Regulation of the immune system by synthetic polynucleotides. 3. Action on antigen-reactive cells of thymic origin.
Polyadenylic-polyuridylic acid complexes, a potent adjuvant to the immune response, were tested for action on thymic-influenced and bone marrow-derived lymphocytes in model systems deficient in one or the other of these cells. Adult mice, thymectomized at birth or mice treated with heterologous antithymocyte serum produced 90-95% fewer splenic rosette-forming cells than normal mice in response to an injection of sheep erythrocytes. Intravenous injection of complexes of homoribopolynucleotides, polyadenylic and polyuridylic acids, poly A:U with SRBC restored immunologic competence to NTx- or ATS-treated mice such that they produced normal or near normal levels of splenic RFC. In addition, injection of poly A:U enabled NTx mice to reject allogeneic skin grafts at the same rate as control mice with an intact thymus. Further reduction in residual thymocytes by combining neonatal thymectomy with ATS treatment reduced the number of anti-SRBC RFC induced by poly A:U. Lethally irradiated mice which received SRBC, excess bone marrow cells, and as few as 40,000 thymic lymphocytes were stimulated by poly A:U to produce RFC. No adjuvant effect was observed when irradiated mice received excess thymic lymphocytes and low doses of bone marrow cells with poly A:U. The results suggested that the adjuvant action of poly A:U was exerted on the thymic-influenced, antigen-reactive cell and that restoration of immunocompetence to NTx- or ATS-treated mice was caused by amplification of a small number of residual antigen-reactive cells which were influenced by the thymus in utero before thymectomy, or which survived treatment with ATS.


The Relationship of Superficial Cutaneous Nerves and Interperforator Connections in the Leg: A Cadaveric Anatomical Study.
The lower limb is a source of many flaps both for closure of local defects and for free transfer. Fasciocutaneous flap techniques have been progressively refined, although the vascular basis for their success needs clarification. Archival studies of 48 lower limbs were reviewed and combined with 20 studies of lower limbs from fresh cadavers, making a total of 68 investigations. Lower limbs were injected with a dilute lead oxide solution; the integument was removed and radiographed; and the cutaneous nerves were dissected, tagged with wire, radiographed again, and their paths traced on the original images. The major cutaneous nerves in the leg are paralleled by a longitudinal vascular axis often comprising long branches with large-caliber true anastomotic connections between perforators. The most highly developed vascular axes followed the medial sural cutaneous and saphenous nerves, together with their accompanying veins, immediately superficial to the deep fascia. The intervening areas were characterized by shorter branches usually connected by small-caliber choke anastomotic connections. These findings provide the anatomical basis for the observed reliability of longitudinal flaps in the leg. The superficial cutaneous nerves of the leg, especially the saphenous and medial sural cutaneous nerves, are paralleled by a vascular axis on or beside the nerve comprising long perforator branches connected usually but not always by large-caliber true anastomotic connections. This emphasizes the importance of understanding the characteristics of interperforator anastomoses when designing and raising flaps.


Two familial cases with tumor necrosis factor receptor-associated periodic syndrome caused by a non-cysteine mutation (T50M) in the TNFRSF1A gene associated with severe multiorganic amyloidosis.
An adolescent boy had had recurrent episodes of fever, abdominal pain, and arthralgias since the age of 7 years. Progressive renal failure due to renal amyloidosis developed, leading to renal transplant at the age of 14.5 years. Five years later, he developed AA amyloidosis in the transplant as well as the thyroid gland. His father had had similar symptoms including systemic amyloidosis since the age of 6 years. DNA sequence analysis revealed a heterozygous mutation in the TNFRSF1A (TNFa-receptor 1) gene (T50M) in both father and son causing tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Previous phenotype/genotype analyses have proposed that this mutation is usually not associated with the occurrence of amyloidosis. This difference in the clinical course in different families may indicate a strong influence of modifier genes. Treatment with a TNFRSF1B fusion protein TNF antagonist (etanercept) favorably influenced the disease course.


Syntheses, crystal structures, and optical properties of five metal complexes constructed from a V-shaped thiophene-containing ligand and different dicarboxylate ligands.
Five new metal complexes, {[Ni(DIDP)(m-bdc)(H2O)]·5H2O}n (1), {[Zn(DIDP)(hfipbb)]·2DMA}n (2), {[Zn(DIDP)(4,4'-sdb)]·H2O}n (3), {[Co(DIDP)(p-bdc)]}n (4), and {[Co2(DIDP)(hfipbb)2]·H2O}n (5), have been synthesized by reactions of the corresponding metal ions with a V-shaped ligand 2,8-di(1H-imidazol-1-yl)dibenzothiophene (DIDP) and different aromatic dicarboxylic acids, namely isophthalic acid (m-H2bdc), terephthalic acid (p-H2bdc), 4,4'-(hexafluoroisopropylidene)bis(benzoic acid) (H2hfipbb), and 4,4'-sulfonyldicarboxylic acid (4,4'-H2sdb), respectively. The structures of the complexes were determined by X-ray single-crystal diffraction. Complex 1 is a 1D chain structure containing a one-dimensional channel along the a direction and is further extended via O-H···S hydrogen bonds and C-H···π stacking interactions into a 3D framework. Complex 2 exhibits a quasi 2D + 2D → 2D with parallel polycatenation of 2D (4, 4) nets. Complex 3 displays an unusual 2D + 2D → 3D parallel polycatenated framework based on a 2D 6(3)-hcb network. Complex 4 shows a 2D 4-connected {4(4)·6(2)}-sql network containing a one-dimensional channel along the b direction. The adjacent 2D networks are further extended via C-H···O hydrogen bonds into a 3D supramolecular framework. Complex 5 features a 2-fold interpenetrating 3D framework with a 6-connected {4(12)·6(3)} pcu topology. Furthermore, the thermal stability for 1-5 and luminescence properties of 2 and 3 have been studied. Moreover, the solid-state UV-visible spectroscopy experiments show that complexes 1-5 are all optical semiconductors with band gaps of 3.06, 3.18, 3.23, 2.98, and 3.17 eV, respectively.


Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents.
A study of the structure-activity relationship of a series of newly synthesized phosphonylmethoxyalkyl purine and pyrimidine derivatives revealed that several adenine derivatives substituted at the N9 position by a 2-phosphonylmethoxyethyl (PME) group inhibited human immunodeficiency virus (HIV)-induced cytopathogenicity and HIV antigen expression in vitro at concentrations significantly below the toxicity threshold for the host cells. In terms of anti-HIV potency in MT-4 cells, the PME 2,6-diaminopurine derivative (50% effective dose [ED50], 1 microM) ranked first, followed by the PME adenine derivative (ED50, 2 microM [MT-4]) and the PME 2-monoaminopurine derivative (ED50, 45 microM). Antiretroviral activity was also demonstrated in ATH8 and H9 cells, which were de novo infected with HIV, and extended to C3H mouse fibroblasts infected with Moloney murine sarcoma virus. Unlike 2',3'-dideoxyadenosine, these compounds were not found to be degraded by deaminases derived from bovine intestine.


Morphologic and temporal characterisation of lesions in an enhanced murine model of Serpulina hyodysenteriae infection.
This laboratory has previously reported a murine model of Serpulina hyodysenteriae infection in which mice fed a defined diet, Teklad 85420 (TD), developed caecal lesions more consistently than mice fed a conventional rodent chow (CRC). The objectives of the current studies were to characterise and compare the time of onset of lesions, the morphological nature and severity of lesions and the extent of colonisation by S. hyodysenteriae in mice fed the two diets. In the first of two experiments, 50 C3H/HeJ and 50 C3H/HeOuJ mice were fed either TD or CRC and then half of each group was infected with S. hyodysenteriae. Mice (n = 5) from each group were killed and examined on days, 1, 2, 4, 9 or 17 after infection. Each mouse was examined grossly and microscopically and assigned lesion scores based on lesion severity. The second experiment was designed in an identical way to the first, but had slightly smaller group sizes (n=20). Mice (n=4) were killed for necropsy at the same five time points after infection and their caeca were homogenised and examined by quantitative bacteriology with media selective for S. hyodysenteriae. There were no differences in any finding due to mouse strain. Group lesion scores over the entire experimental period were significantly higher in mice fed TD (mean total lesion index = 13) than in mice fed CRC (mean total lesion index = 8.8). Lesions were also temporally distributed in a significantly different manner in that they appeared earlier (day 1) and persisted longer in the TD-fed mice in comparison to CRC-fed mice. Furthermore, lesions of equivalent severity from each treatment group presented identical microscopic features. Finally, quantitative bacteriological results indicated that there was no significant difference in the number of cfu of S. hyodysenteriae isolated from mice fed TD and those fed CRC. These results demonstrate that the characteristic severe lesions associated with S. hyodysenteriae infection in mice can occur 1 day after oral challenge in mice fed Teklad diet 85420. Bacteriological results further indicate that the enhancement of lesion formation in this model is not due to any significant effect of the diet on numbers of spirochaetes in the caeca of infected mice.


[Gunshot wounds of the kidneys].
Upon the analysis of the treatment for gunshot wounds of the kidneys (n = 113), it is concluded that in the majority of cases such wounds (91.1%) were associated with additional injuries of other viscera, this complicating the diagnosis and treatment, aggravating the prognosis. At admission, 81.4% of the wounded were in shock, with signs of hemorrhage. Serious condition of the patients dictated urgent surgery imposing limitations on diagnostic examinations, e.g. intravenous urography was performed in 5.3% of the cases only. Therefore, preoperative detection of renal injuries was far from universal. (55.6%). Hematuria prompted renal damage in 74% of cases. 92% of the wounded underwent surgery, in 62.8% of them it was nephrectomy. Serious combined wounds terminated in lethal outcomes in 50.4% of cases, though renal damage was responsible for 4% of deaths only. Introduction of up-to-date methods of examination (CT, ultrasonography, excretory urography) may raise the frequency of the kidney-preserving operations and favourable outcomes.


