Influence of hematoma volume and age on cognitive functions and ADL after putaminal hemorrhage.
After cerebral hemorrhage, cognitive functions and activities of daily living (ADL) are affected by various factors, including hematoma volume and patient age. In the present study, we investigated the effect of age and hematoma volume on cognitive functions and on ADL. The sample comprised 274 patients (183 men and 91 women; mean age 58.2 ± 12.5 years) with putaminal hemorrhage who were hospitalized in a convalescent rehabilitation ward. Hematoma volume was estimated from computed tomography imaging at stroke onset. Cognitive functions were evaluated using Raven's Colored Progressive Matrices test (RCPM) and the Mini-Mental State Examination (MMSE) at hospital admission, while ADL score was assessed at discharge using the Functional Independence Measure motor subscale (FIM-M). In the present study, we classified the patients into six groups according to whether they were non-elderly or elderly (cutoff age, 60 years) and whether their hematoma was small, medium, or large (cutoff volumes, 20 and 40 mL, respectively). Subsequently, the scores on the RCPM, MMSE, and FIM-M were compared among the groups. In both age groups, patients with a larger hematoma volume had lower RCPM and MMSE scores. Patients <60 years old exhibited different trends in their RCPM and MMSE scores, such that the RCPM score showed a step-wise decrease according to hematoma volume, while a difference in the MMSE score was only observed at the 20 mL boundary. Most of the younger patients (<60 years of age) attained high FIM-M scores at discharge, as long as their hematoma volume was either medium or small (<40 mL). This age group had higher RCPM scores on admission, which may have contributed to their higher FIM-M scores on discharge. In the present study, we demonstrated that advancing age increases the effect of hematoma volume on RCPM and MMSE scores and identified differences in the effects observed on these two scores. Thus, it may be important to use the RCPM alongside the MMSE for patient assessment.


Intervertebral disc degeneration is rescued by TGFβ/BMP signaling modulation in an ex vivo filamin B mouse model.
Spondylocarpotarsal syndrome (SCT) is a rare musculoskeletal disorder characterized by short stature and vertebral, carpal, and tarsal fusions resulting from biallelic nonsense mutations in the gene encoding filamin B (FLNB). Utilizing a FLNB knockout mouse, we showed that the vertebral fusions in SCT evolved from intervertebral disc (IVD) degeneration and ossification of the annulus fibrosus (AF), eventually leading to full trabecular bone formation. This resulted from alterations in the TGFβ/BMP signaling pathway that included increased canonical TGFβ and noncanonical BMP signaling. In this study, the role of FLNB in the TGFβ/BMP pathway was elucidated using in vitro, in vivo, and ex vivo treatment methodologies. The data demonstrated that FLNB interacts with inhibitory Smads 6 and 7 (i-Smads) to regulate TGFβ/BMP signaling and that loss of FLNB produces increased TGFβ receptor activity and decreased Smad 1 ubiquitination. Through the use of small molecule inhibitors in an ex vivo spine model, TGFβ/BMP signaling was modulated to design a targeted treatment for SCT and disc degeneration. Inhibition of canonical and noncanonical TGFβ/BMP pathway activity restored Flnb-/- IVD morphology. These most effective improvements resulted from specific inhibition of TGFβ and p38 signaling activation. FLNB acts as a bridge for TGFβ/BMP signaling crosstalk through i-Smads and is key for the critical balance in TGFβ/BMP signaling that maintains the IVD. These findings further our understanding of IVD biology and reveal new molecular targets for disc degeneration as well as congenital vertebral fusion disorders.


Persistence of unrepaired DNA double strand breaks caused by inhibition of ATM does not lead to radio-sensitisation in the absence of NF-κB activation.
The stress-inducible transcription complex NF-κB induces the transcription of genes that regulate proliferation and apoptosis. Constitutively activated NF-κB is common in breast cancers, and contributes to malignant progression and therapeutic resistance. Ataxia telangiectasia mutated (ATM) is a key regulator of the cellular response to DNA double strand breaks (DSBs), and recent reports have demonstrated that ATM is required for the activation of NF-κB following DNA damage. We investigated the role of ATM in the NF-κB signalling cascade induced by ionising radiation (IR) in breast cancer cell lines using KU55933, a novel and specific inhibitor of ATM. KU55933 suppressed IR-induced IκBα degradation, p50/p65 nuclear translocation and binding to kB consensus sequences. KU55933 also suppressed transcription of an NF-κB dependent reporter gene and inhibited IR-induced DSB repair as assessed by the neutral Comet assay. KU55933 sensitised cells to IR, with a concurrent increase in caspase 3 activity. Importantly, KU55933 sensitised IKKβ(+/+) and p65(+/+), but not IKKβ(-/-) or p65(-/-), mouse embryonic fibroblasts to IR, despite the equivalent inhibitory effects of KU55933 on DSB repair in both the proficient and the deficient cell lines. P65 siRNA had no effect on DSB repair in either breast cancer cell line. When combined with KU55933, DSB repair was inhibited to the same extent as KU55933 alone in both breast cancer cell lines. P65 siRNA alone sensitised both cell lines to IR. A combination of p65 siRNA and KU55933 resulted in no further sensitisation compared to either one alone. Taken together these data support the hypothesis that KU55933-mediated radio-sensitisation is solely a consequence of its inhibition of NF-κB activation. We conclude that radiotherapy deploying ATM inhibitors may be particularly advantageous in tumours where NF-κB is constitutively activated.


Combretastatin A-1 phosphate potentiates the antitumor activity of carboplatin and paclitaxel in a severe combined immunodeficiency disease (SCID) mouse model of human ovarian carcinoma.
In search for new therapeutic modalities to target epithelial ovarian carcinomas, we investigated the effect of the antiangiogenic drug combretastatin A-1 phosphate (CA1P) as a single treatment or in combination with established therapy, ie, carboplatin and paclitaxel. Five different human epithelial ovarian carcinoma cell lines were inoculated subcutaneously into FOX CHASE CB-77 severe combined immunodeficiency disease (SCID) mice. When tumors reached a volume of approximately 100 mm(3), the treatment was initiated. All drugs were given intraperitoneally at weekly doses. CA1P was more effective as an antitumor agent than combretastatin A-4 phosphate as a single-drug treatment or in combination with carboplatin and paclitaxel. CA1P had a strong tumor outgrowth inhibiting effect on four out of five tumors included in this study. Comparing animals receiving CA1P with animals receiving a combination of carboplatin and paclitaxel, CA1P was more effective on two out of three tested tumors, whereas carboplatin and paclitaxel were more effective on one out of three of the tumors. We show that treatment of human ovarian carcinomas with CA1P in the SCID mouse model results in a strong antitumor effect both as a single-drug treatment and as an enhancement of the therapeutic effect in a combination treatment protocol with carboplatin and paclitaxel.


Informant discrepancy defines discrete, clinically useful autism spectrum disorder subgroups.
Discrepancy between informants (parents and teachers) in severity ratings of core symptoms commonly arise when assessing autism spectrum disorder (ASD). Whether such discrepancy yields unique information about the ASD phenotype and its clinical correlates has not been examined. We examined whether degree of discrepancy between parent and teacher ASD symptom ratings defines discrete, clinically meaningful subgroups of youth with ASD using an efficient, cost-effective procedure. Children with ASD (N = 283; 82% boys; Mage = 10.5 years) were drawn from a specialty ASD clinic. Parents and teachers provided ratings of the three core DSM-IV-TR domains of ASD symptoms (communication, social, and perseverative behavior) with the Child and Adolescent Symptom Inventory-4R (CASI-4R). External validators included child psychotropic medication status, frequency of ASD-relevant school-based services, and the Autism Diagnostic Observation Schedule (ADOS-2). Four distinct subgroups emerged that ranged from large between-informant discrepancy (informant-specific) to relative lack of discrepancy (i.e. informant agreement; cross-situational): Moderate Parent/Low Teacher or Low Parent/Moderate Teacher Severity (Discrepancy), and Moderate or High Symptom Severity (Agreement). Subgroups were highly distinct (mean probability of group assignment = 94%). Relative to Discrepancy subgroups, Agreement subgroups were more likely to receive psychotropic medication, school-based special education services, and an ADOS-2 diagnosis. These differential associations would not have been identified based solely on CASI-4R scores from one informant. The degree of parent-teacher discrepancy about ASD symptom severity appears to provide more clinically useful information than reliance on a specific symptom domain or informant, and thus yields an innovative, cost-effective approach to assessing functional impairment. This conclusion stands in contrast to existing symptom clustering approaches in ASD, which treat within-informant patterns of symptom severity as generalizable across settings. Within-child variability in symptom expression across settings may yield uniquely useful information for characterizing the ASD phenotype.


[Development of the caudate nucleus of rats in postnatal ontogenesis and formation of cholinergic mediation in it].
Morphological maturation of the rat's caudate nucleus and formation of cholinergic system in it were studied in postnatal ontogenesis. Under investigation were newborn rats, 7, 14, 21 day old rats and adult animals. The growth and maturation of the caudate nucleys were most intesne during the first two postnatal weeks, it was somewhat descreased by the beginning of the third week and continued in later terms as well. The structure of dendrites and axons became complicated during the first two weeks, the axo-dendritic contacts being also formed. The neuron structure in 14 days old rats was similar to that of adult animals. The activity of acetylcholinesterase in the caudate nucleus of 7 and 14 days rats was not great. It sharply increased by the 17th day and reached the level of adults with 3 weeks after birth. Possible correlations of the morpho-chemical maturation of the caudate nucleus and formation of motor activity in rats is discussed.


Mitogen-activated protein kinase Hog1 mediates adaptation to G1 checkpoint arrest during arsenite and hyperosmotic stress.
Cells slow down cell cycle progression in order to adapt to unfavorable stress conditions. Yeast (Saccharomyces cerevisiae) responds to osmotic stress by triggering G(1) and G(2) checkpoint delays that are dependent on the mitogen-activated protein kinase (MAPK) Hog1. The high-osmolarity glycerol (HOG) pathway is also activated by arsenite, and the hog1Delta mutant is highly sensitive to arsenite, partly due to increased arsenite influx into hog1Delta cells. Yeast cell cycle regulation in response to arsenite and the role of Hog1 in this process have not yet been analyzed. Here, we found that long-term exposure to arsenite led to transient G(1) and G(2) delays in wild-type cells, whereas cells that lack the HOG1 gene or are defective in Hog1 kinase activity displayed persistent G(1) cell cycle arrest. Elevated levels of intracellular arsenite and "cross talk" between the HOG and pheromone response pathways, observed in arsenite-treated hog1Delta cells, prolonged the G(1) delay but did not cause a persistent G(1) arrest. In contrast, deletion of the SIC1 gene encoding a cyclin-dependent kinase inhibitor fully suppressed the observed block of G(1) exit in hog1Delta cells. Moreover, the Sic1 protein was stabilized in arsenite-treated hog1Delta cells. Interestingly, Sic1-dependent persistent G(1) arrest was also observed in hog1Delta cells during hyperosmotic stress. Taken together, our data point to an important role of the Hog1 kinase in adaptation to stress-induced G(1) cell cycle arrest.


