Exploring the Association Between Demographics, SLC30A8 Genotype, and Human Islet Content of Zinc, Cadmium, Copper, Iron, Manganese and Nickel.
A widely prevalent single nucleotide polymorphism, rs13266634 in the SLC30A8 gene encoding the zinc transporter ZnT8, is associated with an increased risk for T2DM. ZnT8 is mostly expressed in pancreatic insulin-producing islets of Langerhans. The effect of this variant on the divalent metal profile in human islets is unknown. Additionally, essential and non-essential divalent metal content of human islets under normal environmental exposure conditions has not been described. We therefore examined the correlation of zinc and other divalent metals in human islets with rs13266634 genotype and demographic characteristics. We found that the diabetes risk genotype C/C at rs13266634 is associated with higher islet Zn concentration (C/C genotype: 16792 ± 1607, n = 22, C/T genotype: 11221 ± 1245, n = 18 T/T genotype: 11543 ± 6054, n = 3, all values expressed as mean nmol/g protein ± standard error of the mean, p = 0.040 by ANOVA). A positive correlation between islet cadmium content and both age (p = 0.048, R2 = 0.09) and female gender (women: 36.88 ± 4.11 vs men: 21.22 ± 3.65 nmol/g protein, p = 0.007) was observed. Our results suggest that the T2DM risk allele C is associated with higher islet zinc levels and support prior evidence of cadmium's higher bioavailability in women and its long tissue half-life.


Theoretical analysis of proton relays in electrochemical proton-coupled electron transfer.
The coupling of long-range electron transfer to proton transport over multiple sites plays a vital role in many biological and chemical processes. Recently the concerted proton-coupled electron transfer (PCET) reaction in a molecule with a hydrogen-bond relay inserted between the proton donor and acceptor sites was studied electrochemically. The standard rate constants and kinetic isotope effects (KIEs) were measured experimentally for this double proton transfer system and a related single proton transfer system. In the present paper, these systems are studied theoretically using vibronically nonadiabatic rate constant expressions for electrochemical PCET. Application of this approach to proton relays requires the calculation of multidimensional proton vibrational wave functions and the incorporation of multiple proton donor-acceptor motions. The decrease in proton donor-acceptor distances due to thermal fluctuations and the contributions from excited electron-proton vibronic states play important roles in these systems. The calculated KIEs and the ratio of the standard rate constants for the single and double proton transfer systems are in agreement with the experimental data. The calculations indicate that the standard PCET rate constant is lower for the double proton transfer system because of the smaller overlap integral between the ground state reduced and oxidized proton vibrational wave functions, resulting in greater contributions from excited electron-proton vibronic states with higher free energy barriers. The theory predicts that this rate constant may be increased by modifying the molecule in a manner that decreases the equilibrium proton donor-acceptor distances or alters the molecular thermal motions to facilitate the concurrent decrease of these distances. These insights may guide the design of more efficient catalysts for energy conversion devices.


Public, animal, and environmental health implications of aquaculture.
Aquaculture is important to the United States and the world's fishery system. Both import and export markets for aquaculture products will expand and increase as research begins to remove physiologic and other animal husbandry barriers. Overfishing of wild stock will necessitate supplementation and replenishment through aquaculture. The aquaculture industry must have a better understanding of the impact of the "shrouded" public and animal health issues: technology ignorance, abuse, and neglect. Cross-pollination and cross-training of public health and aquaculture personnel in the effect of public health, animal health, and environmental health on aquaculture are also needed. Future aquaculture development programs require an integrated Gestalt public health approach to ensure that aquaculture does not cause unacceptable risks to public or environmental health and negate the potential economic and nutritional benefits of aquaculture.


Team Dynamics in Hospital Workflows: An Exploratory Study of a Smartphone Task Manager.
Although convenient and reliable modern messaging apps like WhatsApp enable efficient communication among hospital staff, hospitals are now pivoting toward purpose-built structured communication apps for various reasons, including security and privacy concerns. However, there is limited understanding of how we can examine and improve hospital workflows using the data collected through such apps as an alternative to costly and challenging research methods like ethnography and patient record analysis. We seek to identify whether the structure of the collected communication data provides insights into hospitals' workflows. Our analysis also aims to identify ways in which task management platforms can be improved and designed to better support clinical workflows. We present an exploratory analysis of clinical task records collected over 22 months through a smartphone app that enables structured communication between staff to manage and execute clinical workflows. We collected over 300,000 task records between July 2018 and May 2020 completed by staff members including doctors, nurses, and pharmacists across all wards in an Australian hospital. We show that important insights into how teams function in a clinical setting can be readily drawn from task assignment data. Our analysis indicates that predefined labels such as urgency and task type are important and impact how tasks are accepted and completed. Our results show that both task sent-to-accepted (P<.001) and sent-to-completed (P<.001) times are significantly higher for routine tasks when compared to urgent tasks. We also show how task acceptance varies across teams and roles and that internal tasks are more efficiently managed than external tasks, possibly due to increased trust among team members. For example, task sent-to-accepted time (minutes) is significantly higher (P<.001) for external assignments (mean 22.10, SD 91.45) when compared to internal assignments (mean 19.03, SD 82.66). Smartphone-based task assignment apps can provide unique insights into team dynamics in clinical settings. These insights can be used to further improve how well these systems support clinical work and staff.


2'-fluoro-5-iodo-aracytosine, a potent and selective anti-herpesvirus agent.
A newly synthesized pyrimidine analog, 2'-fluoro-5-iodo-aracytosine (FIAC), suppressed by 90% the replication of various strains of herpes simplex virus types 1 and 2 at concentrations of 0.0025 to 0.0126 microM. Cytotoxicity was minimal, as determined by trypan blue dye exclusion with norman Vero, WI-38, and NC-37 cell proliferation; the 50% inhibitory dose was 4 to 10 microM in a 4-day assay. When compared with other antiviral drugs, FIAC was active at much lower concentrations than arabinosylcytosine, iododeoxyuridine, and arabinosyladenine. It was slightly more active against herpes simplex virus type 1 than acycloquanosine and slightly more toxic to normal cells. FIAC was about 8,000 times more active against the replication of wild-type herpes simplex virus type 1 than against a mutant strain lacking the expression of virus-specified thymidine kinase. Since FIAC appears to be preferentially phosphorylated by the viral enzyme, this is probably responsible, at least in part, for the selectivity of its antiviral actions. Although FIAC appears to be an arabinosylcytosine analog, its antiviral activity was not reversed by deoxycytidine. The minimal cytotoxicity exhibited by FIAC for normal cells, however, was reversed by equimolar concentrations of deoxycytidine. Thymidine, which reversed the antiviral activity, was effective only when used in great excess.


Study of different atmospheric-pressure interfaces for LC-MS/MS determination of acrylamide in water at sub-ppb levels.
A rapid, sensitive and selective method based on LC-MS/MS has been developed for the direct determination of acrylamide residues in water in compliance with the current European Union (EU) 98/83 Drinking Water Directive. Given the high polarity of acrylamide, the application of a rapid on-line solid phase extraction step, commonly used for preconcentrating low analyte levels, was not found to be completely satisfactory. Therefore, an alternative approach based on the use of direct large-volume injection into the LC-MS/MS system has been used. Three atmospheric-pressure interfaces (ESI, APCI and Ion Sabre APCI) were checked to reach the required sensitivity (0.1 microg/l). All three interfaces were tested by analysis of six different water samples (surface water, groundwater, drinking water and three treated water samples) spiked at three concentration levels each (0.1, 1 and 10 microg/l). When using ESI, poor sensitivity and high matrix effects were observed. This situation improved when APCI was used as the interface because no matrix effect was found, although sensitivity was not completely satisfactory. The best results were obtained by interfacing the Ion Sabre APCI; its higher sensitivity for acrylamide (LOD 0.03 microg/l) and the absence of matrix effects recommended its selection. Using this approach, satisfactory recoveries (90-97%) and precision (<12%) were obtained for all water samples studied. Besides, the acquisition of two different MS/MS transitions allowed not only the quantification but also the confirmation of acrylamide in water at concentration levels around 0.1 microg/l.


Complete transposition of carotid bifurcation: can it be an additional risk factor of injury to the cranial nerves during carotid endarterectomy?
The internal carotid artery (ICA) usually, lies posterolaterally to the external carotid artery (ECA). Sometimes a complete carotid transposition can occur, with the ECA in a lateral position and the ICA on the medial side can occur. Our study evaluated the significance and impact that this anomaly may have on cranial nerve injuries. From January 2008 to November 2010, 296 patients underwent 360 consecutive primary carotid endarterectomy (CEA) procedures. During carotid isolation, we detected an unexpected lateral position of the ECA in 11 cases (3.6%). χ(2) analysis and the Student's t-test were used to compare the incidence of cranial nerve injuries between the 11 patients with the lateral ECA who underwent CEA (group A) and 11 randomized patients with a normal bifurcation (group B). Statistical significance was inferred at χ(2)>3.84 and P<0.05. A statistical difference in the incidence of superior laryngeal nerve paralysis was detected between groups A and B (18.1%, 2/11 in group A vs. 0%, 0/11 in group B; χ(2)>3.84; P<0.05). No differences in incidence of injury were detected for the other cranial nerves. A very meticulous mobilization of the ECA and ICA is needed to perform CEA, but superior laryngeal nerve injury can occur despite the use of a safe and meticulous surgical technique.


[Morphogenesis of cystic abnormalities of the lung].
The material used was the pathomorphological studies of cystic developmental lung defects with consideration of X-ray and clinical data. In total 126 cases have been studied including: 72 cystic lung hypoplasias, 38 solitary cysts, 8 sequestrations, 8 bronchogenic cysts of mediastinum. Cystic hypoplasia revealed branching of cystic cavities and sometimes their connection with respiratory compartments. The other above mentioned defects reveal sometimes the connection between cysts, bronchi and respiratory compartments. Consequently with the formation of cystic developmental lung defects the development of pneumomers is not stopped but continues in a distorted form (dysplasia) which is necessary to take into consideration in the differential diagnostic of congenital and acquired (postnatal) cystic lung formations.