Advantages of Multidimensional Biasing in Accelerated Dynamics: Application to the Calculation of the Acid pKa for Acetic Acid.
The use of accelerated sampling methods such as metadynamics has shown a significant advantage in calculations that involve infrequent events, which would otherwise require sampling a prohibitive number of configurations to determine the difference in free energies between two or more chemically distinct states such as in the calculation of acid dissociation constants Ka. In this case, the most common method is to bias the system via a single collective variable (CV) representing the coordination number of the proton donor group, which yields results in reasonable agreement with experiments. Here we study the deprotonation of acetic acid using the reactive force field ReaxFF and observe a significant dependence of Ka on the simulation box size when biasing only the coordination number CV, which is due to incomplete sampling of the deprotonated state for small simulation systems and inefficient sampling for larger ones. Incorporating a second CV representing the distance between the H3O+ cation and the acetate anion results in substantially more efficient sampling, both accelerating the dynamics and virtually eliminating the computational box size dependence.


Gloxinia-An Open-Source Sensing Platform to Monitor the Dynamic Responses of Plants.
The study of the dynamic responses of plants to short-term environmental changes is becoming increasingly important in basic plant science, phenotyping, breeding, crop management, and modelling. These short-term variations are crucial in plant adaptation to new environments and, consequently, in plant fitness and productivity. Scalable, versatile, accurate, and low-cost data-logging solutions are necessary to advance these fields and complement existing sensing platforms such as high-throughput phenotyping. However, current data logging and sensing platforms do not meet the requirements to monitor these responses. Therefore, a new modular data logging platform was designed, named Gloxinia. Different sensor boards are interconnected depending upon the needs, with the potential to scale to hundreds of sensors in a distributed sensor system. To demonstrate the architecture, two sensor boards were designed-one for single-ended measurements and one for lock-in amplifier based measurements, named Sylvatica and Planalta, respectively. To evaluate the performance of the system in small setups, a small-scale trial was conducted in a growth chamber. Expected plant dynamics were successfully captured, indicating proper operation of the system. Though a large scale trial was not performed, we expect the system to scale very well to larger setups. Additionally, the platform is open-source, enabling other users to easily build upon our work and perform application-specific optimisations.


Quantification of polycyclic aromatic hydrocarbons in water: a comparative study based on three-dimensional excitation-emission matrix fluorescence.
Excitation-emission matrix fluorescence (EEM) was proposed to quantify three polycyclic aromatic hydrocarbons of anthracene (AN), phenanthrene (PHE) and pyrene (PY) in this paper. Direct analysis through selecting the appropriate areas from the data of EEMs and another approach using all data of EEM combined with the Parallel Factor (PARAFAC) were discussed respectively. The results showed that the predicted concentrations of PHE and PY approached the actual one for both methodologies, and that the room-mean-square errors of the prediction were no more than 0.5 µg L(-1). In addition, a new quantificational method was suggested, in which the sum intensity around the peak value replaced the maximum intensity in the selected regions. The sensitivity can be improved ten times compared with the conventional analysis.


Recent Developments in Nanomaterials-Based Drug Delivery and Upgrading Treatment of Cardiovascular Diseases.
Cardiovascular diseases (CVDs) are the leading causes of morbidity and mortality worldwide. However, despite the recent developments in the management of CVDs, the early and long outcomes vary considerably in patients, especially with the current challenges facing the detection and treatment of CVDs. This disparity is due to a lack of advanced diagnostic tools and targeted therapies, requiring innovative and alternative methods. Nanotechnology offers the opportunity to use nanomaterials in improving health and controlling diseases. Notably, nanotechnologies have recognized potential applicability in managing chronic diseases in the past few years, especially cancer and CVDs. Of particular interest is the use of nanoparticles as drug carriers to increase the pharmaco-efficacy and safety of conventional therapies. Different strategies have been proposed to use nanoparticles as drug carriers in CVDs; however, controversies regarding the selection of nanomaterials and nanoformulation are slowing their clinical translation. Therefore, this review focuses on nanotechnology for drug delivery and the application of nanomedicine in CVDs.


"Renters" or "owners"? Residents' perceptions and behaviors regarding error reduction in teaching hospitals: a literature review.
Residents' attitudes, practices, and behaviors vary in response to medical error within the context of the culture of their institutions. The purpose of this study was to conduct a systematic review of the literature focused on residents' attitudes and behaviors regarding medical errors in teaching hospitals, including a qualitative review of barriers and proposed countermeasures related to residents' engagement in patient safety. The electronic literature databases of MEDLINE, CINAHL, and ERIC were searched for articles published between January 1988 and June 2008. The search strategy yielded 124 articles. A scoring system was developed to assess the quality of the overall literature. Nineteen studies met eligibility criteria, with 17 published since 2005. There were 12 cross-sectional, 5 qualitative, 1 cohort and 1 pre-post intervention study. Quality assessment scores ranged from 5.5 to 12.5 (possible range 1.0-16.0). Three studies obtained a score of < or = 8.0, 5 obtained scores of 8.5 to 10.5, and 11 studies had scores of 11.0 to 12.5. Personal, environmental, and system barriers, and environmental and system countermeasures, were identified. Although the published literature on this topic is limited, those articles that exist identify barriers that make residents reluctant to engage in institutional error identification and/or reduction. Key factors identified included a fear of retribution and the perception of residents as transient care providers. Whereas several countermeasures have been promulgated, the literature reveals scant evidence of their effectiveness. Institutions should recognize and capitalize on the unique experiences of residents and their potential to become owners in patient safety initiatives.


Generalized fractal dimensions of laser Doppler flowmetry signals recorded from glabrous and nonglabrous skin.
The technique of laser Doppler flowmetry (LDF) is commonly used to have a peripheral view of the cardiovascular system. To better understand the microvascular perfusion signals, the authors herein propose to analyze and compare the complexity of LDF data recorded simultaneously in glabrous and nonglabrous skin. Glabrous zones are physiologically different from the others partly due to the presence of a high density of arteriovenous anastomoses. For this purpose, a multifractal analysis based on the partition function and generalized fractal dimensions computation is proposed. The LDF data processed are recorded simultaneously on the right and left forearms and on the right and left hand palms of healthy subjects. The signal processing method is first tested on a multifractal binomial measure. The generalized fractal dimensions of the normalized LDF signals are then estimated. Furthermore, for the first time, the authors estimate the generalized fractal dimensions from a range of scales corresponding to factors influencing the microcirculation flow (cardiac, respiratory, myogenic, neurogenic, and endothelial). Different multifractal behaviors are found between normalized LDF signals recorded in the forearms and in the hand palms of healthy subjects. Thus, the variations in the estimated generalized fractal dimensions of LDF signals recorded in the hand palms are higher than those of LDF signals recorded in the forearms. This shows that LDF signals recorded in glabrous zones may be more complex than those recorded in nonglabrous zones. Furthermore, the results show that the complexity in the hand palms could be more important at scales corresponding to the myogenic control mechanism than at the other studied scales. These findings suggest that the multifractality of the normalized LDF signals is different on glabrous and nonglabrous skin. This difference may rely on the density of arteriovenous anastomoses and differences in nerve supply or biochemical properties. This study provides useful information for an in-depth understanding of LDF data and a more detailed knowledge of the peripheral cardiovascular system.


A reproducible grading scale for histological assessment of inflammation in ulcerative colitis.
Evaluation of histological activity in ulcerative colitis needs to be reproducible but has rarely been tested. This could be useful both clinically and in clinical trials. To develop reproducible criteria which are valid in the assessment of acute inflammation (activity) and chronicity, and to evaluate these features in an interobserver variability study. A six grade classification system for inflammation was developed which could also be fine tuned within each grade. The grades were: 0, structural change only; 1, chronic inflammation; 2, lamina propria neutrophils; 3, neutrophils in epithelium; 4, crypt destruction; and 5, erosions or ulcers. Ninety nine haematoxylin-eosin sections from endoscopically inflamed and non-inflamed mucosa from patients with distal ulcerative colitis were assessed in two separate readings by three pathologists independently and without knowledge of the clinical status. Interobserver agreement was compared pairwise using kappa statistics. Initially, kappa values between the observers were 0.20, 0.42, and 0.26, which are too low to be of value. Following development of a semiquantitative pictorial scale for each criterion, kappa values improved to 0.62, 0.70, and 0.59. For activity defined by neutrophils between epithelial cells, kappa values were 0.903, 1.000, and 0.907. Complete agreement was reached in 64% of samples of endoscopically normal and in 66% of endoscopically inflamed tissue. Neutrophils in epithelium correlated with the presence of crypt destruction and ulceration. A histological activity system was developed for ulcerative colitis that showed good reproducibility and modest agreement with the endoscopic grading system which it complemented. It has potential value both clinically and in clinical trials.


Bone Mineral Density After Transitioning From Denosumab to Alendronate.
There are few studies on patients transitioning from denosumab to bisphosphonates. To investigate patient characteristics and changes in bone mineral density (BMD) after transitioning from denosumab to alendronate. Randomized, open-label, 2-year crossover Denosumab Adherence Preference Satisfaction (DAPS) study (NCT00518531). 25 study centers in the US and Canada. Treatment-naïve postmenopausal women with BMD T-scores from -2.0 to -4.0. This post hoc analysis evaluated women randomized to subcutaneous denosumab 60 mg every 6 months in year 1 followed by once-weekly oral alendronate 70 mg in year 2. A 3% BMD threshold identified participants who lost, maintained, or gained BMD in year 2 on alendronate. Of 126 participants randomized to denosumab, 115 (91%) transitioned to alendronate in year 2. BMD increased by 3% to 6% with denosumab in year 1 and by 0% to 1% with alendronate in year 2. After transitioning to alendronate, most participants maintained or increased BMD; 15.9%, 7.6%, and 21.7% lost BMD at the lumbar spine, total hip, and femoral neck, respectively. Few participants fell below their pretreatment baseline BMD value; this occurred most often in those who lost BMD in year 2. Women who lost BMD with alendronate in year 2 also showed a greater percent change in BMD with denosumab in year 1. The BMD change in year 2 was similar regardless of baseline characteristics or adherence to oral alendronate. Alendronate can effectively maintain the BMD gains accrued after 1 year of denosumab in most patients, regardless of baseline characteristics.