Robust and sparse correlation matrix estimation for the analysis of high-dimensional genomics data.
Microarray technology can be used to study the expression of thousands of genes across a number of different experimental conditions, usually hundreds. The underlying principle is that genes sharing similar expression patterns, across different samples, can be part of the same co-expression system, or they may share the same biological functions. Groups of genes are usually identified based on cluster analysis. Clustering methods rely on the similarity matrix between genes. A common choice to measure similarity is to compute the sample correlation matrix. Dimensionality reduction is another popular data analysis task which is also based on covariance/correlation matrix estimates. Unfortunately, covariance/correlation matrix estimation suffers from the intrinsic noise present in high-dimensional data. Sources of noise are: sampling variations, presents of outlying sample units, and the fact that in most cases the number of units is much larger than the number of genes. In this paper, we propose a robust correlation matrix estimator that is regularized based on adaptive thresholding. The resulting method jointly tames the effects of the high-dimensionality, and data contamination. Computations are easy to implement and do not require hand tunings. Both simulated and real data are analyzed. A Monte Carlo experiment shows that the proposed method is capable of remarkable performances. Our correlation metric is more robust to outliers compared with the existing alternatives in two gene expression datasets. It is also shown how the regularization allows to automatically detect and filter spurious correlations. The same regularization is also extended to other less robust correlation measures. Finally, we apply the ARACNE algorithm on the SyNTreN gene expression data. Sensitivity and specificity of the reconstructed network is compared with the gold standard. We show that ARACNE performs better when it takes the proposed correlation matrix estimator as input. The R software is available at https://github.com/angy89/RobustSparseCorrelation. firstname.lastname@example.com or firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Apolipoprotein AII enrichment of HDL enhances their affinity for class B type I scavenger receptor but inhibits specific cholesteryl ester uptake.
Apolipoproteins of high density lipoprotein (HDL) and especially apolipoprotein (apo)AI and apoAII have been demonstrated as binding directly to the class B type I scavenger receptor (SR-BI), the HDL receptor that mediates selective cholesteryl ester uptake. However, the functional relevance of the binding capacity of each apolipoprotein is still unknown. The human adrenal cell line, NCI-H295R, spontaneously expresses a high level of SR-BI, the major apoAI binding protein in these cells. As previously described for murine SR-BI, free apoAI, palmitoyl-oleoyl-phosphatidylcholine (POPC)-AI, and HDL are good ligands for human SR-BI. In vitro displacement of apoAI by apoAII in HDLs or in Lp AI purified from HDL by immunoaffinity enhances their ability to compete with POPC-AI to bind to SR-BI and also enhances their direct binding capacity. The next step was to determine whether the higher affinity of apoAII for SR-BI correlated with the specific uptake of cholesteryl esters from these HDLs. Free apoAII and, to a lesser extent, free apoAI that were added to the cell medium during uptake experiments inhibited the specific uptake of [(3)H]cholesteryl esters from HDL, indicating that binding sites on cells were the same as cholesteryl ester uptake sites. In direct experiments, the uptake of [(3)H]cholesteryl esters from apoAII-enriched HDL was highly reduced compared with the uptake from native HDL. These results demonstrate that in the human adrenal cell line expressing SR-BI as the major HDL binding protein, efficient apoAII binding has an inhibitory effect on the delivery of cholesteryl esters to cells.


Anisotropic cellulose nanocrystal hydrogel with multi-stimuli response to temperature and mechanical stress.
Conventional hydrogels with isotropic polymer networks usually lack selective response to external stimuli and that limits their applications in intelligent devices. Herein, hydrogels with distinctive anisotropic optical characteristics combined with thermosensitivity were prepared through in situ photopolymerization. Self-assembled cellulose nanocrystals (CNCs) with chiral nematic ordered structure were embedded in polyethylene glycol derivatives/polyacrylamide polymer networks. The arrangement of CNCs showed a strong dependence on the self-assembly angle and standing time, enabling the fabrication of hydrogels with customizable CNCs arrangements. Increasing the self-assembly angle from 0° to 90° changed the CNCs arrangement from chiral nematic to symmetrical nematic order which, together with CNCs dynamic arrangement from isotropic to annealed chiral nematic phase at longer standing time, provided versatile ways to produce CNCs hydrogels with tunable anisotropic properties. In addition, the obtained hydrogel displayed reversible temperature and compression response, showing excellent promise to be used as soft mechanical stress and temperature sensors or novel anti-counterfeiting materials.


The Impact of Race/Ethnicity on the Outcomes of Burn Patients: A Systematic Review of the Literature.
Racial and ethnic disparities are endemic to the United States and are only beginning to attract the attention of researchers. With an increasingly diverse population, focused and tailored medicine to provide more equitable care is needed. For surgical trauma populations, this topic is a small but expanding field and still rarely mentioned in burn medicine. Disparities in prevention, treatment, and recovery outcomes between different racial and ethnic minorities who are burned are rarely discussed. The purpose of this study is to determine the current status of identified disparities of care in the burn population literature and areas of future research. A systematic review was conducted of literature utilizing PubMed for articles published between 2000 and 2020. Searches were used to identify articles that crossed the burn term (burn patient OR burn recovery OR burn survivor OR burn care) and a race/ethnicity and insurance status-related term (race/ethnicity OR African-American OR Black OR Asian OR Hispanic OR Latino OR Native American OR Indigenous OR Mixed race OR 2 or more races OR socioeconomic status OR insurance status). Inclusion criteria were English studies in the United States that discussed disparities in burn injury outcomes or risk factors associated with race/ethnicity. One thousand one hundred and sixty-nine papers were populated, 55 were reviewed, and 36 articles met inclusion criteria. Most studies showed minorities had poorer inpatient and outpatient outcomes. While this is a concerning trend, there is a paucity of literature in this field and more research is needed to create culturally tailored medical care and address the needs of disadvantaged burn survivors.


Combined l-citrulline and tetrahydrobiopterin therapy improves NO signaling and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs.
Newborn pigs with chronic hypoxia-induced pulmonary hypertension (PH) have evidence of endothelial nitric oxide synthase (eNOS) uncoupling. In this model, we showed that therapies that promote eNOS coupling, either tetrahydrobiopterin (BH4), a NOS cofactor, or l-citrulline, a NO-l-arginine precursor, inhibit PH. We wanted to determine whether cotreatment with l-citrulline and a BH4 compound, sapropterin dihydrochloride, improves NO signaling and chronic hypoxia-induced PH more markedly than either alone. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received sole treatment with l-citrulline or BH4, or were cotreated with l-citrulline and BH4, from day 3 through day 10 of hypoxia. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios and NO production. In untreated hypoxic piglets, pulmonary vascular resistance (PVR) was higher and NO production and eNOS dimer-to-monomer ratios were lower than in normoxic piglets. Compared with the untreated hypoxic group, PVR was lower in hypoxic piglets cotreated with l-citrulline and BH4 and in those treated with l-citrulline alone but not for those treated solely with BH4. NO production and eNOS dimer-to-monomer ratios were greater for all three treated hypoxic groups compared with the untreated group. Notably, greater improvements in PVR, eNOS dimer-to-monomer ratios, and NO production were found in hypoxic piglets cotreated with l-citrulline and BH4 than in piglets treated with either alone. Cotreatment with l-citrulline and BH4 more effectively improves NO signaling and inhibits chronic hypoxia-induced PH than either treatment alone. Combination therapies may offer enhanced therapeutic capacity for challenging clinical conditions, such as chronic neonatal PH.


Postinjury Engagement With the Police and Access to Care Among Victims of Violent Street Crime: Does Criminal History Matter?
This study examines whether victims of violent street crimes who are known to the police as past offenders, when compared with victims with no arrest history, have different outcomes related to receipt of victim and health-related services, while taking into consideration whether or not police responded to the victimization incident. The sample is comprised of 103 men and women between the age of 18 and 40 living in one Mid-Atlantic city who were victims of street violence within the year before study recruitment. Logistic regression was used to assess the impact of police response to the victimization incident on receipt of victim services, and receipt of victim services on engagement with counseling and mental health services. The results show that prior arrests were not associated with receipt of services. However, having police officers respond to the victimization was associated with higher odds of receiving victim services, and in turn, victim services were associated with receiving mental health treatment. Police response appears to set victims on a path to accessing services. Although the number of arrests was not associated with service receipt, a small percentage of victims who did not receive services stated they were reluctant to cooperate with the police, thus limiting their opportunity for victim services. Because most victims who did not access victim services did not know that they existed, policies that promote more knowledge of and initial engagement with victim services could improve access to needed health and mental health services.


Disruption of Yarrowia lipolytica biofilms by rhamnolipid biosurfactant.
Yarrowia lipolytica is an ascomycetous dimorphic fungus that exhibits biofilm mode of growth. Earlier work has shown that biosurfactants such as rhamnolipids are efficient dispersants of bacterial biofilms. However, their effectiveness against fungal biofilms (particularly Y. lipolytica) has not been investigated. The aim of this study was to determine the effect of rhamnolipid on a biofilm forming strain of Y. lipolytica. Two chemical surfactants, cetyl-trimethyl ammonium bromide (CTAB) and sodium dodecyl sulphate (SDS) were used as controls for comparison. The methylene blue dye exclusion assay indicated an increase in fungal cell permeability after rhamnolipid treatment. Microtiter plate assay showed that the surfactant coating decreased Y. lipolytica biofilm formation by 50%. Rhamnolipid treatment disrupted pre-formed biofilms in a more effective manner than the other two surfactants. Confocal laser scanning microscopic studies showed that biofilm formation onto glass surfaces was decreased by 67% after sub-minimum inhibitory concentration (sub-MIC) treatment with rhamnolipids. The disruption of biofilms after rhamnolipid treatment was significant (P<0.05) when compared to SDS and CTAB. The results indicate a potential application of the biological surfactant to disrupt Y. lipolytica biofilms.