Developing biologically-based assessment tools for physical therapy management of neck pain.
Neck pain is a common and episodic condition that is treated using a spectrum of interventions known to be moderately effective but is associated with a significant incidence of chronic pain. Recently, there has been increased focus on defining biological aspects of neck pain. Studies have indicated that neurophysiological, biomechanical, and motor control abnormalities are present and may be useful either in prognosis or classification. We review some of these findings in the context of our own work defining biological markers that may form the basis for clinical tests that can be used for prognosis, classification, or outcome evaluation in patients with neck pain. We have identified abnormalities in neurophysiology using quantitative sensory testing (vibration, touch, and current perception) and response to cold provocation that are related to neck disability. We have identified altered muscle biochemistry by measuring circulating muscle proteins in a lumbar surgery model and are now applying those methods to whiplash injury. We have incorporated capnography into treatment to address central physiological changes present in some patients by monitoring and training CO2 levels. We have developed an innovative new test, the Neck Walk Index, that captures abnormal control of head movement during slow gait as a means of differentiating patients with neck pain from either unaffected controls or individuals with other pathologies. We have used time-varying 3-dimensional joint orientation kinematics to assess deficits in motor control during an upper extremity reach task, the results showing that poor coordination and control of the shoulder girdle leads to shoulder guarding and inconsistencies in elbow joint movement. Despite some promising early results, future research is needed to determine how these measures help clinicians to diagnose, evaluate, and forecast future outcome for patients who present with neck pain. Diagnosis, level 5.


Chronic Pain, TBI, and PTSD in Military Veterans: A Link to Suicidal Ideation and Violent Impulses?
The polytrauma clinical triad refers to the co-occurrence of chronic pain, traumatic brain injury (TBI), and posttraumatic stress disorder (PTSD). Despite research implicating dyadic relationships between these conditions and adverse outcomes, scant research has examined the polytrauma clinical triad's relation to suicide or violence. The present cross-sectional study was designed to examine whether this complex clinical presentation increases risk of suicidal ideation and violent impulses after accounting for other established risk factors. Veterans who served in the military since September 11, 2001 (N = 667) who reported chronic pain completed an interview and self-report battery. Bivariate analyses showed that suicidal ideation and violent impulses both correlated with PTSD, TBI+PTSD, pain intensity and interference, drug abuse, and major depressive disorder (MDD). Multiple regression analyses showed that: 1) race, chronic pain with PTSD, alcohol abuse, and MDD significantly predicted suicidal ideation, 2) pain interference, chronic pain with TBI, chronic pain with PTSD, chronic pain with TBI+PTSD, drug abuse, and MDD significantly predicted violent impulses, and 3) pain interference was a more critical predictor of suicidal and violent ideation than pain intensity. Implications for risk assessment and treatment are discussed. This article presents results from a study examining predictors of suicide and violence risk among a sample of post-9/11 U.S. Veterans with chronic pain. Health care professionals should assess for pain interference, TBI, PTSD, depression, and alcohol/drug abuse when conducting risk assessments with this population.


Review for librarians of evidence-based practice in nursing and the allied health professions in the United States.
This paper provides an overview of the state of evidence-based practice (EBP) in nursing and selected allied health professions and a synopsis of current trends in incorporating EBP into clinical education and practice in these fields. This overview is intended to better equip librarians with a general understanding of the fields and relevant information resources. INCLUDED PROFESSIONS: Professions are athletic training, audiology, health education and promotion, nursing, occupational therapy, physical therapy, physician assisting, respiratory care, and speech-language pathology. Each section provides a description of a profession, highlighting changes that increase the importance of clinicians' access to and use of the profession's knowledgebase, and a review of each profession's efforts to support EBP. The paper concludes with a discussion of the librarian's role in providing EBP support to the profession. EBP is in varying stages of growth among these fields. The evolution of EBP is evidenced by developments in preservice training, growth of the literature and resources, and increased research funding. Obstacles to EBP include competing job tasks, the need for additional training, and prevalent attitudes and behaviors toward research among practitioners. Librarians' skills in searching, organizing, and evaluating information can contribute to furthering the development of EBP in a given profession.


In the presence of population structure: From genomics to candidate genes underlying local adaptation.
Understanding the genomic signatures, genes, and traits underlying local adaptation of organisms to heterogeneous environments is of central importance to the field evolutionary biology. To identify loci underlying local adaptation, models that combine allelic and environmental variation while controlling for the effects of population structure have emerged as the method of choice. Despite being evaluated in simulation studies, there has not been a thorough investigation of empirical evidence supporting local adaptation across these alleles. To evaluate these methods, we use 875 Arabidopsis thaliana Eurasian accessions and two mixed models (GEMMA and LFMM) to identify candidate SNPs underlying local adaptation to climate. Subsequently, to assess evidence of local adaptation and function among significant SNPs, we examine allele frequency differentiation and recent selection across Eurasian populations, in addition to their distribution along quantitative trait loci (QTL) explaining fitness variation between Italy and Sweden populations and cis-regulatory/nonsynonymous sites showing significant selective constraint. Our results indicate that significant LFMM/GEMMA SNPs show low allele frequency differentiation and linkage disequilibrium across locally adapted Italy and Sweden populations, in addition to a poor association with fitness QTL peaks (highest logarithm of odds score). Furthermore, when examining derived allele frequencies across the Eurasian range, we find that these SNPs are enriched in low-frequency variants that show very large climatic differentiation but low levels of linkage disequilibrium. These results suggest that their enrichment along putative functional sites most likely represents deleterious variation that is independent of local adaptation. Among all the genomic signatures examined, only SNPs showing high absolute allele frequency differentiation (AFD) and linkage disequilibrium (LD) between Italy and Sweden populations showed a strong association with fitness QTL peaks and were enriched along selectively constrained cis-regulatory/nonsynonymous sites. Using these SNPs, we find strong evidence linking flowering time, freezing tolerance, and the abscisic-acid pathway to local adaptation.


Exhaled Nitric Oxide as Biomarker of Type 2 Diseases.
Nitric oxide (NO) is a short-lived gas molecule which has been studied for its role as a signaling molecule in the vasculature and later, in a broader view, as a cellular messenger in many other biological processes such as immunity and inflammation, cell survival, apoptosis, and aging. Fractional exhaled nitric oxide (FeNO) is a convenient, easy-to-obtain, and non-invasive method for assessing active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid the diagnosis and monitoring of several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory and/or immunological conditions, including allergic rhinitis, chronic rhinosinusitis with/without nasal polyps, atopic dermatitis, eosinophilic esophagitis, and food allergy. In this review, we aim to provide an extensive overview of the current state of knowledge about FeNO as a biomarker in type 2 inflammation, outlining past and recent data on the application of its measurement in patients affected by a broad variety of atopic/allergic disorders.


Immunogenicity of a recombinant hepatitis B vaccine in adults.
To evaluate the immunogenicity and reactogenicity of a recombinant hepatitis B vaccine in health care staff under routine use and unselected conditions and to investigate factors that influence the response to vaccination. This prospective postmarketing surveillance study was performed in unselected health care staff and their relatives (age range, 12-60 years) at 58 hospitals. Overall, 880 subjects were administered a 20-microgram dose of a vaccine at 0, 1, and 6 months according to the prescribing information and under routine hospital practice, and they were tested for antibody to hepatitis B surface antigen after the third dose at the hospitals routine laboratory. The principal outcome measures were antibody to hepatitis B surface antigen titers that were expressed as the seroprotection rate (SPR) (SPR [given as a percentage], > or = 10 mlU/ mL), spontaneously reported adverse events, and geometric mean titers (in milli-international units per milliliter). The compliance to the 3-dose schedule under routine hospital practice was 98.1%. The immune response was good in all age groups, and the overall SPR was 97.8% at 1 month after the third dose in field conditions with unselected health care workers. The SPR in vaccinees (age range, 40-59 years) was close to 95%. Age (P < .001), smoking (> or = 10 cigarettes per day) (P < .001), Broca index (> 110%) (P < .001), antibody to hepatitis B surface antigen testing (> 8 weeks after the last dose) (P = .03), chronic underlying disease (P = .04), and male gender (P = .04) were factors associated with lower geometric mean titers in routine vaccine use. No serious adverse events were reported. The large immune response that was elicited by this hepatitis B vaccine in adults under daily routine field conditions reflected reality, with a high SPR also found in elderly and other persons with risk factors associated with a lower immune response.


Towards biotracing in food chains.
Biotracing is tracing (backward)/tracking (forward) biological contamination in the food/feed chain. Advances in detection technologies, improvements in molecular marker identification, clearer understanding of pathogenicity markers, improved modelling methodologies and, more importantly, the integration of these disciplines will lead to better capability in full-chain tracing and tracking biological contaminations (biotracing). The advantages of improved biotraceability are faster intervention, limited recalls and more targeted remedial action. The project is not dealing with risk assessments but developing tools that can be used in "second-generation" risk assessments involving quantitative microbiology. This concept is the core activity of BIOTRACER, which is an Integrated Project (2007-2011) funded by the EU 6th Framework Programme. The research in biotracing is organised into five Research Areas, and 21 cross-disciplinary work packages that cover tracing and tracking of contamination in feed, meat and dairy chains, in addition to accidental and deliberate contamination of bottled water. The BIOTRACER Consortium consists of 46 partners, including Europe's largest food/feed industries, several SMEs, and relevant International Cooperation (INCO) countries. The Consortium includes experts in predictive microbiology, database developers, software companies, risk assessors, risk managers, system biologists, food and molecular microbiologists, legislative officers, standardization and validation members and food retailers. The outcomes will ensure a more reliable and rapid response to a microbial contamination event.


