Thermal Behavior of d-Ribose Adsorbed on Silica: Effect of Inorganic Salt Coadsorption and Significance for Prebiotic Chemistry.
Understanding ribose reactivity is a crucial step in the "RNA world" scenario because this molecule is a component of all extant nucleotides that make up RNA. In solution, ribose is unstable and susceptible to thermal destruction. We examined how ribose behaves upon thermal activation when adsorbed on silica, either alone or with the coadsorption of inorganic salts (MgCl2 , CaCl2 , SrCl2 , CuCl2 , FeCl2 , FeCl3 , ZnCl2 ). A combination of 13 C NMR, in situ IR, and TGA analyses revealed a variety of phenomena. When adsorbed alone, ribose remains stable up to 150 °C, at which point ring opening is observed, together with minor oxidation to a lactone. All the metal salts studied showed specific interactions with ribose after dehydration, resulting in the formation of polydentate metal ion complexes. Anomeric equilibria were affected, generally favoring ribofuranoses. Zn2+ stabilized ribose up to higher temperatures than bare silica (180 to 200 °C). Most other cations had an adverse effect on ribose stability, with ring opening already upon drying at 70 °C. In addition, alkaline earth cations catalyzed the dehydration of ribose to furfural and, to variable degrees, its further decarbonylation to furan. Transition-metal ions with open d-shells took part in redox reactions with ribose, either as reagents or as catalysts. These results allow the likelihood of prebiotic chemistry scenarios to be evaluated, and may also be of interest for the valorization of biomass-derived carbohydrates by heterogeneous catalysis.


Two methods of self-sampling compared to clinician sampling to detect reproductive tract infections in Gugulethu, South Africa.
To assess the validity, feasibility, and acceptability of 2 methods of self-sampling compared to clinician sampling during a speculum examination. To improve screening for reproductive tract infections (RTIs) in resource-poor settings. In a public clinic in Cape Town, 450 women underwent a speculum examination and were randomized to self-sample with either a tampon or vaginal swabs. All specimens were tested for the same pathogens using the same diagnostic tests. Self-sampling resulted in satisfactory validity for N gonorrhoeae, C trachomatis, bacterial vaginosis, and Candida species (tampons and swabs) and high-risk human papillomavirus (swabs only) when tested with molecular tests or microscopy, but not for T vaginalis by culture. Self-sampling was feasible and acceptable, but some women preferred speculum examinations, which allow the clinician to view the vagina and cervix. Although self-sampling should not replace speculum examinations in all circumstances, it should be explored further as an RTI screening strategy.


A novel microfluidic-based approach to formulate size-tuneable large unilamellar cationic liposomes: Formulation, cellular uptake and biodistribution investigations.
Extensive research has been undertaken to investigate the effect of liposome size in vitro and in vivo. However, it is often difficult to generate liposomes in different size ranges that offer similar low polydispersity and lamellarity. Conventional methods used in the preparation of liposomes, such as lipid film hydration or reverse phase evaporation, generally give rise to liposomal suspensions displaying broad, multimodal size distribution combined with uncontrolled degree of lamellarity. In contrast, microfluidics allows highly homogeneous liposome dispersions to be produced and adjustment of microfluidic operating parameters (flow rate ratio (FRR) and total flow rate (TFR)) can offer size-tuning of liposomes (up to 300 nm, depending on the formulation). Herein, we demonstrate a novel method which allows the production of highly monodisperse, cationic liposomes over a wide particle size range (up to 750 nm in size). This is achieved through controlling the concentration of the aqueous buffer during production. Using this method, liposomes composed of 1,2-dioleoyl-sn-3-phosphoethanolamine (DOPE) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or dimethyldioctadecylammonium (DDA) - DOPE:DOTAP and DOPE:DDA liposomes - of up to 750 nm were prepared and investigated. These investigations demonstrate that the in vitro cellular uptake of small (40 nm) and large (>500 nm) liposomes in bone marrow-derived macrophages (BMDM) is similar terms of percentage of liposome+ cells and mean fluorescence intensity (MFI). However, significant differences are observed in BMDM uptake when represented in terms of number of liposomes, liposome surface area or liposome internal volume. In vivo biodistribution studies in mice show that by creating small (<50 nm) liposomes we can modify the clearance rates of these liposomes from the injection site and increase accumulation to the draining lymphatics.


Vasculitis-like Palpable Purpuric Rash Induced by Decapeptyl in a Pediatric Patient Diagnosed Central Precocious Puberty
Central precocious puberty (CPP) is defined as the appearance of secondary sexual signs in girls younger than eight years of age or the onset of menarche before the age of 10 years. Gonadotropin-releasing hormone analogs (GnRHa) are the most effective therapy in CPP. Drug-induced hypersensitivity vasculitis is an inflammation of blood vessels, which may be due to the use of a number of pharmacologic agents. This case report describes drug-induced vasculitis in a girl being treated with Decapeptyl. A 7.25 year-old girl was admitted to Pediatric Endocrinology outpatients with premature breast development. She was diagnosed with CPP on the basis of physical examination and laboratory findings and tripoteline acetate (Decapeptyl®) treatment was initiated. She experienced multiple widespread skin rashes and mild abdominal pain with high temperature eight hours after the second dose of Decapeptyl. She was admitted to hospital with the diagnosis of drug-induced vasculitis and a single dose of intravenous methyl-prednisolone (1 mg/kg) and oral cetirizine was given. Her blood and urine analysis revealed no other organ involvement, other than skin. On the third day, the purpuric lesions began to resolve and had completely disappeared by the sixth day. Her treatment for CPP was switched to Depot Leuprolide acetate and she continued her treatment for two years uneventfully. To the best of our knowledge, this is the first report of a child with CPP experiencing drug-induced vasculitis due to tripotelin injection. Effective treatment may be continued by switching to an alternative gonadotropin releasing hormone analog.


Prey morphology constrains the feeding ecology of an aquatic generalist predator.
Resource availability and accessibility are primary factors guiding the distribution and abundance of organisms. For generalists, prey availability reflects both prey abundance and differences in quality among prey taxa. Although some aspects of prey quality, such as nutritional composition, are well studied, our understanding of how prey morphology contributes to overall prey quality is limited. Because snakes cannot reduce prey size by mastication, many aspects of their feeding ecology (e.g., maximum prey size, feeding performance, and the degree of postprandial locomotor impairment) may be affected by prey shape. We conducted a uniquely comprehensive comparison of prey quality for a generalist species, the banded watersnake (Nerodia fasciata), using prey that were similar in mass and presumably similar in nutritional composition but different in shape and habitat association. Specifically, we compared nutritional composition and shape of paedomorphic salamanders (Ambystoma talpoideum) and sunfish (Lepomis MARGINATUS) and used a series of repeated-measures experiments to examine feeding performance (number of prey consumed, maximum prey size, and intra-oral transport time), digestive metabolism (specific dynamic action, SDA), and postprandial locomotor performance of snakes fed Ambystoma and Lepomis. Cost of digestion was similar between the prey types, likely reflecting their similar nutritional composition. However, snakes consumed larger Ambystoma than Lepomis and intra-oral transport time was much shorter for Ambystoma. Snakes fed Lepomis also suffered greater reduction in crawling speed than those fed Ambystoma. These differences highlight the need for behaviorally integrated approaches to understanding prey quality and support field observations of the importance of amphibian prey for juvenile watersnakes.


Controlled comparison of pharmacological and psychological treatment of generalized anxiety disorder in primary care.
A sample of 101 patients with generalized anxiety disorder were randomly allocated to one of five groups--diazepam, placebo, cognitive-behaviour therapy, diazepam plus cognitive-behaviour therapy, or placebo plus cognitive-behaviour therapy--and treated over 10 weeks in a primary care setting. All groups received a similar amount of contact with the psychologist and general practitioner. The greatest improvement in ratings of severity of symptoms and overall change in symptoms occurred with cognitive-behaviour therapy combined with diazepam; cognitive-behaviour therapy alone also performed well and cognitive-behaviour therapy plus placebo performed slightly less well. Diazepam alone showed improvement relative to placebo alone. There was a high level of agreement between ratings by the general practitioners, psychologist, and the patients of the response to treatment. At six months follow-up there was no difference between treatment groups in the proportion of patients receiving psychotropic medication after the end of the study. However, cognitive-behaviour therapy, either alone or in combination with drug or placebo, showed the lowest incidence of referral for psychological or psychiatric treatment at six months follow-up.


Critical pathways. A systematic review.
Critical pathways are care plans that detail the essential steps in patient care with a view to describing the expected progress of the patient. The authors' review of the literature suggest the use of critical pathways reduces the cost of care and the length of patient stay in hospital. They also have a positive impact on outcomes, such as increased quality of care and patient satisfaction, improved continuity of information, and patient education.


Radiation and Immune Checkpoint Inhibitors: Combination Therapy for Treatment of Hepatocellular Carcinoma.
The liver tumor immune microenvironment has been thought to possess a critical role in the development and progression of hepatocellular carcinoma (HCC). Despite the approval of immune checkpoint inhibitors (ICIs), such as programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitors, for several types of cancers, including HCC, liver metastases have shown evidence of resistance or poor response to immunotherapies. Radiation therapy (RT) has displayed evidence of immunosuppressive effects through the upregulation of immune checkpoint molecules post-treatment. However, it was revealed that the limitations of ICIs can be overcome through the use of RT, as it can reshape the liver immune microenvironment. Moreover, ICIs are able to overcome the RT-induced inhibitory signals, effectively restoring anti-tumor activity. Owing to the synergetic effect believed to arise from the combination of ICIs with RT, several clinical trials are currently ongoing to assess the efficacy and safety of this treatment for patients with HCC.


1994 survey--healthcare materiel management and central service professions.
Our 1994 professional survey shows an industry in flux. Institutions seem to be getting smaller, job tenure is shrinking for CS managers and materiel managers are convinced there will be fewer of them around. Salaries seem to be flattening for materiel managers, female materiel managers are being financially discriminated against and CS managers, though making more money, are losing benefits. Job dissatisfaction appears to be on the rise for both professions.


