced synthesis of RNA in non-nucleate cytoplasm of mammalian cells indicates that poliovirus infection and growth occurred independently of immediate contribution from the nucleus.


Structural Studies on the Shapeshifting Murine Norovirus.
Noroviruses are responsible for almost a fifth of all cases of gastroenteritis worldwide. The calicivirus capsid is composed of 180 copies of VP1 with a molecular weight of ~58 kDa. This coat protein is divided into the N-terminus (N), the shell (S) and C-terminal protruding (P) domains. The S domain forms a shell around the viral RNA genome, while the P domains dimerize to form protrusions on the capsid surface. The P domain is subdivided into P1 and P2 subdomains, with the latter containing the binding sites for cellular receptors and neutralizing antibodies. Reviewed here are studies on murine norovirus (MNV) showing that the capsid responds to several physiologically relevant cues; bile, pH, Mg2+, and Ca2+. In the initial site of infection, the intestinal tract, high bile and metal concentrations and low pH cause two significant conformational changes: (1) the P domain contracts onto the shell domain and (2) several conformational changes within the P domain lead to enhanced receptor binding while blocking antibody neutralization. In contrast, the pH is neutral, and the concentrations of bile and metals are low in the serum. Under these conditions, the loops at the tip of the P domain are in the open conformation with the P domain floating on a linker or tether above the shell. This conformational state favors antibody binding but reduces interactions with the receptor. In this way, MNV uses metabolites and environmental cues in the intestine to optimize cellular attachment and escape antibody binding but presents a wholly different structure to the immune system in the serum. To our knowledge, this is the first example of a virus shapeshifting in this manner to escape the immune response.


Upregulation of human immunodeficiency virus-1 in chronically infected monocytic cell line by both contact with endothelial cells and cytokines.
Cells of monocytic lineage (Mo) persistently infected with human immunodeficiency virus (HIV) have been suspected to be a major reservoir for in vivo transmission of virus to susceptible target cells. Cellular events and mechanisms that upregulate viral gene expression in such cells are important issues. Because the traffic of such cells is central to biodistribution of HIV, we have explored the impact of interaction of endothelium with HIV-1-infected U1 promonocytic cells. Coculturing of U1 with human umbilical endothelial cells (HUVEC) for 24 to 72 hours in the absence of stimulation induced HIV-1 p24 biosynthesis significantly. Antibody-blocking experiments indicated that CD11/CD18 integrins play a role in upregulation of HIV expression elicited by interaction with HUVEC. Engagement of CD11b/CD18 by adherence of U1 to surfaces coated with either the cognate ligand fibrinogen or monoclonal antibody specific for CD11b/CD18 also enhanced p24 biosynthesis. Furthermore, endothelial cells were found to constitutively synthesize and secrete soluble factors that enhanced HIV-1 synthesis. The enhancing factors, of estimated size 10 to 45 kD, were induced in HUVEC to high levels by monokines or by lipopolysaccharide, resulting in markedly enhanced HIV-1 expression by U1. These endothelial cell-derived HIV-1-enhancing factors consist of, among others, interleukin-6 (IL-6), IL-1 beta, and granulocyte-macrophage CSF (GM-CSF). Our results suggest that activation of HIV biosynthesis in infected Mo via interaction with endothelium may impact significantly on the tissue distribution and pathogenesis of HIV infections.