Phylogenetic utility of histone H3 intron sequences in the perennial relatives of soybean (Glycine: Leguminosae).
Histone H3 loci form a large multigene family in most plant species. In Glycine, some of these loci possess introns, whose sequences can provide characters for assessing phylogenetic relationships among species of the genus. Phylogenetic analyses of two closely related H3-B loci revealed a complex evolutionary pattern, producing trees from which species relationships could not be inferred readily. The single H3-D locus, in contrast, provided data suitable for the construction of gene trees whose topologies were sufficiently similar to other hypotheses of relationships within the subgenus Glycine to give confidence that evolution at this locus is tracking species phylogenies. H3-D topologies identified several of the same groupings found in previous phylogenetic studies using the chloroplast genome. However, histone H3-D and chloroplast genome data sets were in other respects incongruent, as revealed by both topological differences and numerical measures of congruence. The principal difference involved Glycine falcata, whose chloroplast genome belongs to one of the three strongly supported clades in the subgenus, but whose histone H3-D allele was sister to those of the remaining members of the subgenus. The H3-D topology is more in keeping with the morphologically, ecologically, and genetically divergent nature of this species. The H3-D locus appears to be a useful source of phylogenetic characters for interspecific studies in Glycine, providing resolution among taxa whose relationships were unresolved in previous studies.


Impairments of procedures for implementing complex language are due to disruption of frontal attention processes.
Production of complex discourse-lengthy, open-ended utterances and narratives-requires intact basic language operations, but it also requires a series of learned procedures for construction of complex, goal-directed communications. The progression of clinical disorders from transcortical motor aphasia to dynamic aphasia to discourse impairments represents a progression of procedural deficits from basic morpho-syntax to complex grammatical structures to narrative and a progression of lesions from posterior frontal to polar and/or lateral frontal to medial frontal. Two cases of impaired utilization of language exemplify the range of impairments from clearly aphasic agrammatic, nonfluency to less and less "aphasic" and more and more executive impairments from transcortical motor aphasia to dynamic aphasia to narrative discourse disorder. The clinical phenomenology of these disorders gradually comes to be more accurately defined in the terminology of executive deficits than that of aphasia. The executive deficits are, in turn, based on impairments in various components of attention. Specific impairments in energizing attention and setting response criteria associated, respectively, with lesions in superior medial and left ventrolateral frontal regions may cause defective recruitment of the procedures of complex language assembly.


Polygenic Risk Scores Augment Stroke Subtyping.
To determine whether the polygenic risk score (PRS) derived from MEGASTROKE is associated with ischemic stroke (IS) and its subtypes in an independent tertiary health care system and to identify the PRS derived from gene sets of known biological pathways associated with IS. Controls (n = 19,806/7,484, age ≥69/79 years) and cases (n = 1,184/951 for discovery/replication) of acute IS with European ancestry and clinical risk factors were identified by leveraging the Geisinger Electronic Health Record and chart review confirmation. All Geisinger MyCode patients with age ≥69/79 years and without any stroke-related diagnostic codes were included as low risk control. Genetic heritability and genetic correlation between Geisinger and MEGASTROKE (EUR) were calculated using the summary statistics of the genome-wide association study by linkage disequilibrium score regression. All PRS for any stroke (AS), any ischemic stroke (AIS), large artery stroke (LAS), cardioembolic stroke (CES), and small vessel stroke (SVS) were constructed by PRSice-2. A moderate heritability (10%-20%) for Geisinger sample as well as the genetic correlation between MEGASTROKE and the Geisinger cohort was identified. Variation of all 5 PRS significantly explained some of the phenotypic variations of Geisinger IS, and the R 2 increased by raising the cutoff for the age of controls. PRSLAS, PRSCES, and PRSSVS derived from low-frequency common variants provided the best fit for modeling (R 2 = 0.015 for PRSLAS). Gene sets analyses highlighted the association of PRS with Gene Ontology terms (vascular endothelial growth factor, amyloid precursor protein, and atherosclerosis). The PRSLAS, PRSCES, and PRSSVS explained the most variance of the corresponding subtypes of Geisinger IS suggesting shared etiologies and corroborated Geisinger TOAST subtyping. We provide the first evidence that PRSs derived from MEGASTROKE have value in identifying shared etiologies and determining stroke subtypes.


Variations in morphological and epidermal features of shade and sun leaves of two species: Quercus bambusifolia and Q. myrsinifolia.
Microclimatic differences between the periphery and the interior of tree crowns result in a variety of adaptive leaf macromorphological and anatomical features. Our research was designed to reveal criteria for sun/shade leaf identification in two species of evergreen oaks, applicable to both modern and fossil leaves. We compared our results with those in other species similarly studied. For both Quercus bambusifolia and Q. myrsinifolia (section Cyclobalanopsis), leaves from single mature trees with well-developed crowns were collected in the South China Botanical Garden, Guangzhou, China. We focus on leaf characters often preserved in fossil material. SVGm software was used for macromorphological measurement. Quantitative analyses were performed and box plots generated using R software with IDE Rstudio. Leaf cuticles were prepared using traditional botanical techniques. Principal characters for distinguishing shade and sun leaves in the studied oaks were identified as leaf lamina length to width ratio (L/W), and the degree of development of venation networks. For Q. myrsinifolia, shade and sun leaves differ in tooth morphology and the ratio of toothed lamina length to overall lamina length. The main epidermal characters are ordinary cell size and anticlinal wall outlines. For both species, plasticity within shade leaves exceeds that of sun leaves. Morphological responses to sun and shade in the examined oaks are similar to those in other plant genera, pointing to useful generalizations for recognizing common foliar polymorphisms that must be taken into account when determining the taxonomic position of both modern and fossil plants.


Evolution of SARS-CoV-2 Envelope, Membrane, Nucleocapsid, and Spike Structural Proteins from the Beginning of the Pandemic to September 2020: A Global and Regional Approach by Epidemiological Week.
Monitoring acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversity and emerging mutations in this ongoing pandemic is crucial for understanding its evolution and assuring the performance of diagnostic tests, vaccines, and therapies against coronavirus disease (COVID-19). This study reports on the amino acid (aa) conservation degree and the global and regional temporal evolution by epidemiological week for each residue of the following four structural SARS-CoV-2 proteins: spike, envelope, membrane, and nucleocapsid. All, 105,276 worldwide SARS-CoV-2 complete and partial sequences from 117 countries available in the Global Initiative on Sharing All Influenza Data (GISAID) from 29 December 2019 to 12 September 2020 were downloaded and processed using an in-house bioinformatics tool. Despite the extremely high conservation of SARS-CoV-2 structural proteins (>99%), all presented aa changes, i.e., 142 aa changes in 65 of the 75 envelope aa, 291 aa changes in 165 of the 222 membrane aa, 890 aa changes in 359 of the 419 nucleocapsid aa, and 2671 changes in 1132 of the 1273 spike aa. Mutations evolution differed across geographic regions and epidemiological weeks (epiweeks). The most prevalent aa changes were D614G (81.5%) in the spike protein, followed by the R203K and G204R combination (37%) in the nucleocapsid protein. The presented data provide insight into the genetic variability of SARS-CoV-2 structural proteins during the pandemic and highlights local and worldwide emerging aa changes of interest for further SARS-CoV-2 structural and functional analysis.


Morphometric evaluation of the renal arterial system of Dahl salt-sensitive and salt-resistant rats on a high salt diet. I. Interlobar and arcuate arteries.
Structural changes in intrarenal arteries of inbred Dahl salt-sensitive and salt-resistant rats with acute hypertension were studied morphometrically. After a week on a normal salt diet (1% NaCl), animals were placed on a high salt diet (8% NaCl) for 4 weeks. Systolic blood pressure (BP) and body weights (BW) were recorded, and six salt-sensitive and six salt-resistant animals were sacrificed weekly for a total of five sampling periods. Corrected cross-sectional (C/S) areas of adventitia, media (MAC), intima, wall (WAC), and lumen (LAC) were measured by planimetry. Although significant increases (p less than 0.01) in both BW and systolic BP were observed over time in both strains, salt-sensitive rats became hypertensive (systolic BP greater than 150 mm Hg) by week 2 on a high salt diet, while salt-resistant rats remained normotensive. In interlobar arteries, significant increases over time were observed for the WAC, MAC, and LAC in salt-resistant rats and in the WAC, adventitia, MAC, and LAC for salt-sensitive rats. Significant increases over time were observed for the WAC, adventitia, MAC, and LAC in arcuate arteries from salt-sensitive rats only. Increased C/S areas observed over time in both strains were observed by week 3 on the high salt diet, after the elevated systolic BP. Analysis of covariance indicated that increased C/S areas observed over time in salt-sensitive rats paralleled elevated systolic BP but did not follow an increase in BW. On the other hand, in salt-resistant rats, increased C/S areas observed over time correlated with BW but not systolic BP. The documented rapid development of vascular changes in salt-sensitive rats in conjunction with the development of acute hypertension demonstrates the potential usefulness of this model for investigating the pathogenesis of hypertensive renal vascular alterations.