Measuring tolerance to herbivory: accuracy and precision of estimates made using natural versus imposed damage.
Tolerance to herbivory (the ability of a plant to incur herbivore damage without a corresponding reduction in fitness) can be measured using either naturally occurring or imposed herbivore damage. After briefly reviewing some of the advantages and disadvantages of these approaches, we present calculations describing the degree to which estimates of tolerance will be biased by environmental variables that affect both herbivory and fitness. With naturally occurring herbivory the presence of environmental variables that are correlated with herbivory and fitness will result in biased estimates of tolerance. In contrast, estimates obtained from experiments in which herbivory is artificially imposed will be unbiased; however, under a wide range of parameter values these estimates will be less precise than estimates obtained from experiments in which herbivory is not manipulated.


Relapse of multiple myeloma presenting as extramedullary plasmacytomas in multiple organs.
Multiple myeloma is a neoplastic plasma cell disorder. It is characterized by collections of abnormal plasma cells accumulating in the bone marrow, where they interfere with the production of normal blood cells. It usually presents as a multisystemic involvement, whose symptoms and signs vary greatly. Some patients have slowly progressive disease while others have aggressive clinical behavior by extramedullary involvement. In addition to renal failure, anemia, hypercalcemia, lytic bone lesions, and immunodeficiency, it also affects multiple organ system, such as pancreas, adrenal glands, kidney, skin, lung, liver, spleen, lymph nodes, and bone. To raise awareness of the variable presentations of this disease, we report a 53-year-old male patient, with multiple myeloma in his first remission who relapsed with extramedullary plasmacytomas (EMPs) involving multiple organs, such as pancreas, adrenal glands, kidney, skin, lung, liver, spleen, and lymph nodes.


[Structural changes in the pulmonary vessels and parenchyma in experimental hypercholesterolemia and atherosclerosis].
Light and electron microscopy were employed to study the microcirculatory bed (MCB), intraorganic vessels and lung tissue in rabbits in the first hours (1, 3, 6, 15, 24 and 48 h) after a single administration of cholesterol (ChS) and in the course of the development of experimental atherosclerosis. The MCB demonstrated changes such as dilatation of the venular part, arteriolar constriction, red cell aggregation in capillaries and venules, and stases. At the early stages of experimental atherosclerosis induced by the diet the permeability of the air-blood barrier and the synthesis of lung surfactant were found to be deranged. Vessel-tissue changes in the lungs progressed with an increase in the length of the diet (1-8 months) and were alike the picture seen in chronic nonspecific lung diseases, particularly in what is called senile emphysema. A relationship was established between the degree of changes in the MCB and HCh gravity. Atherosclerotic lesions in the intraorganic arteries occur and progress parallel with the development of this process in the intramural arteries of the myocardium. The data obtained attest to an important role of lipid metabolism disorders in the development of lung pathology and may have a certain significance in specifying the pathogenesis of chronic nonspecific lung diseases, especially.


[Correlation of Twist and YB-1 up-regulation and epithelial-mesenchymal transition during tumorigenesis and progression of cervical carcinoma].
To investigate the clinicopathological significance of Twist and YB-1 up-regulation in cervical cancer, and to correlate the expression of the two genes with E-cadherin, a marker of epithelial-mesenchymal transition (EMT). A total of 202 tissue samples were collected during January 2008 to December 2013, including 50 cases of normal cervical tissues, 100 cases of cervical intraepithelial neoplasia (CIN) and 52 cases of squamous cell carcinoma (SCC). Twist, YB-1 and E-cadherin expression was investigated by MaxVision. Increased expression levels of Twist and YB-1 were found and correlated with the malignant transformation of cervical epithelium, histological progression and metastasis of cervical cancer. In addition, Twist and YB-1 overexpression was also associated with aberrant expression of E-cadherin. Regression analysis revealed that Twist expression was an independent factor for the histological progression of cervical cancer. It is suggested that Twist and YB-1 overexpression is significantly linked to cervical cancer tumorigenesis and progression, likely related to EMT through (YB-1)-Twist-(E-cadherin) pathway. Twist and YB-1 may be markers for determining the metastatic potential of cervical cancer.


Asymmetric copolymer vesicles to serve as a hemoglobin vector for ischemia therapy.
Self-aggregated vesicles have been considered to be promising candidates for hemoglobin-based oxygen carriers. Here, amphiphilic hetero-triblock copolymers are designed and synthesized with the capacity to self-assemble into polymer vesicles (polymersomes). Conceivably, vesicles are formed with asymmetric membranes, which achieve enhanced encapsulation efficiency of hemoglobin (Hb) beyond the diblock counterpart. Furthermore, hemoglobin-loaded vesicles (HbV) are fabricated with high Hb content and submicron particle sizes. The gas-binding capability, oxygen affinity and methemoglobin (metHb) level of the HbV dispersions are all comparable to the natural erythrocytes. In vitro HbV stability studies further reveal that the encapsulation of Hb within vesicles can greatly avoid the existence of free Hb and shows no interference with cells, especially for blood components. To evaluate the efficacy on ischemia reperfusion, HbV suspended in a plasma expander is transfused as a resuscitation fluid into an acute anemia rat model. Results demonstrate that the combined infusion of the plasma expander with HbV effectively ameliorates the lethal shock symptom and reduces short-term mortality. Concurrently, rats transfused with HbV are void of the acute tubular necrosis caused by the filtration of dissociated Hb dimers from glomeruli. We envision that the oxygen carriers derived from polymer self-assembly technology will become an alternative strategy for future development of blood substitutes.


Origins and projections of peptide-immunoreactive nerves in the male rat genitofemoral nerve.
Following injection of retrograde tracer to one genitofemoral nerve of male rats, motoneurones and dorsal root ganglion cells of segmental levels L1/L2 were labelled ipsilaterally. Many labelled motoneurones were calcitonin gene-related peptide- (CGRP) immunoreactive. In the ganglia, a proportion of the labelled cells were CGRP-, tachykinin- or galanin-immunoreactive (10%:6%:53% respectively). In comparison with ganglia of the contralateral side, galanin-immunoreactive cells were significantly increased in the ipsilateral ganglia. Unilateral genitofemoral nerve section induced a loss of CGRP- or tachykinin- and an increase of galanin-immunoreactive cells in the ipsilateral L1/L2 ganglia. In the ipsilateral L1/L2 dorsal horn, CGRP and tachykinin, but not galanin, immunoreactivity was reduced. In the cremaster muscle and scrotal skin of either side galanin-immunoreactive fibres were not visible and CGRP- and tachykinin-immunoreactive fibres were depleted in the ipsilateral side. Capsaicin induced a loss of CGRP- and tachykinin-immunoreactive ganglion cells and of CGRP, tachykinin or galanin immunoreactivity from the dorsal horn. In the scrotal skin, CGRP- and tachykinin-immunoreactive fibres were depleted. By contrast in the muscle, a few CGRP-immunoreactive fibres persisted. The data demonstrate that (i) the genitofemoral nerve originates at segmental levels L1/L2; (ii) CGRP- and tachykinin-immunoreactive sensory and CGRP-immunoreactive motor neurones project to the cremaster muscle and scrotal skin; and (iii) nerve pertubation induces an increase of galanin-immunoreactive sensory neurones, the significance of which remains to be elucidated.


Social science methods for twins data: integrating causality, endowments, and heritability.
Twins have been extensively used in economics, sociology, and behavioral genetics to investigate the role of genetic endowments on a broad range of social, demographic, and economic outcomes. However, the focus in these literatures has been distinct.: The economic literature has been primarily concerned with the need to control for unobserved endowments--including as an important subset, genetic endowments--in analyses that attempt to establish the impact of one variable, often schooling, on a variety of economic, demographic, and health outcomes. Behavioral genetic analyses have mostly been concerned with decomposing the variation in the outcomes of interest into genetic, shared environmental, and non-shared environmental components, with recent multivariate analyses investigating the contributions of genes and the environment to the correlation and causation between variables. Despite the fact that twins studies and the recognition of the role of endowments are central to both of these literatures, they have mostly evolved independently. In this paper we develop formally the relationship between the economic and behavioral genetic approaches to the analyses of twins, and we develop an integrative approach that combines the identification of causal effects, which dominates the economic literature, with the decomposition of variances and covariances into genetic and environmental factors that are the primary goal of behavioral genetic approaches. We apply this integrative ACE-beta approach to an illustrative investigation of the impact of schooling on several demographic outcomes such as fertility and nuptiality and health.


Gut Microbiota Modulation and Its Implications on Neuropathic Pain: A Comprehensive Literature Review.
Neuropathic pain (NP) is a chronic pain disorder arising from somatosensory nervous system impairment. Extensive evidence supports the notion that the gut microbiota (GM) is crucial in maintaining human health by performing vital tasks. At the same time, its disruption has been linked to the emergence and advancement of an expanding range of disorders, including NP, in which GM could play a role in its pathophysiology. The crosstalk between the nervous system and GM happens through immune mediators, metabolites, and nervous structures and involves both central and peripheral nervous systems. This literature review aims to thoroughly investigate the function of modulating GM in the treatment of NP. It will achieve this by integrating existing knowledge, identifying underlying mechanisms, and evaluating the possible clinical consequences of exploiting the gut-brain axis. We will cover the main therapeutic applications of the described GM-modulators, such as probiotics, faecal microbiota transplantation, dietary supplements and emotional support, to the main kinds of NP in which any evidence, even if only pre-clinical, has been unravelled in recent years. The explored NP areas include chemotherapy-induced peripheral neuropathy, diabetic neuropathy, trauma-induced neuropathic pain, trigeminal neuralgia, postherpetic neuralgia and low back pain.


