Hormonal regulation of alveolarization: structure-function correlation.
Dexamethasone (Dex) limits and all-trans-retinoic acid (RA) promotes alveolarization. While structural changes resulting from such hormonal exposures are known, their functional consequences are unclear. Neonatal rats were treated with Dex and/or RA during the first two weeks of life or were given RA after previous exposure to Dex. Morphology was assessed by light microscopy and radial alveolar counts. Function was evaluated by plethysmography at d13, pressure volume curves at d30, and exercise swim testing and arterial blood gases at both d15 and d30. Dex-treated animals had simplified lung architecture without secondary septation. Animals given RA alone had smaller, more numerous alveoli. Concomitant treatment with Dex + RA prevented the Dex-induced changes in septation. While the results of exposure to Dex + RA were sustained, the effects of RA alone were reversed two weeks after treatment was stopped. At d13, Dex-treated animals had increased lung volume, respiratory rate, tidal volume, and minute ventilation. On d15, both RA- and Dex-treated animals had hypercarbia and low arterial pH. By d30, the RA-treated animals resolved this respiratory acidosis, but Dex-treated animals continued to demonstrate blood gas and lung volume abnormalities. Concomitant RA treatment improved respiratory acidosis, but failed to normalize Dex-induced changes in pulmonary function and lung volumes. No differences in exercise tolerance were noted at either d15 or d30. RA treatment after the period of alveolarization also corrected the effects of earlier Dex exposure, but the structural changes due to RA alone were again lost two weeks after treatment. We conclude that both RA- and corticosteroid-treatments are associated with respiratory acidosis at d15. While RA alone-induced changes in structure andrespiratory function are reversed, Dex-treated animals continue to demonstrate increased respiratory rate, minute ventilation, tidal and total lung volumes at d30. Concomitant treatment with Dex + RA prevents decreased septation induced by Dex alone and results in correction of hypercarbia. However, these animals continue to have abnormal pulmonary function and lung volumes. Increased septation as a result of RA treatment alone is reversed upon discontinuation of treatment. These data suggest that Dex + RA treatment results in improved gas exchange likely secondary to normalized septation.


Iron chelator alleviates tubulointerstitial fibrosis in diabetic nephropathy rats by inhibiting the expression of tenascinC and other correlation factors.
Tubulointerstitial fibrosis is the final common pathway to diabetic nephropathy. However, only a few drugs are responsible for this pathologic process. We investigated the possible effect of deferiprone (iron chelator) treatment on experimental diabetic nephropathy (DN) rats, as well as the mechanisms involved in this process. Diabetic nephropathy was induced in rats by feeding on high-carbohydrate-fat food and injecting streptozotocin. After 20 weeks of deferiprone treatment, tubulointerstitial morphology was detected by staining with hematoxylin-eosin and Masson's trichrome. Tubulointerstitial fibrosis was measured using the point-counting technique. Biochemical parameters including fasting glucose, insulin resistance (IR), serum iron, ferritin, transferrin saturation (TS), and urinary albumin/creatinine ratio (UA/C) were detected in diabetic nephropathy models. Semiquantitative RT-PCR, western blot, and immunohistochemistry were utilized for evaluating mRNA and protein levels of tenascin C, fibronectin 1 (Fn1), TGF-β1, and collagen IV in nephridial tissue, respectively. Malonialdehyde (MDA) and superoxide dismutase (SOD) were determined by pyrogallol and thiobarbituric acid method. Tubulointerstitial fibrosis was significantly ameliorated after deferiprone treatment, and both mRNA and protein expressions of profibrotic factors were inhibited in treatment groups. Meanwhile, high levels of serum iron, ferritin, TS, and UA/C were observed in DN rats. These factors were down-regulated by deferiprone treatment. Furthermore, deferiprone effectively relieved serum IR and regulated oxidative stress process. Our results demonstrated the anti-fibrosis potential and renoprotective effects of deferiprone for diabetic nephropathy, and this process was partially mediated by tenascin C blocking.