Fibrous astrocytes and reactive astrocyte-like cells in transplants of cultured astrocyte precursor cells.
Mouse neopallium was disaggregated at 3 developmental stages (E15, E18, PO) and grown in colony cultures for 7 days. On the seventh day of culturing the colonies of cells were transplanted into the cerebellums of neonatal mice. After 3 weeks the astrocytes within the transplants were identified with GFAP immunoperoxidase staining and by morphometric nuclear measurements of the GFAP positive cells. Cultures of E15 and E18 disaggregated neopallium gave rise to typical fibrous astrocytes in the transplants which were similar to fibrous astrocytes in the cerebral white matter of adult mice. Cultures of PO disaggregated neopallium gave rise to reactive astrocyte-like cells in the transplants which stained intensely for GFAP and had nuclei significantly larger than the astrocytes in the cerebral white matter of adult mice and in transplants of the E15 and E18 cultures.


Propagating solitary waves along a rapidly moving crack front.
A rapidly moving crack in a brittle material is often idealized as a one-dimensional object with a singular tip, moving through a two-dimensional material. However, in real three-dimensional materials, tensile cracks form a planar surface whose edge is a rapidly moving one-dimensional singular front. The dynamics of these fronts under repetitive interaction with material inhomogeneities (asperities) and the morphology of the fracture surface that they create are not yet understood. Here we show that perturbations to a crack front in a brittle material result in long-lived and highly localized waves, which we call 'front waves' These waves exhibit a unique characteristic shape and propagate along the crack front at approximately the Rayleigh wave speed (the speed of sound along a free surface). Following interaction, counter-propagating front waves retain both their shape and amplitude. They create characteristic traces along the fracture surface, providing cracks with both inertia and a new mode of dissipation. Front waves are intrinsically three-dimensional, and cannot exist in conventional two-dimensional theories of fracture. Because front waves can transport and distribute asperity-induced energy fluctuations throughout the crack front, they may help to explain how cracks remain a single coherent entity, despite repeated interactions with randomly dispersed asperities.


Some factors influencing purification of potato virus A (PVA).
Potato virus A (PVA) was purified from mechanically infected plants Nicotiana tabacum cv Samsun by high speed centrifugation and subsequent isopycnic density gradient centrifugation in CsCl gradient. From different procedures tested 0.05 mol/l phosphate buffer (PBS) pH 8 seemed optimal for virus purification and 0.1 mol/l borate buffer pH 8.0 for virus storage; other pH of PBS, Tris and Hepes buffers were less suitable. Additives preventing virus aggregation were beneficial. The average yield ranged about 40 mg virus protein per kg starting material. The purified virus has remained serologically active after 30 days storage.


Testicular Structure and Seminal Pathway in the Yellowtail Tetra Astyanax altiparanae (Characiforms: Characidae).
This study aimed to describe testicular and its main ducts structure in the yellowtail tetra Astyanax altiparanae, contributing to the knowledge of the region in which semen is produced, storage and released, focusing mainly on the dynamic of germinal epithelium and Sertoli cells during germ cell maturation. Ten sexually mature male A. altiparanae had their testes processed according to the routine protocols to optical microscopy. Moreover, spermatic ducts and tubular compartment of the testes of three specimens were perfused with vinyl resin for gross anatomy and scanning electron microscopy. Astyanax altiparanae testes are paired organs, separated for most of their extension, joining posteriorly in a spermatic duct formed by a squamous simple epithelium. Seminiferous compartment presents anastomosing tubular type organisation, and spermatogonia spread along its extent. Spermatogenesis is of cystic type, and there is no main testicular duct. Spermatogenesis develops in 'waves', from posterior to anterior part of the gonad. Thus, while sperm is storage posteriorly, spermatogenesis keeps maturing germ cells anteriorly, making the germinal epithelium very dynamic, holding Sertoli cells that change their function as a cystic envelope to produce secretions of the seminal fluid and store sperm. Such kind of development is thought to be responsible by the high prolificacy of this species.


Detection of clonality by heteroduplex analysis of amplified junctional region of T-cell receptor gamma in patients with T-cell acute lymphoblastic leukemias.
Traditional gel electrophoresis of PCR amplification products of regions from T-cell receptor genes often does not differentiate monoclonal from polyclonal rearrangements. We used polymerase chain reaction (PCR) and heteroduplex analysis on polyacrylamide gels to improve the detection of monoclonal rearrangements. We investigated heteroduplex analysis of the amplified V gamma-J gamma junctions of the rearranged T-cell receptor gamma (TcR-gamma) gene by electrophoretic separation on non-denaturing polyacrylamide gel (PAGE) in 8 T-cell acute lymphoblastic leukemia (T-ALL) patients analyzed at diagnosis. Clonal homoduplex and heteroduplex bands were present only in the T-ALL samples and not in controls. We confirmed clonality by direct sequencing of the V gamma-J gamma junction. In 2 instances the analysis was performed on samples obtained from the same patient at diagnosis and at relapse, respectively; the presence of the same clonal TcR-gamma rearranged cell remained detectable during clinical progression of the disease. Our heteroduplex analysis showed that separation of the PCR product by electrophoresis on non-denaturing PAGE is a rapid and convenient method for the detection of clonal TcR-gamma rearrangements in T-ALL.


Retinoid metabolism in the rat small intestine.
Vitamin A (retinol) is essential for epithelial cell growth, differentiation and proliferation. The absorption of retinol occurs in the small intestine, and the metabolism of this vitamin is not well studied in this organ. The intestinal epithelium has a high rate of cell proliferation and differentiation, and the present study looked at the level of retinoids and metabolizing enzymes involved in their interconversion along the villus-crypt axis under normal conditions. Intestine was removed from control rats, and enterocytes at various stages of maturation and differentiation were quantified by the metal chelation method. Using HPLC, various retinoid concentrations in the cell homogenate and the metabolizing enzymes in the cytosol were quantified. The proliferating crypt cells were found to have a higher level of retinoic acid as well as of the enzymes involved in its formation, such as retinaldehyde oxidase and retinol dehydrogenase, compared with the villus cells, suggesting a possible role for this compound in intestinal epithelial cell proliferation and differentiation. The high level of retinol and high retinaldehyde reductase activity in the villus cells suggest the important role played by this enzyme in the conversion of dietary beta-carotene to retinol via retinaldehyde. In summary, this study has given for the first time a detailed analysis of the retinoid levels and metabolizing enzymes in different cell populations in the rat small intestinal epithelium.


Natural polymorphism of ZmICE1 contributes to amino acid metabolism that impacts cold tolerance in maize.
Cold stress negatively affects maize (Zea mays L.) growth, development and yield. Metabolic adjustments contribute to the adaptation of maize under cold stress. We show here that the transcription factor INDUCER OF CBF EXPRESSION 1 (ZmICE1) plays a prominent role in reprogramming amino acid metabolome and COLD-RESPONSIVE (COR) genes during cold stress in maize. Derivatives of amino acids glutamate/asparagine (Glu/Asn) induce a burst of mitochondrial reactive oxygen species, which suppress the cold-mediated induction of DEHYDRATION RESPONSE ELEMENT-BINDING PROTEIN 1 (ZmDREB1) genes and impair cold tolerance. ZmICE1 blocks this negative regulation of cold tolerance by directly repressing the expression of the key Glu/Asn biosynthesis genes, ASPARAGINE SYNTHETASEs. Moreover, ZmICE1 directly regulates the expression of DREB1s. Natural variation at the ZmICE1 promoter determines the binding affinity of the transcriptional activator ZmMYB39, a positive regulator of cold tolerance in maize, resulting in different degrees of ZmICE1 transcription and cold tolerance across inbred lines. This study thus unravels a mechanism of cold tolerance in maize and provides potential targets for engineering cold-tolerant varieties.


Sublamina densa-type linear IgA bullous dermatosis with IgA autoantibodies specific for type VII collagen: a case report and clinicopathological review of 32 cases.
Linear IgA bullous dermatosis (LABD) is a rare autoimmune bullous disorder characterized by linear deposits of IgA at the basement membrane zone(BMZ) and/or by circulating IgA anti-BMZ antibodies. Comparing with other immuno-bullous diseases, LABD represents a heterogeneous disease entitywith diversity of pathogenic IgA autoantibodies to different hemidesmosomal antigens and an association with malignancies and occasional drug use. We herein present an 82-year-old Japanese man with LABD, whose indirect immunofluorescence using 1M NaCl-split skin showed positive staining for IgA at the dermal side alone. Fluorescence overlay antigen mapping using laser scanning confocal microscopy (FOAM-LSCM) was employed to examine the in vivo bound patient's IgA, which was specific for type VII collagen (COL7), a prominent antigen of the sublamina densa. One year later, he developed malignant lymphoma, suggesting the diagnosis of paraneoplastic LABD. We reviewed 32 cases of sublamina-densa type LABD with anti-COL7 IgA antibodies thus far reported in the literature to compare the clinicopathological characteristics of this rare disease variant and emphasize that COL7 is the main autoantigen in sublamina densa disease.