Screening Bambara Groundnut (Vigna subterranea L. Verdc) Genotypes for Drought Tolerance at the Germination Stage under Simulated Drought Conditions.
Bambara groundnut (Vigna subterranean L. Verdc) is grown by smallholders and subsistence farmers in the marginal parts of sub-Saharan Africa. This legume is native to Africa and is cultivated throughout semi-arid sub-Saharan Africa. It is hardy and has been recognized as a nutritious food source in times of scarcity. Drought can negatively affect the germination or establishment of seedlings in the early stages of crop growth. Drought can limit the growing season of certain crops and create conditions that encourage the invasion of insects and diseases. Drought can also lead to a lack of crop yield, leading to rising food prices, shortages, and possibly malnutrition in vulnerable populations. A drought-tolerant genotype can be identified at the germination stage of Bambara groundnut by screening for drought-tolerance traits, and this knowledge can be applied to Bambara crop improvement programs to identify drought-tolerant traits during early growth phases. As an osmolyte, polyethylene glycol (PEG 6000) reduced water potential and simulated drought stress in Bambara groundnut seeds of different genotypes. Osmolytes are low-molecular-weight organic compounds that influence biological fluid properties. In this study, 24 Bambara groundnut genotypes were used. Data were collected on seed germination percentage (G%), germination velocity index (GVI), mean germination time (MGT), root dry mass (RDM), root fresh mass (RFM), and seven drought tolerance indices: mean productivity (MP), tolerance index (TOL), geometric mean productivity (GMP), stress susceptibility index (SSI), yield index (YI), yield stability index (YSI), stress tolerance index (STI) as well as seed coat color measurements. The data were applied to the mean observation of genotypes under simulated drought conditions (Ys) and the mean observation of genotypes under controlled conditions (Yp). Germination%, germination velocity index (GVI), mass germination time (MGT), and root fresh mass (RFM) differed significantly (p < 0.001) between the two stress conditions. Bambara genotypes Acc 82 and Acc 96 were found to be the most drought-tolerant.


Transplantation options for therapeutic central nervous system remyelination.
Persistent demyelination, in addition to being the major pathology of multiple sclerosis and the leucodystrophies, is also a feature of spinal cord trauma where there is evidence that it contributes to the functional deficit. In experimental animals it is possible to remyelinate demyelinated CNS axons by transplanting cultures containing central or peripheral myelinogenic cells. Using functional testing we have been able to show that transplant-mediated remyelination results in restoration of function lost as a consequence of demyelination. Glial cell transplantation may therefore provide a therapeutic strategy for remyelinating areas of chronic demyelination. This article reviews issues that have to be addressed before glial transplantation can be undertaken in humans. These include: what cells to use, where would the cells come from, and can we predict how much remyelination will be achieved? It concludes that the most promising approach will be to use neural multipotential stem cells isolated from embryonic CNS, expanded in vitro as neurospheres and then committed to oligodendrocyte lineage differentiation prior to implantation. However, even with such preparations, which have considerable myelinating potential, the extent of remyelination that will be achieved cannot currently be predicted with any degree of certainty.


Spatial variation in water loss predicts terrestrial salamander distribution and population dynamics.
Many patterns observed in ecology, such as species richness, life history variation, habitat use, and distribution, have physiological underpinnings. For many ectothermic organisms, temperature relationships shape these patterns, but for terrestrial amphibians, water balance may supersede temperature as the most critical physiologically limiting factor. Many amphibian species have little resistance to water loss, which restricts them to moist microhabitats, and may significantly affect foraging, dispersal, and courtship. Using plaster models as surrogates for terrestrial plethodontid salamanders (Plethodon albagula), we measured water loss under ecologically relevant field conditions to estimate the duration of surface activity time across the landscape. Surface activity time was significantly affected by topography, solar exposure, canopy cover, maximum air temperature, and time since rain. Spatially, surface activity times were highest in ravine habitats and lowest on ridges. Surface activity time was a significant predictor of salamander abundance, as well as a predictor of successful recruitment; the probability of a juvenile salamander occupying an area with high surface activity time was two times greater than an area with limited predicted surface activity. Our results suggest that survival, recruitment, or both are demographic processes that are affected by water loss and the ability of salamanders to be surface-active. Results from our study extend our understanding of plethodontid salamander ecology, emphasize the limitations imposed by their unique physiology, and highlight the importance of water loss to spatial population dynamics. These findings are timely for understanding the effects that fluctuating temperature and moisture conditions predicted for future climates will have on plethodontid salamanders.


PET/CT Myocardial Perfusion Imaging Acquisition and Processing: Ten Tips and Tricks to Help You Succeed.
Positron emission tomography (PET) is a leading non-invasive modality for the diagnosis of coronary artery disease due to its diagnostic accuracy and high image quality. With the latest advances in PET systems, clinicians are able to assess for myocardial ischemia and myocardial blood flow while exposing patients to extremely low radiation doses. This review will focus on the basics of acquisition and processing of hybrid PET/CT systems from appropriate patient selection to common artifacts and pitfalls. The continued development of hybrid PET/CT technology is producing scanners with exquisite sensitivity capable of generating high-quality images while exposing patients to low radiation doses. List mode acquisition is an essential component in all modern PET/CT scanners allowing simultaneous dynamic and ECG-gated imaging without lengthening scan duration. Various PET radiotracers are currently being developed but rubidium-82 and 13N-ammonia remain the most commonly used perfusion radiotracers. The development of mini 13N-ammonia cyclotrons is a promising tool that should increase access to this radiotracer. Misregistration, attenuation from extra-cardiac activity, and patient motion are the most common causes of artifacts during perfusion imaging. Techniques to automatically realign images and correct respiratory or patient motion artifacts continue to evolve. Despite the continuous evolution of PET imaging techniques, basic knowledge of scan parameters, acquisition techniques, and post processing tools remains essential to ensure high-quality images are produced and artifacts are recognized and corrected. Future research should focus on optimizing scanners to allow for shorter scan protocols and lower radiation exposure as well as continue developing techniques to minimize and correct for motion and misregistration artifacts.


Shell-isolated nanoparticle-enhanced Raman spectroscopy: expanding the versatility of surface-enhanced Raman scattering.
Surface-enhanced Raman scattering (SERS) is a powerful technique for detection and characterization because of its extremely high sensitivity and the rich structural information that it can offer. However, most SERS substrates are composed of Au, Ag, or Cu, and a lack of substrate generality has greatly limited the breadth of the use of SERS. Recently, we have devised a method by which SERS can be obtained from virtually any surface. Au nanoparticles are coated with ultrathin silica shells. The Au core provides Raman signal enhancement; the silica shell prevents the core from coming into direct contact with probe/analyte molecules or the surface over which these particles are spread (i.e., prevents the contamination of the chemical system under study). In the present review, we expand upon previous discussion of the enhancement mechanism; procedures for the synthesis and characterization of our nanoparticles; and applications in surface chemistry, electrochemistry, and inspection.


Women's breastfeeding experiences following a significant primary postpartum haemorrhage: A multicentre cohort study.
Postpartum haemorrhage (PPH) is a significant and increasing contributor to maternal mortality and morbidity. Following a PPH, women may have difficulties initiating and sustaining breastfeeding, although little has been published on this issue. The aim of this study was to describe breastfeeding experiences in a cohort of women following a significant PPH. This is a descriptive study based on quantitative and qualitative data collected via questionnaires completed in the first week postpartum and at two and four months postpartum, by 206 women participating in a multicentre study of women's experiences of a significant primary postpartum haemorrhage (blood loss of 1500 mL or more in the 24 hours following childbirth, and/or a peripartum fall in haemoglobin (Hb) concentration to 7g/dL or less, or of >/= 4g/dL). Among women with a significant PPH, 63% fully breastfed their babies from birth, whereas 85% said they had hoped to do so (p < 0.001). Only 52% of mothers who intended to either fully or partially breastfeed were able to give their baby the opportunity to suckle within an hour of the birth. Delays were longer in women with greater estimated blood loss and women with the longest delays in breastfeeding were less likely to initiate full breastfeeding. 70% of women with PPH of < 2000 mL were fully breastfeeding in the first postpartum week, whereas less than 50% of those with blood loss >/= 3000 mL were able to do so. Overall, 58% of women with significant PPH were fully breastfeeding at two and 45% at four months postpartum.In qualitative data, three major themes were identified: 1) Difficulty initiating or sustaining breastfeeding, 2) Need for education and support; and 3) Emotional sequelae. Following a significant PPH, women with greater blood loss are less likely to initiate and sustain full breastfeeding and this may be related, in part, to delays in initial contact with their baby as a consequence of the PPH. These findings have implications for postnatal care as these women may require greater support, education and assistance in initiating and sustaining breastfeeding. In particular, enabling the opportunity for the newborn to suckle as soon as is practicable should be encouraged.


Anti-Angiogenic Drugs, Vascular Toxicity and Thromboembolism in Solid Cancer.
Neo-angiogenesis, a key step in cancer progression, is a highly regulated process, in which Vascular Endothelial Growth Factor (VEGF) plays a fundamental role, thus representing the most suitable anti-angiogenic target. In the last year, a number of anti-VEGF drugs have been developed and approved for therapeutic use, especially in combination with standard chemotherapy. VEGF, however, is not only crucial for physiological and pathological angiogenesis, but also for the maintenance of vascular homeostasis, at a point that its pharmacological blockade may lead to endothelial dysfunction and adverse vascular effects, such as venous thromboembolism. The picture is further complicated by the understanding that the amount of VEGF production is influenced by genetic factors, with environmental ones accounting only for 20-30% of its variations. This has recently prompted the design of various pharmacogenetic studies to investigate the role of VEGF polymorphisms in determining the pharmacological response and safety profile of various anti-angiogenic drugs, suggesting that the analysis of VEGF genetic variants in cancer patients may further help personalize anti-angiogenic pharmacological strategies. In this review, we initially focused on the biological mechanisms involved in vascular maintenance and angiogenesis. Then, discussed the efficacy and toxicity profile of some of the antiangiogenic drugs most commonly used in the treatment of solid cancer, with a particular focus on the thromboembolic complications of anti-angiogenic treatments in cancer patients. Finally, the impact of VEGF gene polymorphisms on clinical outcome and toxicity was briefly reviewed.