Intracavitary ethanol ablation for the management of uterine hemorrhage refractory to uterine artery embolization.
A 57-year-old postmenopausal woman with end-stage liver disease secondary to alcoholic cirrhosis, esophageal varices, severe alcoholic cardiomyopathy, and metrorrhagia causing persistent anemia despite multiple transfusions presented with heavy vaginal bleeding. The patient underwent two uterine artery embolizations with proximal coils instead of directed particles due to difficult anatomy but the bleeding continued despite these interventions. Since she was a poor surgical candidate for hysterectomy, the decision was made to attempt achievement of hemostasis via ethanol injection into the uterine cavity. The patient's bleeding ceased, her hemoglobin and hematocrit stabilized post-procedure, and she was discharged home in stable condition.


A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses.
Long-term potentiation (LTP) has been studied extensively at CA1 synapses of the hippocampus, and there is evidence implicating both postsynaptic and presynaptic changes in this process. These changes include (i) addition of AMPA channels to the extrasynaptic membrane and diffusional equilibrium of extrasynaptic receptors with synaptic receptors, (ii) sudden addition of AMPA channels to the synapse in large groups, (iii) a change in the mode of glutamate release (presumably from kiss-and-run to full fusion), and (iv) a delayed increase in the number of vesicles released. However, it remains unclear whether (or how) these changes work together. We have incorporated all of these processes into a structural model of the synapse. We propose that the synapse is composed of transsynaptic modules that function quasi-independently in AMPA-mediated transmission. Under basal conditions, synapses are partially silent; some modules are AMPA-silent (but contribute to NMDA-mediated transmission), whereas others are functional (and contribute to both AMPA- and NMDA-mediated transmission). During LTP, there is both a rapid change in the mode of vesicle fusion and a rapid insertion of a postsynaptic complex (a hyperslot) containing many proteins (slots) capable of binding AMPA channels. The combined effect of these pre- and postsynaptic changes is to convert AMPA-silent modules into functional modules. Slot filling is transiently enhanced by a rapid increase in extrasynaptic GluR1, a form of the AMPA-type receptor. A slower transsynaptic growth process adds AMPA-silent modules to the synapse, enhancing the number of vesicles released and thereby enhancing the NMDA response. This model accounts for a broad range of data, including the LTP-induced changes in quantal parameters. The model also provides a coherent explanation for the diverse effects of GluR1 knockout on basal transmission, LTP, and distance-dependent scaling.


Helicobacter: Inflammation, immunology, and vaccines.
Helicobacter pylori infection induces a chronic gastric inflammation which can lead to gastric ulcers and cancer. The mucosal immune response to H. pylori is first initiated by the activation of gastric epithelial cells that respond to numerous bacterial factors, such as the cytotoxin-associated gene A or the lipopolysaccharide intermediate heptose-1,7-bisphosphate. The response of these cells is orchestrated by different receptors including the intracellular nucleotide-binding oligomerization domain-containing protein 1 or the extracellular epidermal growth factor receptor. This nonspecific response leads to recruitment and activation of various myeloid (macrophages and dendritic cells) and T cells (T helper-17 and mucosal-associated invariant T cells), which magnify and maintain inflammation. In this review, we summarize the major advances made in the past year regarding the induction, the regulation, and the role of the innate and adaptive immune responses to H. pylori infection. We also recapitulate efforts that have been made to develop efficient vaccine strategies.


Design and synthesis of some new thiazolo [3,2-b]-1,2,4-triazole-5(6H)-ones substituted with flurbiprofen as anti-inflammatory and analgesic agents.
In the course of our ongoing studies, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones substituted with flurbiprofen (CAS 5104-49-4) has been prepared. The compounds were synthesized by the cyclization of the 3-[(2-fluoro-4-biphenyl)ethyl]-5-mercapto-1,2,4-triazole (3) with chloroacetic acid and relevant benzaldehydes in the presence of acetic acid, acetic anhydride and anhydrous sodium acetate in one step. The product of this one-pot synthesis that precipitated on cooling of the reaction mixture was identified undoubtedly by X-ray crystallographic analysis as thiazolo[3,2-b]-1,2,4-triazole. In-vivo anti-inflammatory and analgesic activities of the compounds were assessed by carrageenan-induced hind paw edema and p-benzoquinone-induced abdominal constriction tests in mice, respectively. In addition, the ulcerogenic risks were evaluated. It is worthy of saying that the compounds which maintained analgesic/antiinflammatory activity of the starting compound were found to be safer with regard to gastric lesion risks at 100 mg/kg oral dose when compared with flurbiprofen. Among the synthesized compounds 3d showed the highest analgesic and antiinflammatory activity without inducing any gastric lesion and deserves further attention in order to develop new lead drug candidates.