Single-cell transcriptomics of blood reveals a natural killer cell subset depletion in tuberculosis.
Tuberculosis (TB) continues to be a critical global health problem, which killed millions of lives each year. Certain circulating cell subsets are thought to differentially modulate the host immune response towards Mycobacterium tuberculosis (Mtb) infection, but the nature and function of these subsets is unclear. Peripheral blood mononuclear cells (PBMC) were isolated from healthy controls (HC), latent tuberculosis infection (LTBI) and active tuberculosis (TB) and then subjected to single-cell RNA sequencing (scRNA-seq) using 10 × Genomics platform. Unsupervised clustering of the cells based on the gene expression profiles using the Seurat package and passed to tSNE for clustering visualization. Flow cytometry was used to validate the subsets identified by scRNA-Seq. Cluster analysis based on differential gene expression revealed both known and novel markers for all main PBMC cell types and delineated 29 cell subsets. By comparing the scRNA-seq datasets from HC, LTBI and TB, we found that infection changes the frequency of immune-cell subsets in TB. Specifically, we observed gradual depletion of a natural killer (NK) cell subset (CD3-CD7+GZMB+) from HC, to LTBI and TB. We further verified that the depletion of CD3-CD7+GZMB+ subset in TB and found an increase in this subset frequency after anti-TB treatment. Finally, we confirmed that changes in this subset frequency can distinguish patients with TB from LTBI and HC. We propose that the frequency of CD3-CD7+GZMB+ in peripheral blood could be used as a novel biomarker for distinguishing TB from LTBI and HC. FUND: The study was supported by Natural Science Foundation of China (81770013, 81525016, 81772145, 81871255 and 91942315), National Science and Technology Major Project (2017ZX10201301), Science and Technology Project of Shenzhen (JCYJ20170412101048337) and Guangdong Provincial Key Laboratory of Regional Immunity and Diseases (2019B030301009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


ZNF668 functions as a tumor suppressor by regulating p53 stability and function in breast cancer.
Genome-wide sequencing studies in breast cancer have recently identified frequent mutations in the zinc finger protein 668 (ZNF668), the function of which is undefined. Here, we report that ZNF668 is a nucleolar protein that physically interacts with and regulates p53 and its negative regulator MDM2. Through MDM2 binding, ZNF668 regulated autoubiquitination of MDM2 and its ability to mediate p53 ubiquitination and degradation. ZNF668 deficiency also impaired DNA damage-induced stabilization of p53. RNA interference-mediated knockdown of ZNF668 was sufficient to transform normal mammary epithelial cells. ZNF668 effectively suppressed breast cancer cell proliferation in vitro and tumorigenicity in vivo. Taken together, our studies identify ZNF668 as a novel breast tumor suppressor gene that functions in regulating p53 stability.


Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes.
Islet allografts from 2 to 4 donors can reverse type 1 diabetes. However, for islet transplants to become a widespread clinical reality, diabetes reversal must be achieved with a single donor to reduce risks and costs and increase the availability of transplantation. To assess the safety of a single-donor, marginal-dose islet transplant protocol using potent induction immunotherapy and less diabetogenic maintenance immunosuppression in recipients with type 1 diabetes. A secondary objective was to assess the proportion of islet transplant recipients who achieve insulin independence in the first year after single-donor islet transplantation. Prospective, 1-year follow-up trial conducted July 2001 to August 2003 at a single US center and enrolling 8 women with type 1 diabetes accompanied by recurrent hypoglycemia unawareness or advanced secondary complications. Study participants underwent a primary islet allotransplant with 7271 (SD, 1035) islet equivalents/kg prepared from a single cadaver donor pancreas. Induction immunosuppression was with antithymocyte globulin, daclizumab, and etanercept. Maintenance immunosuppression consisted of mycophenolate mofetil, sirolimus, and no or low-dose tacrolimus. Safety (assessed by monitoring the severity and duration of adverse events) and efficacy (assessed by studying the recipients' insulin requirements, C-peptide levels, oral and intravenous glucose tolerance results, intravenous arginine stimulation responses, glycosylated hemoglobin levels, and hypoglycemic episodes) associated with the study transplant protocol. There were no serious, unexpected, or procedure- or immunosuppression-related adverse events. All 8 recipients achieved insulin independence and freedom from hypoglycemia. Five remained insulin-independent for longer than 1 year. Graft failure in 3 recipients was preceded by subtherapeutic sirolimus exposure in the absence of measurable tacrolimus trough levels. The tested transplant protocol restored insulin independence and protected against hypoglycemia after single-donor, marginal-dose islet transplantation in 8 of 8 recipients. These results may be related to improved islet engraftment secondary to peritransplant administration of antithymocyte globulin and etanercept. These findings may have implications for the ongoing transition of islet transplantation from clinical investigation to routine clinical care.


Molecular characterization of Oryza sativa WRKY6, which binds to W-box-like element 1 of the Oryza sativa pathogenesis-related (PR) 10a promoter and confers reduced susceptibility to pathogens.
WRKY proteins are transcription factors (TFs) that regulate the expression of defense-related genes. The salicylic acid (SA)-inducible Oryza sativa WRKY6 (OsWRKY6) was identified as a positive regulator of Oryza sativa pathogenesis-related 10a (OsPR10a) by transient expression assays. A physical interaction between OsWRKY6 and W-box-like element 1 (WLE1), which positively regulates OsPR10a/probenazole induced protein 1 expression, was verified in vitro. Several pathogenesis-related (PR) genes were constitutively activated, including OsPR10a, and transgenic rice (Oryza sativa) plants overexpressing (ox) OsWRKY6 exhibited enhanced disease resistance to pathogens. By contrast, PR gene induction was compromised in transgenic OsWRKY6-RNAi lines, suggesting that OsWRKY6 is a positive regulator of defense responses. OsWRKY6-ox lines displayed leaf lesions, and increased OsWRKY6 levels caused cell death. Salicylic acid (SA) concentrations were higher in OsWRKY6-ox lines than in wild-type (WT) plants, and transcript levels of Oryza sativa isochorismate synthase 1 (OsICS1), which encodes a major enzyme involved in SA biosynthesis, were higher in OsWRKY6-ox lines than in WT. OsWRKY6 directly bound to the OsICS1 promoter in vivo. This indicates that OsWRKY6 can directly regulate OsICS1 expression and thereby increase SA concentrations. OsWRKY6 autoregulates its own expression. OsWRKY6 protein degradation is possibly regulated by ubiquitination. Our results suggest that OsWRKY6 positively regulates defense responses through activation of OsICS1 expression and OsWRKY6 stabilization.


An autosomal recessive polycystic kidney disease gene homolog is involved in intraflagellar transport in C. elegans ciliated sensory neurons.
In this report, we show that the Caenorhabditis elegans gene osm-5 is homologous to the Chlamydomonas gene IFT88 and the mouse autosomal recessive polycystic kidney disease (ARPKD) gene, Tg737. The function of this ARPKD gene may be evolutionarily conserved: mutations result in defective ciliogenesis in worms [1], algae [2], and mice [2, 3]. Intraflagellar transport (IFT) is essential for the development and maintenance of motile and sensory cilia [4]. The biochemically isolated IFT particle from Chlamydomonas flagella is composed of 16 polypeptides in one of two Complexes (A and B) [5, 6] whose movement is powered by kinesin II (anterograde) and cytoplasmic dynein (retrograde) [7-9]. We demonstrate that OSM-5 (a Complex B polypeptide), DAF-10 and CHE-11 (two Complex A polypeptides), and CHE-2 [10], a previously uncategorized IFT polypeptide, all move at the same rate in C. elegans sensory cilia. In the absence of osm-5, the C. elegans autosomal dominant PKD (ADPKD) gene products [11] accumulate in stunted cilia, suggesting that abnormal or lack of cilia or defects in IFT may result in diseases such as polycystic kidney disease (PKD).


Differential Effects of Sepsis and Chronic Inflammation on Diaphragm Muscle Fiber Type, Thyroid Hormone Metabolism, and Mitochondrial Function.
The diaphragm is the main respiratory muscle, and its function is compromised during severe illness. Altered local thyroid hormone (TH) metabolism may be a determinant of impaired muscle function during illness. This study investigates the effects of bacterial sepsis and chronic inflammation on muscle fiber type, local TH metabolism, and mitochondrial function in the diaphragm. Two mouse models were used: sepsis induced by S. pneumoniae infection or chronic inflammation induced by subcutaneous turpentine injection. In vitro, the effect of bacterial endotoxin (LPS) on mitochondrial function in C2C12 myotubes was studied. Sepsis induced a transient increase in the fiber type I profile and increased Dio3 expression while decreasing Dio2, Thra1, and Slc16a2 expression. Triiodothyronine positively regulated genes Tnni2 and Myog were decreased, indicating reduced TH signaling in the diaphragm. In contrast, chronic inflammation increased the fiber type II profile in the diaphragm as well as Thra1, Thrb1, and Myog expression while decreasing Dio3 expression, suggesting increased TH responsiveness during chronic inflammation. LPS-stimulated C2C12 myotubes showed decreased Dio2 expression and reduced basal oxygen consumption as well as non-mitochondrial respiration. The same respiratory profile was induced by Dio2 knockdown in myotubes. The in vivo results show differential effects of sepsis and chronic inflammation on diaphragm muscle fiber type, TH metabolism, and mitochondrial function, while the in vitro results point to a causal role for altered TH metabolism in functional muscle impairment. These findings may be relevant for the pathogenesis of impaired respiratory function in critical illness.


Synthesis, identification, and acute toxicity of alpha-benzylphenethylamine and alpha-benzyl-N-methylphenethylamine. Contaminants in clandestine preparation of amphetamine and methamphetamine.
Amphetamine samples obtained from clandestine laboratories often contain other by-product amines. The most common of these are the alpha-benzylphenethylamine derivatives. This article reports the independent synthesis of reference samples of these amines, spectrophotometric and chromatographic methods for their identification, as well as acute toxicological studies. The utility of the analytical methods is demonstrated by the analysis of several amphetamine samples containing these alpha-benzylphenethylamines.