2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells.
We studied the actions of 2-phenylacetylenesulfonamide (PAS) on B-chronic lymphocytic leukemia (CLL) cells. PAS (5-20 microM) initiated apoptosis within 24 hours, with maximal death at 48 hours asassessed by morphology, cleavage of poly(ADP-ribose) polymerase (PARP), caspase 3 activation, and annexin V staining. PAS treatment induced Bax proapoptotic conformational change, Bax movement from the cytosol to the mitochondria, and cytochrome c release, indicating that PAS induced apoptosis via the mitochondrial pathway. PAS induced approximately 3-fold up-regulation of proapoptotic Noxa protein and mRNA levels. In addition, Noxa was found unexpectedly to be bound to Bcl-2 in PAS-treated cells. PAS treatment of CLL cells failed to up-regulate p53, suggesting that PAS induced apoptosis independently of p53. Furthermore, PAS induced apoptosis in CLL isolates with p53 gene deletion in more than 97% of cells. Normal B lymphocytes were as sensitive to PAS-induced Noxa up-regulation and apoptosis as were CLL cells. However, both T lymphocytes and bone marrow hematopoietic progenitor cells were relatively resistant to PAS. Our data suggest that PAS may represent a novel class of drug that induces apoptosis in CLL cells independently of p53 status by a mechanism involving Noxa up-regulation.


Label-free biological and chemical sensors.
Highly sensitive, label-free biodetection methods have applications in both the fundamental research and healthcare diagnostics arenas. Therefore, the development of new transduction methods and the improvement of the existing methods will significantly impact these areas. A brief overview of the different types of biosensors and the critical parameters governing their performance will be given. Additionally, a more in-depth discussion of optical devices, surface functionalization methods to increase device specificity, and fluidic techniques to improve sample delivery will be reviewed.


Climate Change and Global Food Systems: Potential Impacts on Food Security and Undernutrition.
Great progress has been made in addressing global undernutrition over the past several decades, in part because of large increases in food production from agricultural expansion and intensification. Food systems, however, face continued increases in demand and growing environmental pressures. Most prominently, human-caused climate change will influence the quality and quantity of food we produce and our ability to distribute it equitably. Our capacity to ensure food security and nutritional adequacy in the face of rapidly changing biophysical conditions will be a major determinant of the next century's global burden of disease. In this article, we review the main pathways by which climate change may affect our food production systems-agriculture, fisheries, and livestock-as well as the socioeconomic forces that may influence equitable distribution.


Using Frameshift Peptide Arrays for Cancer Neo-Antigens Screening.
It has been demonstrated that DNA mutations generating neo-antigens are important for an effective immune response to tumors as evident from recent clinical studies of immune checkpoint inhibitors (ICIs). Further, it was shown that frameshift peptides (FSP) generated in tumors from insertions and deletions (INDELs) of microsatellites (MS) in coding region are a very good correlate of positive response to PD1 treatment. However, these types of DNA-sourced FSPs are infrequent in cancer. We hypothesize that tumors may also generate FSPs in transcription errors through INDELs in MS or by exon mis-splicing. Since there are a finite number of predictable sequences of such possible FSPs in the genome, we propose that peptide arrays with all possible FSPs could be used to analyze antibody reactivity to FSPs in patient sera as a FS neo-antigen screen. If this were the case it would facilitate finding common tumor neoantigens for cancer vaccines. Here we test this proposal using an array of 377 predicted FS antigens. The results of screening 9 types of dog cancer sera indicate that cancer samples had significantly higher antibody responses against FSPs than non-cancer samples. Both common reactive FSPs and cancer-type specific immune responses were detected. In addition, the protection of a common reactive FSP was tested in mouse tumor models, comparing to the non-reactive FSPs. The mouse homologs non-reactive FSPs did not offer protection in either the mouse melanoma or breast cancer models while the reactive FSP did in both models. The tumor protection was positively correlated to antibody response to the FSP. These data suggest that FSP arrays could be used for cancer neo-antigen screening.


Long-time saturation of the Loschmidt echo in quantum chaotic billiards.
The Loschmidt echo (LE) (or fidelity) quantifies the sensitivity of the time evolution of a quantum system with respect to a perturbation of the Hamiltonian. In a typical chaotic system the LE has been previously argued to exhibit a long-time saturation at a value inversely proportional to the effective size of the Hilbert space of the system. However, until now no quantitative results have been known and, in particular, no explicit expression for the proportionality constant has been proposed. In this paper we perform a quantitative analysis of the phenomenon of the LE saturation and provide the analytical expression for its long-time saturation value for a semiclassical particle in a two-dimensional chaotic billiard. We further perform extensive (fully quantum mechanical) numerical calculations of the LE saturation value and find the numerical results to support the semiclassical theory.


Extended-release hydrocodone: the devil in disguise or just misunderstood?
Opioid abuse in the United States increased significantly over the past decade, leading to opioid-related deaths. Approval of Zohydro ER, a product that lacks an abuse-deterrent formulation, has provoked media controversy and aggressive legislative action from multiple stakeholders. Only the American Academy of Pain Management has released a position statement on this medication, and individual opinion varies. Additional single-entity extended-release hydrocodone formulations are in the pipeline, and Zohydro ER's limited clinical utility may make the controversy associated with its approval a moot point. As with other opioids, providers will need to assess individual patient risk versus benefit when prescribing Zohydro ER.


Polylactide-based renewable green composites from agricultural residues and their hybrids.
Agricultural natural fibers like jute, kenaf, sisal, flax, and industrial hemp have been extensively studied in green composites. The continuous supply of biofibers in high volumes to automotive part makers has raised concerns. Because extrusion followed by injection molding drastically reduces the aspect ratio of biofibers, the mechanical performance of injection molded agricultural residue and agricultural fiber-based composites are comparable. Here, the use of inexpensive agricultural residues and their hybrids that are 8-10 times cheaper than agricultural fibers is demonstrated to be a better way of getting sustainable materials with better performance. Green renewable composites from polylactide (PLA), agricultural residues (wheat straw, corn stover, soy stalks, and their hybrids) were successfully prepared through twin-screw extrusion, followed by injection molding. The effect on mechanical properties of varying the wheat straw amount from 10 to 40 wt % in PLA-wheat straw composites was studied. Tensile moduli were compared with theoretical calculations from the rule of mixture (ROM). Combination of agricultural residues as hybrids is proved to reduce the supply chain concerns for injection molded green composites. Densities of the green composites were found to be lower than those of conventional glass fiber composites.


Study design and subject baseline characteristics in the ADVANCE Study: effects of cinacalcet on vascular calcification in haemodialysis patients.
The ADVANCE (A Randomized Study to Evaluate the Effects of Cinacalcet plus Low-Dose Vitamin D on Vascular Calcification in Subjects with Chronic Kidney Disease Receiving Haemodialysis) Study objective is to assess the effect of cinacalcet plus low-dose active vitamin D versus flexible dosing of active vitamin D on progression of coronary artery calcification (CAC) in haemodialysis patients. We report the ADVANCE Study design and baseline subject characteristics. ADVANCE is a multinational, multicentre, randomized, open-label study. Adult haemodialysis patients with moderate to severe secondary hyperparathyroidism (intact parathyroid hormone [iPTH] >300 pg/mL or bio-intact PTH >160 pg/mL) and baseline CAC score >or=30 were stratified by CAC score (>or=30-399, >or=400-999, >or=1000) and randomized in a 1:1 ratio to cinacalcet (30-180 mg/day) plus low-dose active vitamin D (cinacalcet group) or flexible dosing of active vitamin D alone (control). The study had three phases: screening, 20-week dose titration and 32-week follow-up. CAC scores obtained by cardiac computed tomography were determined at screening and weeks 28 and 52. The primary end point was percentage change in CAC score from baseline to Week 52. Subjects (n = 360) were randomized to cinacalcet or control. Mean age was 61.5 years, 43% were women, and median dialysis vintage was 36.7 months (range, 2.7-351.5 months). The baseline geometric mean CAC score by the Agatston method was 548.7 (95% confidence interval, 480.5-626.6). Baseline CAC score was independently associated with age, sex, dialysis vintage, diabetes and iPTH. Subjects also had extensive aortic and valvular calcification at baseline. Subjects enrolled in ADVANCE have extensive CAC at baseline. The ADVANCE Study should help determine whether cinacalcet attenuates progression of vascular calcification.


Glycogen storage and degradation during in vitro growth and differentiation of Giardia intestinalis.
Giardia intestinalis is the causative agent of human giardiasis, a common diarrheal illness worldwide. Despite its global distribution and prevalence, many questions regarding its basic biology and metabolism remain unanswered. In this study, we examine the accumulation and degradation of glycogen, an important source of stored carbon and energy, during the in vitro growth and differentiation of G. intestinalis . We report that, as G. intestinalis progresses through its growth cycle, cultures of trophozoites accumulate glycogen during the lag and early logarithmic phases of growth and then utilize this compound during their remaining logarithmic growth. As cultures enter the stationary phase of growth, they re-accumulate glycogen stores. The activity of glycogen phosphorylase, an enzyme involved in glycogen metabolism, also varied throughout in vitro trophozoite growth. During the in vitro induction of trophozoite differentiation into water-resistant cyst forms, the cultures initially accumulated stores of glycogen which diminished throughout transition to the cyst form. This observation is suggestive of a role for glycogen in the differentiation process. These studies represent the first thorough analysis of changes in glycogen content and glycogen phosphorylase activity during G. intestinalis growth and differentiation.


Acute rupture of the diaphragm in blunt trauma: analysis of 60 patients.
During a 9-year period, 60 patients with acutely ruptured diaphragms following blunt trauma were treated in our institution. Diaphragmatic injury was detected within 24 hours of hospital admission in all but two patients. The diagnosis was suggested by upright chest X-ray in 40% of the patients. Diaphragmatic tears were discovered at laparotomy for hemoperitoneum in the remaining patients. At initial evaluation hypotension was present in 67% of the patients, and respiratory distress was evident in 52%. In contrast to traditional teaching, there was a 30% incidence of right hemidiaphragmatic disruption. One patient experienced bilateral diaphragmatic rupture, and two had isolated tears of the pericardial diaphragm. Intra-abdominal organs were herniated through the diaphragmatic defect in only 32% of the patients. There was a 90% incidence of associated intra-abdominal injuries. The diaphragmatic tear was repaired via the abdomen in 53 patients, through a thoracoabdominal incision in five patients, and through the chest in only two cases. All defects were closed primarily. Twelve patients also required thoracotomy for resuscitation and/or correction of intrathoracic injury. Atelectasis was the most frequent postoperative complication, occurring in 65% of the patients. The mortality was 26.7% and was related to associated injuries in all cases.