Scabies in residential care homes: Modelling, inference and interventions for well-connected population sub-units.
In the context of an ageing population, understanding the transmission of infectious diseases such as scabies through well-connected sub-units of the population, such as residential care homes, is particularly important for the design of efficient interventions to mitigate against the effects of those diseases. Here, we present a modelling methodology based on the efficient solution of a large-scale system of linear differential equations that allows statistical calibration of individual-based random models to real data on scabies in residential care homes. In particular, we review and benchmark different numerical methods for the integration of the differential equation system, and then select the most appropriate of these methods to perform inference using Markov chain Monte Carlo. We test the goodness-of-fit of this model using posterior predictive intervals and propagate forward the resulting parameter uncertainty in a Bayesian framework to consider the economic cost of delayed interventions against scabies, quantifying the benefits of prompt action in the event of detection. We also revisit the previous methodology used to assess the safety of treatments in small population sub-units-in this context ivermectin-and demonstrate that even a very slight relaxation of the implicit assumption of homogeneous death rates significantly increases the plausibility of the hypothesis that ivermectin does not cause excess mortality based upon the data of Barkwell and Shields.


The relationship between perceived burden of chronic conditions and colorectal cancer screening among Appalachian residents.
As the population living with several concurrent chronic conditions or multiple morbidity (MM) increases, understanding how to effectively fit prevention efforts into disease management becomes more important, particularly among rural, underserved populations. Compared to their urban counterparts, rural residents suffer higher rates of disease, receive fewer preventive services, and often live in environments limiting access to optimal medical care. This study describes rural residents' perceived burdens of disease management and explores the relationship between these burdens, as proxies of individuals' competing demands, and colorectal cancer screening (CRCS). We conducted a cross-sectional study, based on telephone survey data from 1,012 Appalachian residents, ages 50-75, with 1 or more chronic conditions. Measures of perceived MM burdens were developed based on 85 pilot interviews previously undertaken with providers and patients with MM residing in Appalachian Kentucky. Many participants (81%) agreed with 1 or more statements indicating perceived burdens of disease management effects on receiving CRCS. A higher percentage of rural (vs nonrural) Appalachians perceived burdens related to physician's recommendation, preparation to colonoscopy, and time management and affordability of both current diseases and screening. These differences did not modify the overall association between perceiving MM as burdensome and forgoing CRCS. The negative effect on CRCS of perceived burdens related to interaction with physician and time management was lower for participants with multiple rather than single morbidity. Future research designed to address perceived burdens of MM and improved interaction with health care providers may enhance critical prevention efforts among vulnerable populations.


Real-time chest-wall-motion tracking by a single optical fibre grating: a prospective method for ventilator triggering.
The ventilators involved in non-invasive mechanical ventilation commonly provide ventilator support via a facemask. The interface of the mask with a patient promotes air leaks that cause errors in the feedback information provided by a pneumatic sensor and hence patient-ventilator asynchrony with multiple negative consequences. Our objective is to test the possibility of using chest-wall motion measured by an optical fibre-grating sensor as a more accurate non-invasive ventilator triggering mechanism. The basic premise of our approach is that the measurement accuracy can be improved by using a triggering signal that precedes pneumatic triggering in the neuro-ventilatory coupling sequence. We propose a technique that uses the measurement of chest-wall curvature by a long-period fibre-grating sensor. The sensor was applied externally to the rib-cage and interrogated in the lateral (edge) filtering scheme. The study was performed on 34 healthy volunteers. Statistical data analysis of the time lag between the fibre-grating sensor and the reference pneumotachograph was preceded by the removal of the unwanted heartbeat signal by wavelet transform processing. The results show a consistent fibre-grating signal advance with respect to the standard pneumatic signal by (230 ± 100) ms in both the inspiratory and expiratory phases. We further show that heart activity removal yields a tremendous improvement in sensor accuracy by reducing it from 60 ml to 0.3 ml. The results indicate that the proposed measurement technique may lead to a more reliable triggering decision. Its imperviousness to air leaks, non-invasiveness, low-cost and ease of implementation offer good prospects for applications in both clinical and homecare ventilation.