Nuclear, biological, and chemical terrorism: understanding the threat and designing responses.
Today nuclear, biological, and chemical (NBC) terrorism is a serious issue. The threat of terrorist or rogue states acquiring and using NBC weapons has ushered in a new age of terrorism; an age that is far more dangerous than any previous period. It is an age of terrorism with which no one yet knows how to deal. This article reviews recent trends in terrorism, and identifies groups that have both the potential and the motive to use weapons of mass destruction. In addition, it discusses the design and implemention of effective measures to meet this threat, as well as the role of CISM teams in preparation for, and in the aftermath of, an incident involving NBC weapons.


Census of mental hospital patients and life expectancy of those unlikely to be discharged.
A census in a London mental hospital was performed so that the numbers of patients requiring permanent care for the next 20 to 40 years could be estimated. Of 1467 resident patients 20% had been admitted in the preceding five months and 15% in the year before that. Of the 65% who had been in hospital for over 17 months 1% (16 patients) had been in hospital for over 5o years. Altogether 257 (18%) patients would probably be discharged, 339 (23%) might possibly be discharged if there were adequate community facilities, but 871 (59%) were not likely to be discharged; 239 patients under the age of 65 who had been admitted between 1950 and 1973 were unlikely to be discharged. There were about 10 new younger long-stay patients from each year's admissions. Three conditions--schizophrenia, organic brain syndrome, and affective illness--affected 79% of the population. Fourteen per cent had been employed on admission and 28% were considered employable or possibly employable. Half of those who might be considered for discharge (296) would need a hostel. No rehabilitation was needed or possible for 40% of the patients; 299 (20%) patients were chairbound or bedridden and 400 (27%) were totally dependent on nursing and 587 (40%) partly dependent. Twenty months after the census 361 (25%) patients had left (59 had been readmitted), 284 (19%) had died, and 822 (56%) had remained as inpatients. The most realistic future prediction was that 210 (14%) of these patients would still be in the hospital in 20 years and 43 (3%) in 40 years. In the light of these findings and the scarceness of resources current Department of Health and Social Security plans for phasing out mental hospitals must be challenged.


DNA damage triggers genetic exchange in Helicobacter pylori.
Many organisms respond to DNA damage by inducing expression of DNA repair genes. We find that the human stomach pathogen Helicobacter pylori instead induces transcription and translation of natural competence genes, thus increasing transformation frequency. Transcription of a lysozyme-like protein that promotes DNA donation from intact cells is also induced. Exogenous DNA modulates the DNA damage response, as both recA and the ability to take up DNA are required for full induction of the response. This feedback loop is active during stomach colonization, indicating a role in the pathogenesis of the bacterium. As patients can be infected with multiple genetically distinct clones of H. pylori, DNA damage induced genetic exchange may facilitate spread of antibiotic resistance and selection of fitter variants through re-assortment of preexisting alleles in this important human pathogen.


Evidence-based neonatology: making a difference beyond discharge from the neonatal nursery.
The number of controlled clinical trials in neonatal medicine has increased steadily over recent years. However, most of these trials examine only short-term outcomes during the initial hospital stay. To determine whether a common neonatal intervention does more good than harm, it is important to study its long-term efficacy and safety. This review summarizes randomized trials of neonatal therapies published between October 2000 and September 2001. Only trials that examine outcomes beyond the initial hospital discharge were considered. Four beneficial interventions were identified: promotion of breast-feeding, comprehensive follow-up care for high-risk, very low birthweight infants, cryotherapy for threshold retinopathy of prematurity, and extracorporeal membrane oxygenation for mature infants with severe respiratory failure. Indomethacin prophylaxis in extremely low birthweight infants is of questionable use. Thyroxine supplementation for premature infants and head cooling for asphyxiated term infants require further study and should not be prescribed outside of rigorous clinical trials.


Low-pressure capnoperitoneum reduces stress responses during pediatric laparoscopic high ligation of indirect inguinal hernia sac: A randomized controlled study.
We aimed to evaluate the effect of different capnoperitoneum pressures on stress responses in pediatric laparoscopic inguinal hernia repair. In this prospective randomized controlled study, 68 children with indirect inguinal hernia who underwent high ligation of hernia sac were randomly divided into 3 groups: high-pressure group (12 mm Hg, HP group, n = 26); low-pressure group (8 mm Hg, LP group, n = 20); open operation group (OP group, n = 22). Heart rate (HR), blood pressure, and end-tidal CO2 (PetCO2) were recorded, as well as the levels of adrenocorticotropic hormone (ACTH) and cortisol (COR) were measured by ELISAs before operation, during operation, and after operation, respectively. After establishing capnoperitoneum, HR, blood pressure, and PetCO2 were significantly increased in the HP group compared with the OP and LP groups (P < 0.05). Comparing the intraoperatively measured ACTH and COR concentrations of the HP group to the LP group, we noted higher values in the first (P < 0.05). There was no significant difference in the postoperative concentrations of ACTH and COR among the HP, LP, and OP groups. Laparoscopic surgery under LP capnoperitoneum or open operation may reduce stress responses and are superior to HP capnoperitoneum.


Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells.
Chronic graft-versus-host-disease (cGVHD) can cause multiorgan system disease, typically with autoimmune-like features, resulting in high mortality and morbidity caused by treatment limitations. Invariant natural killer T cells (iNKTs), a small population characterized by expression of a semi-invariant T-cell receptor, rapidly produce copious amounts of diverse cytokines on activation that exert potent immune regulatory function. Here, we show that iNKTs are significantly reduced in a cGVHD murine model that recapitulates several aspects of autoimmunity and organ fibrosis observed in patients with cGVHD. Low iNKT infused doses effectively prevented and, importantly, reversed established cGVHD, as did third-party iNKTs. iNKTs suppressed the autoimmune response by reducing the germinal center (GC) reaction, which was associated with an increase in total Tregs and follicular Tregs (Tfr) that control the GC reaction, along with pathogenic antibody production. Treg depletion during iNKT infusions completely abolished iNKT efficacy in treating cGVHD. iNKT cell interleukin 4 production and GC migration were critical to cGVHD reversal. In vivo stimulation of iNKT cells by α-galactosyl-ceramide was effective in both preventing and treating cGVHD. Together, this study demonstrates iNKT deficiency in cGVHD mice and highlights the key role of iNKTs in regulating cGVHD pathogenesis and as a potentially novel prophylactic and therapeutic option for patients with cGVHD.


Effect of central venous pressure on spinal cord oxygenation.
To analyze the effect of central venous pressure on cerebrospinal fluid oxygen tension and intrathecal pressure, multiparameter sensors were introduced into the intrathecal space for continuous monitoring of cerebrospinal fluid Po(2), Pco(2), and intrathecal pressure in 15 pigs. After 20 min of aortic clamping, hypervolemia was established for 20 min, followed by normovolemia. The animals were divided into 3 groups: in group 1, cerebrospinal fluid Po(2) = 0% at some time during crossclamping; in group 2, cerebrospinal fluid Po(2) was <50%; and in group 3, cerebrospinal fluid Po(2) remained > or = 50%. Mean decreases in cerebrospinal fluid Po(2) during the initial 20 min of crossclamping were 82%, 57%, and 15% in groups 1, 2, and 3, respectively. Following induction of hypervolemia, central venous and cerebrospinal fluid pressures increased simultaneously; this caused a significant decrease in cerebrospinal fluid Po(2) in group 2 only. In this model, aortic clamping did not increase cerebrospinal fluid pressure if central venous pressure was not elevated. The detrimental effect of elevated intrathecal pressure on cerebrospinal fluid oxygenation was seen only in animals with an intermediate degree of spinal cord ischemia. This might have important implications for the prevention of paraplegia during thoracoabdominal aortic replacement.


Three dimensional modeling of N-terminal region of galanin and its interaction with the galanin receptor.
The neuropeptide galanin comes under the powerful and versatile modulators of classical neurotransmitters and is present in brain tissues, which are intimately involved in epileptogenesis. It acts as appealing targets for studying basic mechanisms of seizure initiation and arrest, and for the development of novel approaches for various neurodegenerative diseases. Galanin is widely distributed in the mammalian brain which controls various processes such as sensation of pain, learning, feeding, sexual behaviour, carcinogenesis, pathophysiology of neuroendocrine tumors and others. The function of galanin can be exploited through its interaction with three G-protein coupled receptors subtypes such as GalR1, GalR2 and GalR3. The N-terminal region of galanin comprises about highly conserved 15 amino acid residues, which act as the crucial region for agonist-receptor binding. We have constructed a theoretical structural model for the N-terminal region of galanin from Homo sapiens by homology modeling. The stereochemistry of the model was checked using PROCHECK. The functionally conserved regions were identified by surface mapping of phylogenetic information generated by online web algorithm ConSurf. The docking studies on the pharmacologically important galanin receptors with the theoretical model of N-terminal region of galanin predicted crucial residues for binding which would be useful in the development of novel leads for neurodegenerative disorders.


Bacterial natural product discovery by heterologous expression.
Natural products have found important applications in the pharmaceutical and agricultural sectors. In bacteria, the genes that encode the biosynthesis of natural products are often colocalized in the genome, forming biosynthetic gene clusters. It has been predicted that only 3% of natural products encoded in bacterial genomes have been discovered thus far, in part because gene clusters may be poorly expressed under laboratory conditions. Heterologous expression can help convert bioinformatics predictions into products. However, challenges remain such as gene cluster prioritization, cloning of the complete gene cluster, high level expression, product identification, and isolation of products in practical yields. Here we reviewed the literature from the past five years (January 2018 to June 2023) to identify studies that discovered natural products by heterologous expression. From the 50 studies identified, we present analyses of the rationale for gene cluster prioritization, cloning methods, biosynthetic class, source taxa, and host choice. Combined, the 50 studies led to the discovery of 63 new families of natural products, supporting heterologous expression as a promising way to access novel chemistry. However, the success rate of natural product detection varied from 11% to 32% based on four large-scale studies that were part of the reviewed literature. The low success rate makes it apparent that much remains to be improved. The potential reasons for failure and points to be considered to improve the chances of success are discussed.