Leaping through tree space: continuous phylogenetic inference for rooted and unrooted trees.
Phylogenetics is now fundamental in life sciences, providing insights into the earliest branches of life and the origins and spread of epidemics. However, finding suitable phylogenies from the vast space of possible trees remains challenging. To address this problem, for the first time, we perform both tree exploration and inference in a continuous space where the computation of gradients is possible. This continuous relaxation allows for major leaps across tree space in both rooted and unrooted trees, and is less susceptible to convergence to local minima. Our approach outperforms the current best methods for inference on unrooted trees and, in simulation, accurately infers the tree and root in ultrametric cases. The approach is effective in cases of empirical data with negligible amounts of data, which we demonstrate on the phylogeny of jawed vertebrates. Indeed, only a few genes with an ultrametric signal were generally sufficient for resolving the major lineages of vertebrates. Optimisation is possible via automatic differentiation and our method presents an effective way forwards for exploring the most difficult, data-deficient phylogenetic questions.


Acquired resistance of horses to Amblyomma cajennense (Fabricius, 1787) ticks.
Acquired immunity of horses to larvae, nymphs and adults of the Amblyomma cajennense tick was evaluated through three consecutive experimental infestations of tick-bite naïve hosts. Data from these infestations were compared to those from field-sensitized horses and donkeys. It was observed that tick-bite naïve horses developed a low level of resistance after two infestations as shown by a significant decrease in larval yield and a tendency for lower engorged weight of nymphs during third infestation. Ticks fed on field-sensitized horses had a similar biological performance to that observed on the third infestation of tick-bite naïve horses but the mean engorged nymph weight was significantly lower than that of the first infestation from tick-bite naïve horses. Donkeys presented the strongest resistance with significantly lower engorged weights of all instars and of the egg mass compared to the first infestation of tick-bite naïve horses. Donkeys also displayed a significantly higher resistance than field-sensitized horses as demonstrated by significantly lower egg mass weights. Overall these results indicate that donkeys but not horses maintain a strong resistance to A. cajennense ticks. The importance of these findings in relation to vectoring of tick-borne diseases is discussed.


Losartan blocks aldosterone and renal vascular responses to angiotensin II in humans.
In vitro and animal studies have demonstrated that the effect of angiotensin II (Ang II) on aldosterone is mediated through the Ang II type 1 receptor. However, it has been difficult to demonstrate an effect of Ang II type 1 receptor blockade on aldosterone levels in human studies. One possible explanation is that subjects have not been studied under salt-controlled conditions. Therefore, we examined the effects of losartan on the aldosterone and renal plasma flow responses to Ang II infusion in six normotensive subjects under low and high salt conditions. Ang II was infused in graded doses (0.3 to 10 ng/kg per minute) in the presence and absence of losartan (a single 50-mg oral dose). Renal plasma flow was assessed by measurement of para-aminohippurate clearance. Blood pressure, plasma aldosterone levels (low salt conditions only), and para-aminohippurate clearance were measured before and after each Ang II dose. Losartan had no effect on baseline systolic pressure but attenuated the systolic pressure response to exogenous Ang II during both low salt (0.7 +/- 1.9 versus 6.7 +/- 1.4 mm Hg, P = .001) and high salt (2.0 +/- 1.9 versus 12.3 +/- 2.1 mm Hg, P = .006) conditions. Under low salt conditions, losartan reduced the baseline plasma aldosterone level from 1135 +/- 204 to 558 +/- 102 pmol/L (P = .015) and blocked the aldosterone response to Ang II (-49 +/- 110 versus +436 +/- 83 pmol/L, P = .019). During high salt conditions, losartan had no effect on baseline renal plasma flow but attenuated the renal plasma flow response to Ang II (-90.1 +/- 15.1 versus -185.1 +/- 2.6 mL/min per 1.73 m2, P = .013). These data confirm that losartan lowers both basal and exogenous Ang II-stimulated aldosterone levels under low salt conditions. Losartan does not significantly affect baseline renal plasma flow but does attenuate the renal plasma flow response to exogenous Ang II under high salt conditions.


Evaluation of metastatic celiac axis lymph nodes in patients with esophageal carcinoma: accuracy of EUS.
Endosonography (EUS) is the most accurate modality for assessing depth of tumor invasion and local lymph node metastasis. However, its accuracy in the identification of metastatic (celiac axis) lymph nodes is less well defined. Our objective in this study was to determine the accuracy of Eus in detecting celiac axis lymph node metastasis in patients with esophageal carcinoma. Two hundred fourteen patients with esophageal carcinoma underwent preoperative EUS. Of these, 145 underwent attempted surgical resection and staging, and 4 underwent EUS-guided fine-needle aspiration of mediastinal and celiac lymph nodes. Local (mediastinal) and distant (celiac axis) lymph nodes were assessed for malignancy on the basis of four criteria (larger than 1 cm, round, homogeneous echo pattern, sharp borders). Accuracy of EUS was determined by means of correlating histopathologic findings for the resected lymph nodes or results of EUS-guided fine-needle aspiration cytologic examination. Surgical exploration (n = 145) and fine-needle aspiration cytologic examination (n = 4) revealed metastatic celiac axis lymph nodes in 23 and metastatic mediastinal (local) lymph nodes in 93 of 149 patients with esophageal carcinoma. According to defined criteria for malignant lymph nodes, there were 19 true-positive and 4 falsenegative results. Sensitivity for the diagnosis of celiac lymph node metastasis with EUS was 83% with a 98% specificity. For the diagnosis of mediastinal lymph node metastasis, sensitivity was 79% and specificity was 63%. All patients with malignant celiac axis lymph nodes had local T3 (tumor breaching adventitia) or T4 (tumor invading adjacent organs) disease. EUS is an excellent modality in the evaluation of metastatic celiac axis lymph nodes in patients with esophageal carcinoma. These findings should be used in selecting options for treatment. Sensitivity for detecting malignancy is consistent with that of prior studies, and local and regional lymph nodes and specificity is significantly higher.


Translation and cross-cultural adaptation of the Temperament & Personality Questionnaire into Brazilian Portuguese.
The Temperament & Personality Questionnaire (T&P) is a self-report instrument designed to evaluate personality styles overrepresented in patients with depression. This report briefly describes the translation and adaptation of the T&P into Brazilian Portuguese. The procedures, which included 10 steps, followed guidelines for the adaptation of self-report instruments defined by the International Society For Pharmacoeconomics and Outcomes Research (ISPOR) Task Force for Translation and Cultural Adaptation. The author of the original T&P questionnaire authorized and participated in the translation conducted by the authors and independent native speakers. Evaluation of the translated questionnaire indicated that only minor adjustments were required in the Portuguese version. The Brazilian version of T&P, translated and adapted following a rigid standardized process, is available for use free of charge and may be especially useful in pursuing links between personality styles and depressive conditions.


Rapid high-resolution three-dimensional mapping of T1 and age-dependent variations in the non-human primate brain using magnetization-prepared rapid gradient-echo (MPRAGE) sequence.
The use of quantitative T(1) mapping in neuroscience and neurology has raised strong interest in the development of T(1)-mapping techniques that can measure T(1) in the whole brain, with high accuracy and precision and within short imaging and computation times. Here, we present a new inversion-recovery (IR) based T(1)-mapping method using a standard 3D magnetization-prepared rapid gradient-echo (MPRAGE) sequence. By varying only the inversion time (TI), but keeping other parameters constant, MPRAGE image signals become linear to exp(-TI/T(1)), allowing for accurate T(1) estimation without flip angle correction. We also show that acquiring data at just 3 TIs, with the three different TI values optimized, gives maximum T(1) precision per unit time, allowing for new efficient approaches to measure and compute T(1). We demonstrate the use of our method at 7 T to obtain 3D T(1) maps of the whole brain in common marmosets at 0.60mm resolution and within 11 min. T(1) maps from the same individuals were highly reproducible across different days. Across subjects, the peak of cerebral gray matter T(1) distribution was 1735±52 ms, and the lower edge of cerebral white matter T(1) distribution was 1270±43 ms. We found a significant decrease of T(1) in both gray and white matter of the marmoset brain with age over a span of 14 years, in agreement with previous human studies. This application illustrates that MPRAGE-based 3D T(1) mapping is rapid, accurate and precise, and can facilitate high-resolution anatomical studies in neuroscience and neurological diseases.


Cloning and DNA sequence analysis of an X-prolyl dipeptidyl aminopeptidase gene from Lactococcus lactis subsp. lactis NCDO 763.
Lactococcus lactis subsp. lactis NCDO 763 (also designated ML3) possesses an X-prolyl dipeptidyl aminopeptidase (X-PDAP; EC 220.127.116.11). X-PDAP mutants were selected by an enzymatic plate assay on the basis of their inability to hydrolyze an L-phenylalanyl-L-proline-beta-naphthylamide substrate. A DNA bank from L. lactis subsp. lactis NCDO 763 was constructed in one of these X-PDAP mutants, and one clone in which the original X-PDAP phenotype was restored was detected by the enzymatic plate assay. The X-PDAP gene, designated pepXP, was further subcloned and sequenced. It codes for a protein containing 763 residues. Comparison of the amino-terminal sequence of the X-PDAP enzyme with the amino acid sequence deduced from the pepXP gene indicated that the enzyme is not subjected to posttranslational modification or exported via processing of a signal peptide. The pepXP gene from L. lactis subsp. lactis NCDO 763 in more than 99% homologous to the pepXP gene from L. lactis subsp. cremoris P8-2-47 described elsewhere (B. Mayo, J. Kok, K. Venema, W. Bockelmann, M. Teuber, H. Reinke, and G. Venema, Appl. Environ. Microbiol. 57:38-44, 1991) and is also conserved in other lactococcal strains.


Structural diversity in multinuclear tantalum polyhydrides formed via reductive hydrogenolysis of metal-carbon bonds.
Using H2 as a reducing agent, we demonstrate controlled reduction of tri- and tetramethyl tantalum bis(N-heterocyclic carbene)borate complexes to yield low-valent, multinuclear tantalum polyhydrides. Reaction of a Ta(v)Me3 complex with H2 afforded a bimetallic, hydride-bridged Ta(iv) complex. The analogous reaction of a Ta(v)Me4 complex in benzene or toluene yielded bimetallic Ta(iii) complexes in which both metals are bound to the same face of a μ-η4:η4-arene2- ligand.