Biomechanical Evaluation of Glenoid Reconstruction With an Implant-Free J-Bone Graft for Anterior Glenoid Bone Loss.
The anatomic restoration of glenoid morphology with an implant-free J-shaped iliac crest bone graft offers an alternative to currently widely used glenoid reconstruction techniques. No biomechanical data on the J-bone grafting technique are currently available. To evaluate (1) glenohumeral contact patterns, (2) graft fixation under cyclic loading, and (3) the initial stabilizing effect of anatomic glenoid reconstruction with the implant-free J-bone grafting technique. Controlled laboratory study. Eight fresh-frozen cadaveric shoulders and J-shaped iliac crest bone grafts were used for this study. J-bone grafts were harvested, prepared, and implanted according to a previously described, clinically used technique. Glenohumeral contact patterns were measured using dynamic pressure-sensitive sensors under a compressive load of 440 N with the humerus in (a) 30° of abduction, (b) 30° of abduction and 60° of external rotation, (c) 60° of abduction, and (d) 60° of abduction and 60° of external rotation. Using a custom shoulder-testing system allowing positioning with 6 degrees of freedom, a compressive load of 50 N was applied, and the peak force needed to translate the humeral head 10 mm anteriorly at a rate of 2.0 mm/s was recorded. All tests were performed (1) for the intact glenoid, (2) after the creation of a 30% anterior osseous glenoid defect parallel to the longitudinal axis of the glenoid, and (3) after anatomic glenoid reconstruction with an implant-free J-bone graft. Furthermore, after glenoid reconstruction, each specimen was translated anteriorly for 5 mm at a rate of 4.0 mm/s for a total of 3000 cycles while logging graft protrusion and mediolateral bending motions. Graft micromovements were recorded using 2 high-resolution, linear differential variable reluctance transducer strain gauges placed in line with the long leg of the graft and the mediolateral direction, respectively. The creation of a 30% glenoid defect significantly decreased glenohumeral contact areas ( P < .05) but significantly increased contact pressures at all abduction and rotation positions ( P < .05). Glenoid reconstruction restored the contact area and contact pressure back to levels of the native glenohumeral joint in all tested positions. The mean (±SD) force to translate the humeral head anteriorly for 10 mm (60° of abduction: 31.7 ± 12.6 N; 60° of abduction and 60° of external rotation: 28.6 ± 7.6 N) was significantly reduced after the creation of a 30% anterior bone glenoid defect (60° of abduction: 12.2 ± 6.8 N; 60° of abduction and 60° of external rotation: 11.4 ± 5.4 N; P < .001). After glenoid reconstruction with a J-bone graft, the mean peak translational force significantly increased (60° of abduction: 85.0 ± 8.2 N; 60° of abduction and 60° of external rotation: 73.6 ± 4.5 N; P < .001) compared with the defect state and baseline. The mean total graft protrusion under cyclical translation of the humeral head over 3000 cycles was 138.3 ± 169.8 µm, whereas the mean maximal mediolateral graft deflection was 320.1 ± 475.7 µm. Implant-free anatomic glenoid reconstruction with the J-bone grafting technique restored near-native glenohumeral contact areas and pressures, provided secure initial graft fixation, and demonstrated excellent osseous glenohumeral stability at time zero. The implant-free J-bone graft is a viable alternative to commonly used glenoid reconstruction techniques, providing excellent graft fixation and glenohumeral stability immediately postoperatively. The normalization of glenohumeral contact patterns after reconstruction could potentially avoid the progression of dislocation arthropathy.


Exploiting Dynamic Quantum Circuits in a Quantum Algorithm with Superconducting Qubits.
To date, quantum computation on real, physical devices has largely been limited to simple, time-ordered sequences of unitary operations followed by a final projective measurement. As hardware platforms for quantum computing continue to mature in size and capability, it is imperative to enable quantum circuits beyond their conventional construction. Here we break into the realm of dynamic quantum circuits on a superconducting-based quantum system. Dynamic quantum circuits not only involve the evolution of the quantum state throughout the computation but also periodic measurements of qubits midcircuit and concurrent processing of the resulting classical information on timescales shorter than the execution times of the circuits. Using noisy quantum hardware, we explore one of the most fundamental quantum algorithms, quantum phase estimation, in its adaptive version, which exploits dynamic circuits, and compare the results to a nonadaptive implementation of the same algorithm. We demonstrate that the version of real-time quantum computing with dynamic circuits can yield results comparable to an approach involving classical asynchronous postprocessing, thus opening the door to a new realm of available algorithms on real quantum systems.


Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas.
Activating mutations of BRAF have been frequently observed in microsatellite unstable (MSI+) colorectal carcinomas (CRCs), in which mutations of BRAF and KRAS are mutually exclusive. Previously, we reported that hypermethylation of hMLH1 might play an important role in the tumorigenesis of right-sided sporadic CRCs with MSI showing less frequency of KRAS/TP53 alteration. Therefore, we have assumed that BRAF mutations might be highly associated with hMLH1 methylation status rather than MSI status. In this study, mutations of BRAF and KRAS and their relationship with MSI and hMLH1 methylation status were examined in 140 resected specimens of CRC. The methylation status was classified into 3 types: full methylation (FM), partial methylation (PM) and nonmethylation (NM). Only FM closely linked to reduced expression of hMLH1 protein. BRAF mutations were found in 16 cases (11%), all leading to the production of BRAF(V599E). As for MSI status, BRAF mutations were found in 43% of MSI+ and 4% of MSI- cases (p < 0.0001). Among the MSI+ individuals, BRAF mutations were more frequent in cases with hMLH1 deficiency (58%) than those with hMSH2 deficiency (0%; p=0.02). Moreover, they were found in 69% of FM, 4% of PM and 4% of NM, revealing a striking difference between FM and the other 2 groups (FM vs. PM or NM; p < 0.0001). These findings suggest that BRAF activation may participate in the carcinogenesis of sporadic CRCs with hMLH1 hypermethylation in the proximal colon, independently of KRAS activation.


FGF21 Is an Insulin-Dependent Postprandial Hormone in Adult Humans.
Fibroblast growth factor 21 (FGF21) secretion has been shown to respond directly to carbohydrate consumption, with glucose, fructose, and sucrose all reported to increase plasma levels of FGF21 in rodents and humans. However, carbohydrate consumption also results in secretion of insulin. The aim of this study was to examine the combined and independent effects of hyperglycemia and hyperinsulinemia on total and bioactive FGF21 in the postprandial period in humans, and determine whether this effect is attenuated in conditions of altered insulin secretion and action. Circulating glucose, insulin, total and bioactive FGF21, and fibroblast activation protein were measured in adults with and without type 2 diabetes (T2D) following an oral glucose tolerance test (OGTT), and under a series of insulin and glucose clamp conditions and following high-fat diet in healthy adults. Circulating total and bioactive FGF21 levels responded acutely to OGTT, and their ratio was attenuated in T2D patients with reduced postprandial insulin response. The clamp studies revealed that insulin but not glucose accounts for the postprandial rise in FGF21. Finally, there was an attenuated rise in FGF21 in response to a high-fat dietary intervention that is known to alter insulin-stimulated substrate utilization in metabolically active tissues. Insulin rather than glucose per se increases total and bioactive FGF21 in the postprandial period in adult humans. Understanding the impact of T2D on bioactive FGF21 will have a significant effect upon the efficacy of therapeutic agents designed to target the FGF21 pathway.


ASAVACT: Arabic sentiment analysis for vaccine-related COVID-19 tweets using deep learning.
COVID-19 has become a global pandemic that has affected not only the health sector but also economic, social, and psychological well-being. Individuals are using social media platforms to communicate their feelings and sentiments about the pandemic. One of the most debated topics in that regard is the vaccine. People are divided mainly into two groups, pro-vaccine and anti-vaccine. This article aims to explore Arabic Sentiment Analysis for Vaccine-Related COVID-19 Tweets (ASAVACT) to quantify sentiment polarity shared publicly, and it is considered the first and the largest human-annotated dataset in Arabic. The analysis is done using state-of-the-art deep learning models that proved superiority in the field of language processing and analysis. The models are the stacked gated recurrent unit (SGRU), the stacked bidirectional gated recurrent unit (SBi-GRU), and the ensemble architecture of SGRU, SBi-GRU, and AraBERT. Additionally, this article presents the largest Arabic Twitter corpus on COVID-19 vaccination, with 32,476 annotated Tweets. The results show that the ensemble model outperformed other singular models with at least 7% accuracy enhancement.


Immunoelectron microscopic localization of growth factors and other markers in human long-term bone marrow cultures.
Ultrastructural immunocytochemical characterization of human long-term bone marrow cultures has shown positive localization for growth factors on cell surface and on extracellular matrix (ECM). In some cases double-labelling indicated co-localization of growth factors and specific cell surface labels. Specific markers for endothelial cells and fibroblasts showed that growth factor (GM-CSF, G-CSF and b-FGF) were present at the surface of these cell types. Both scanning and transmissiorr electron microscopy indicated intense labelling for growth factors on the extracellular matrix. Double-labelling of heparan sulphate proteoglycans and GM-CSF showed a co-localization of the labelling, which indicated the binding of growth factor to the extracellular matrix.


Xanthorrhizol, a natural sesquiterpenoid from Curcuma xanthorrhiza, has an anti-metastatic potential in experimental mouse lung metastasis model.
Xanthorrhizol is a sesquiterpenoid compound isolated from the rhizome of Curcuma xanthorrhiza. In this study, the anti-metastatic activity of xanthorrhizol was evaluated by using an in vivo mouse lung metastasis model and a tumor mass formation assay. Interestingly, xanthorrhizol dramatically inhibited the formation of tumor nodules in the lung tissue and the intra-abdominal tumor mass formation. Next, to examine the mechanism of the anti-metastatic action of xanthorrhizol in the mouse lung metastasis, expression patterns of the several intracellular signaling molecules were evaluated using the lung tissues with tumor nodules. Higher expression levels of cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), and phosphorylated extracellular signal-regulated kinase (ERK) were observed in the metastatic group compared with control, but these were attenuated by the treatment of xanthorrhizol. In conclusion, xanthorrhizol exerts anti-metastatic activity in vivo and this effect could be highly linked to the metastasis-related multiplex signal pathway including ERK, COX-2, and MMP-9.


Locked plates reduce displacement of vertically unstable pelvic fractures in a Mechanical Testing Model.
The purpose of this study is to compare a locked screw construct to a single iliosacral screw for fixation of a vertically unstable pelvic ring injury in a transforaminal sacral fracture model. Orthopaedic Trauma Association type 61-C1.3a2c5 fractures were created in 10 fresh frozen cadaveric pelvis specimens. Specimens were divided into two groups of five. In both groups, the anterior ring was stabilized with a six-hole 3.5-mm reconstruction plate. In the locked plate (LP) group, the posterior injury was stabilized using a two-hole locking plate with one solid 5.0-mm locking iliosacral screw directed onto the S1 body and a second locking screw directed into the lateral sacral ala. In the iliosacral screw group, the posterior injury was stabilized using a single cannulated 7.3-mm screw. Testing was conducted on a Materials Testing System. Values for displacement and rotation were recorded. Each pelvis was axially loaded with a compressive sine wave from 175 N to 350 N for 10,000 cycles to simulate limited weight bearing, with data recorded at 1,000 cycle increments. Two specimens in the iliosacral screw group displaced more than 1 cm during the first 1,000 cycles. These two specimens displayed gross fracture motion in all planes. All five specimens in the LP group completed 10,000 cycles of testing with less than 1 cm of displacement. A vector displacement calculation from the plane displacement data revealed that the LP group had significantly less displacement (median 1.9 mm) than the specimens in the iliosacral group (median 6.7 mm; p = 0.008) after 10,000 cycles. A two-hole plate locked head screw construct resulted in less displacement than a single iliosacral screw in a transforaminal sacral fracture model.