[Mesenteric cyst. A case report].
Mesenteric cysts are rare, it had been reported a frequency of 1 in 250,000 hospital admissions. We present a case of a 17-year-old female, attended at gynecology service with 8 weeks amenorrhea and diffuse pain in all abdominal regions. Without preceding pathological history of importance, menarche at 14 year, menstrual cycles of 30-45 x 5, nuligesta. She had negative immunology pregnancy tests, and sonography showed left ovary with anecoique ovoid area of approximately 15 x 8.8 x 7 cm. Physical examination showed a soft abdomen, depressible, with pain on the left side, where presence of a tumor of approximately 8 cm was perceived. Vaginal examination showed cervix of 3 x 2 cm, not painful to mobilization, uterus in a head position of 6 x 5 x 4 cm, a tumor of 18 x 10 cm was delimited in left salpinge, not painful to the compressedness. It was carried out a laparotomy with diagnostic of cyst in left ovary, but it was a tumor of 18 x 14 x 10 cm of cyst aspect that was dependented of mesenterious at sigmoid colon level, which could be eradicated without difficulty. Mesenteric tumors are difficult for diagnosis, and can be asymptomatic or to be suspect as cause of recurrent abdominal pain, abdominal tumor or acute abdomen. Unfortunately, it is difficult to establish the diagnosis with precision before surgery, still employing diagnostic resources of high technology, as sonography and tomography.


Chiral Amplification through the Interplay of Racemizing Conditions and Asymmetric Crystal Growth.
Amplification of enantiomeric excesses (ee) is routinely observed during chiral crystallization of conglomerate crystals for which the enantiomers undergo racemization in solution. Although routes comprising a combination of crystal growth and dissolution are frequently used to obtain enantiopure molecules, crystal growth by itself has rather been considered as a source of enantiomeric erosion and discounted as a potential source of enantiomeric amplification. Counterintuitively, we here demonstrate striking enantiomeric amplification during crystal growth for clopidogrel and tert-leucine precursors. Based on a mechanistic framework, we identify that the interplay between racemization and crystal growth rates elicits this surprising effect. The asymmetric amplification of the solid-phase ee can be enhanced by increasing the mass of grown material relative to the product such that small amounts of seeds of only 60% ee already result in virtually exclusive growth of the majority phase. These results impact our understanding of asymmetric amplification mechanisms during crystallization and offer a tangible basis for practical production of enantiopure molecules.


Maternal high-fat diet associated with altered gene expression, DNA methylation, and obesity risk in mouse offspring.
We investigated maternal obesity in inbred SM/J mice by assigning females to a high-fat diet or a low-fat diet at weaning, mating them to low-fat-fed males, cross-fostering the offspring to low-fat-fed SM/J nurses at birth, and weaning the offspring onto a high-fat or low-fat diet. A maternal high-fat diet exacerbated obesity in the high-fat-fed daughters, causing them to weigh more, have more fat, and have higher serum levels of leptin as adults, accompanied by dozens of gene expression changes and thousands of DNA methylation changes in their livers and hearts. Maternal diet particularly affected genes involved in RNA processing, immune response, and mitochondria. Between one-quarter and one-third of differentially expressed genes contained a differentially methylated region associated with maternal diet. An offspring high-fat diet reduced overall variation in DNA methylation, increased body weight and organ weights, increased long bone lengths and weights, decreased insulin sensitivity, and changed the expression of 3,908 genes in the liver. Although the offspring were more affected by their own diet, their maternal diet had epigenetic effects lasting through adulthood, and in the daughters these effects were accompanied by phenotypic changes relevant to obesity and diabetes.


Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebo-controlled trial.
Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and modestly delayed HIV-1 disease progression in one clinical trial. We investigated the effect of daily suppressive aciclovir on HIV-1 disease progression in Rakai, Uganda. We did a single site, parallel, randomised, controlled trial of HIV-1, HSV-2 dually infected adults with CD4 cell counts of 300-400 cells per μL. We excluded individuals who had an AIDS-defining illness or active genital ulcer disease, and those that were taking antiretroviral therapy. Participants were randomly assigned (1:1) with computer-generated random numbers in blocks of four to receive either aciclovir 400 mg orally twice daily or placebo; participants were followed up for 24 months. All study staff and participants were masked to treatment, except for the two statisticians. The primary outcome was CD4 cell count less than 250 cells per μL or initiation of antiretroviral therapy for WHO stage 4 disease. Our intention-to-treat analysis used Cox proportional hazards models, adjusting for baseline log(10) viral load, CD4 cell count, sex, and age to assess the risk of disease progression. We also investigated the effect of suppressive HSV-2 treatment stratified by baseline HIV viral load with a Cox proportional hazards model. This trial is registered with ClinicalTrials.gov, number NCT00405821. 440 participants were randomly assigned, 220 to each group. 110 participants in the placebo group and 95 participants in the treatment group reached the primary endpoint (adjusted hazard ratio [HR] 0·75, 95% CI 0·58-0·99; p=0·040). 24 participants in the placebo group and 22 in the treatment group were censored, but all contributed data for the final analysis. In a subanalysis stratified by baseline HIV viral load, participants with a baseline viral load of 50,000 copies mL or more in the treatment group had a reduced HIV disease progression compared with those in the placebo group (0·62, 0·43-0·96; p=0·03). No significant difference in HIV disease progression existed between participants in the treatment group and those in the placebo group who had baseline HIV viral loads of less than 50,000 copies per mL (0·90, 0·54-1·5; p=0·688). No safety issues related to aciclovir treatment were identified. Aciclovir reduces the rate of disease progression, with the greatest effect in individuals with a high baseline viral load. Suppressive aciclovir might be warranted for individuals dually infected with HSV-2 and HIV-1 with viral loads of 50,000 copies per mL or more before initiation of antiretroviral treatment. National Institute of Allergy and Infectious Diseases, National Cancer Institute (National Institutes of Health, USA).


Synthetic Principles of Spiky Au Nanoparticles.
In this work, the synthetic principles of spiky Au nanoparticles (spiky Au NPs) with an average number of spikes of less than or equal to six and controlled core sizes by using Au nanorods as seeds (Au-NR seeds) are summarized on the basis of the results of a series of control experiments. In addition, one empirical equation that can roughly estimate the number of spiky Au NPs is proposed, demonstrated by the results of the products prepared from different aspect ratios of Au-NRs as seeds and non-Au-NR seeds. Moreover, the synthetic principles of spiky Au NPs are further demonstrated by taking the successful synthesis of a serials of spiky Au21×7 NPs. Furthermore, the as-prepared spiky firstname.lastname@example.com NPs with ultrathin AuPd shells, which are derived from spiky Au21×7 NPs with the smallest cores, can bear excellent catalytic activity (say, E1/2 = 0.947 V) and durability toward the oxygen reduction reaction (ORR) in alkaline conditions, compared with commercial Pt/C catalysts (E1/2 = 0.883 V).


The Benefits of Being a "Buddy": Exploring the Medical Student Experience As Mentor to Minority High-School Students.
Purpose: The Aspiring Doctors Precollege Program at Ohio University Heritage College of Osteopathic Medicine serves to introduce underrepresented minority (URM) high-school students to careers in health care as well as introducing URM high-school students to medical student mentors. Each month, medical students and their student mentees connect through a variety of activities on the medical college campus. While the program has significant benefit for the mentees, it also provides professional development opportunities for the medical students as mentors. Many researchers have written on the value of mentored relationships between medical students and established physicians; however, exploring the benefits of medical student mentorship has yet to be discussed in the literature. Objectives: The primary objectives of this study are to understand medical student perceptions of being a mentor and describe the contributions to their medical education. Methods: Semistructured interviews were conducted with student mentors regarding their experiences serving in this program. These interviews were inductively coded for significant ideas, themes, and patterns. Results: A series of 12 research interviews were conducted with medical students who have participated in The Aspiring Doctors program for at least three semesters. Major themes that emerged from the analysis include the following: the importance of guidance in medicine through person-to-person mentoring, and identification of future career aspirations. Summary/Conclusions: Medical student mentors found this program to be a valuable addition to their educational experience. Mentoring URM high-school students offers pre-clinical medical students the opportunity to connect with their community and envision themselves serving as physicians in underresourced communities. Simultaneously, it provides a meaningful way of paying-it-forward during their education. Further studies can be done to track the outcomes of the medical students with respect to their designations stated while participating in this program, the role of mentorship on professional identity development, and possible effects on preventing/mitigating burnout.


Identification of RTX toxin target cell specificity domains by use of hybrid genes.
The Escherichia coli hemolysin (HlyA) and Pasteurella haemolytica leukotoxin (LktA) are cytolytic toxins encoded by genes belonging to the recently described RTX gene family. These cytotoxins are, respectively, 1,023 and 953 amino acids in length and are encoded by genes within identically organized operons. They share 45% amino acid sequence identities but differ in their target cell specificities. In vitro-derived recombinant hybrid genes between hlyA and lktA were constructed by using restriction endonuclease sites created by oligonucleotide site-directed mutagenesis. The cytolytic activity of hybrid proteins was investigated using as targets sheep erythrocytes and two cultured cell lines from different species (BL3, bovine leukemia-derived B lymphocytes; and Raji, human B-cell lymphoma cells). HlyA is cytolytic to all three cell types. LktA lyses only BL3 cells. Among the hybrid proteins displaying cytolytic activity, the striking finding is that the hemolytic activity of several LktA-HlyA hybrids was independent of any cytolytic activity against either cultured cell species. The hemolytic activity was associated with the HlyA region between amino acids 564 and 739. Structures that are critical for HlyA cytolytic activity against BL3 or Raji cells were destroyed when LktA-HlyA and HlyA-LktA hybrids were made, respectively, at amino acid positions 564 and 739 of HlyA. In contrast to HlyA, which lysed the two different cultured cell lines with equal efficiency, Lkt-HlyA hybrids possessing the amino-terminal 169 residues of LktA lysed BL3 cells more efficiently than Raji cells. This suggests that a significant but not exclusive element of the LktA ruminant cell specificity resides in the amino-terminal one-fifth of the protein. A molecular model of the functional domains of HlyA and LktA is presented.