Targeting of a heterologous protein to a regulated secretion pathway in cultured endothelial cells.
The stimulation of regulated exocytosis in vascular endothelial cells (EC) by a variety of naturally occurring agonists contributes to the interrelated processes of inflammation, thrombosis, and fibrinolysis. The Weibel-Palade body (WPB) is a well-described secretory granule in EC that contains both von Willebrand factor (vWF) and P-selectin, but the mechanisms responsible for the targeting of these proteins into this organelle remain poorly understood. Through adenoviral transduction, we have expressed human growth hormone (GH) as a model of regulated secretory protein sorting in EC. Immunofluorescence microscopy of EC infected with GH-containing recombinant adenovirus (GHrAd) demonstrated a granular distribution of GH that colocalized with vWF. In contrast, EC infected with an rAd expressing the IgG(1) heavy chain (IG), a constitutively secreted protein, did not demonstrate colocalization of IG and vWF. In response to phorbol ester, GH as well as endogenously synthesized vWF were rapidly released from GHrAd-infected EC. By immunofluorescence microscopy, granular colocalization of GH with endogenous tissue-type plasminogen activator (tPA) was also demonstrated, and most of the tPA colocalized with vWF. These data indicate that EC are capable of selectively targeting heterologous proteins, such as GH, to the regulated secretory pathway, which suggests that EC and neuroendocrine cells share common protein targeting recognition signals or receptors.


Surviving intensive care: a systematic review of healthcare resource use after hospital discharge*.
Intensive care survivors continue to experience significant morbidity following acute hospital discharge, but healthcare costs associated with this ongoing morbidity are poorly described. As the demand for intensive care increases, understanding the magnitude of postacute hospital healthcare costs is of increasing relevance to clinicians and healthcare planners. We undertook a systematic review of the literature reporting major healthcare resource use by intensive care survivors following discharge from the hospital and identified factors associated with increased resource use. Seven electronic databases (1990 to August 2012), conference proceedings, and reference lists were searched. Studies published in English were included that reported postacute hospital discharge healthcare resource use at the individual level for survivors of intensive care. Two reviewers screened abstracts and one abstracted data using standardized templates. Study quality was assessed using recognized appraisal methods specific to economic evaluation, epidemiological studies, and randomized trials. From 4,909 articles, 18 articles representing 14 cohorts fulfilled inclusion criteria. There was substantial variation in methodology, especially the resource categories included in the studies. Following standardization to a common currency and year, variation in cost of resource use was evident (range 2011 US $18,847-$148,454 for year 1 postdischarge). Studies undertaken within the United States reported the highest costs; those in the United Kingdom reported substantially lower costs. Factors associated with increased resource use included increasing age, comorbidities, organ dysfunction score, and previous resource use. Wide variation in methodological approaches limited study comparability and external validity of findings. We found substantial variation in the cost of resource use, especially among countries. Careful description of patient cohorts and healthcare systems is required to maximize generalizability. We give recommendations for a more standardized approach to improve design and reporting of future studies.


Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Updated Modeling Study for the US Preventive Services Task Force.
The US Preventive Services Task Force (USPSTF) is updating its 2016 recommendation on the use of aspirin for the primary prevention of cardiovascular disease (CVD) and colorectal cancer (CRC). To provide updated model-based estimates of the net balance in benefits and harms from routine use of low-dose aspirin for primary prevention. Microsimulation modeling was used to estimate long-term benefits and harms for hypothetical US cohorts of men and women aged 40 to 79 years with up to 20% 10-year risk for an atherosclerotic CVD event and without prior history of CVD or elevated bleeding risks. Low-dose (≤100 mg/d) aspirin for lifetime use, unless contraindicated by a bleeding event, and with stopping ages in 5-year intervals from age 65 to 85 years. Primary outcomes were lifetime net benefits measured in quality-adjusted life-years (QALYs) and life-years. Benefits included reduced nonfatal myocardial infarction and ischemic stroke. Harms included increased nonfatal major gastrointestinal bleeding and intracranial hemorrhage. Reduced CRC incidence was considered in sensitivity analysis. Estimated lifetime net QALYs were positive for both men and women at 5% or greater 10-year CVD risk when starting between ages 40 and 59 years and at 10% or greater 10-year CVD risk when starting between ages 60 and 69 years. These estimates ranged from 2.3 (95% CI, -2.7 to 7.4) to 66.2 (95% CI, 58.2 to 74.1) QALYs per 1000 persons. Lifetime net life-years were positive for men at 5% or greater and women at 10% or greater 10-year CVD risk starting aspirin at ages 40 to 49 years and for men at 7.5% or greater and women at 15% or greater 10-year CVD risk at ages 50 to 59 years. These estimates ranged from 0.4 (95% CI, -6.1 to 6.9) to 52.4 (95% CI, 43.9 to 60.9) life-years per 1000 persons. Lifetime net life-years were negative in most cases for persons starting aspirin between ages 60 and 79 years, as were lifetime net QALYs for persons aged 70 to 79 years. Stopping aspirin between ages 65 and 85 years generally showed little advantage compared with lifetime use. Sensitivity analyses showed lifetime net benefits may be higher if aspirin reduced CRC incidence or CVD mortality and lower if aspirin increased fatal major gastrointestinal bleeding or reduced quality of life with routine use. This microsimulation study suggested that several population groups may benefit from taking aspirin for the primary prevention of CVD, primarily in persons starting at younger ages with higher 10-year CVD risk.


The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism.
VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, in which it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knock-out mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nm), and tPA STOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75(NTR) function-blocking antiserum, or previous tetanic stimulation. Although LTP was normal in slices from VGF knock-out mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior.


Methods for calculating factors of safety for plant stems.
The concept of a 'factor of safety' is used by biologists and engineers who generally agree that structures must be mechanically reliable, i.e. that structures must be capable of coping with unprecedented loads without failing. These factors can be calculated for individual structures or for a population of otherwise equivalent mechanical structures differing in their load capabilities. Objective methods for quantifying factors of safety for biological structures are nevertheless difficult to devise because (1) actual (working) loads are defined by environmental conditions that can vary widely, (2) breaking loads (capability) of otherwise mechanically equivalent structures can likewise vary as a result of developmental variation, and (3) specific criteria for failure must be determined a priori. In this paper, we illustrate and discuss two methods for computing factors of safety for plants. One method works well for individual stems or entire plants, the other is useful when dealing with a population of conspecifics exhibiting a norm of reaction. Both methods require estimates of the actual and breaking bending (or torsional) moments experienced by stems, and both are amenable to dealing with any biologically reasonable criterion for failure. However, the two methods differ in terms of the assumptions made and the types of data that need to be gathered. The advantage of the first method is that it estimates the potential for survival of an individual stem or plant. The disadvantage is that it neglects natural variation among otherwise mechanically homologous individuals. The advantage of the second (statistical) approach is that it estimates the probability of survival of a population in a particular habitat. The disadvantage of this approach is that it sheds little light on the probability of an individual's survival.


Mental health concerns of gay and bisexual men seeking mental health services.
Little data exist about the mental health needs of gay and bisexual men. This is due to limitations of existing studies such as small and nonrepresentative samples, failure to assess sexual orientation, and concerns about stigmatization, possibly causing sexual minority individuals to be reluctant to disclose their sexual orientation to researchers. Fenway Community Health is a large urban health center that serves the LGBT community. The large number of gay and bisexual men who present for mental health treatment allows for a unique opportunity to gain insight into mental health, prevention, and intervention needs for this group. The current study is a review of the mental health information from all of the gay and bisexual men who reported that they were HIV-negative during their mental health intake over a six-month period at Fenway Community Health (January to June 2000; N = 92). The most frequent presenting problems were depression, anxiety, and relationship issues. Additionally, presenting problems included current or past abuse, substance abuse, finance and employment, recent loss, and family issues. The most frequent diagnoses were depression, anxiety disorders, and adjustment disorders. These findings support the notion that presenting problems and mental health concerns among gay and bisexual men are similar to those frequently reported by individuals in other mental health facilities, however, specific psychosocial stressors are unique to this population.


Being treated differently: stigma experiences with family, peers, and school staff among adolescents with mental health disorders.
Stigma directed at adolescents diagnosed with emotional and behavioral disorders by individuals in their interpersonal network likely undermines their wellbeing, yet little is known about their subjective stigma experiences. In particular, the prospect of diagnosed youth experiencing prejudice and discrimination by family members has not previously been examined. This study examines adolescents' perceptions of being treated 'differently' because of mental health problems by family members, peers, and school staff. Qualitative analysis of narratives from mixed method interviews with 56 adolescents in a mid-western US city demonstrated variation in the perceived extent and nature of stigma and in contextual factors perceived as promoting or protecting from stigmatization, depending on the interpersonal domain. The greatest number of participants experienced stigmatization in relationships with peers (62%); this often led to friendship losses and transitions. Participants reporting no peer stigmatization often reported socializing with others "in the same boat" or concealing problems--methods of avoiding potentially stigmatizing interactions. Close to half (46%) described experiencing stigmatization by family members, which often took the form of unwarranted assumptions, distrust, avoidance, pity, and gossip. About one third (35%) of participants reported stigma perpetrated by school staff, who expressed fear, dislike, avoidance, and under-estimation of their abilities. Fortunately, 22% reported "different" treatment by school staff, but this treatment was interpreted as positive and supportive. Results showed that perceived stigmatization in one domain was associated with perceived stigma in other domains. The results suggest that efforts to combat stigmatization of youth with mental health disorders must help family members, peers, and school staff overcome their inclinations to make negative assumptions and discriminate against these youth.