Microring-based ratio-metric wavelength monitor on silicon.
An integrated dual-ring ratio-metric wavelength monitor (DR-RMWM) with ultra-high wavelength resolution and compact size is demonstrated. Two microrings are used as the edge filters and designed to achieve an "X-type" spectral response in a particular wavelength range. It is fabricated with the CMOS-compatible fabrication process on the silicon-on-insulator. The measured wavelength resolution is 5 pm in a 1.2 nm wide wavelength range. By tuning the resonant wavelength thermally, the functional wavelength range can be shifted. The DR-RMWM can find applications in wavelength monitoring systems, especially the on-chip systems.


The optimal cut-off values for tumor size, number of lesions, and CEA levels in patients with surgically treated colorectal cancer liver metastases: An international, multi-institutional study.
Despite the long-standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long-term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut-offs for these variables have not been established. Patients who underwent curative-intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi-institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut-offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut-offs in the surgical literature. A total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut-offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut-offs. The current study was able to identify optimal cut-offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut-offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores.


The clinical use of plasma clozapine levels in a maximum security setting.
Background. Research suggests a correlation between clozapine dose, plasma level and therapeutic response. Plasma clozapine levels may, therefore, be useful in practice. Little evidence exists, however, on the indications for, and outcome of, levels being undertaken or their use in maximum security settings. Objective. To determine if plasma clozapine levels are useful in clinical practice by analysing their use at the maximum-security State Hospital, Carstairs. Methods. All plasma clozapine levels (until March 2004) undertaken at the State Hospital, clinical indication and outcome were analysed by retrospective case note analysis. These results were compared with the published literature. Results. A total of 140 plasma clozapine levels were analysed. The average level was 0.61 mg/l and dose was 622.9 mg/day. The indications for and consequences of levels are demonstrated. A positive correlation of 0.217 was calculated. Conclusion. This paper shows that plasma clozapine levels are most useful in managing side effects and suspected non-compliance. Plasma clozapine levels are, therefore, useful in clinical practice.


Non-Hodgkin's lymphoma in US children: biometeorological approach.
Previous studies have shown cyclicity in the incidence of malignant melanoma of the skin (Houghton e.a. 1981, Dimitrov 1998, etc.) and associations of such variations with heliogeophysical activity (HGA). The purpose of this study was to investigate trends and patterns of variations in the incidence of non-Hodgkin's lymphoma (NHL) in US children (1973-1989) and their possible relationships to variations in HGA (Rz-index, aa-index). Linear and non-linear regression, autocorrelation, periodogram regression analysis and phase-correlation analysis were applied. No significant trend in incidence of NHL has been found but high-frequency cyclic patterns of variations were revealed (period T = 4 years, p < 0.05). Similar cyclicity has been described also in HGA (period T = 5 divided by 6 years, p < 0.05). Lag-periods in associations of NHL incidence with Rz-index and aa-index have been described--dT = 6, 8, 10, 12 and 12 years, respectively (p < 0.05). To conclude, maximal rates of NHL incidence are most likely to appear on the descending slopes and about minima of HGA cycles, i.e. out of phase. Our results are consistent with the hypothesis of positive associations between incidence of non-Hodgkin's lymphoma and solar phenomena (Cartwright e.a. 1994, etc.)


The effect of galanthamine hydrobromide on plasma ACTH in patients undergoing anaesthesia and surgery.
The effects of two anticholinesterases, galanthamine and neostigmine, on ACTH and, in some cases, cortisol were compared in 16 patients undergoing relaxant anaesthesia and surgery for varicose veins. The procedures produced increases both in ACTH and cortisol. Following administration of the study drugs to reverse the non-depolarising neuromuscular block, a statistically significant elevation of ACTH occurred in those patients who received galanthamine. It was concluded, therefore, that the rise in plasma cortisol is ACTH-dependent and not due to a peripheral cholinergic mechanism.


Placental abruption and long-term maternal cardiovascular disease mortality: a population-based registry study in Norway and Sweden.
Women with preeclamptic pregnancies have increased long-term cardiovascular disease (CVD) mortality. We explored this mortality risk among women with placental abruption, another placental pathology. We used linked Medical Birth Registry and Death Registry data to study CVD mortality among over two million women with a first singleton birth between 1967 and 2002 in Norway and 1973 and 2003 in Sweden. Women were followed through 2009 and 2010, respectively, to ascertain subsequent pregnancies and mortality. Cox regression analysis was used to estimate associations between placental abruption and cardiovascular mortality adjusting for maternal age, education, year of the pregnancy and country. There were 49,944 deaths after an average follow-up of 23 years, of which 5453 were due to CVD. Women with placental abruption in first pregnancy (n = 10,981) had an increased risk of CVD death (hazard ratio 1.8; 95 % confidence interval 1.3, 2.4). Results were essentially unchanged by excluding women with pregestational hypertension, preeclampsia or diabetes. Women with placental abruption in any pregnancy (n = 23,529) also had a 1.8-fold increased risk of CVD mortality (95 % confidence interval 1.5, 2.2) compared with women who never experienced the condition. Our findings provide evidence that placental abruption, like other placental complications of pregnancy, is associated with women's increased risk of later CVD mortality.


A prospective, blinded study of diagnostic esophagoscopy with a superthin, stand-alone, battery-powered esophagoscope.
A more widely available, well-tolerated, and cost-effective technique is needed to screen a broad population at risk for esophageal cancer. An ideal solution might be to perform unsedated esophagoscopy with an entirely self-contained, small-caliber endoscope. In a prospective, blinded study in three phases, we compared the feasibility, patient tolerance, and diagnostic accuracy of esophagoscopy performed with a prototype, superthin, battery-powered esophagoscope (BPE) with standard video esophagogastroduodenoscopy (SVE). In phase I, 10 healthy volunteers underwent both peroral and transnasal esophagoscopy with BPE to evaluate the technical feasibility of the examination. For phases II and III, patients were recruited to have BPE before SVE. In phase II, both procedures were performed with conscious sedation. In phase III, the BPE was performed with only topical anesthesia. Two endoscopists assessed the technical performance of the endoscope and patient tolerance and recorded the esophageal findings independently. In phase I, all endoscopists reported adequate visualization of the esophagus in the 10 volunteers. A total of 181 patients were evaluated in phases II and III (89 in phase II, 92 in phase III). The sensitivity for detecting columnar lined esophagus was 94% in phase II and 95% in phase III. The sensitivity for all esophageal findings was 87% and 86% in phases II and III, respectively. The technical performance of the endoscope was significantly worse for BPE compared with the SVE. The patient tolerance as evaluated by the endoscopist was similar for both procedures. Ninety-five percent of the patients undergoing unsedated BPE were willing to have the procedure repeated under similar circumstances. Unsedated esophagoscopy with a 3.1-mm, battery-powered, stand-alone esophagoscope is feasible, well tolerated, and accurate in detecting esophageal pathologies. It might be an efficient and cost-effective screening tool for the detection of columnar lined esophagus.


LiberRoad: Probing into the Journey of Chinese Classics through Visual Analytics.
Books act as a crucial carrier of cultural dissemination in ancient times. This work involves joint efforts between visualization and humanities researchers, aiming at building a holistic view of the cultural exchange and integration between China and Japan brought about by the overseas circulation of Chinese classics. Book circulation data consist of uncertain spatiotemporal trajectories, with multiple dimensions, and movement across hierarchical spaces forms a compound network. LiberRoad visualizes the circulation of books collected in the Imperial Household Agency of Japan, and can be generalized to other book movement data. The LiberRoad system enables a smooth transition between three views (Location Graph, map, and timeline) according to the desired perspectives (spatial or temporal), as well as flexible filtering and selection. The Location Graph is a novel uncertainty-aware visualization method that employs improved circle packing to represent spatial hierarchy. The map view intuitively shows the overall circulation by clustering and allows zooming into single book trajectory with lenses magnifying local movements. The timeline view ranks dynamically in response to user interaction to facilitate the discovery of temporal events. The evaluation and feedback from the expert users demonstrate that LiberRoad is helpful in revealing movement patterns and comparing circulation characteristics of different times and spaces.


The effect of NOD2 polymorphism on postsurgical recurrence in Crohn's disease: a systematic review and meta-analysis of available literature.
Up to 70% of patients requiring surgery for Crohn's disease (CD) develop recurrence within 10 years. Unequivocal markers predicting recurrence are needed to tailor postoperative therapy appropriately. NOD2 (nucleotide-binding oligomerization domain 2) polymorphisms increase the risk of developing CD; however, their ability to predict recurrence is uncertain. This study aims to determine the association between NOD2 variants and surgical recurrence after initial disease-modifying surgery. A comprehensive search for published series comparing the effect of NOD2 polymorphisms on postoperative surgical recurrence in patients with CD was performed. Random-effects methods were used to combine data. Six cohort studies comprising 1003 patients with CD were included. A total of 340 patients (33.9%) expressed at least 1 of the 3 common NOD2 polymorphisms. The 1003 patients underwent surgical resection with 335 (33%) developing surgical recurrence. Of 340 NOD2-expressing patients, 130 (39%) required further resection, whereas 202 of 663 patients (30.5%) without the variant underwent repeat resection. NOD2 was not significantly associated with surgical recurrence (odds ratio: 1.58, 95% confidence interval: 0.97-2.57, P = 0.064), most likely because of study heterogeneity (Cochran Q: 12.36, P = 0.030, I: 59.6%). The sensitivity of any mutation in predicting disease recurrence was 39.7% and specificity was 69%, with the area under the receiver operating characteristic curve being 0.64. Patients with CD with a NOD2 polymorphism do not have an increased risk of surgical recurrence compared with patients without the variant. These data provide insufficient evidence to support postoperative medical prophylaxis based solely on the presence of NOD2 polymorphism.