Doubt and belief in physicians' ability to prognosticate during critical illness: the perspective of surrogate decision makers.
Although discussing a prognosis is a duty of physicians caring for critically ill patients, little is known about surrogate decision-makers' beliefs about physicians' ability to prognosticate. We sought to determine: 1) surrogates' beliefs about whether physicians can accurately prognosticate for critically ill patients; and 2) how individuals use prognostic information in their role as surrogate decision-makers. Multicenter study in intensive care units of a public hospital, a tertiary care hospital, and a veterans' hospital. We conducted semistructured interviews with 50 surrogate decision-makers of critically ill patients. We analyzed the interview transcripts using grounded theory methods to inductively develop a framework to describe surrogates' beliefs about physicians' ability to prognosticate. Validation methods included triangulation by multidisciplinary analysis and member checking. Overall, 88% (44 of 50) of surrogates expressed doubt about physicians' ability to prognosticate for critically ill patients. Four distinct themes emerged that explained surrogates' doubts about prognostic accuracy: a belief that God could alter the course of the illness, a belief that predicting the future is inherently uncertain, prior experiences where physicians' prognostications were inaccurate, and experiences with prognostication during the patient's intensive care unit stay. Participants also identified several factors that led to belief in physicians' prognostications, such as receiving similar prognostic estimates from multiple physicians and prior experiences with accurate prognostication. Surrogates' doubts about prognostic accuracy did not prevent them from wanting prognostic information. Instead, most surrogate decision-makers view physicians' prognostications as rough estimates that are valuable in informing decisions, but are not determinative. Surrogates identified the act of prognostic disclosure as a key step in preparing emotionally and practically for the possibility that a patient may not survive. Although many surrogate decision-makers harbor some doubt about the accuracy of physicians' prognostications, they highly value discussions about prognosis and use the information for multiple purposes.


[Different effect of angiotensin convertase inhibitors and AT1 receptor blockers on renal function in patients with chronic renal failure: report of two cases].
In two patients with chronic renal failure (CRF) different effects of angiotensin convertase inhibitors (ACEI) and angiotensin receptor 1 blockers (AT1B) were observed. In patient 1 with CRF due to hemolytic-uremic syndrome (HUS), with arterial hypertension (HT) and proteinuria, a switch from AT1B to ACEI led to significant deterioration of renal function. After restitution of AT1B, renal function returned to previous range. The 2nd patient with CRF and severe HT, without proteinuria, due to atypical HUS, was on CAPD. Because of severe HT he received 3-4 hypertensives and ACEI in full dose was the main medication. Despite relatively low urea and creatinine values while on dialysis and high residual diuresis several attempts an end of CAPD was unsuccessful because of hyperkalemia and unacceptable increase of urea and creatinine concentrations after few days. Conversion from ACEI to AT1B enabled withholding CAPD, stabilisation of renal function and good control of HT. It seems that in patients with CRF without hyperfiltration syndrome and sensitive to changes in glomerular hemodynamics, in whom blockade of angiotensin action is needed AT1B may be a better option than ACEI. When using ACEI in patients with CRF, it is important to adjust the dose to renal function.


A mathematical model for analysis of pharmacologically induced changes in the kinetics of cardiac muscle.
A mathematical model of the isometric contraction of cardiac muscle is developed and utilized to characterize the inotropic and lusitropic effects of cardioactive compounds in isolated guinea pig left atria. In contrast to metrics that are based on minima and maxima of an isometric twitch and its derivative function, the entire time course of the twitch is used to quantify the kinetics of the contraction-relaxation cycle. The model relates observed tension to a time-dependent activation function that describes generation of internal force and a coupling function that determines mechanical response to the activation function. The model is structured so that it is suitable for nonlinear curve fitting to observed data. Results obtained using the model for fitting experimental data from tissues treated with different classes of cardioactive compounds agree with more qualitative results presented by other authors. Experiments using the model to fit data over an extended (90 min) time course revealed differences in the kinetic profiles of milrinone and forskolin. Computer simulations that demonstrate the effect of each model parameter on twitch kinetics are presented, and the relationships between the model and other theoretical and empirical models of cardiac muscle are discussed. The mathematical model is useful to enable a more quantitative understanding of the kinetics of cardiac muscle contraction and relaxation and identify compounds that may be selective for inotropic or lusitropic effects.


Race, obesity, and the renin-angiotensin-aldosterone system: treatment response in children with primary hypertension.
Pediatric primary hypertension (HTN) is increasingly recognized, but the effect of patient characteristics such as obesity and race on treatment outcomes is not well described. The renin-angiotensin-aldosterone system (RAAS) may also contribute to HTN. We hypothesized patient parameters of these factors, including baseline RAAS, influence blood pressure (BP) response to pharmacological treatment in HTN. This was a retrospective cohort of 102 consecutive patients with HTN. Primary outcomes were changes per year in systolic and diastolic BP (SBP, DBP). Secondary outcome was change per year in left ventricular mass index (LVMI). We evaluated whether baseline plasma renin activity (PRA), aldosterone, renin-to-aldosterone ratio, overweight/obesity, race, initial drug choice, and multidrug therapy were associated with the outcomes using general linear regression models adjusted for confounding variables. Racially diverse (43% Hispanic, 28% black, 25% white) and predominantly overweight/obese (75%) patients were studied. Median length of follow-up was 14.5 months. Higher baseline aldosterone was associated with decreased SBP (-1.03 mmHg/year), DBP (-0.95 mmHg/year), and DBP z score (-0.07/year) during the study period. Higher baseline PRA was associated with decreased SBP z score (-0.04/year) and LVMI (-2.89 g/m2.7/year). Stratified analyses revealed the relationships between baseline aldosterone and PRA, and annual reductions in outcomes were strengthened in nonobese and white patients. Pretreatment aldosterone and PRA predicted short-term follow-up BP and LVMI, especially in nonobese and white patients. The RAAS profile could guide treatment of HTN and suggests consideration of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers as first-line treatment options.


A specific exercise program and modification of postural alignment for treatment of cervicogenic headache: a case report.
Case report. To describe an intervention approach consisting of a specific active-exercise program and modification of postural alignment for an individual with cervicogenic headache. The patient was a 46-year-old male with a 7-year history of cervicogenic headache. He reported constant symptoms with an average intensity of 5/10 on a visual analogue scale where 0 indicated no pain and 10 the worst pain imaginable. Average pain intensity in the week prior to the initial evaluation was 3/10 secondary to trigger point injections. The patient's headache symptoms worsened with activities that involved use of his arms and prolonged sitting. The patient was treated 7 times over a 3-month period. Impairments of alignment, muscle function, and movement of the cervical, scapulothoracic, and lumbar regions were identified. Outcome measurements included headache frequency, intensity, and the Neck Disability Index (NDI) questionnaire. Intervention included modification of alignment and movement during active cervical and upper extremity movements. The patient also received functional instructions focused on diminishing the effect of the weight of the upper extremities on the cervical spine. The patient reported a decrease in headache frequency and intensity (1 headache in 3 weeks, intensity 1/10) and a decrease in his NDI score from 31 (severe disability) to 11 (mild disability). The patient also demonstrated improvement in upper cervical joint mobility, cervical range of motion, scapular alignment, and scapulothoracic muscle strength. Interventions that included modification of alignment in the cervical, scapulothoracic, and lumbar region, along with instruction in a specific active-exercise program to address movement impairments in these 3 regions, appeared to have been successful in relieving headaches and improving function in this patient.


Population-based outcome analysis of diffuse large B-cell lymphoma in people living with HIV infection and competent individuals.
The prognostic factors and outcome of 58 acquired immunodeficiency syndrome-related diffuse large B-cell lymphoma (AR-DLBCL) patients from the Swiss HIV Cohort Study, diagnosed from 2004 to 2011, were compared with those of 326 immunocompetent (IC)-DLBCL from the Hematology Division of the Amedeo Avogadro University (Italy) and the Oncology Institute of Southern Switzerland. Median follow-up was 6 years; 5-year overall survival (OS) was 68% (95% CI: 63%-73%) in IC-DLBCL and 63% (95% CI: 49%-75%) in AR-DLBCL (P = .220). The acquired immunodeficiency syndrome-related lymphoma international prognostic index predicted OS in AR-DLBCL. Among 148 patients younger than 61 years (40 AR-DLBCL and 108 IC-DLBCL) treated with RCHOP/RCHOP-like regimens, 20 IC-DLBCL and 9 AR-DLBCL patients died and OS was not significantly different. A higher proportion of early deaths occurred in the AR-DLBCL: indeed, 1-year OS was 94% (95% CI: 87%-97%) in IC-DLBCL and 82% (95% CI: 66%-91%) in AR-DLBCL patients. After rituximab and active antiretroviral therapy introduction, AR-DLBCL and IC-DLBCL patients treated with curative intent have similar long-term survival.


Large area optical mapping of surface contact angle.
Top-down contact angle measurements have been validated and confirmed to be as good if not more reliable than side-based measurements. A range of samples, including industrially relevant materials for roofing and printing, has been compared. Using the top-down approach, mapping in both 1-D and 2-D has been demonstrated. The method was applied to study the change in contact angle as a function of change in silver (Ag) nanoparticle size controlled by thermal evaporation. Large area mapping reveals good uniformity for commercial Aspen paper coated with black laser printer ink. A demonstration of the forensic and chemical analysis potential in 2-D is shown by uncovering the hidden CsF initials made with mineral oil on the coated Aspen paper. The method promises to revolutionize nanoscale characterization and industrial monitoring as well as chemical analyses by allowing rapid contact angle measurements over large areas or large numbers of samples in ways and times that have not been possible before.


Comparison of hepatic in vitro metabolism of the pyrrolizidine alkaloid senecionine in sheep and cattle.
To compare hepatic metabolism of pyrrolizidine alkaloids (PAs) between sheep and cattle and elucidate the protective mechanism of sheep. Liver microsomes and cytosol from 8 sheep and 8 cattle. The PA senecionine, senecionine N-oxide (nontoxic metabolite) and 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP; toxic metabolite) were measured in microsomal incubations. The kcat (turnover number) was determined for DHP and N-oxide formation. Chemical and immunochemical inhibitors were used to assess the role of cytochrome P450s, flavin-containing monooxygenases (FMOs), and carboxylesterases in senecionine metabolism. The CYP3A, CYP2B, and FMO concentrations and activities were determined, in addition to the role of glutathione (GSH) in senecionine metabolism. DHP concentration did not differ between species. Sheep formed more N-oxide, had higher N-oxide kcat, and metabolized senecionine faster than cattle. The P450 concentrations and isoforms had a large influence on DHP formation, whereas FMOs had a large influence on N-oxide formation. In cattle, CYP3A played a larger role in DHP formation than in sheep. FMO activity was greater in sheep than in cattle. Addition of GSH to in vitro microsomal incubations decreased DHP formation; addition of cytosol decreased N-oxide formation. Hepatic metabolism differences alone do not account for the variation in susceptibility seen between these species. Rather, increased ruminal metabolism in sheep appears to be an important protective mechanism, with hepatic enzymes providing a secondary means to degrade any PAs that are absorbed from the rumen.