The MARINA model (Model to Assess River Inputs of Nutrients to seAs): Model description and results for China.
Chinese agriculture has been developing fast towards industrial food production systems that discharge nutrient-rich wastewater into rivers. As a result, nutrient export by rivers has been increasing, resulting in coastal water pollution. We developed a Model to Assess River Inputs of Nutrients to seAs (MARINA) for China. The MARINA Nutrient Model quantifies river export of nutrients by source at the sub-basin scale as a function of human activities on land. MARINA is a downscaled version for China of the Global NEWS-2 (Nutrient Export from WaterSheds) model with an improved approach for nutrient losses from animal production and population. We use the model to quantify dissolved inorganic and organic nitrogen (N) and phosphorus (P) export by six large rivers draining into the Bohai Gulf (Yellow, Hai, Liao), Yellow Sea (Yangtze, Huai) and South China Sea (Pearl) in 1970, 2000 and 2050. We addressed uncertainties in the MARINA Nutrient model. Between 1970 and 2000 river export of dissolved N and P increased by a factor of 2-8 depending on sea and nutrient form. Thus, the risk for coastal eutrophication increased. Direct losses of manure to rivers contribute to 60-78% of nutrient inputs to the Bohai Gulf and 20-74% of nutrient inputs to the other seas in 2000. Sewage is an important source of dissolved inorganic P, and synthetic fertilizers of dissolved inorganic N. Over half of the nutrients exported by the Yangtze and Pearl rivers originated from human activities in downstream and middlestream sub-basins. The Yellow River exported up to 70% of dissolved inorganic N and P from downstream sub-basins and of dissolved organic N and P from middlestream sub-basins. Rivers draining into the Bohai Gulf are drier, and thus transport fewer nutrients. For the future we calculate further increases in river export of nutrients. The MARINA Nutrient model quantifies the main sources of coastal water pollution for sub-basins. This information can contribute to formulation of effective management options to reduce nutrient pollution of Chinese seas in the future.


Alcohol consumption debut: predictors and consequences.
The aim of this study was to investigate the predictors of the timing of alcohol consumption debut and to analyze possible associations between the timing of debut and later alcohol consumption and possible alcohol-related problems. A population sample of 465 adolescents (249 girls) from the greater Oslo area was followed up through five data collections over a 6-year span. By means of generalized structural equation modeling--accommodating survival variables--parental and friends' influences on debut age were estimated. Further, the consequences of the age of debut on subsequent alcohol consumption and alcohol problems were studied, taking other influences into consideration. In particular, possible gender differences were investigated. The mean age for alcohol consumption debut was 14.8 years. The age of alcohol debut had an independent effect on both future alcohol consumption and the development of alcohol-related problems, and the effects were invariant across sex. According to the estimated model, a 10% delay in debut age will lead to a 35% decrease in subsequent expected alcohol consumption. Alcohol debut was an excellent predictor of subsequent alcohol consumption and alcohol problems. The strong preventive implication is that interventions should be implemented in order to postpone alcohol debut age. A weak implication is that preventive measures should be implemented for the early onset drinkers. Further, it seems to be important to give high priority to more thorough studies on the exact nature of the relationships we have investigated here.


The role of angiotensin II type 1 receptor-activating antibodies in renal allograft vascular rejection.
Acute rejection with vascular involvement remains a challenging problem in renal allotransplantation. Fibrinoid necrosis of the arteries with secondary thrombotic occlusions is C4d negative in 50% of cases and has the worst prognosis among all allograft vascular lesions. Nonhuman leukocyte antigen (HLA) non-complement-fixing antibodies reacting to artery-specific antigens have been speculated to be responsible for causing severe vascular injury. We recently reported the presence of agonistic antibodies against the angiotensin II type 1 receptor (AT(1)R-AA) in 16 recipients of renal allografts who had severe vascular rejection and malignant hypertension but who did not have anti-HLA antibodies. AT(1)R-AA stimulate AT(1)R and induce mediators of inflammation and thrombosis. Removal of AT(1)R-AA by plasmapheresis in combination with pharmacologic AT(1)R blockade leads to improved renal function and graft survival in AT(1)R-AA-positive patients. We have shown that the analysis of the subtle diagnostic and mechanistic differences may help to identify patients at particular risk and improve outcome of rejections with vascular pathology.


Structure-function relationships in replication origins of the yeast Saccharomyces cerevisiae: higher-order structural organization of DNA in regions flanking the ARS consensus sequence.
In order to better understand the involvement of the DNA molecule in the replication initiation process we have characterized the structure of the DNA at Autonomously Replicating Sequences (ARSs) in Saccharomyces cerevisiae. Using a new method for anti-bent DNA analysis, which allowed us to take into account the bending contribution of each successive base plate, we have investigated the higher-order structural organization of the DNA in the region which immediately surrounds the ARS consensus sequence (ACS). We have identified left- and right-handed anti-bent DNAs which flank this consensus sequence. The data show that this organization correlates with an active ACS. Analysis of the minimum nucleotide sequence providing ARS function to plasmids reveals an example where the critical nucleotides are restricted to the ACS and the right-handed anti-bent DNA domain, although most of the origins considered contained both left- and right-handed anti-bent DNAs. Moreover, mutational analysis shows that the right-handed form is necessary in order to sustain a specific DNA conformation which is correlated with the level of plasmid maintenance. A model for the role of these individual structural components of the yeast replication origin is presented. We discuss the possible role of the right-handed anti-bent DNA domain, in conjunction with the ACS, in the process of replication initiation, and potentialities offered by the combination of left- and right-handed structural components in origin function.


Prevention of non-contact anterior cruciate ligament injuries in soccer players. Part 2: a review of prevention programs aimed to modify risk factors and to reduce injury rates.
Soccer is the most commonly played sport in the world, with an estimated 265 million active soccer players participating in the game as on 2006. Inherent to this sport is the higher risk of injury to the anterior cruciate ligament (ACL) relative to other sports. ACL injury causes a significant loss of time from competition in soccer, which has served as the strong impetus to conduct research that focuses to determine the risk factors for injury, and more importantly, to identify and teach techniques to reduce this injury in the sport. This research emphasis has afforded a rapid influx of literature aimed to report the effects of neuromuscular training on the risk factors and the incidence of non-contact ACL injury in high-risk soccer populations. The purpose of the current review is to sequence the most recent literature relating the effects of prevention programs that were developed to alter risk factors associated with non-contact ACL injuries and to reduce the rate of non-contact ACL injuries in soccer players. To date there is no standardized intervention program established for soccer to prevent non-contact ACL injuries. Multi-component programs show better results than single-component preventive programs to reduce the risk and incidence of non-contact ACL injuries in soccer players. Lower extremity plyometrics, dynamic balance and strength, stretching, body awareness and decision-making, and targeted core and trunk control appear to be successful training components to reduce non-contact ACL injury risk factors (decrease landing forces, decrease varus/valgus moments, and increase effective muscle activation) and prevent non-contact ACL injuries in soccer players, especially in female athletes. Pre-season injury prevention combined with an in-season maintenance program may be advocated to prevent injury. Compliance may in fact be the limiting factor to the overall success of ACL injury interventions targeted to soccer players regardless of gender. Thus, interventional research must also consider techniques to improve compliance especially at the elite levels which will likely influence trickle down effects to sub-elite levels. Future research is also needed for male soccer athletes to help determine the most effective intervention to reduce the non-contact ACL injury risk factors and to prevent non-contact ACL injuries.


Nestin-expressing cells in the pancreatic islets of Langerhans.
The pancreatic islets of Langerhans produce several peptide hormones, predominantly the metabolically active hormones insulin and glucagon, which are critical for maintaining normal fuel homeostasis. Some evidence exists that pancreatic endocrine cells turn over at a slow rate and can regenerate in certain conditions. This could be due to the presence of pluripotent cells residing in the pancreas. Recently the intermediate filament protein nestin has been identified to be a marker for a multipotent stem cell in the central nervous system. Given the similarity between the pancreatic islets and neuronal cells, we hypothesized that stem cells expressing nestin might be present in the pancreas. Here we present evidence that a subset of cells in the pancreatic islets express the stem cell marker nestin. These cells might serve as precursors of differentiated pancreatic endocrine cells.


Using Electronic Data Collection Platforms to Assess Complementary and Integrative Health Patient-Reported Outcomes: Feasibility Project.
The Veteran Administration (VA) Office of Patient-Centered Care and Cultural Transformation is invested in improving veteran health through a whole-person approach while taking advantage of the electronic resources suite available through the VA. Currently, there is no standardized process to collect and integrate electronic patient-reported outcomes (ePROs) of complementary and integrative health (CIH) into clinical care using a web-based survey platform. This quality improvement project enrolled veterans attending CIH appointments within a VA facility and used web-based technologies to collect ePROs. This study aimed to (1) determine a practical process for collecting ePROs using patient email services and a web-based survey platform and (2) conduct analyses of survey data using repeated measures to estimate the effects of CIH on patient outcomes. In total, 100 veterans from one VA facility, comprising 11 cohorts, agreed to participate. The VA patient email services (Secure Messaging) were used to manually send links to a 16-item web-based survey stored on a secure web-based survey storage platform (Qualtrics). Each survey included questions about patient outcomes from CIH programs. Each cohort was sent survey links via Secure Messaging (SM) at 6 time points: weeks 1 through 4, week 8, and week 12. Process evaluation interviews were conducted with five primary care providers to assess barriers and facilitators to using the patient-reported outcome survey in usual care. This quality improvement project demonstrated the usability of SM and Qualtrics for ePRO collection. However, SM for ePROs was labor intensive for providers. Descriptive statistics on health competence (2-item Perceived Health Competence Scale), physical and mental health (Patient-Reported Outcomes Measurement Information System Global-10), and stress (4-item Perceived Stress Scale) indicated that scores did not significantly change over time. Survey response rates varied (18/100, 18.0%-42/100, 42.0%) across each of the 12 weekly survey periods. In total, 74 of 100 participants provided ≥1 survey, and 90% (66/74) were female. The majority, 62% (33/53) of participants, who reported the use of any CIH modality, reported the use of two or more unique modalities. Primary care providers highlighted specific challenges with SM and offered solutions regarding staff involvement in survey implementation. This quality improvement project informs our understanding of the processes currently available for using SM and web-based data platforms to collect ePROs. The study results indicate that although it is possible to use SM and web-based survey platforms for ePROs, automating scheduled administration will be necessary to reduce provider burden. The lack of significant change in ePROs may be due to standard measures taking a biomedical approach to wellness. Future work should focus on identifying ideal ePRO processes that would include standardized, whole-person measures of wellness.