Biomechanical testing of a novel osteosynthesis plate for the ulnar coronoid process.
The present study aimed to biomechanically evaluate a novel locking plate intended for osteosynthesis of coronoid fracture compared to mini L-plates and cannulated screws. Biomechanical tests were performed on a fracture model in synthetic bones. Three groups, each with eight implant-bone-constructs, were analyzed in quasi-static and dynamic tests. Finally, samples were tested destructively for maximum strength. The mean (SD) highest stiffness was measured for the novel plate [693 (18) N/mm], followed by the mini L-plate [646 (37) N/mm] and the cannulated screws [249 (113) N/mm]. During the cycling testing of the novel plate and the mini L-plate, no failures occurred, although three of the eight samples of cannulated screws failed during the test. The mean (SD) maximum strength during the destructive testing was 1333 (234) N for the novel plate, 1338 (227) N for the mini-L-plate and 459 (56) N for the cannulated screws. No statistical differences were found during the destructive testing between the two plates (p = 0.999), although statistical differences were found between both plates and the cannulated screws (p = 0.000 each). Osteosynthesis of the coronoid process using the novel plate is mechanically similar to the mini L-plate. Both plates were superior to osteosynthesis with cannulated screws.


piRNAs and epigenetic conversion in Drosophila.
Transposable element (TE) activity is repressed in the Drosophila germline by Piwi-Interacting RNAs (piRNAs), a class of small non-coding RNAs. These piRNAs are produced by discrete genomic loci containing TE fragments. In a recent publication, we tested for the existence of a strict epigenetic induction of piRNA production capacity by a locus in the D. melanogaster genome. We used 2 lines carrying a transgenic 7-copy tandem cluster (P-lacZ-white) at the same genomic site. This cluster generates in both lines a local heterochromatic sector. One line (T-1) produces high levels of ovarian piRNAs homologous to the P-lacZ-white transgenes and shows a strong capacity to repress homologous sequences in trans, whereas the other line (BX2) is devoid of both of these capacities. The properties of these 2 lines are perfectly stable over generations. We have shown that the maternal transmission of a cytoplasm carrying piRNAs from the first line can confer to the inert transgenic locus of the second, a totally de novo capacity to produce high levels of piRNAs as well as the ability to induce homology-dependent silencing in trans. These new properties are stably inherited over generations (n>50). Furthermore, the converted locus has itself become able to convert an inert transgenic locus via cytoplasmic maternal inheritance. This results in a stable epigenetic conversion process, which can be performed recurrently--a phenomenon termed paramutation and discovered in Maize 60 y ago. Paramutation in Drosophila corresponds to the first stable paramutation in animals and provides a model system to investigate the epigenetically induced emergence of a piRNA-producing locus, a crucial step in epigenome shaping. In this Extra View, we discuss some additional functional aspects and the possible molecular mechanism of this piRNA-linked paramutation.


Methylation‑associated inactivation of LATS1 and its effect on demethylation or overexpression on YAP and cell biological function in human renal cell carcinoma.
Large tumor suppressor 1 (LATS1) gene is one of the key factors in Hippo signaling pathway. Inactivation of LATS1 by promoter methylation was found in colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), astrocytoma, breast cancer and it was proved to be a tumor suppressor. However, its role is unclear in renal cell carcinoma (RCC). In this study, the expression of LATS1 was determined by reverse transcription polymerase chain reaction (RT‑PCR) and immunohistochemistry in 30 pairs of RCC tissues and matched normal kidney tissues and RCC cells. We found that the expression of LATS1 was markedly reduced in RCC tissues and cells, in the RCC tissue in 46.7% (14/30), while in the normal kidney tissues in 76.7% (23/30), and was associated with pathological grade and clinical stage of RCC. We detected methylation status of LATS1 by bisulfite sequence-PCR (BSP) in renal cancer cell line 786-O which lowers expression of LATS1, and we found it hypermethy-lated (in 97.5%). In addition, pharmacological demethylation using 5-Aza-2'-deoxycytidine (5-Aza) restored the expression of LATS1 mRNA and protein in 786-O cells, both LATS1 demethylation and overexpression of LATS1 downregulated the expression of Yes-associated protein (YAP), inhibited cell proliferation, induced cell apoptosis and cell cycle G1 arrest in 786-O cells. Thus, this report for the first time demonstrates the inactivation of LATS1 by promoter methy-lation and it is a tumor suppressor in kidney cancer. LATS1 may serve as a biomarker for possible early diagnosis and as a potential therapeutic target for human RCC.


Altered posttranslational processing of glycoproteins in cerulein-induced pancreatitis.
Acute pancreatitis is an auto-digestive disease resulting in inflammation. At the cellular level, acute pancreatitis disrupts posttranslational protein processing and traffic in the secretory pathway, and zymogens become activated in the acinar cell. To better understand the disruption of the secretory pathway in pancreatitis, pulse-chase [(35)S]met/cys analysis was used to study the effects of supramaximal cerulein stimulation on posttranslational modification in the secretory pathway of the major sulfated glycoprotein of the mouse pancreas, pro-Muclin, and the lysosomal membrane protein LAMP1. Maximal cerulein or high concentration bombesin stimulation had little effect on glycoprotein processing. By contrast, supramaximal cerulein stimulation strongly inhibited pro-Muclin processing as measured by the failure of Muclin to attain its normal mature size of 300 kDa and to become highly sulfated and decreased proteolytic cleavage of pro-Muclin to produce apactin. Digestion of immunoprecipitated [35S]met/cys-labeled Muclin and LAMP1 with endoglycosidase H demonstrated that the supramaximal cerulein-induced block in processing occurred before the medial Golgi compartment. With supramaximal cerulein stimulation, vacuoles formed which contained Muclin, amylase, and LAMP1. Earlier autoradiographic studies showed that newly synthesized proteins end up in pancreatitis-associated vacuoles, so it is likely that glycoproteins with incomplete posttranslational processing are also present in vacuoles. Because glycoproteins are believed to protect the membranes of lysosomes and zymogen granules, when they are not correctly processed, their defensive mechanisms may be impaired, and this could contribute to vacuole fragility in pancreatitis.


Magnetic resonance spectroscopy detects biochemical changes in the brain associated with chronic low back pain: a preliminary report.
Magnetic resonance (MR) spectroscopy is a noninvasive technique that can be used to detect and measure the concentration of metabolites and neurotransmitters in the brain and other organs. We used in vivo (1)H MR spectroscopy in subjects with low back pain compared with control subjects to detect alterations in biochemistry in three brain regions associated with pain processing. A pattern recognition approach was used to determine whether it was possible to discriminate accurately subjects with low back pain from control subjects based on MR spectroscopy. MR spectra were obtained from the prefrontal cortex, anterior cingulate cortex, and thalamus of 32 subjects with low back pain and 33 control subjects without pain. Spectra were analyzed and compared between groups using a pattern recognition method (Statistical Classification Strategy). Using this approach, it was possible to discriminate between subjects with low back pain and control subjects with accuracies of 100%, 99%, and 97% using spectra obtained from the anterior cingulate cortex, thalamus, and prefrontal cortex, respectively. These results demonstrate that MR spectroscopy, in combination with an appropriate pattern recognition approach, is able to detect brain biochemical changes associated with chronic pain with a high degree of accuracy.


[Influence of various trace elements on tryptic hydrolysis].
The rate of hydrolysis of the synthetic trypsin substrate N alpha-benzoyl-L-arginine-p-nitroanilide was determined from turnover rate curves, when the trace elements zinc, iron, cobalt, and nickel were added in the concentration range from 0.9 . 10(-7) to 0.9 . 10(-3) mol Men+/l. The enzyme substrate ratio was 1:50. An influence on the activity of trypsin, depending on the element used and on its concentration could be determined. Cobalt and iron accelerated the enzyme's capacity of hydrolysis at all concentrations used, whereas addition of higher but not toxic amounts of zinc or nickel resulted in an inhibition.


Outpatient management of pulmonary embolism.
Despite clear potential benefits of outpatient care, most patients suffering from pulmonary embolism (PE) are currently hospitalized due to the fear of possible adverse events. Nevertheless, some teams have increased or envisage to increase outpatient treatment or early discharge. We performed a narrative systematic review of studies published on this topic. We identified three meta-analyses and 23 studies, which involved 3671 patients managed at home (n=3036) or discharged early (n=535). Two main different approaches were applied to select patients eligible for outpatient in recent prospective studies, one based on a list of pragmatic criteria as the HESTIA rule, the other adding severity criteria (i.e. risk of death) as the Pulmonary Embolism Severity Criteria (PESI) or simplified PESI. In all these studies, a specific follow-up was performed for patients managed at home involving a dedicated team. The overall early (i.e. between 1 to 3 months) complication rate was low, <2% for thromboembolic recurrences or major bleedings and <3% for deaths with no evidence in favour of one selection strategy or another. Outpatient management appears to be feasible and safe for many patients with PE. In the coming years, outpatient treatment may be considered as the first line management for hemodynamically stable PE patients, subject to the respect of simple eligibility criteria and on the condition that a specific procedure for outpatient care is developed in advance.


Facile synthesis of core-shell structured magnetic covalent organic framework composite nanospheres for selective enrichment of peptides with simultaneous exclusion of proteins.
Selective enrichment of peptides from complex biosamples is essential for mass spectrometry-based proteomics but still remains a challenge. In this work, a facile approach was developed for rapid room-temperature synthesis of core-shell structured magnetic covalent organic framework composite nanospheres (denoted as Fe3O4@TbBd) by using monodisperse Fe3O4 nanoparticles as the magnetic core and 1,3,5-triformylbenzene (Tb) and benzidine (Bd) as two building blocks in the presence of dimethyl sulfoxide (DMSO). The resultant core-shell structured Fe3O4@TbBd nanospheres exhibited high adsorption capacity (28.5 mg g-1), fast adsorption kinetics (<5 min) and excellent reusability (more than 30 times) for peptides, owing to their specific properties of high surface area (196.21 m2 g-1), large pore volume (0.63 cm3 g-1), narrow pore size distribution (∼2.8 nm), strong magnetic response (41.5 emu g-1), as well as good thermal and chemical stability. Moreover, the Fe3O4@TbBd nanospheres also showed good selectivity towards hydrophobic peptides and a size-exclusion effect against proteins due to the inherent π-π stacking interaction and interconnected mesoporous channels of covalent organic framework (COF) shells. Taking advantage of these composite nanospheres, selective extraction and efficient enrichment of low abundance hydrophobic peptides from human serum in the presence of high abundance proteins were achieved. Based on the HPLC-Q-TOF/MS results, 29 hydrophobic peptides assigned to 12 proteins were clearly identified in 5 ng μL-1 human serum digestion upon treatment with Fe3O4@TbBd nanospheres, much better than those obtained without treatment, confirming the outstanding performance of the Fe3O4@TbBd nanospheres in proteome analysis.