Endovascular treatment of complicated type-B aortic dissection with stent-grafts:: midterm results.
To report the midterm results of the endovascular treatment of complicated type-B aortic dissection with use of stent-grafts. Ten patients with acute (n = 4) or chronic (n = 6) complicated type-B dissection were treated with custom-made stent-grafts. Indications for treatment included uncontrollable hypertension with dissection extension (n = 3), renal ischemia (n = 1), and false lumen aneurysm (n = 6). Stainless-steel Z-stents covered with polyester grafts were placed in the initial six patients. Nitinol stents covered with ultrathin polytetrafluoroethylene were used in the remaining four patients. The patients were followed-up with helical computed tomography for a maximum of 30 months (mean, 20 mo). There was one technical failure related to the access site. Early complications included deep venous thrombosis (n = 1) and embolic stroke (n = 1). Complete thrombosis of the thoracic false lumen was achieved in six patients and partial thrombosis was achieved in three. Aneurysms developed at the ends of the stainless-steel stents in two patients, requiring additional stent-graft placement. Despite successful remodeling of the thoracic aorta, three of four patients with distal reentry into the abdominal aorta experienced progressive abdominal aortic aneurysm (AAA). AAA rupture developed in two patients; one rupture was fatal and the other was treated with emergency surgery. Endovascular treatment of complicated type-B aortic dissection is technically feasible and effective. Closely monitoring the treated aorta is essential to detect early aneurysm formation at the ends of rigid stents. Despite adequate sealing of the tears in the thoracic aorta, dissection with distal reentry phenomenon into the abdominal aorta may evolve into AAA with late rupture.


Health risks to cytapheresis donors.
Platelets and granulocytes collected by cytapheresis techniques are recognized as drugs by the US Food and Drug Administration. Though potentially life-saving, like all drugs or therapeutic modalities they have many side-effects, and untoward reactions occur in recipients. However, unlike any other class of drug, cytapheresis products cause untoward and occasionally serious reactions in humans during their preparation. Since the only source for these medications is healthy, human blood donors we should be doubly certain that we use them with care and for very specific indications. Primum non nocere--first, do no harm--is an old and valuable medical axiom , and it applies to our blood donors as well as to our patients. Careful review of our use of these products and intelligent monitoring of appropriate medical and laboratory data in our donors are absolute necessities that we owe to our patients and our various publics . To do less reduces medical practice to mere technology, a state of affairs already too commonplace.


Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma.
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are common in white persons and are associated with pancreatic disease. The purpose of this case-control study was to determine whether CFTR mutations confer a higher risk of pancreatic cancer. In a case-control study, the authors compared the rates of 39 common cystic fibrosis-associated CFTR mutations between 949 white patients with pancreatic adenocarcinoma and 13,340 white controls from a clinical laboratory database for prenatal testing for CFTR mutations. The main outcome measure was the CFTR mutation frequency in patients and controls. Overall, 50 (5.3%) of 949 patients with pancreatic cancer carried a common CFTR mutation versus 510 (3.8%) of 13,340 controls (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.04-1.89; P = .027). Among patients who were younger when their disease was diagnosed (<60 years), the carrier frequency was higher than in controls (OR, 1.82; 95% CI, 1.14-2.94; P = .011). In patient-only analyses, the presence of a mutation was associated with younger age (median 62 vs 67 years; P = .034). In subgroups, the difference was seen only among ever-smokers (60 vs 65 years, P = .028). Subsequent sequencing analysis of the CFTR gene detected 8 (16%) compound heterozygotes among the 50 patients initially detected to have 1 mutation. Carrying a disease-associated mutation in CFTR is associated with a modest increase in risk for pancreatic cancer. Those affected appear to be diagnosed at a younger age, especially among smokers. Clinical evidence of antecedent pancreatitis was uncommon among both carriers and noncarriers of CFTR mutations.


Nitrogen fixation in the marine environment.
Cyanobacteria of the genus Oscillatoria (Trichodesmium) account for annual inputs of nitrogen to the world's oceans of about 4.8 x 10(12) grams while benthic environments contribute 15 x 10(12) grams. The sum of these inputs is one-fifth of current estimates of nitrogen fixation in terrestrial environments and one-half of the present rate of industrial synthesis of ammonia. When the total of all nitrogen inputs to the sea is compared with estimated losses through denitrification, the marine nitrogen cycle approximates a steady state. Oceanic nitrogen fixation can supply less than 0.3 percent of the calculated demand of marine phytoplankton. The minor contribution by nitrogen fixation to the overall nitrogen economy of the sea is not consistent with the supposition that nitrogen is the primary limiting nutrient and suggests that factors other than nitrogen availability limit phytoplankton growth rates.