Promoting an interprofessional approach to chronic pain management in primary care using Project ECHO.
Chronic pain is a complex multidimensional condition that requires management with multiple professions' expertise. Healthcare training programs tend to adhere to curricula within their own profession with very few interactions with other groups. Project ECHO (Extension for Community Healthcare Outcomes) Chronic Pain and Opioid Stewardship is a model for interprofessional education, using tele-mentoring, case-base discussions and clinically focused presentations. The goal is to improve competency and confidence in managing complex cases in primary care. This qualitative study engaged twenty healthcare practitioners from multiple professions who had participated in ECHO in focus group discussions about managing patients with chronic pain, about their reasons for and the effect of participating in Project ECHO Ontario Chronic Pain/Opioid Stewardship, and about their perspectives on interprofessional care. The results show that participating in ECHO resulted in personal and professional benefit, and increased understanding about their own roles and limitations, as well as other healthcare professionals' roles. The participants described changes in their attitudes toward patients with chronic pain, and their colleagues from other professions. Non-physician participants were more likely to approach physicians to discuss their assessment and diagnosis as well as prescriptions. The interprofessional nature of the program was seen as positive and contributed to perceived changes in practice collaboration. These results show that healthcare professionals from multiple professions expressed mainly positive views of ECHO's emphasis on interprofessional care, with different professions appreciating different aspects of that approach.


Neo-ligands for innate immune receptors and the etiology of sterile inflammatory disease.
Microbe recognition based on a small collection of germline-encoded receptors carries a hidden liability: the possibility that mutational changes in the proteome will lead to self-recognition. The risk of self-recognition is enhanced, because innate immune receptors display low specificity, as they are driven to accommodate heterogeneous signature molecules found in the microbial world. The proteome structure is globally constrained by the innate immune sensing apparatus to satisfy a proscription against self-reactivity. But accidents happen, and here it is proposed that mutations creating neo-ligands for innate immune receptors are the proximal cause of sterile inflammatory diseases, which in turn embody the selective pressure that constrains the proteome. Such mutations are predictably dominant and may occur in the germline and also in somatic cells (e.g. in lymphocytes), causing inflammatory effects upon clonal expansion. They may also account for the inflammatory character of selected neoplastic diseases. The neo-ligand hypothesis accounts for the heritability, ambiguous linkage characteristics, phenotypic heterogeneity, and natural history of diverse forms of sterile inflammation. It explains sterile inflammatory diseases as conditions in which aberrant immune signaling is caused by proteome encroachment upon the ligand-recognition space over which the innate immune system stands guard.


Epigenetics and Vasculitis: a Comprehensive Review.
Vasculitides represent a group of relatively rare systemic inflammatory diseases of the blood vessels. Despite recent progress in understanding the genetic basis and the underlying pathogenic mechanisms in vasculitis, the etiology and pathogenesis of vasculitis remain incompletely understood. Epigenetic dysregulation plays an important role in immune-mediated diseases, and the contribution of epigenetic aberrancies in vasculitis is increasingly being recognized. Histone modifications in the PR3 and MPO gene loci might be mechanistically involved in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Similarly, other studies revealed important epigenetic contribution to other vasculitides, including Kawasaki disease and IgA vasculitis. More recently, genome-wide epigenomic studies have been performed in several vasculitides. A recent genome-wide DNA methylation study uncovered an important role for epigenetic remodeling of cytoskeleton-related genes in the pathogenesis of Behçet's disease and suggested that reversal of some of these DNA methylation changes associates with disease remission. Genome-wide DNA methylation profiling characterized the inflammatory response in temporal artery tissue from patients with giant cell arteritis and showed increased activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling, prompting the suggestion that a specific calcineurin/NFAT inhibitor that is well tolerated and with the added beneficial anti-platelet activity, such as dipyridamole, might be of therapeutic potential in giant cell arteritis. While epigenetic studies in systemic vasculitis are still in their infancy, currently available data clearly indicate that investigating the epigenetic mechanisms underlying these diseases will help to better understand the pathogenesis of vasculitis and provide novel targets for the development of disease biomarkers and new therapies.


Optimization of surgical approach for thoracoscopic-assisted pulmonary surgery in dogs.
To determine the optimal intercostal space (ICS) to perform thoracoscopic-assisted lung lobectomy. Cadaveric study. Six mature, medium-sized canine cadavers. Cadavers were placed in right or left lateral recumbency. A 15-mm thoracoscopic cannula was inserted in the middle third of the 9th or 10th ICS. A wound retraction device was placed into a 7-cm minithoracotomy incision created in the middle third of the 4th-7th ICS on the left side and the 4th-8th ICS on the right side. The pulmonary ligaments were sectioned by using a combined intracorporeal and extracorporeal technique. Each lung lobe was sequentially withdrawn from the wound retraction device at the respective ICS and side. A thoracoabdominal stapler was positioned to simulate lung lobectomy, and the distance from the stapler anvil to the hilus was measured. Simulated thoracoscopic-assisted lung lobectomy performed at left or right ICS 4 and 5, compared with other ICS evaluated, resulted in a significantly shorter median distance from the stapler anvil to the pulmonary hilus of the left cranial and caudal lung lobes and right cranial and middle lung lobes, respectively (all P < .05). Lobectomy at right ICS 5 or 6 resulted in a significantly shorter median distance from the stapler anvil to the pulmonary hilus of the right caudal and accessory lung lobes, respectively (both P < .05). These data may inform minithoracotomy positioning to optimize tumor margin excision during thoracoscopic-assisted lung lobectomy for treatment of pulmonary neoplasia in dogs. Complete lung lobectomy is possible by using the described thoracoscopic-assisted technique in normal, cadaveric lungs.


Evaluation of the Clinical Efficacy of Stem Cell Transplantation in the Treatment of Spinal Cord Injury: A Systematic Review and Meta-analysis.
Stem cell transplantation has been applied to treat spinal cord injury (SCI) in clinical trials for many years. However, the clinical efficacies of stem cell transplantation in SCI have been quite diverse. The purpose of our study was to systematically investigate the efficacy of stem cell transplantation in patients with SCI. The PubMed, Web of Science, Ovid-Medline, Cochrane Library, China National Knowledge Infrastructure, VIP, Wanfang, and SinoMed databases were searched until October 27, 2020. Quantitative and qualitative data were analyzed by Review Manager 5.3 and R. Nine studies (n = 328) were included, and the overall risk of bias was moderate. The ASIA Impairment Scale (AIS) grading improvement rate was analyzed in favor of stem cell transplantation group [odds ratio (OR) = 6.06, 95% confidence interval (CI): 3.16-11.62, P < 0.00001]. Urodynamic indices also showed improvement in bladder function. In subgroup analyses, the results indicated that in patients with complete (AIS A) SCI, with the application of cell numbers between n*(107-108), two cell types (i.e., bone marrow-derived mesenchymal stem cells and bone marrow mononuclears), and treatment time of more than 6 months, stem cell transplantation was more beneficial for sensorimotor function (P < 0.05 for all groups). The risk of fever incidence in the stem cell transplantation group was 4.22 (95% CI: 1.7-10.22, P = 0.001), and principal component analysis (PCA) suggested it was more related to transplanted cell numbers. Thus, stem cell transplantation can promote functional recovery in SCI patients. Moreover, the type and quantity of transplanted stem cells and treatment time are important factors affecting the therapeutic effect of stem cell transplantation in SCI. Further studies are needed to evaluate the effects and elucidate the mechanisms of these factors on stem cell therapy in SCI.


Are pinnipeds functionally different from fissiped carnivores? The importance of phylogenetic comparative analyses.
It is widely assumed that adaptations to an aquatic lifestyle are so profound as to produce only obvious differences between pinnipeds and the remaining, largely terrestrial carnivore species ("fissipeds"). Thus, comparative studies of the order Carnivora routinely examine these groups independently. This approach is invalid for two reasons. First, fissipeds are a paraphyletic assemblage, which raises the general issue of when it is appropriate to ignore monophyly as a criterion for inclusion in comparative studies. Second, the claim that most functional characters (beyond a few undoubted characteristic features) are different in pinnipeds and fissipeds has never been quantitatively examined, nor with phylogenetic comparative methods. We test for possible differences between these two groups in relation to 20 morphological, life-history, physiological, and ecological variables. Comparisons employed the method of independent contrasts based on a complete and dated species-level phylogeny of the extant Carnivora. Pinnipeds differ from fissipeds only through evolutionary grade shifts in a limited number of life-history traits: litter weight (vs. gestation length), birth weight, and age of eyes opening (both vs. size). Otherwise, pinnipeds display the same rate of evolution as phylogenetically equivalent fissiped taxa for all variables. Overall functional differences between pinnipeds and fissipeds appear to have been overstated and may be no greater than those among major fissiped groups. Recognition of this fact should lead to a more complete understanding of carnivore biology as a whole through more unified comparative tests. Comparative studies that do not include monophyletic groups for phylogenetically based comparative tests should be reconsidered.


Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.
Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.


Serial observations of angiotensin-converting enzyme and pulmonary function in sarcoidosis.
Fifty-six measurements of angiotensin-converting enzyme (ACE) level, diffusing capacity (DLCO), and total lung capacity (TLC) were made in 18 sarcoid patients with a maximum of 25 months of follow-up observation. During spontaneous or corticosteroid-induced changes in disease activity, there was a significant inverse correlation between changes in ACE level and changes in DLCO and between changes in ACE level and changes in TLC. These observations suggest that ACE measurement may be a useful adjunct to pulmonary function tests to follow the course of sarcoidosis and to monitor the effects of corticosteroid therapy on the lung.