Modulations of immune functions and oxidative status induced by noise stress.
Noise has long been realized as an environmental stress causing physiological, psychological and behavioral changes in humans. The aim of the present study was to determine the effect of acute or chronic noise stress on both cellular and humoral immune responses and oxidative status. BALB/c mice were exposed to 90 dB (A) white noise 5 h per day for either 3 d or 4 wk. Hormone levels, splenic lymphocyte proliferation, lymphocyte subsets in spleen and thymus, serum antibody and oxidative status were determined. A 3-d exposure to noise stress resulted in increased hormone levels, splenic lymphoproliferation and serum IgM. On the other hand, a 4-wk exposure to noise stress caused a reduction of splenic lymphoproliferation, splenic CD4(+) cells and serum IgG, but hormone levels and urinary 8-hydroxy-2'deoxyguanosine (8-OHdG) were increased. These results imply that acute exposure to noise stress may enhance immune responses, whereas chronic exposure to noise stress may suppress both cellular and humoral immune functions. The effect of noise stress on immune functions may be related to neuroendocrine modulation and oxidative imbalance as well.


The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1.
The signaling phosphatidylinositol lipids PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind nuclear receptor 5A family (NR5As), but their regulatory mechanisms remain unknown. Here, the crystal structures of human NR5A1 (steroidogenic factor-1, SF-1) ligand binding domain (LBD) bound to PIP2 and PIP3 show the lipid hydrophobic tails sequestered in the hormone pocket, as predicted. However, unlike classic nuclear receptor hormones, the phosphoinositide head groups are fully solvent-exposed and complete the LBD fold by organizing the receptor architecture at the hormone pocket entrance. The highest affinity phosphoinositide ligand PIP3 stabilizes the coactivator binding groove and increases coactivator peptide recruitment. This receptor-ligand topology defines a previously unidentified regulatory protein-lipid surface on SF-1 with the phosphoinositide head group at its nexus and poised to interact with other proteins. This surface on SF-1 coincides with the predicted binding site of the corepressor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X), and importantly harbors missense mutations associated with human endocrine disorders. Our data provide the structural basis for this poorly understood cluster of human SF-1 mutations and demonstrates how signaling phosphoinositides function as regulatory ligands for NR5As.


Long-term follow-up of polyneuropathy in diabetic kidney transplant recipients.
Nerve conduction and electromyography (EMG) of insulin-dependent (type 1) diabetic patients with end-stage nephropathy was studied before and up to 10 yr after kidney transplantation (KTx). A series of nondiabetic KTx patients served as a comparison group. Motor nerve conduction velocity (NCV) was measured in the ulnar, median, peroneal, and tibial nerves; sensory NCV was measured in the median nerve. EMG was performed in the first dorsal interosseus, flexor carpi radialis, anterior tibialis, and gastrocnemius muscles. In 68 pre-KTx diabetic patients, the mean NCV was below normal in all nerves, and the mean amplitudes of the evoked muscle action potential (MAP) were low normal in the upper extremity and below normal in the lower extremity. The values of the comparison group were within the normal range. At 1 (n = 57), 5 (n = 23), and 10 (n = 10) yr after KTx, the mean NCV of the diabetic patients remained essentially unchanged, but MAP amplitudes of all muscles had declined. EMG revealed progression of the denervation process, especially in muscles of the lower extremities. We conclude that diabetic neuropathy continues to progress by a progressive axonal loss after correction of uremia by KTx.


Interpretation of fractional flow reserve in ST-elevation myocardial infarction culprit lesions.
Pressure wire assessment of the infarct-related artery (IRA) in ST-elevation myocardial infarction (STEMI) is not recommended until microcirculatory dysfunction recovers. The objective of this study was to assess serial fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) in the IRA of STEMI patients to better understand and interpret FFR during primary percutaneous coronary intervention (PPCI). Forty-one patients undergoing PPCI for STEMI were studied with a pressure wire at baseline after thrombectomy and after stenting. The majority of STEMI culprit lesions in the IRA were haemodynamically significant (mean FFR pre-PPCI: 0.54±0.20); only 4/41 culprit lesions had FFR greater than 0.80. The FFR of the culprit lesion and the initial IMR were correlated (r=0.45, P=0.004). Patients with a normal initial IMR of less than 25 exhibited lower culprit lesion FFR values (0.47±0.20 vs. 0.60±0.18, P=0.03) despite milder angiographic stenoses [angiographic stenoses (%): 80.4±10.4 vs. 86.6±8.0, P=0.03] but showed a reduction in the IMR during PPCI (pre-PPCI: 16.9±5.7 vs. post-PPCI: 32.2±22.6, P=0.009). STEMI culprit lesions are haemodynamically significant. A subset of STEMI IRAs has initially preserved microcirculatory function; thus, the culprit stenosis may feasibly be assessed through FFR.


Superradiance lattice.
We show that the timed Dicke states of a collection of three-level atoms can form a tight-binding lattice in momentum space. This lattice, coined the superradiance lattice (SL), can be constructed based on electromagnetically induced transparency (EIT). For a one-dimensional SL, we need the coupling field of the EIT system to be a standing wave. The detuning between the two components of the standing wave introduces an effective uniform force in momentum space. The quantum lattice dynamics, such as Bloch oscillations, Wannier-Stark ladders, Bloch band collapsing, and dynamic localization can be observed in the SL. The two-dimensional SL provides a flexible platform for Dirac physics in graphene. The SL can be extended to three and higher dimensions where no analogous real space lattices exist with new physics waiting to be explored.


B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events.
To understand the molecular mechanisms that are responsible for the B cell overactivity that is observed in patients with SLE, we have conducted experiments in which the surface immunoglobulin (sIg)-mediated early cell signaling events were studied. The anti-sIgM-mediated free intracytoplasmic calcium ([Ca2+]i) responses were significantly higher in SLE B cells compared with responses of normal individuals and to those of patients with other systemic autoimmune rheumatic diseases. The anti-IgD mAb induced [Ca2+]i responses were also higher in lupus B cells than in controls. The magnitude of anti-sIgM-mediated Ca2+ release from intracellular stores was also increased in B cells from SLE patients compared with normal controls. The amount of inositol phosphate metabolites produced upon crosslinking of sIgM was slightly higher in patients with lupus than in normal controls, although the difference was not statistically significant. In contrast, the degree of anti-sIgM-induced protein tyrosine phosphorylation was obviously increased in lupus patients. Our study demonstrates clearly for the first time that SLE B cells exhibit aberrant early signal transduction events, including augmented calcium responses after crosslinking of the B cell receptor and increased antigen-receptor-mediated phosphorylation of protein tyrosine residues. Because the above abnormalities did not correlate with disease activity or treatment status, we propose that they may have pathogenic significance.


Adult vector control, mosquito ecology and malaria transmission.
Standard advice regarding vector control is to prefer interventions that reduce the lifespan of adult mosquitoes. The basis for this advice is a decades-old sensitivity analysis of 'vectorial capacity', a concept relevant for most malaria transmission models and based solely on adult mosquito population dynamics. Recent advances in micro-simulation models offer an opportunity to expand the theory of vectorial capacity to include both adult and juvenile mosquito stages in the model. In this study we revisit arguments about transmission and its sensitivity to mosquito bionomic parameters using an elasticity analysis of developed formulations of vectorial capacity. We show that reducing adult survival has effects on both adult and juvenile population size, which are significant for transmission and not accounted for in traditional formulations of vectorial capacity. The elasticity of these effects is dependent on various mosquito population parameters, which we explore. Overall, control is most sensitive to methods that affect adult mosquito mortality rates, followed by blood feeding frequency, human blood feeding habit, and lastly, to adult mosquito population density. These results emphasise more strongly than ever the sensitivity of transmission to adult mosquito mortality, but also suggest the high potential of combinations of interventions including larval source management. This must be done with caution, however, as policy requires a more careful consideration of costs, operational difficulties and policy goals in relation to baseline transmission.


The physicochemical properties of geraniin, a potential antihyperglycemic agent.
Natural products play a vital role in the discovery of leads for novel pharmacologically active drugs. Geraniin (GE) was identified as the major compound in the rind of Nephelium lappaceum L. (Sapindaceae), while ellagic and gallic acids have been shown to be its main metabolites. GE and its metabolites possess a range of bioactive properties including being an anti-infective, anticarcinogenic, antihyperglycemic, and antihypertensive. GE and its metabolites were investigated to establish its gastrointestinal absorption and physicochemical properties. GE was purified from N. lappaceum rind extract using reverse-phase C18 column chromatography. Lipophilicity (log P) was determined using the 1-octanol/water shake-flask method. Equilibrium solubility of GE and its metabolites (20 mg) was determined in water and four biorelevant media: simulated gastric, simulated intestinal, fasted state-simulated intestinal, and fed state-simulated intestinal after 72 h. The purification yield was 10.8%; where a 97-99% pure GE was obtained. Log P values for GE, ellagic, and gallic acids were established as -0.73 ± 0.17, 0.11 ± 0.06, and 0.71 ± 0.21, respectively, establishing them as polar compounds. All three compounds were found to exhibit poor solubility in gastric (0.61-8.10 mg/mL) but good solubility in intestinal fluids (3.59-14.32 mg/mL). The above results indicate that the compounds have limited gastrointestinal absorption due to its polarities. To consider these compounds as oral drug candidates, formulation strategies are being developed.


Eradication of poliomyelitis in countries affected by conflict.
The global initiative to eradicate poliomyelitis is focusing on a small number of countries in Africa (Angola, Democratic Republic of the Congo, Liberia, Sierra Leone, Somalia, Sudan) and Asia (Afghanistan, Tajikistan), where progress has been hindered by armed conflict. In these countries the disintegration of health systems and difficulties of access are major obstacles to the immunization and surveillance strategies necessary for polio eradication. In such circumstances, eradication requires special endeavours, such as the negotiation of ceasefires and truces and the winning of increased direct involvement by communities. Transmission of poliovirus was interrupted during conflicts in Cambodia, Colombia, El Salvador, Peru, the Philippines, and Sri Lanka. Efforts to achieve eradication in areas of conflict have led to extra health benefits: equity in access to immunization, brought about because every child has to be reached; the revitalization and strengthening of routine immunization services through additional externally provided resources; and the establishment of disease surveillance systems. The goal of polio eradication by the end of 2000 remains attainable if supplementary immunization and surveillance can be accelerated in countries affected by conflict.