Secondary haemophagocytic lymphohistiocytosis in hospitalised COVID-19 patients as indicated by a modified HScore is infrequent and high scores do not associate with increased mortality.
A significant proportion of COVID-19 patients show evidence of hyperinflammation (HI), of which secondary haemophagocytic lymphohistiocytosis (sHLH) is the most severe manifestation and diagnosed with HScore. Using a COVID-relevant modification of the HScore (%HScore), we set out to determine the prevalence of sHLH in 567 COVID-19 inpatient cases.The overall incidence of individuals with an 80% probability of sHLH in our COVID-19 cohort was 1.59% on admission and only rose to 4.05% if calculated at any time during admission. This small cohort as defined by %HScore showed no excess mortality compared with the whole cohort. Overall, %HScores were lower in older patients (p<0.0001) and did not reliably predict outcome at any cut-off value (AUROC 0.533, p=0.211, odds ratio 0.99).Our study demonstrates that a modified version (%HScore) of the conventional sHLH scoring system (HScore) does not enable risk stratification in people hospitalised with COVID. We propose further work is needed to develop novel approaches to predict HI and improve trial stratification for HI directed therapy in people with COVID-19.


Trauma care in the tropics: addressing gaps in treating injury in rural and remote Australia.
In Australia, over half a million people are admitted to hospital every year as a result of injury, and where you live matters. Rural populations have disproportionately higher injury hospitalisation rates (1.5-2.5-fold), higher rates of preventable secondary complications, higher mortality rates (up to fivefold), and higher costs (threefold) than patients injured in major cities. These disparities scale up rapidly with increased remoteness, and shift the service needle from 'scoop and run' to 'continuum of care'. Poorer outcomes, however, are not solely due to longer retrieval distances or delays; they arise from inefficiencies in one or more potentially modifiable factors in the chain of survival. After discussing the burden of injury in Australia, we present a brief history of retrieval services in Queensland and discuss how remoteness requires a different kind of service delivery with many moving parts from point of injury to definitive care. We next address the ongoing challenges for the Australian Trauma Registry, and how centralisation of data from the metropolitan cities masks the inequities in rural and remote trauma. There is an urgent need for accurate data from all service providers around Australia to inform state and federal governments, and we highlight the paucity of trauma data analysis in North Queensland. Last, we identify some major gaps in treating rural and remote polytrauma and en-route patient stabilisation, and discuss the relevance of combat casualty care research and practices. We conclude that a greater emphasis should be placed on collecting more robust trauma patient records, as only accurate data will drive change.


Atrial fibrillation among Russian men and women aged 55 years and older: prevalence, mortality, and associations with biomarkers in a population-based study.
To examine the prevalence of atrial fibrillation (AF), its impacts on cardiovascular disease (CVD) and all-cause mortality, and the associations between AF and inflammatory and serum biomarkers in a population-based sample of Muscovites. The study is a secondary analysis of data from the Stress, Aging and Health in Russia (SAHR) survey that includes information on 1800 individuals with an average age of 68.5 years at baseline, and on their subsequent mortality during 7.4 years on average. AF is detected by 12-lead electrocardiogram (ECG) and 24-hour Holter monitoring. The statistical analysis includes proportional hazard and logistic regression models. Of the 1732 participants with relevant Holter data, AF was detected in 100 (74 by ECG and Holter, 26 by Holter only). The prevalence of AF was 5.8% for men and 7.4% for women. The fully adjusted model showed strongly elevated hazard of CVD and all-cause mortality in men and women with long non-self-limiting AF (LAF). LAF was found to be negatively associated with elevated total and low-density lipoprotein cholesterol and to be positively associated with elevated markers of inflammation in women. The study assessed for the first time the prevalence and the risks of death related to AF among older Russians. LAF was shown to be a strong and independent predictor of CVD and all-cause mortality. AF is unlikely to contribute to the large excess male mortality in Russia. The finding that one-quarter of AF cases were detected only by Holter monitoring demonstrates the usefulness of diagnostics with prolonged ECG registration.