Hearing loss in Japanese macaques following bilateral auditory cortex lesions.
The hearing ability of five Japanese macaques (Macaca fuscata) was assessed following two-stage bilateral auditory cortex lesions. The animals were tested using a shock-avoidance procedure with a conditioned-suppression procedure used for comparison in two cases. The animals initially were unable to respond to sound, and the first signs of hearing appeared as late as 13 wk after surgery. Hearing levels improved gradually over time, with maximal recovery reached at 24-35 wk after surgery. Recovery was most pronounced for low frequencies (63-250 Hz) and very high frequencies (32 kHz), which generally returned to normal or near-normal levels. However, the monkeys appeared to have suffered a permanent hearing loss throughout most of their hearing range, especially in the midfrequency range, where they are normally most sensitive. A review of the animal literature reveals little support for the previous view that bilateral auditory cortex lesions have little or no effect on absolute sensitivity in primates and carnivores. Most previous studies did not conduct detailed hearing tests, and those that did often noted a hearing loss. The hearing loss found in monkeys is similar to that noted in human cases following bilateral auditory cortex lesions. The current findings thus provide experimental verification of the clinical phenomenon of cortical deafness.


Isolation of tetra-acyl sucrose esters from turkish tobacco using supercritical fluid CO2 and comparison with conventional solvent extraction.
Pure supercritical CO2 at various pressures and temperatures was used to effect the fractionation of tetra-acyl sucrose esters (SE) from dried, ground Turkish tobacco without any further pretreatment of the matrix. It was determined that SE cannot be extracted using low density CO2 (150 atm, 60 degrees C, and 0.62 gm/mL or 200 atm, 100 degrees C, and 0.49 gm/mL), whereas other analytes, which strongly interfere with the conventional solvent extraction of SE, can be easily removed under the same conditions. At the higher temperature (100 degrees C), these same analytes that interfere with the conventional solvent extraction of SE are even more readily removed, while the very poor extractability of SE is not affected. It was demonstrated, however, that SE can be removed from the pre-extracted tobacco with supercritical CO2 if the density is greater than (or equal to) 0.73 gm/mL. The supercritical fluid extraction method has been compared with other previous extraction methods that employ conventional solvents. This study provides one of the clearest examples of how the variable density property of a supercritical fluid can be utilized to effect the fractionation of a complex mixture.


Controlled Tyrosine Kinase Inhibitor Delivery to Liver Cancer Cells by Gate-Capped Mesoporous Silica Nanoparticles.
Hepatocellular carcinoma is the most common type of primary malignancy in the liver and one of the most common types of cancer worldwide. Its readily increasing mortality rate highlights the urgent need for the development of efficient therapeutic strategies. Tyrosine kinase inhibitors (TKIs) such as sorafenib and sunitinib are used as efficient angiogenesis inhibitors for this purpose. However, despite their pharmacological effects, their transfer into clinical practice is characterized by their poor aqueous solubility and accumulation in off-target tissues, resulting in unfavorable side effects. Here, we report a nanocomposite made of amine-functionalized mesoporous silica nanocomposites (MSNs) that are surface-coated with cerium oxide nanoparticles (CNPs) for the controlled delivery and release of TKIs. Amine-functionalized MSNs were prepared using a sol-gel method and loaded with TKIs. To trap drug molecules into the mesoporous structure, CNPs were covalently conjugated to the surface of MSNs. The synthesis and functionalization steps were controlled using different characterization methods, confirming the desired morphology and structure, the identity of functional groups on the surface, successful coating, and appropriate loading efficiency. Under physiological conditions, CNP-capped MSNs demonstrated a sustained drug release over time as a result of CNPs' gatekeeping effect on the payloads. Strong cellular interactions with different liver cancer cells and enhanced cellular uptake were also observed in vitro for the gate-capped MSNs. Internalization of nanocomposites induced cell death via the production of reactive oxygen species, and subsequent activation of apoptosis pathways. This study demonstrates that gate-capped MSNs are promising chemotherapeutic vehicles characterized by a sustained drug release profile and high cellular internalization.


Motion measurement errors and autofocus in bistatic SAR.
This paper discusses the effect of motion measurement errors (MMEs) on measured bistatic synthetic aperture radar (SAR) phase history data that has been motion compensated to the scene origin. We characterize the effect of low-frequency MMEs on bistatic SAR images, and, based on this characterization, we derive limits on the allowable MMEs to be used as system specifications. Finally, we demonstrate that proper orientation of a bistatic SAR image during the image formation process allows application of monostatic SAR autofocus algorithms in postprocessing to mitigate image defocus.


Determinants of occurrence and volume of transpyloric flow during gastric emptying of liquids in dogs: importance of vagal input.
The precise factors and their relative contributions that lead to individual flow pulses across the pylorus during liquid gastric emptying remain unclear. Our objective was to determine the factors leading to individual flow pulses, their relative contributions and the role of the vagus nerve in their modulation. Proximal gastric tone had a strong positive correlation with the volume of the corresponding transpyloric flow pulse whereas pyloric tone had an inverse correlation. Antral contractions were associated with the presence but not the volume of the pulse. Acute vagal blockade retarded emptying via loss of proximal gastric tone and increased outflow resistance and loss of propagating antral pressure waves. In conclusion, the major determinants of the volume of pulsatile transpyloric flow are proximal gastric and pyloric tone. The vagus nerve plays a key role in regulating both proximal gastric and pyloric tone as well as moderating propagating antral contractions.


Optical coherence tomography and histologic measurements of nerve fiber layer thickness in normal and glaucomatous monkey eyes.
To investigate optical coherence tomography (OCT) measurements of retinal nerve fiber layer (RNFL) thickness change associated with elevated intraocular pressure (IOP) over a period of time, and to compare in vivo OCT RNFL thickness measurements with morphologic measurements of the same tissues. One eye of each of 12 cynomolgus monkeys was treated with argon laser to the anterior chamber angle to induce elevated IOP. OCT measurements were made weekly in the treated and the contralateral eyes of each monkey for 14 weeks after the laser insult. The monkeys were killed at the conclusion of the experiment, and comparisons were made between the terminal OCT RNFL measurements and quantitative histomorphometric assessments in the same eyes. Effects of exposure to elevated IOP on RNFL were characterized by a mixed-effects model. Linear mixed-effects models provided unbiased analysis of balanced and unbalanced repeated-measures data, detection of group effects (fixed effects), and individual subject effects (random effects), thereby making the best use of all available data. Increased IOP was achieved in 10 eyes. Exposure to high IOP was associated with the loss of mean RNFL thickness at a median rate of 3.77 +/- 0.08 microm/wk. On average, OCT RNFL thickness measurements were higher than histomorphologic measurements by 5.7 microm (95% confidence interval, 3.6-7.8; P = 0.003). Thinning of the RNFL associated with elevated IOP was demonstrated with OCT in a group of experimentally glaucomatous monkey eyes over a period. OCT measurements corresponded with histomorphometric measurements of the same tissues.


Acute pancreatitis: a newly recognised potential complication of canine babesiosis.
This retrospective study describes 4 cases of canine babesiosis with histologically confirmed acute pancreatitis. In addition, 16 dogs with babesiosis are reported with serum amylase (>3500 U/l) and/or lipase (>650 U/l) activity elevations of a magnitude that would support a diagnosis of probable acute pancreatitis, although extra-pancreatic sources of the enzymes could not be excluded in these cases. Median time of pancreatitis diagnosis was 2.5 days post-admission, with primarily young (median age 3 years), sexually intact dogs affected. The development of pancreatitis was unrelated to the degree of anaemia at time of admission. In addition to pancreatitis, 80% of cases suffered from other babesial complications, namely icterus (13), acute respiratory distress syndrome (6), immune-mediated haemolytic anaemia (6), renal failure (3), haemoconcentration (2) and cerebral syndrome (2). Acute respiratory distress syndrome, renal failure and cerebral syndrome were associated with a poor prognosis, with 4 of the 5 dogs included in the overall 26% mortality rate having at least 1 of these complications. Haemolytic anaemia with ischaemia-reperfusion injury to the pancreas is proposed as a possible primary pathophysiological mechanism in babesial pancreatitis. Hypotensive shock, immune-mediated haemolytic anaemia, haemoconcentration and possibly altered lipid metabolism in babesiosis may also be involved. The previously postulated pro-inflammatory cytokine milieu of complicated babesiosis may underlie the progression, if not the primary initiation, of pancreatic pathology. Acute pancreatitis may represent the previously reported 'gut' form of babesiosis.


Menthol enhances nicotine-induced locomotor sensitization and in vivo functional connectivity in adolescence.
Mentholated cigarettes capture a quarter of the US market, and are disproportionately smoked by adolescents. Menthol allosterically modulates nicotinic acetylcholine receptor function, but its effects on the brain and nicotine addiction are unclear. To determine if menthol is psychoactive, we assessed locomotor sensitization and brain functional connectivity. Adolescent male Sprague Dawley rats were administered nicotine (0.4 mg/kg) daily with or without menthol (0.05 mg/kg or 5.38 mg/kg) for nine days. Following each injection, distance traveled in an open field was recorded. One day after the sensitization experiment, functional connectivity was assessed in awake animals before and after drug administration using magnetic resonance imaging. Menthol (5.38 mg/kg) augmented nicotine-induced locomotor sensitization. Functional connectivity was compared in animals that had received nicotine with or without the 5.38 mg/kg dosage of menthol. Twenty-four hours into withdrawal after the last drug administration, increased functional connectivity was observed for ventral tegmental area and retrosplenial cortex with nicotine+menthol compared to nicotine-only exposure. Upon drug re-administration, the nicotine-only, but not the menthol groups, exhibited altered functional connectivity of the dorsal striatum with the amygdala. Menthol, when administered with nicotine, showed evidence of psychoactive properties by affecting brain activity and behavior compared to nicotine administration alone.