Intravitreal sustained-release cyclosporine in the treatment of experimental uveitis.
Uveitis often is a chronic disease requiring long-term medical therapy. Despite treatment, the disease may be difficult to control and may produce serious, vision-threatening ocular complications. In this study, the authors determined whether an intravitreal cyclosporine-sustained delivery device was effective in the treatment of ocular inflammation in a rabbit model of uveitis. New Zealand White rabbits were immunized subcutaneously with Mycobacterium tuberculosis H37Ra antigen. Fourteen days later, sustained-release cyclosporine devices were implanted into the vitreous cavity of the right eye of experimental rabbits. Control animals received sham devices. Seven days after device implantation, rabbits were challenged with an intravitreal injection of tuberculin antigen. To simulate chronic inflammation with exacerbations, some animals were rechallenged with intravitreal antigen on day 21 after device implantation. Inflammation was assessed clinically by a masked observer who graded anterior chamber cells, flare, corneal neovascularization, iris congestion, and vitreous opacity daily until day 7 and on day 13 after the initial intravitreous challenge, and on days 1 and 2 after the rechallenge. Retinal function was evaluated by electroretinography. Animals were killed 3, 6, 8, and 14 days after the initial intravitreal challenge and on the second day after rechallenge for aqueous leukocyte count, protein measurement, and histologic examination. The number of aqueous and peripheral blood proliferating lymphocytes and the subset of CD4+ T cells were determined by flow cytometry. High-performance liquid chromatography was used to measure cyclosporine A levels in vitreous and peripheral blood. Light microscopy was used to evaluate the eyes histopathologically. By clinical criteria, treated eyes had significantly less inflammation than untreated eyes. The number of aqueous cells and protein concentration determined quantitatively paralleled the clinical assessment of anterior chamber cells and flare. The electroretinography B-wave was depressed significantly in untreated eyes compared with that of treated eyes (P < 0.02). Histopathologic examination results showed marked inflammation and tissue disorganization in untreated eyes, whereas cyclosporine-treated eyes had preserved architecture and greatly reduced inflammatory cells. Intravitreal cyclosporine remained at therapeutic levels for at least 6 months after intravitreal device implantation, whereas blood levels were low to nondetectable. The intravitreal cyclosporine A device effectively suppresses ocular inflammation in a rabbit model of uveitis. This device may be useful in the treatment of patients with severe chronic uveitis who are intolerant to currently available therapies.


[Mucosal morphology in the latent form of terminal ileitis in children based on biopsy data].
Morphological study of serial section biopsies from 22 children was made to develop new diagnostic criteria of a latent form of terminal ileitis. The following changes were observed: fibroblastic reaction around the lymphoid follicles, degenerative changes of enterocytes close to the lymphoid follicles; disruption of basal membrane over the lymphoid follicles; penetration of lymphoid cells into the intestinal lumen and their adhesion to the apical membrane of enterocytes; neuroma-like structures as an issue of productive vasculitis. The frequency of the symptoms above 62% does not depend on the sex, age and treatment method.


Role of bacterial products in periodontitis: immune response in gnotobiotic rats monoinfected with Eikenella corrodens.
The development of humoral and cell-mediated immune responses to Eikenella corrodens (a bacterium that causes periodontal lesions in gnotobiotic rats) was measured and compared with the rate of appearance of macroscopic lesions. A possible inverse relationship was found. A strong cell-mediated immune response, as measured by skin reactivity and lymphocyte mitogenesis, occurred between 4 and 6 weeks after infection and subsided soon thereafter to a low response level. Humoral antibodies to endotoxin from E. corrodens could not be detected at any time. The disease developed only after the cell-mediated immune response diminished, thus suggesting that lack of an efficient immune response may permit the development of the disease. This is seemingly in contradiction to the assumption that tissue destruction in such cases is caused by the immune response and its products. We are inclined to believe, based on our findings reported here, that the lack of immune responsiveness to the bacterium and/or its products is the major causative factor in the development of periodontitis. At the same time, we wish to emphasize that occurrence of both phenomena during the long development of periodontal disease is possible.


Early Achilles tendon healing in sheep.
The biomechanics of early tendon healing is important for designing post-injury training, but this has not been described in an animal model, similar to humans in size. We measured elastic and viscoelastic properties of a tendon regenerate in sheep, in a study designed to see the effects of exogenously applying the growth and differentiation factor CDMP-2. This is the first description of early tendon healing in sheep Achilles tendons. Twenty female sheep underwent Achilles tendon transection without suturing or immobilization. Two hours after the operation, 100 mug of CDMP-2 or placebo was injected into the hematoma. The sheep were slaughtered after 3 weeks, and tendon regenerates tested for viscoelastic properties by cyclical loading, before a destructive tensile test. Thereafter, all specimens were examined by high resolution computerized tomography (CT), and histology. The tendon regenerate formed a sleeve, around the tendon stumps. Failure occurred between the regenerate sleeve and the tendon stumps. There was an unexpectedly large variation in force at failure. In the CDMP-2 group, force correlated with regenerate transverse area, but not in the controls. Thus, the variation in maximum stress was smaller in the CDMP-2 group (P = 0.009). Although the force at failure was only a tenth of normal, the capacity to store elastic energy was already near normal (hysteresis 16%). The mean transverse area, force at failure and stiffness were all about 30% larger in the CDMP-2 group, but this was not significant. There were no signs of bone or cartilage formation on CT or histology. Results are compatible with a positive effect of CDMP-2, but the power was too low to demonstrate any such effect. Considering that spontaneous ruptures in humans are likely to have a more variable geometry than in this model, humans can also be expected to vary a lot in early mechanical characteristics. This emphasizes the importance of individualized rehabilitation programs. The low hysteresis suggests that the energy storing capacity is rather easy for the tissues to develop; possibly it is harder to create appropriate energy dissipation, in order to avoid re-rupture.


Pubertal Development and Pregnancy Outcomes in 46,XX Patients With Nonclassic Lipoid Congenital Adrenal Hyperplasia.
Lipoid congenital adrenal hyperplasia (LCAH) is characterized by a disorder of steroidogenesis in both adrenal glands and gonads. 46,XX patients with classic LCAH usually have thelarche and menarche but show anovulatory menstruations and subsequent premature menopause. Only three patients with classic LCAH have been reported to successfully achieve delivery with the aid of assisted reproductive therapies for conception and progesterone replacement therapy during early pregnancy. In contrast, pubertal development and pregnancy outcomes in patients with nonclassic LCAH have not been fully elucidated. We report four Japanese women who had a diagnosis of primary adrenal insufficiency during infancy or childhood and carried compound heterozygous STAR mutations (p.Gln258* and p.Arg188His, p.Gln258* and p.Met225Thr, and p.Gln258* and p.Arg272Cys). In all four patients, thelarche and menarche spontaneously occurred from 10 to 11 years of age and from 12 to 14 years of age, respectively. Subsequently, their menstruation cycles were regular at almost 1-month intervals. Patient 1 conceived naturally twice, and patient 2 conceived with the use of clomiphene citrate for ovulation induction. These two patients maintained the pregnancies without progesterone replacement therapy and successfully delivered children. Patients with nonclassic LCAH maintain ovarian function, which enables normal pubertal development and a successful pregnancy outcome without progesterone replacement therapy.


Bistability in a model of early B cell receptor activation and its role in tonic signaling and system tunability.
Activation of the antigen receptors on the surface of B cells in response to their cognate ligands is tightly controlled by feedback mechanisms. Apart from ligand induced signaling, B cell receptors (BCRs) emanate ligand independent tonic signaling crucial for B cell survival and development. In the absence of a ligand, BCR tonic signaling is controlled by the basal activity of the Src family protein tyrosine kinase Lyn and the protein tyrosine phosphatase SHP. The binding of an antigen to the BCR causes receptor clustering or aggregation which is one of the earliest events in B cell activation. Lyn binds to aggregated receptors and phosphorylates them. In turn phosphorylation enhances the stability of receptor clusters against dissociation into monomers as well as the binding of Lyn to the receptor clusters, thereby producing positive feedback loops that enhance receptor clustering and activation. Apart from Lyn mediated positive feedback loops, SHP and BCR aggregates mutually inhibit each other to form a double negative feedback loop. Here, we present a simple computational model of BCR proximal signaling that incorporates these multiple feedback loops between the three molecules BCR, Lyn and SHP and their complexes. The model predicts bistable behaviour in the system that explains both the tonic signaling and ligand mediated receptor activation and a range of other biological phenomena in a unified manner. We find the bistability to be highly tunable by changes in the protein levels while remaining sufficiently robust to changes in the rate constants. The nested architecture of multiple feedback loops enhances the robustness of the bistability. Our model explains the recent experimental observation of the lack of response of germinal center B cells to ligand stimulation in terms of the tunability of the bistable switch by modification of SHP levels.


[Essential hypertension, dementia, and antihypertensive therapy in geriatric patients].
The review summarizes the current views on the pathogenesis of dementia and the significance of blood pressure levels for its development. The present status of the prevention of cognitive disorders and dementia is detailed in the use of antihypertensive therapy: there are the data of prospective cohort studies of the impact of antihypertensive therapy on the risk of dementia, the results of placebo-controlled studies in the groups of elderly and senile patients with a history of cerebrovascular complications, and the data of meta-analyses of studies. As for cognitive function, the effects of different classes of the currently available antihypertensive agents, such as diuretics, calcium antagonists, angiotensin-converting enzyme inhibitors, and angiotensin II type 1 receptor antagonists, are analyzed.


In-vitro regulation of odontogenic gene expression in human embryonic tooth cells and SHED cells.
The bud-to-cap stage transition during early tooth development is a time when the tooth-inducing potential becomes restricted to the mesenchyme. Several key genes, expressed in the mesenchyme at this stage, are an absolute requirement for the progression of tooth development. These include the transcription factors Msx1 and Pax9. The inductive potential of tooth mesenchyme cells is a key requisite for whole-tooth bioengineering and thus identification of cells that can retain this property following expansion in culture is an important as yet unresolved, goal. We show here that in-vitro culture of embryonic human tooth mesenchyme cells and SHED cells express low levels of PAX9 and MSX1 and that these levels can be significantly upregulated by activation of different signalling pathways. Such in-vitro manipulation may thus offer a simple way of maintaining/restoring/inducing the odontogenic-inducing capacity in mesenchymal cells.