In vitro anti-mycobacterial activity of nine medicinal plants used by ethnic groups in Sonora, Mexico.
Sonoran ethnic groups (Yaquis, Mayos, Seris, Guarijíos, Pimas, Kikapúes and Pápagos) use mainly herbal based preparations as their first line of medicinal treatment. Among the plants used are those with anti-tuberculosis properties; however, no formal research is available. Organic extracts were obtained from nine medicinal plants traditionally used by Sonoran ethnic groups to treat different kinds of diseases; three of them are mainly used to treat tuberculosis. All of the extracts were tested against Mycobacterium tuberculosis H37Rv using the Alamar Blue redox bioassay. Methanolic extracts from Ambrosia confertiflora, Ambrosia ambrosioides and Guaiacum coulteri showed minimal inhibitory concentration (MIC) values of 200, 790 and 1000 μg/mL, respectively, whereas no effect was observed with the rest of the methanolic extracts at the concentrations tested. Chloroform, dichloromethane, and ethyl acetate extracts from Ambrosia confertiflora showed a MIC of 90, 120 and 160 μg/mL, respectively. A. confertiflora and A. ambrosioides showed the best anti-mycobacterial activity in vitro. The activity of Guaiacum coulteri is consistent with the traditional use by Sonoran ethnic groups as anti-tuberculosis agent.For these reasons, it is important to investigate a broader spectrum of medicinal plants in order to find compounds active against Mycobacterium tuberculosis.


Normal pressure hydrocephalus caused by a spinal neurinoma at the cauda equina level: a case report.
Neurinomas are common space-occupying lesions located in the spinal canal. Many reports concerning their clinical characteristics, diagnoses, treatments, and operative results have been published. Some case reports have discussed spinal neurinomas located at the cauda equina level. However, there is little information on their natural history. Here, we report a case of spinal neurinoma located at the cauda equina level, which caused normal pressure hydrocephalus (NPH). All symptoms resulting from the NPH were resolved by tumor removal. These findings suggested that if a spinal neurinoma located at the cauda equina level causes symptoms due to NPH, then removal of the tumor should be considered, when appropriate removal procedures are possible.


Effects of tomato inoculation with the entomopathogenic fungus Metarhizium brunneum on spider mite resistance and the rhizosphere microbial community.
Entomopathogenic fungi have been well exploited as biocontrol agents that can kill insects through direct contact. However, recent research has shown that they can also play an important role as plant endophytes, stimulating plant growth, and indirectly suppressing pest populations. In this study, we examined the indirect, plant-mediated, effects of a strain of entomopathogenic fungus, Metarhizium brunneum on plant growth and population growth of two-spotted spider mites (Tetranychus urticae) in tomato, using different inoculation methods (seed treatment, soil drenching and a combination of both). Furthermore, we investigated changes in tomato leaf metabolites (sugars and phenolics), and rhizosphere microbial communities in response to M. brunneum inoculation and spider mite feeding. A significant reduction in spider mite population growth was observed in response to M. brunneum inoculation. The reduction was strongest when the inoculum was supplied both as seed treatment and soil drench. This combination treatment also yielded the highest shoot and root biomass in both spider mite-infested and non-infested plants, while spider mite infestation increased shoot but reduced root biomass. Fungal treatments did not consistently affect leaf chlorogenic acid and rutin concentrations, but M. brunneum inoculation via a combination of seed treatment and soil drenching reinforced chlorogenic acid (CGA) induction in response to spider mites and under these conditions the strongest spider mite resistance was observed. However, it is unclear whether the M. brunneum-induced increase in CGA contributed to the observed spider mite resistance, as no general association between CGA levels and spider mite resistance was observed. Spider mite infestation resulted in up to two-fold increase in leaf sucrose concentrations and a three to five-fold increase in glucose and fructose concentrations, but these concentrations were not affected by fungal inoculation. Metarhizium, especially when applied as soil drench, impacted the fungal community composition but not the bacterial community composition which was only affected by the presence of spider mites. Our results suggest that in addition to directly killing spider mites, M. brunneum can indirectly suppress spider mite populations on tomato, although the underlying mechanism has not yet been resolved, and can also affect the composition of the soil microbial community.


Metabolic and genetic response to probiotics supplementation in patients with diabetic nephropathy: a randomized, double-blind, placebo-controlled trial.
This study was carried out to evaluate the effects of probiotics administration on the metabolic and genetic profiles in patients with diabetic nephropathy (DN). This was a randomized, placebo-controlled clinical trial with homeostasis model of assessment-estimated insulin resistance (HOMA-IR) as the primary and other metabolic profiles, and biomarkers of inflammation and oxidative stress as the secondary outcomes. This randomized, double-blind, placebo-controlled clinical trial was performed on 60 patients with DN. The patients were randomly assigned into two groups to receive either 8 × 109 CFU day-1 probiotic supplements or placebo (n = 30 in each group) for 12 weeks. Fasting blood was collected at the baseline and end of intervention to measure glycemic control, lipid profiles, biomarkers of inflammation and oxidative stress. Multiple linear regression models were used to assess the treatment effects on the outcomes adjusting for confounding variables. Probiotics supplementation, compared with the placebo, resulted in a significant reduction in fasting plasma glucose (P = 0.01), serum insulin concentrations (P = 0.01) and HOMA-IR (P = 0.007), and a significant increase in the quantitative insulin sensitivity check index (P = 0.04). Additionally, compared with the placebo, probiotic intake resulted in a significant reduction in triglycerides (P = 0.001) and total-/HDL-cholesterol ratio (P < 0.001), and a significant increase in HDL-cholesterol levels (P < 0.001). Supplementation with probiotics, compared with the placebo, was associated with a significant reduction in high-sensitivity C-reactive protein (P = 0.001), malondialdehyde (P < 0.001) and advanced glycation end products (P < 0.001), and a significant elevation in plasma total glutathione (P < 0.001). Overall, our study indicated that probiotics supplementation had beneficial effects on glycemic control and markers of cardio-metabolic risk.


Volumetric analysis of functional diffusion maps is a predictive imaging biomarker for cytotoxic and anti-angiogenic treatments in malignant gliomas.
Anti-angiogenic agents targeting brain tumor neovasculature may increase progression-free survival in patients with recurrent malignant gliomas. However, when these patients do recur it is not always apparent as an increase in enhancing tumor volume on MRI, which has been the standard of practice for following patients with brain tumors. Therefore alternative methods are needed to evaluate patients treated with these novel therapies. Furthermore, a method that can also provide useful information for the evaluation of conventional therapies would provide an important advantage for general applicability. Diffusion-weighted magnetic resonance imaging (DWI) has the potential to serve as a valuable biomarker for these purposes. In the current study, we explore the prognostic ability of functional diffusion maps (fDMs), which examine voxel-wise changes in the apparent diffusion coefficient (ADC) over time, applied to regions of fluid-attenuated inversion recovery (FLAIR) abnormalities in patients with malignant glioma, treated with either anti-angiogenic or cytotoxic therapies. Results indicate that the rate of change in fDMs is an early predictor of tumor progression, time to progression and overall survival for both treatments, suggesting the application of fDMs in FLAIR abnormal regions may be a significant advance in brain tumor biomarker technology.


Fatty acid metabolism by the porcine placenta.
Two experiments were performed to determine whether esterification is a major pathway of fatty acid utilization within porcine placenta and to determine what metabolic parameters may limit fatty acid transfer to the fetal pig. Maternal (endometrium) and fetal (chorioallantois) placenta were obtained by Caesarean section at d 110 of gestation in both experiments. Eight gilts were used in the first experiment. Tissue sections were incubated with palmitate at concentrations ranging from .25 to 2.0 mM. Maternal placenta metabolized palmitate at a higher rate than fetal placenta, although fetal placenta was more efficient in esterifying palmitate. Esterification composed the majority of palmitate utilization within fetal and maternal placenta. The second experiment evaluated the effect of dietary lipid on placental fatty acid metabolism and evaluated the ability of placenta to mobilize lipids. Fourteen gilts were divided into two groups of seven and fed a diet containing 15% tallow diet or a diet not supplemented with tallow (control) from d 90 to 110 of gestation. Dietary lipid had no detectable effects on lipoprotein lipase activity, [14C]palmitate metabolism, or lipolysis by the maternal or fetal placenta. Lipolytic activity of placental tissues was minimally affected by incubation with various proposed lipolytic activity of placental tissues was minimally affected by incubation with various proposed lipolytic agents. The data indicate that supply of fatty acids to the fetal pig may be limited by transfer of plasma fatty acids into the cytoplasm of placental cells or by regulatory enzymes for intermediate esterification; both types of limitations have been proposed to be influenced by fatty-acid binding proteins.


Ligament force and joint motion in the intact ankle: a cadaveric study.
The aims of this study were to measure the forces in the anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) and the motion in the tibiotalar and subtalar joints during simulated weight-bearing in eight cadaver ankle specimens. An MTS test machine was used to apply compressive loads to specimens held in a specially designed testing apparatus in which the ankle position (dorsiflexion-plantarflexion and supination-pronation) could be varied in a controlled manner. The forces in the ATFL and CFL were measured with buckle transducers. Tibiotalar motion and total ankle joint motion were measured with an instrumented spatial linkage. The specimens were positioned sequentially at 10 degrees dorsiflexion, neutral, and 10 degrees and 20 degrees plantarflexion, and this sequence was repeated at 15 degrees supination, neutral pronation/supination, and 15 degrees pronation. Force and motion measurements were recorded in each of these positions with and without a 375 N compressive load simulating weight-bearing. From 10 degrees dorsiflexion to 20 degrees plantarflexion, all motion occurred in the tibiotalar joint. In contrast, the ratio of subtalar motion to tibiotalar motion was 3:1 for supination-pronation and 4:1 for internal-external rotation. Inverse loading patterns were observed for the ATFL and CFL from plantarflexion to dorsiflexion. Compressive loading did not affect CFL tension, but it magnified the pattern of increasing ATFL tension with plantarflexion. The largest increase in ATFL force was observed in supination and plantarflexion with a compressive load (76 +/- 23 N), whereas CFL tension mainly increased in supination and dorsiflexion with a compressive load (109 +/- 28 N). In conclusion, the results showed that the ATFL acted as a primary restraint in inversion, where injuries typically occur (combined plantarflexion, supination and internal rotation). Also, the subtalar joint was of primary importance for normal supination-pronation and internal-external rotation.