Clinical comparison of an enamel matrix derivative used alone or in combination with a bovine-derived xenograft for the treatment of periodontal osseous defects in humans.
The combination of bone replacement graft materials has been suggested for the treatment of periodontal osseous defects. The purpose of this study was to evaluate the effectiveness of enamel matrix derivative (EMD) combined with a bovine-derived xenograft (BDX) as compared to EMD alone in the treatment of intraosseous defects in patients with moderate to advanced periodontitis. Sixteen adult patients with at least 2 intrabony defects were entered in this split-mouth design study. Defects were treated with EMD alone or EMD + BDX. Reentries were performed 6 to 8 months after initial surgery. The following soft and hard tissue measurements were recorded prior to initial surgery and at reentry: probing depth (PD), gingival margin location, clinical attachment level (CAL), depth of defect, and crestal bone level. Statistical analyses were performed to determine changes in PD, CAL, fill of osseous defect, and crestal resorption. Percentages of bone fill (%BF) and defect resolution (%DR) were also calculated. The most significant results were that gingival recession was greater for the group treated with EMD alone (0.8 +/- 0.8 mm) compared to EMD + BDX (0.3 +/- 0.6 mm) (P = 0.04) and bone fill was greater for EMD + BDX (4.0 +/- 0.8 mm) compared to EMD alone (3.1 +/- 1.0 mm) (P = 0.02). The measures for PD reduction, attachment level gain, crestal resorption, %BF, and %DR did not present a statistically significant difference (P > 0.10). This study evaluated the performance of EMD + BDX and EMD alone. The results demonstrated that a significant improvement in clinical parameters was observed. When comparing both modalities, a statistically significant difference was only found for gingival recession and bone fill, yielding a more favorable outcome towards the combined approach.


Variation in Bariatric Surgery Episode Costs in the Commercially Insured: Implications for Bundled Payments in the Private Sector.
To describe hospital-level variation in roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) in Michigan. Bariatric surgery is an increasingly prevalent elective surgical procedure that will likely be considered for future bundled payment programs, both public and private. Past research in the Medicare population found that the index hospitalization is responsible for the majority of payment variation among hospitals. However, this research largely excluded SG, now the most commonly performed bariatric surgery procedure nationally. We used data from a state-wide quality collaborative to calculate the average risk and price-adjusted 30-day episode payment for patients undergoing RYGB and SG procedures at Michigan hospitals between January 2009 and October 2014. We organized hospitals into quintiles and compared the variation in payments between highest and lowest-cost quintiles, and also the payment categories that drove this variation. We identified 9035 patients undergoing RYGB (n = 4194) or SG (n = 4841) procedures at 31 hospitals. The average price and risk-adjusted episode payment ranged from $11,874 in the lowest hospital quintile to $13,394 in the highest quintile, representing a difference of $1519 (12.8%). Payments for the index hospitalization accounted for the largest share of total episode costs for both procedure types. Despite representing 2.7% to 6.0% of payments across quintiles, postdischarge payments explained 22.6% of hospital variation in SG. Similarly, readmissions explained 24.5% of payment variation for SG episodes, despite representing between 1.2% and 4.4% of payments. Collectively, our findings suggest that there are previously underappreciated differences in episode payment variation between bariatric surgery procedures. SG may be more amenable to cost containment under bundled payment initiatives by virtue of the greater share of variation explained by readmission and postdischarge payments, components of episode payment more likely to be influenced by provider discretion.


Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice.
Lack of fragile X mental retardation protein (FMRP) causes Fragile X Syndrome, the most common form of inherited mental retardation. FMRP is an RNA-binding protein and is a component of messenger ribonucleoprotein complexes, associated with brain polyribosomes, including dendritic polysomes. FMRP is therefore thought to be involved in translational control of specific mRNAs at synaptic sites. In mice lacking FMRP, protein synthesis-dependent synaptic plasticity is altered and structural malformations of dendritic protrusions occur. One hypothesized cause of the disease mechanism is based on exaggerated group I mGluR receptor activation. In this study, we examined the effect of the mGluR5 antagonist MPEP on Fragile X related behavior in Fmr1 KO mice. Our results demonstrate a clear defect in prepulse inhibition of startle in Fmr1 KO mice, that could be rescued by MPEP. Moreover, we show for the first time a structural rescue of Fragile X related protrusion morphology with two independent mGluR5 antagonists.


Interventions for improving communication with children and adolescents about a family member's cancer.
A diagnosis of cancer creates multiple problems for affected families, including major changes in living patterns, roles and relationships. It has not been common practice for families and health practitioners to share information with children or adolescents about a family member's cancer, or to allow them to express their feelings about this. In recent years, however, researchers and practitioners have begun to recognise that children and adolescents might appreciate and benefit by being better informed about, and having more opportunity to communicate their responses to, cancer in the family. To examine the effects of different ways of enhancing communication with children and/or adolescents about a family member's cancer and its treatment. We searched the following sources: Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, Issue 1 2003; MEDLINE (1966 to January week 2 2003); EMBASE (1985 to 2003 week 6); CINAHL (1982 to February Week 1 2003); ERIC (1966 to 23 January 2003); PsycINFO (1985 to February week 1 2003). For the original (1999) version of this review we also searched the following databases: CancerLIT, Health Management Information Consortium, British Nursing Index, IAC Health & Wellness, JICSTE-Plus, Pascal, Linguistics and Language Behavior Abstracts, Mental Health Abstracts, AMED, HUMN, MANTIS and ASSIA. Bibliographies of identified studies were also checked and contact made with experts in the field. Randomised and non-randomised controlled trials, and controlled and uncontrolled before and after studies that evaluated the effects of interventions to enhance communication with children and/or adolescents about a family member's cancer and its treatment. Data on knowledge and understanding, coping, adjustment and wellbeing were extracted by one reviewer and checked by another reviewer. Study quality was assessed using six criteria. A qualitative synthesis of the results is presented. Five studies satisfied the selection criteria: one non-randomised controlled before and after study, and four uncontrolled before and after studies. They differed in terms of the interventions evaluated and the outcomes measured. One study of a camping program and two studies of structured group interventions reported improvements in cancer-related knowledge. One out of two structured group intervention studies found significant reductions in psychological and social problems. The camping program study reported significant improvements in siblings' behaviour. One structured group intervention study reported significantly more positive mood states after the intervention. Another structured group intervention study reported significantly lower levels of anxiety after the intervention. Different methods of communicating with children and adolescents about a family member's cancer have not been widely evaluated in controlled trials. There is weak evidence to suggest that some interventions, such as structured group interventions, may lead to improvements in knowledge and understanding, in coping, anxiety, adjustment and wellbeing. More research is needed to investigate the comparative value of these interventions.


Characterization of the two tryptophan residues of the lactose repressor from Escherichia coli by phosphorescence and optical detection of magnetic resonance.
The native lactose repressor from Escherichia coli (Lac Rep) and two single-point mutants, W220Y and W201Y, were investigated using low-temperature phosphorescence and optical detection of magnetic resonance (ODMR) spectroscopy. Emission from two tryptophan residues was evident in the phosphorescence spectrum of native Lac Rep at 77 K. Using the single-point mutants, the triplet-state properties of tryptophans 201 and 220 were obtained independently. Trp 220 was characterized as a partially solvent-exposed residue (0,0 band centered at 409.5 nm), while tryptophan 201 exhibited the properties of a buried residue (0,0 band centered at 413.5 nm). Both single-point mutant proteins experienced changes in tryptophan triplet-state properties as a result of binding either of two inducer sugars: isopropyl beta-D-thiogalactoside, a monosaccharide, or melibiose, a disaccharide. Putative singlet-singlet energy transfer from tryptophan 220 to tryptophan 201 was also investigated, but the quantitative results must be viewed with some caution.


Pseudomonas exotoxin and recombinant immunotoxins derived from it.
Pseudomonas exotoxin (PE) is a bacterial toxin that kills mammalian cells by gaining entry to the cytosol and inactivating protein synthesis. The toxin binds and enters cells via the alpha 2-macroglobulin receptors. Within cells, the toxin is processed in several steps to produce an enzymatically active 37-kDa C-terminal fragment which translocates to the cytosol and ADP-ribosylates elongation factor 2. Because PE is a very potent toxin, derivatives of it have been produced which, when joined to various binding ligands, are capable of killing specific target cells. It is hoped that this strategy will lead to the development of effective therapeutic agents for the treatment of human diseases such as cancer, AIDS, and various immunologic disorders.


Prolonged effect of CGRP in Raynaud's patients: a double-blind randomised comparison with prostacyclin.
1. Calcitonin gene related peptide (CGRP) is a potent endogenous vasodilator to which we have previously demonstrated a specific hypersensitivity in skin blood flow in the hands in patients with Raynaud's disease. 2. We have now investigated whether long infusion of CGRP can relieve symptoms of patients with Raynaud's disease using prostacyclin as a control. 3. Six patients were randomised to receive intravenous infusion of either human alpha-CGRP on one occasion, or prostacyclin (PGI2) on another occasion in a double-blind and cross-over design. The dose of each agent was initially titrated up to 8 ng kg-1 min-1 or to a maximum increase in heart rate of 25 beats min-1. 4. In addition to blood pressure, heart rate and skin blood flow measurements, infrared thermography and cold stress challenge was performed before, immediately after infusion and at 3 and 14 days post-infusion. 5. CGRP caused an increase in hand skin blood flow throughout its infusion, whilst PGI2 caused only a short lived increase. The thermographic results showed significant improvement in hand rewarming 3 days after CGRP but not after PGI2. 6. We conclude that 3 h infusion of CGRP was better tolerated than PGI2 and caused objective improvement up to 3 days. CGRP may be an alternative to PGI2 in some patients.


Submucosal Inferior Turbinoplasty Using a New Continuous Suction Irrigation Method.
Numerous surgical techniques for inferior turbinate hypertrophy (ITH) have been reported, each with advantages and disadvantages. Submucosal turbinoplasty with removal of the bony component of the inferior turbinate (IT) is an excellent procedure to expand the nasal cavity. However, this procedure requires a large incision to remove the inferior turbinate bone (ITB) and is associated with hemorrhage, crust formation, and adhesion. A smaller incision would avoid such complications. We developed a continuous suction irrigation method that maintains a clear view of the limited surgical field of the IT. Only a single small incision is needed to insert the rigid endoscope. The surgeon can flush blood with continuous water flow and perform IT surgery without difficulty. We performed this method in 39 cases from January 2016 to January 2017. This video article demonstrates our new submucosal inferior turbinoplasty technique. Submucosal turbinoplasty using a continuous suction irrigation method was performed under general anesthesia. An irrigation-suction straw sheath system was used to create an underwater surgical field. The ITB was removed safely with no severe complications. An expanded common nasal cavity was confirmed postoperatively on computed tomographic images. We resected the ITB safely using a continuous suction irrigation method without difficulty or complications. We believe that this method may become one of the best surgical options for ITH.