Silencing of MBD1 and MeCP2 in prostate-cancer-derived PC3 cells produces differential gene expression profiles and cellular phenotypes.
Alterations in genomic CpG methylation patterns have been found to be associated with cell transformation and neoplasia. Although it is recognized that methylation of CpG residues negatively regulates gene expression, how the various MBPs (methyl-binding proteins) contribute to this process remains elusive. To determine whether the two well characterized proteins MeCP2 (methyl-CpG-binding protein 2) and MBD1 (methyl-CpG-binding domain 1) have distinct or redundant functions, we employed RNAi (RNA interference) to silence their expression in the prostate cancer-derived PC3 cell line, and subsequently compared cell growth, invasion and migration properties of these cell lines in addition to their respective mRNA-expression profiles. Cells devoid of MeCP2 proliferated more poorly compared with MBD1-deficient cells and the parental PC3 cells. Enhanced apoptosis was observed in MeCP2-deficient cells, whereas apoptosis in parental and MBD1-deficient cells appeared to be equivalent. Boyden chamber invasion and wound-healing migration assays showed that MBD1-silenced cells were both more invasive and migratory compared with MeCP2-silenced cells. Finally, gene chip microarray analyses showed striking differences in the mRNA-expression profiles obtained from MeCP2- and MBD1-depleted cells relative to each other as well as when compared with control cells. The results of the present study suggest that MeCP2 and MBD1 silencing appear to affect cellular processes independently in vivo and that discrete sets of genes involved in cellular proliferation, apoptosis, invasion and migration are targeted by each protein.


Targeting the hsp70 gene delays mammary tumor initiation and inhibits tumor cell metastasis.
Elevated levels of the inducible heat-shock protein 70 (Hsp72) have been implicated in mammary tumorigenesis in histological investigations of human breast cancer. We therefore examined the role of Hsp72 in mice, using animals in which the hsp70 gene was inactivated. We used a spontaneous tumor system with mice expressing the polyomavirus middle T (PyMT) oncogene under control of the mouse mammary tumor virus (MMTV) long-terminal repeat (MMT mice). These mice developed spontaneous, metastatic mammary cancer. We then showed Hsp72 to be upregulated in a fraction of mammary cancer initiating cells (CIC) within the MMT tumor cell population. These cells were characterized by elevated surface levels of stem cell markers CD44 and Sca1 and by rapid metastasis. Inactivation of the hsp70 gene delayed the initiation of mammary tumors. This delay in tumor initiation imposed by loss of hsp70 was correlated with a decreased pool of CIC. Interestingly, hsp70 knockout significantly reduced invasion and metastasis by mammary tumor cells and implicated its product Hsp72 in cell migration and formation of secondary neoplasms. Impaired tumorigenesis and metastasis in hsp70-knockout MMT mice was associated with downregulation of the met gene and reduced activition of the oncogenic c-Met protein. These experiments therefore showed Hsp72 to be involved in the growth and progression of mammary carcinoma and highlighted this protein as a potential target for anticancer drug development.


Traditional and complementary medicine used with curative intent in childhood cancer: A systematic review.
Traditional and complementary medicine (T&CM) strategies are widely utilized in pediatric oncology, with many families reporting T&CM use with the intention to cure cancer. Study of T&CM agents presents many challenges, as a heterogeneous group of agents and techniques are used for a variety of different purpose in many different oncologic conditions. We present a systematic review of the literature examining published reports in which T&CM agents are used with an intention of cure. Twenty-two reports were identified, with most reports being of poor quality. Novel paradigms are likely needed to further investigate T&CM agents.