Demographic and clinical variables affecting mid- to late-life trajectories of plasma ceramide and dihydroceramide species.
It has been increasingly recognized at the basic science level that perturbations in ceramide metabolism are associated with the development and progression of many age-related diseases. However, the translation of this work to the clinic has lagged behind. Understanding the factors longitudinally associated with plasma ceramides and dihydroceramides (DHCer) at the population level and how these lipid levels change with age, and by sex, is important for the clinical development of future therapeutics and biomarkers focused on ceramide metabolism. We, therefore, examined factors cross-sectionally and longitudinally associated with plasma concentrations of ceramides and DHCer among Baltimore Longitudinal Study of Aging participants (n = 992; 3960 total samples), aged 55 years and older, with plasma at a mean of 4.1 visits (range 2-6). Quantitative analyses were performed on a high-performance liquid chromatography-coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess the relationships between plasma ceramide and DHCer species and demographics, diseases, medications, and lifestyle factors. Women had higher plasma concentrations of most ceramide and DHCer species and showed steeper trajectories of age-related increases compared to men. Ceramides and DHCer were more associated with waist-hip ratio than body mass index. Plasma cholesterol and triglycerides, prediabetes, and diabetes were associated with ceramides and DHCer, but the relationship showed specificity to the acyl chain length and saturation. These results demonstrate the importance of examining the individual species of ceramides and DHCer, and of establishing whether intra-individual age- and sex-specific changes occur in synchrony to disease onset and progression.


Application of negative pressure wound therapy in patients with wound dehiscence after abdominal open surgery: a single center experience.
Since the 1990's, negative pressure wound therapy (NPWT) has been used to treat soft tissue defects, burn wounds, and to achieve skin graft fixation. In the field of abdominal surgery, the application of NPWT is increasing in cases with an open abdominal wound requiring temporary wound closure and a second look operation. In the present study, the authors analyzed patients that underwent NPWT for postoperative wound dehiscence. The computerized records of patients that had undergone an abdominal operation from November 2009 to May 2012 were retrospectively analyzed. The number of total enrolled patients was 50, and 30 patients (60%) underwent an emergency operation. Diagnoses were as follows: panperitonitis or intra-abdominal abscess (24 cases, 48%), intestinal obstruction (10 cases, 20%), cancer (7 cases, 14%), mesentery ischemia (3 cases, 6%), and hemoperitoneum (1 case, 2%). NPWT was applied at a mean of 12.9 ± 8.2 days after surgery and mean NPWT duration was 17.9 days (2 to 96 days). The 11 patients (22%) with unsuccessful wound closure had a deeper and more complex wound than the other 39 patients (78%) (90.9% vs. 38.5%, P = 0.005). There were two complication cases (4%) due to delayed wound healing. Most patients recovered well due to granulation formation and suturing. NPWT was found to be convenient and safe, but a prospective comparative study is needed to confirm the usefulness of NPWT in patients whose wounds are dehisced.


Tribological and Dynamical Mechanical Behavior of Prototyped PLA-Based Polymers.
It is essential to combine current state-of-the-art technologies such as additive manufacturing with current ecological needs. Due to the increasing demand for non-toxic biodegradable materials and products, human society has been searching for new materials. Consequently, it is compulsory to identify the qualities of these materials and their behavior when subjected to various external factors, to find their optimal solutions for application in various fields. This paper refers to the biodegradable Polylactic acid (PLA)-based filament (commercially known as Extrudr BDP (Biodegradable Plastic) Flax) compared with the biodegradable composite material PLA-lignin filament whose constituent's trade name is Arboblend V2 Nature as a lignin base material and reinforcement with Extrudr BDP Pearl, a PLA based polymer, 3D printed by Fused Deposition Modeling technology. Certain mechanical properties (tensile strength, bending strength and DMA-Dynamic Mechanical Analysis) were also determined. The tribology behavior (friction coefficient and wear), the structure and the chemical composition of the biodegradable materials were investigated by SEM-Scanning Electron Microscopy, EDX-Energy Dispersive X-Ray Analysis, XRD-X-Ray Diffraction Analysis, FTIR-Fourier Transform Infrared Spectrometer and TGA-Thermogravimetric Analysis. The paper also refers to the influence of technological parameters on the 3D printed filaments made of Extrudr BDP Flax and the optimization those of technological parameters. The thermal behavior during the heating of the sample was analyzed by Differential scanning calorimetry (DSC). As a result of the carried-out research, we intend to recommend these biodegradable materials as possible substituents for plastics in as many fields of activity as possible.


Only particular cytogenetic events are related to disease progression in sequential cytogenetic studies in myelodysplastic syndromes.
We performed prospective sequential cytogenetic studies in 76 patients with myelodysplastic syndromes (MDS) followed up to 82 months. Their karyotypes were followed routinely, regardless of clinical status. The incidence of evolutive karyotypes was similar in patients with a normal karyotype at referral and in patients with clonal abnormalities at diagnosis (24.5 and 26.1%, respectively). We did not find association between karyotype evolution and leukemic transformation or reduced survival, since the majority of secondary cytogenetic changes in evolutive karyotypes of our patients were aberrations with good or intermediate prognosis. Therefore, we concluded that only particular cytogenetic events are related to disease progression, while others represent secondary changes of little biologic and prognostic significance.


[Lymphatic axillary metastasis in cancer of the breast].
From 1978 at the Gynecology service of the Hospital Civil of Guadalajara we conducted a study with 50 patients with breast cancer in which we related the size tumor with some risk factors of breast cancer with axilar ganglionar metastasis. The average size of the tumor was 4.9 cm, 21 patients (42%) had evidence of ganglionar axilar metastasis, 64% were located in the upper-outer quadrant, the average age was 52.7 years, 52% were pre-menopausic, 20% had backgrounds of bening disease of the breast and 20% had familiar backgrounds of breast cancer. 31.8% of the tumors from 2-4 cm had axillar metastasis vs 52.2% of tumors from the upper-outer quadrant and 80% from the upper-outer and inner quadrant had axillar metastasis. Only in 33.3% of the patients under 40 years old, axillar metastasis was found. The hormonal state, the background of bening disease and familiar backgrounds of breast cancer had no relationship with the incidence of axillar ganglionar metastasis. In conclusion, axillar ganglionar metastasis has a direct relation with the size of the breast tumor and its location.


Bovine mastitis bacteria resolved by MALDI-TOF mass spectrometry.
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a fast and reliable method to identify the most common pathogenic bacteria in humans and animals. The goals of this study were to amend a commercial database with additional species, evaluate the amended database for identification of bacterial genera and species causing bovine mastitis, and describe the plethora of species involved. In total, 500 udder pathogenic isolates were subjected to MALDI-TOF MS using bacterial or fungal colony material; 93.5% could be identified to the species level, and 6.5% were identified only to the genus level. Isolates identified to the genus level required further identification to the species level by conventional methods or 16S rDNA sequencing. Mass spectra from verified species were used to expand the MALDI-TOF MS database to improve future identification ability. A total of 24 genera and 61 species were identified in this study. Identified isolates were mainly staphylococci, streptococci, Enterobacteriaceae, and coryneforme bacteria. In conclusion, MALDI-TOF MS is a powerful, rapid, and reliable technique to identify the most common microorganisms causing bovine mastitis, and the database can be continuously expanded and improved with additional species.


Killed poliovaccine: an evaluation of safety testing.
Several important changes in the production process of killed poliovaccine have recently taken place or are taking place concerning cell substrate as well as production techniques. Some of the consequences of these changes for the safety testing of the vaccine will be briefly discussed. Data will be presented to show that tests in tissue culture are more sensitive than those in monkeys for the detection of residual live poliovirus in vaccine. It is concluded that there is no need for an additional test in monkeys when tests in tissue culture are carried out according to W.H.O. requirements.


Acute and chronic effects of naltrexone and naloxone on schedule-controlled behavior of squirrel monkeys and pigeons.
Dose-effect curves were obtained for the influence of naltrexone, of naloxone and of morphine on lever-pressing responses of squirrel monkeys and key-pecking responses of pigeons maintained by food presentation during fixed-interval (FI) and fixed-ratio (FR) components of a multiple schedule. Morphine caused dose-related decreases in FI and FR responding, with complete suppression occurring after 3 mg/kg was administered to monkeys and after 10 mg/kg was administered to pigeons. Naltrexone doses as low as 0.03 mg/kg (monkeys) or 0.1 mg/kg (pigeons) and naloxone doses as low as 0.1 mg/kg (monkeys) or 1 mg/kg (pigeons) shifted morphine dose-effect curves by one or more log units to the right. The effects of a 3 mg/kg injection of morphine were blocked completely by naltrexone (0.1-0.3 mg/kg) injected up to 16 hr before morphine, but not by naloxone (0.3-1 mg/kg) injected more than 2 hr before morphine. Thus, naltrexone was 3 to 10 times more potent than naloxone as an antagonist of morphine and was longer acting. Given alone, only high doses of naltrexone or naloxone (10 mg/kg, monkeys; 56 mg/kg, pigeons) had pronounced actions; FR and FI responding were markedly decreased and vomiting often occurred. Repeated daily injections of these high doses of naltrexone or naloxone resulted in little or no tolerance. One to 6 months after termination of chronic treatment, dose-effect curves for naltrexone on FR and FI responding maintained by food presentation were shifted markedly to the left with the monkeys, but not with the pigeons.


Shorter spontaneous fixation durations in infants with later emerging autism.
Little is known about how spontaneous attentional deployment differs on a millisecond-level scale in the early development of autism spectrum disorders (ASD). We measured fine-grained eye movement patterns in 6-to 9-month-old infants at high or low familial risk (HR/LR) of ASD while they viewed static images. We observed shorter fixation durations (i.e. the time interval between saccades) in HR than LR infants. Preliminary analyses indicate that these results were replicated in a second cohort of infants. Fixation durations were shortest in those infants who went on to receive an ASD diagnosis at 36 months. While these findings demonstrate early-developing atypicality in fine-grained measures of attentional deployment early in the etiology of ASD, the specificity of these effects to ASD remains to be determined.