Is there enough evidence to use bisphosphonates in HIV-infected patients? A systematic review and meta-analysis.
An increased prevalence of osteopenia and osteoporosis has been observed in HIV-infected cohorts. We investigated the effect of bisphosphonates on bone mineral density in adults with HIV infection. Outcomes of interest were bone mineral density changes measured by dual-energy X-ray absorptiometry at the lumbar spine, femoral neck, and total hip, and adverse events. Data were pooled using the fixed-effects model. We identified eight randomized controlled trials meeting our inclusion criteria, involving 328 participants. Five trials compared alendronate with placebo or no intervention; in three trials the intervention arm received zoledronate. A significant increase in bone mineral density at the lumbar spine was observed in the bisphosphonate group at 48 weeks (MD: 2.84%; 95% CI: 2.11-3.57) and 96 weeks (MD: 6.76%; 95% CI: 4.98-8.54); analogously, bisphosphonates were associated with an increase in total hip bone mineral density at 48 weeks (MD: 2.12%; 95% CI: 1.43-2.81) and 96 weeks (MD: 3.2%; 95% CI: 1.52-4.88). Bisphosphonates were generally well tolerated; no drug-related withdrawals were reported in the five randomized controlled trials assessing alendronate, whereas two patients out of 104 receiving zoledronate experienced acute-phase reactions. In conclusion, administration of oral and intravenous bisphosphonates was associated with increased bone mineral density at the lumbar spine and total hip over two years in HIV-positive patients. However, none of the included trials were long enough to detect the impact of bisphosphonates on a clinically important outcome such as fracture risk. Larger studies with extended follow-up are warranted.


Potential Benefits of Neoadjuvant Chemotherapy in Clinically Node-Positive Luminal Subtype- Breast Cancer.
Neoadjuvant chemotherapy (NAC) is less effective for luminal breast cancer because luminal breast cancer has a lower rate of pathological complete response (pCR) after NAC than human epidermal growth factor receptor 2 (HER2)-type and triple-negative breast cancer (TNBC). We investigated the efficacy of NAC and the predictive factors of a better response in luminal breast cancer. Between 2010 and 2016, we retrieved data of 244 patients with clinically node-positive breast cancer who were treated with NAC followed by surgery from a prospectively collected database. We classified breast cancer into luminal HER2- and non-luminal HER2- breast cancer (luminal HER2+, HER2+, and TNBC types). We analyzed each subtype with respect to surgical outcomes, response to NAC, and determined variables associated with surgical outcomes and response in patients with luminal HER2- breast cancer. The total, breast, and axillary pCR rates were significantly lower in 114 patients with luminal HER2- breast cancer than in those with other subtypes (7.9%, 12.3%, and 22.8%, respectively). However, breast-conserving surgery (BCS) conversion and tumor response rates did not significantly differ between patients with luminal HER2- and those with non-luminal HER2- breast cancer (p = 0.836 and p = 0.180, respectively). In the multivariate analysis, high tumor response rate (≥ 46.4%) was significantly associated with an increased BCS conversion rate. In the subgroup analysis of luminal HER2- breast cancer, the multivariate analysis showed that higher Ki67 expression and axilla pCR and BCS conversion rates were significantly associated with tumor response to NAC. Despite the low pCR rate, the tumor response and BCS conversion rates after NAC of luminal HER2- breast cancer were similar to those of other subtypes. NAC has the potential benefit of reducing the size of breast cancer, thereby increasing the BCS conversion rate in luminal HER2- breast cancer.


[Importance of electrogastrography and pharmacological tests in assessing gastric motor function in vagotomy].
The effect of 6 pharmacological drugs on the motor function of the stomach in patients with ulcer disease was studied. It was established that Cerucal was the best modulator of gastric motor activity. There were three types of reaction of electrogastrogram to the administration of Cerucal. It was noted that in the first type there was a real danger of the development of postvagotomic kinetic disorders. In the second and third types such a danger was as a rule absent. This method of prognosis of motor disorders after vagotomy was successfully used in 81 patients with ulcer disease of the duodenum treated with the help of vagotomy.


Structural determinants of the capacity of heparin to inhibit the proliferation of vascular smooth muscle cells. II. Evidence for a pentasaccharide sequence that contains a 3-O-sulfate group.
Earlier work from our laboratory demonstrated that heparin inhibited the proliferation of vascular smooth muscle cells in vivo and in vitro. Both anticoagulant and non-anticoagulant heparin species were equally effective as antiproliferative agents. Previous structure-function studies indicated that hexasaccharide and larger fragments retained antiproliferative activity, whereas tetra- and disaccharides were inactive. These experiments also suggested that both N- and O-sulfates of heparin were necessary for growth inhibitory capacity. In this paper, we have further analyzed the structural determinants of the antiproliferative activity of heparin. These experiments were done using synthetically prepared and therefore chemically defined heparin oligosaccharides. We present evidence that a pentasaccharide fragment retains antiproliferative activity, and that the 3-O-sulfate on the internal glucosamine residue is critical for growth inhibitory capacity of the pentasaccharide. We also show that heparins obtained from different manufacturers differ significantly in their ability to suppress smooth muscle cell proliferation.


One-pot synthesis of carbon dots with intrinsic folic acid for synergistic imaging-guided photothermal therapy of prostate cancer cells.
Photothermal therapy (PTT) is performed using near-infrared-responsive agents, which is proven to be an effective therapeutic strategy against cancer with several advantages including minimal invasion, high effectiveness, and easy implementation. Herein, we report a facile and novel one-pot synthetic approach for the fabrication of polydopamine-folate carbon dots (PFCDs) as theranostic nanocarriers for the image-guided PTT targeting of prostate cancer (PCa) cells that express a prostate-specific membrane antigen (PSMA) (folate hydrolase 1). The as-fabricated PFCDs exhibited several advantages such as easy preparation, high biocompatibility, low toxicity, good water-solubility, and excellent photothermal effect with robust blue fluorescence emission. The PSMA-directed imaging of PCa using PFCDs showed remarkable fluorescence enhancement in LNCap cells as compared to the case of other cells that did not express PSMA. PFCDs exhibited a photothermal effect in the PCa cells when irradiated with an 808 nm laser, which possibly resulted in the complete elimination of the tumor. Thus, these features make PFCDs a promising candidate for PTT. Moreover, PFCD-based PTT provides an effective biomedical platform for cancer therapy.


A RETROSPECTIVE STUDY OF MORBIDITY AND MORTALITY IN THE NORTH AMERICAN AMUR LEOPARD ( PANTHERA PARDUS ORIENTALIS) POPULATION IN ZOOLOGIC INSTITUTIONS FROM 1992 TO 2014.
The Amur leopard ( Panthera pardus orientalis) is one of the most critically endangered leopards on the International Union for the Conservation of Nature red list. The primary objective of this retrospective study was to identify common and significant causes of morbidity and mortality in the North American Amur leopard zoo population. This information provides insights that contribute to their improved care, health, and medical management and, ultimately, affects the sustainability of this leopard subspecies in the wild. Medical records and complete postmortem reports were requested from all North American zoologic institutions that held Amur leopards in their collections from 1992 to 2014. Information from 175 individuals, representing 93% of the population (188 animals), was received. Data were reviewed generally and by subdivision into the following age groups: neonate: 0 day-3 mo ( n = 45); juvenile-young adult: 3 mo-5 yr ( n = 21); adult: 5-10 yr ( n = 17); senior: 10-15 yr ( n = 31); or geriatric: >15 yr ( n = 61). The major causes of morbidity, listed by body system for the study population, excluding neonates, were musculoskeletal (40%), reproductive (24%), dental (19%), cardiopulmonary (13%), gastrointestinal (13%), and urogenital (12%). The two most common causes of death or euthanasia, primarily in senior and geriatric animals, were chronic renal disease and neoplasia; maternal neglect and maternal trauma were most common in neonates. The largest populations in this study were neonates and geriatrics, indicating that if animals survive the neonatal period, they often live into their late teens to early 20s. This is the first comprehensive study of the causes of morbidity and mortality in the Amur leopard zoo population in North America.


Pathogenic parasites in sewage irrigated crops and soil: pattern of occurrence and health implications.
The current study aimed to determine the contamination level by human parasite eggs and cysts of sewage-irrigated soil, food crops and fodder crops. Field trials were conducted on spray-irrigated lettuce and flood-irrigated crops using raw wastewater and fresh water. Findings showed that irrigation by raw wastewater led to crops contamination with parasite eggs and cysts in varying levels. Lettuce samples were positive (27.7%) for one or more helminth eggs including the pathogens Ascaris and Trichuris with an average of 4.7 eggs/kg. Wastewater application caused an increase in lettuce contamination, followed by a decreasing phase. Cessation of irrigation resulted in helminth eggs disappearance within a week. Flood-irrigated crops were contaminated with helminth eggs in levels ranging from 1.5 eggs/kg in alfalfa to 4.75 eggs/kg in coriander. The pathogenic Giardia,Entamoeba histolytica/dispar and commensal amoeba cysts were highly detected reaching 9.97x103 cysts/kg in alfalfa. Parasites highly concentrated in soil, with levels up to 159 eggs/100gdw and 1.3x103 cysts/gdw. Ascaris and Trichuris eggs developed in soil and crops attaining the infective stage. Crops and soil irrigated with fresh water were free from parasite eggs and cysts. The occurrence of pathogens in soil and crops implies health risks for farmers, produce handlers and consumers.


Peripheral opioids in inflammatory pain.
Topically applied opioids have provided effective analgesia without adverse effects, including tolerance, in adult patients with painful inflammatory conditions. The presumed mechanism of action is by interaction with opioid receptors which are sited on sensory nerve terminals and which may be up-regulated in inflammation. The use of peripherally acting opioids has not been studied in paediatric patients. The use of topical morphine gel is reported in two children with epidermolysis bullosa, where acute inflammatory pain is a major symptom and where effective analgesia is a major clinical problem. The gel provided rapid reduction in pain scores in the patients and without any reported adverse effects or tolerance. A topical route of analgesia might be extremely beneficial for children with other painful skin lesions, including burns or post-surgical wounds, and further studies are now required.