Walking faster and farther with a soft robotic exosuit: Implications for post-stroke gait assistance and rehabilitation.
Soft robotic exosuits can improve the mechanics and energetics of walking after stroke. Building on this prior work, we evaluated the effects of the first prototype of a portable soft robotic exosuit. Exosuit-induced changes in the overground walking speed, distance, and energy expenditure of individuals post-stroke were evaluated statistically with alpha set to 0.05 and compared to minimal clinically important difference scores. Compared to baseline walking without the exosuit worn, the <5kg exosuit did not substantially modify walking speed, distance, or energy expenditure when worn unpowered. In contrast, when the exosuit was powered on to provide an average 22.87±0.58 %bodyweight of plantarflexor force assistance during the paretic limb's stance phase and assist the paretic dorsiflexors during swing phase to reduce drop-foot, study participants walked a median 0.14±0.06 m/s faster during the 10-meter walk test and traveled 32±8 m farther during the six minute walk test. Individuals post-stroke can leverage the paretic plantarflexor and dorsiflexor assistance provided by soft robotic exosuits to achieve clinically-meaningful increases in speed and distance.


Dissecting the impact of chemotherapy on the human hair follicle: a pragmatic in vitro assay for studying the pathogenesis and potential management of hair follicle dystrophy.
Chemotherapy-induced alopecia represents one of the major unresolved problems of clinical oncology. The underlying molecular pathogenesis in humans is virtually unknown because of the lack of adequate research models. Therefore, we have explored whether microdissected, organ-cultured, human scalp hair follicles (HFs) in anagen VI can be exploited for dissecting and manipulating the impact of chemotherapy on human HFs. Here, we show that these organ-cultured HFs respond to a key cyclophosphamide metabolite, 4-hydroperoxycyclophosphamide (4-HC), in a manner that resembles chemotherapy-induced HF dystrophy as it occurs in vivo: namely, 4-HC induced melanin clumping and melanin incontinence, down-regulated keratinocyte proliferation, massively up-regulated apoptosis of hair matrix keratinocytes, prematurely induced catagen, and up-regulated p53. In addition, 4-HC induced DNA oxidation and the mitochondrial DNA common deletion. The organ culture system facilitated the identification of new molecular targets for chemotherapy-induced HF damage by microarray technology (eg, interleukin-8, fibroblast growth factor-18, and glypican 6). It was also used to explore candidate chemotherapy protectants, for which we used the cytoprotective cytokine keratinocyte growth factor as exemplary pilot agent. Thus, this novel system serves as a powerful yet pragmatic tool for dissecting and manipulating the impact of chemotherapy on the human HF.


Prospective validation of ELF test in comparison with Fibroscan and FibroTest to predict liver fibrosis in Asian subjects with chronic hepatitis B.
Liver stiffness measurement (LSM) and FibroTest (FT) are frequently used as non-invasive alternatives for fibrosis staging to liver biopsy. However, to date, diagnostic performances of Enhanced Liver Fibrosis (ELF) test, which consists of hyaluronic acid, aminoterminal propeptide of procollagen type-III, and tissue inhibitor of matrix metalloproteinases-1, have not been compared to those of LSM and FT in Asian chronic hepatitis B (CHB) patients. Between June 2010 and November 2011, we prospectively enrolled 170 CHB patients who underwent liver biopsies along with LSM, FT, and ELF. The Batts system was used to assess fibrosis stages. Areas under receiver operating characteristic curves (AUROCs) to predict significant fibrosis (F≥2), advanced fibrosis (F≥3), and cirrhosis (F = 4) were 0.901, 0.860, and 0.862 for ELF, respectively; 0.937, 0.956, and 0.963 for LSM; and 0.896, 0.921, and 0.881 for FT. AUROCs to predict F≥2 were similar between each other, whereas LSM and FT had better AUROCs than ELF for predicting F≥3 (both p<0.05), and LSM predicted F4 more accurately than ELF (p<0.05). Optimized cutoffs of ELF to maximize sum of sensitivity and specificity were 8.5, 9.4, and 10.1 for F≥2, F≥3, and F = 4, respectively. Using suggested ELF, LSM and FT cutoffs to diagnose F1, F2, F3, and F4, 91 (53.5%), 117 (68.8%), and 110 (64.7%) patients, respectively, were correctly classified according to histological results. ELF demonstrated considerable diagnostic value in fibrosis staging in Asian CHB patients, especially in predicting F≥2. However, LSM consistently provided better performance for predicting F≥3 and F4.