Cavernous sinus and generalized venous thrombosis following rhinoplasty in a young patient.
Venous thromboembolism at lower age groups and in the absence of other known risk factors should raise doubt of underlying genetic disorders and thombophilia. It is discovered unexpectedly in various medical procedures and may cause severe complications and life threatening problems. In the current study, potentially life threatening complications of a genetic disorder in a previously healthy case is discussed. The important point in this case was delay onset of complication and its severity when was unexpectedly discovered. This situation may happen in almost every cosmetic operation and when the surgeon is not well prepared for managing this medical condition that it may lead to a dramatically poor prognosis for the patient.


Nanoparticle accumulation and transcytosis in brain endothelial cell layers.
The blood-brain barrier (BBB) is a selective barrier, which controls and limits access to the central nervous system (CNS). The selectivity of the BBB relies on specialized characteristics of the endothelial cells that line the microvasculature, including the expression of intercellular tight junctions, which limit paracellular permeability. Several reports suggest that nanoparticles have a unique capacity to cross the BBB. However, direct evidence of nanoparticle transcytosis is difficult to obtain, and we found that typical transport studies present several limitations when applied to nanoparticles. In order to investigate the capacity of nanoparticles to access and transport across the BBB, several different nanomaterials, including silica, titania and albumin- or transferrin-conjugated gold nanoparticles of different sizes, were exposed to a human in vitro BBB model of endothelial hCMEC/D3 cells. Extensive transmission electron microscopy imaging was applied in order to describe nanoparticle endocytosis and typical intracellular localisation, as well as to look for evidence of eventual transcytosis. Our results show that all of the nanoparticles were internalised, to different extents, by the BBB model and accumulated along the endo-lysosomal pathway. Rare events suggestive of nanoparticle transcytosis were also observed for several of the tested materials.


MEFV mutations in multiplex families with familial Mediterranean fever: is a particular genotype necessary for amyloidosis?
Familial Mediterranean fever (FMF) is an autosomal recessive disease. It is characterized by recurrent febrile episodes in association with peritonitis, pleuritis, and arthritis. Progressive systemic amyloidosis is the most important complication of FMF that inevitably leads to chronic renal failure. Recently, the gene for FMF, MEFV, has been cloned and four missense mutations have been described: M694V, M680I, V726A, and M694I. Initial studies have suggested that the presence of the M694V mutation carries a significant risk for the development of amyloidosis. In this study, we present seven families, in which at least two individuals have been diagnosed with FMF and at least one with amyloidosis. Among 18 individuals, in whom molecular testing was performed for the four aforementioned mutations, ten had amyloidosis. None of these ten individuals was found to be homozygous for the M694V mutation. In three families, there were two sibs with amyloidosis. None of the sib-pairs with amyloidosis was found to have the same genotype. There were two or more sibs with the same genotype in four families. Only one sib from each family developed amyloidosis in these families. These results provide evidence that FMF patients without the M694V mutation are also at risk for the development of amyloidosis. Particular mutations themselves do not appear to be sufficient to explain the occurrence of amyloidosis in all cases with FMF.


Nanostructured photoelectrodes based on WO3: applications to photooxidation of aqueous electrolytes.
Some recent studies mainly addressing the preparation and the modification of nanostructured thin films based on WO(3) and their application to photoelectrolysis of aqueous electrolytes are reviewed with the aim of rationalizing the main factors at the basis of an efficient photoanodic response. WO(3) represents one of the few materials which can achieve efficient water photo-oxidation under visible illumination, stably operating under strongly oxidizing conditions; thus the discussion of the structure-related photoelectrochemical properties of WO(3) thin films and their optimization for achieving almost quantitative photon to electron conversion constitutes the core of this contribution.


Reproductive factors and serum uric acid levels in females from the general population: the KORA F4 study.
Hyperuricemia is associated with an increased risk of metabolic and cardiovascular diseases. There are pronounced sex differences in the levels of uric acid. It is largely unknown whether or not reproductive parameters which induce hormonal changes are responsible for this. We examined if there are associations between reproductive parameters and uric acid levels in a female population-based sample. In this cross-sectional analysis, data of 1530 women aged 32 to 81 years participating in the KORA F4 study, conducted between 2006 and 2008 in Southern Germany were used. Reproductive parameters were obtained by standardized interviews. Uric acid levels were tested by the uricase method. The whole study sample and stratified in pre- and postmenopausal women was analyzed. Menopausal status and earlier age at menarche were associated with higher serum uric acid levels (age-adjusted: p-values 0.003, <0.001 respectively; after multivariable adjustment, including BMI: p-values 0.002, 0.036). A history of oral contraceptive use showed an association with uric acid levels only after multivariable adjustment (p-value 0.009). Hot flushes showed an association with uric acid levels only after age-adjustment (p-value 0.038), but lost significance after adding other confounders. Other reproductive factors, including parity, current or ever use of hormone replacement therapy, current use of oral contraceptives, hysterectomy, bilateral oophorectomy, or depressive mood related to menopausal transition were not associated with uric acid levels. Postmenopausal status, earlier age at menarche and a history of oral contraceptive use were independently associated with higher serum uric acid concentrations in women from the general population. Further studies, especially longitudinal population-based studies investigating the relationship of female reproductive parameters with uric acid levels are necessary to confirm our findings.


Defining core patient descriptors for perforated peptic ulcer research: international Delphi.
Perforated peptic ulcer (PPU) remains a common condition globally with significant morbidity and mortality. Previous work has demonstrated variation in reporting of patient characteristics in PPU studies, making comparison of studies and outcomes difficult. The aim of this study was to standardize the reporting of patient characteristics, by creating a core descriptor set (CDS) of important descriptors that should be consistently reported in PPU research. Candidate descriptors were identified through systematic review and stakeholder proposals. An international Delphi exercise involving three survey rounds was undertaken to obtain consensus on key patient characteristics for future research. Participants rated items on a scale of 1-9 with respect to their importance. Items meeting a predetermined threshold (rated 7-9 by over 70 per cent of stakeholders) were included in the final set and ratified at a consensus meeting. Feedback was provided between rounds to allow refinement of ratings. Some 116 clinicians were recruited from 29 countries. A total of 63 descriptors were longlisted from the literature, and 27 were proposed by stakeholders. After three survey rounds and a consensus meeting, 27 descriptors were included in the CDS. These covered demographic variables and co-morbidities, risk factors for PPU, presentation and pathway factors, need for organ support, biochemical parameters, prognostic tools, perforation details, and surgical history. This study defines the core descriptive items for PPU research, which will allow more robust synthesis of studies.


Solving the shepherding problem: heuristics for herding autonomous, interacting agents.
Herding of sheep by dogs is a powerful example of one individual causing many unwilling individuals to move in the same direction. Similar phenomena are central to crowd control, cleaning the environment and other engineering problems. Despite single dogs solving this 'shepherding problem' every day, it remains unknown which algorithm they employ or whether a general algorithm exists for shepherding. Here, we demonstrate such an algorithm, based on adaptive switching between collecting the agents when they are too dispersed and driving them once they are aggregated. Our algorithm reproduces key features of empirical data collected from sheep-dog interactions and suggests new ways in which robots can be designed to influence movements of living and artificial agents.


Mexican American Mobility: Early Life Processes and Adult Wealth Ownership.
Mexican Americans are a large group whose mobility patterns can provide important insight into immigrant assimilation processes. It is well known that Mexicans have not attained economic parity with whites, but there is considerable debate about the degree to which Mexican immigrants and their American-born children experience mobility over their lives. We contribute to this literature by studying Mexican American wealth ownership, focusing on three interrelated processes. First, we examine childhood poverty and inheritances to establish financial starting points and to identify the degree to which resources from prior generations affect wealth ownership. Second, we study impediments to mobility in young adulthood to understand how childhood conditions create early adult obstacles to wellbeing. Third, we study midlife net worth and homeownership to better understand whether childhood and young adult impediments necessarily reduce adult wealth ownership. We find high levels of early life disadvantage among Mexican Americans, but these disadvantages are least pronounced in the second and third generations compared to the first generation. Consistent with prior research, we also find high levels of young adult impediments to mobility for Mexican Americans. However, we find that these early roadblocks do not necessarily translate into lower adult wealth: we show that Mexican Americans have less total wealth than whites but more than African Americans, even when early life impediments are controlled. Our results suggest that Mexican Americans are establishing a solid financial foundation that is likely to lead to long-term class stability.


[Body build and soft tissue malignancies].
The distribution of somatotypes in 143 patients with tumors of soft tissues and in more than 980 apparently healthy subjects is presented. A relationship between this disease and body build was established. It was shown to depend upon sex, age and the degree of somatotype expression greatly. Men revealed a clearcut prevalence of the underdeveloped transitory somatotypes in all age groups, ectomorphic occurring in males under 44. In women, the number of pronounced endomorphic somatotypes was relatively high in all age groups, ectomorphic types prevailing at the age below 44 years.


An Update on the Management of Advanced Phase Chronic Myeloid Leukemia.
While most patients with chronic myeloid leukemia (CML) present in a chronic phase and are expected to have a normal life expectancy, some patients present with or progress to a more aggressive accelerated phase (AP) or blast phase (BP) of CML. Herein, we discuss the diagnostic considerations of advanced phase CML and review its contemporary management. Later-generation, more potent BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as ponatinib may result in superior outcomes in patients with advanced phase CML. For CML-BP, combination approaches directed against the blast immunophenotype appear superior to TKI monotherapy. The role of allogeneic stem cell transplantation is controversial in CML-AP but has consistently been shown to improve outcomes for patients with CML-BP. Advanced phase CML, particularly CML-BP, remains a poor risk subtype of CML. However, novel combination approaches using later-generation TKIs are being explored in clinical trials and may lead to improved outcomes.


Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): evolutions in classification, etiopathogenesis, assessment and management.
Eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome) is a peculiar hybrid condition of a systemic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and a hypereosinophilic disorder with frequent lung involvement that occurs in people with asthma. This review focuses on areas of evidence or persistent uncertainty in the classification, epidemiology, clinical presentation, diagnosis, prognosis and management of EGPA and attempts to identify clues to the mechanisms in the development or course of the disease. The 2013 revision of the EGPA definition formally placed the disease in the subset of ANCA-associated vasculitides. Recently published large case series underlined that the presence of ANCAs, found in 30-40% of EGPA, determines distinct but partly overlapping disease expression and the major detrimental effect of heart involvement on survival. There is some evidence that asthma in EGPA resembles a nonallergic eosinophilic asthma phenotype. Encouraging results have been reported for the treatment of EGPA with rituximab or with the eosinophil-targeted antiinterleukin-5 agent mepolizumab. The understanding of EGPA continues to advance, but many gaps in knowledge remain. The nomenclature remains a source of conceptual variance in terms of demonstrated presence or not of vessel inflammation or ANCAs in the diagnosis of EGPA. Distinguishing EGPA from hypereosinophilic syndromes can be problematic, and an understanding of the mechanistic relation between the vasculitis and the eosinophilic proliferation is profoundly lacking. Some evidence suggests distinct disease phenotypes, but this concept has not yet been translated to phenotype-adapted therapy.


Molecular foundations of chiropractic therapy.
Alternative medicine is a broad term used to encompass different therapies, including chiropractic. Chiropractic was called "a science of healing without drugs" by its founder, David Daniel Palmer. It is based on the idea that the body has a powerful self-healing ability and that there is a relationship between body structure and function that affects health. In particular, chiropractic assumes that the nervous system controls the human body through nerves branching from the vertebral column and spinal cord. Researchers do not fully understand how chiropractic therapies affect pain, but chiropractic is widely used today to treat chronic pain, such as back pain. Different studies with animal models have demonstrated that chiropractic therapies mediate neuroplasticity, specifically through modulation of neurotrophins. No studies have yet been published on interaction between neurotrophin gene polymorphisms and chiropractic treatment. We searched PubMed with the following keywords: chiropractic, neuroplasticity, neurotrophin gene polymorphism for a panorama of on the molecular mechanisms of chiropractic therapy. From the material collected, we identified a set of genes and some functional polymorphisms that could be correlated with better response to chiropractic therapy. Further association studies will be necessary to confirm hypotheses of a correlation between single nucleotide polymorphisms in specific genes and better response to chiropractic therapy.


Effects of dorsal fornix section and hippocampectomy on adrenocortical responses to sensory stimulation in the rat.
With the purpose of identifying the neural structures which are involved in the mediation of the adrenocortical responses to photic, acoustic and sciatic nerve stimulation, experiments were conducted on male rats with bilateral section of the dorsal fornix and dorsal or ventral hippocampectomies. The basal corticosterone levels in these animals were not significantly different from those in controls. Stimulation of the 3 sensory modalities produced normal adrenocortical responses in rats with fornix section. The hippocampectomies had no effect or only a marginal effect on the response to ether stress and to photic and acoustic stimulation; however, the adrenal response to sciatic stimulation was very significantly reduced. The data demonstrate the participation of the hippocampus in the transmission of somatosensory responses which promote adrenocortical activity. The efferent connections of the hippocampus to the hypothalamus which are involved in this mechanism are discussed.


Biomarker kinetics in the prediction of VAP diagnosis: results from the BioVAP study.
Prediction of diagnosis of ventilator-associated pneumonia (VAP) remains difficult. Our aim was to assess the value of biomarker kinetics in VAP prediction. We performed a prospective, multicenter, observational study to evaluate predictive accuracy of biomarker kinetics, namely C-reactive protein (CRP), procalcitonin (PCT), mid-region fragment of pro-adrenomedullin (MR-proADM), for VAP management in 211 patients receiving mechanical ventilation for >72 h. For the present analysis, we assessed all (N = 138) mechanically ventilated patients without an infection at admission. The kinetics of each variable, from day 1 to day 6 of mechanical ventilation, was assessed with each variable's slopes (rate of biomarker change per day), highest level and maximum amplitude of variation (Δ (max)). A total of 35 patients (25.4 %) developed a VAP and were compared with 70 non-infected controls (50.7 %). We excluded 33 patients (23.9 %) who developed a non-VAP nosocomial infection. Among the studied biomarkers, CRP and CRP ratio showed the best performance in VAP prediction. The slope of CRP change over time (adjusted odds ratio [aOR] 1.624, confidence interval [CI]95% [1.206, 2.189], p = 0.001), the highest CRP ratio concentration (aOR 1.202, CI95% [1.061, 1.363], p = 0.004) and Δ (max) CRP (aOR 1.139, CI95% [1.039, 1.248], p = 0.006), during the first 6 days of mechanical ventilation, were all significantly associated with VAP development. Both PCT and MR-proADM showed a poor predictive performance as well as temperature and white cell count. Our results suggest that in patients under mechanical ventilation, daily CRP monitoring was useful in VAP prediction. Trial registration NCT02078999.


Absence of spin liquid in nonfrustrated correlated systems.
The question of the existence of a spin liquid state in the half-filled Hubbard model on the honeycomb (also known as graphene) lattice is revisited. The variational cluster approximation, the cluster dynamical mean field theory, and the cluster dynamical impurity approximation are applied to various cluster systems. Assuming that the spin liquid phase coincides with the Mott insulating phase in this nonfrustrated system, we find that the Mott transition is preempted by a magnetic transition occurring at a lower value of the interaction U, and therefore the spin liquid phase does not occur. This conclusion is obtained using clusters with two bath orbitals connected to each boundary cluster site. We argue that using a single bath orbital per boundary site is insufficient and leads to the erroneous conclusion that the system is gapped for all nonzero values of U.


Family violence, war, and natural disasters: a study of the effect of extreme stress on children's mental health in Sri Lanka.
The consequences of war violence and natural disasters on the mental health of children as well as on family dynamics remain poorly understood. Aim of the present investigation was to establish the prevalence and predictors of traumatic stress related to war, family violence and the recent Tsunami experience in children living in a region affected by a long-lasting violent conflict. In addition, the study looked at whether higher levels of war violence would be related to higher levels of violence within the family and whether this would result in higher rates of psychological problems in the affected children. 296 Tamil school children in Sri Lanka's North-Eastern provinces were randomly selected for the survey. Diagnostic interviews were carried out by extensively trained local Master level counselors. PTSD symptoms were established by means of a validated Tamil version of the UCLA PTSD Index. Additionally, participants completed a detailed checklist of event types related to organized and family violence. 82.4% of the children had experienced at least one war-related event. 95.6% reported at least one aversive experience out of the family violence spectrum. The consequences are reflected in a 30.4% PTSD and a 19.6% Major Depression prevalence. Linear regression analyses showed that fathers' alcohol intake and previous exposure to war were significantly linked to the amount of maltreatment reported by the child. A clear dose-effect relationship between exposure to various stressful experiences and PTSD was found in the examined children. Data argue for a relationship between war violence and violent behavior inflicted on children in their families. Both of these factors, together with the experience of the recent Tsunami, resulted as significant predictors of PTSD in children, thus highlighting the detrimental effect that the experience of cumulative stress can have on children's mental health.


Stent fracture: case report and literature review.
We report the case of a man presenting with acute myocardial infarction and a history of percutaneous coronary intervention with implantation of a drug-eluting stent, which was now fractured. This case highlights the growing recognition of stent fracture as a potential mechanism for late stent thrombosis in the drug-eluting stent era. Following the case report, we review the literature on the incidence, contributing factors and clinical impact of stent fracture.


Betaine ameliorates heat stress-induced apoptosis by affecting oxidative and endoplasmic reticulum stress in mouse Leydig cells.
In order to explore the potential protective role of betaine in heat stress (HS)-elicited apoptosis in mouse Leydig cells (mLCs). Betaine at 16 mM exerted a greater inhibitory effect on HS-induced viability attenuation of cells, which also significantly suppressed the heat shock protein 70 level in HS-treated cells. Furthermore, betaine ameliorated certain negative effects, including increased cell apoptotic ratio, enhancement of apoptosis-related modulator caspase-3 activity, reduced activity levels of such antioxidant enzymes as SOD, CAT, GSH-Px and MDA upregulation, and inhibited the protein levels of critical endoplasmic reticulum (ER) stress indices like CHOP and GRP78 in mLCs exposed to HS. Besides, treatment of cells with betaine significantly restored diminished testosterone production in response to HS. Correspondingly, betaine effectively rescued the reduced serum testosterone concentration in vivo. In summary, betaine ameliorated HS-induced apoptosis by affecting oxidative and ER stress, thereby providing benefits for the treatment of hyperthermia-related impairment in mLCs.


The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation.
The acute vanishing bile duct syndrome can be defined as an irreversible, rejection-related condition that affects hepatic allografts within 100 days after orthotopic liver transplantation and whose presence requires retransplantation. We have observed the acute vanishing bile duct syndrome in 5 of 48 consecutive patients (approximately 10%) who underwent orthotopic liver transplantation. In 4 cases, the condition progressed relentlessly within approximately 7 to 11 weeks after orthotopic liver transplantation from mild rejection to severe rejection to acute vanishing bile duct syndrome. A fifth patient had severe rejection in the first week and required retransplantation after 17 days because of thrombotic venoocclusive disease complicating the acute vanishing bile duct syndrome. Clinically, signs of impending acute vanishing bile duct syndrome included abrupt onset of fever and jaundice and marked elevation of serum bilirubin and alkaline phosphatase levels which persisted despite antirejection treatment. Biopsy specimens revealed destructive cholangitis (rejection cholangitis), ductopenia, and, if retransplantation was delayed, presence of noninflammatory, "burnt-out" portal tracts without bile ducts. We recommend to base the diagnosis of acute vanishing bile duct syndrome on documentation of severe ductopenia in at least 20 portal tracts which may require several consecutive needle biopsies. Rejection arteriopathy which was found in 3 of our 5 cases might have been another important diagnostic clue but could not be recognized prior to retransplantation. The pathogenesis of acute vanishing bile duct syndrome is not clear; until the condition had manifested itself, we found no qualitative differences between acute reversible and irreversible rejection.(ABSTRACT TRUNCATED AT 250 WORDS)