What have NHS managers ever done for us?
The image of the UK National Health Service manager has not always been positive. Like others in the public sector, NHS managers are sometimes associated in the media with waste and inefficiency, in contrast to those in 'front line roles'. Thus healthcare professionals and members of the public might ask, in the tradition of Monty Python's Life of Brian, what NHS managers have ever done for us. In this short article, we outline some of the evidence from the literature on attitudes to, and role of, healthcare managers, before drawing on our own interview and observation based fieldwork with managers themselves. We argue that the role of the healthcare manager is not always well understood, and that in a sector facing ever more intense and large scale organisational challenges, managers should be seen as important partners in a health service focused on clinical outcomes.


On-bead tryptic proteolysis: an attractive procedure for LC-MS/MS analysis of the Drosophila caspase 8 protein complex during immune response against bacteria.
This study aims to characterize the immune response against bacteria in Drosophila melanogaster. Obtaining a description of the in vivo state of protein complexes requires their isolation as a snapshot of physiological conditions before their identification. Affinity purification with streptavidin-biotin system is widely used to address this issue. However, because of the extraordinary stability of the interaction between streptavidin and biotin, the release of biotin-labeled bait remains a challenge. We transfected Drosophila cells with a DNA construct encoding a biotin-tagged Dredd protein (ortholog of caspase 8). After affinity purification, different strategies were evaluated, and proteins analyzed by LC-MS/MS mass spectrometry. The on-bead digestion allowed the identification of more proteins associated to the Dredd complex than different protocols using competitive or acid elution. A functional assay showed that a large part of the proteins specifically identified in the Dredd sample are functionally involved in the activation of the Imd pathway. These proteins are immune response proteins (BG4, Q9VP57), stress response proteins (HSP7C, Q9VXQ5), structural proteins (TBB1, CP190), a protein biosynthesis protein (Q9W1B9) and an antioxidant system protein (SODC). Our results clearly show that on-bead digestion of proteins is an attractive procedure for the study of protein complexes by mass spectrometry. This article is part of a Special Issue entitled: Translational Proteomics.


Imaging-Concordant Benign MRI-Guided Vacuum-Assisted Breast Biopsy May Not Warrant MRI Follow-Up.
The follow-up of breast lesions with imaging-concordant benign histopathology results on MRI-guided vacuum-assisted biopsy (VAB) is not currently standardized. We determined the false omission rate of breast MRI-guided VAB with benign histopathology (negative results) to assess whether breast MRI follow-up is needed. The medical records of patients who underwent 9-gauge breast MRI-guided VAB during 2007-2012 were reviewed retrospectively. Lesions with imaging-concordant benign histopathology results from MRI-guided VAB and surgery or 2 years or more of imaging follow-up were included. The false omission rate (1 - negative predictive value; [number of false-negative results / number of negative results]) of MRI-guided VAB was calculated. One hundred sixty-nine lesions were included, and 135 had only imaging follow-up (mammography follow-up: range, 17-107 months [median, 52 months]; MRI follow-up: range, 5-95 months [median, 35 months]). Of the 135 lesions with only imaging follow-up, 48 had mammography only (range, 26-86 months; median, 52 months), and 87 had mammography (range, 17-107 months; median, 52 months) and MRI (range, 5-95 months; median, 35 months). Thirty-four lesions had surgical correlation, and there were no cases of imaging-surgical discordance. Four malignancies were later diagnosed in the same breast in which MRI-guided VAB had been performed. One (0.6%) malignancy was invasive ductal carcinoma at 1 cm from the MRI-guided VAB site; it was mammographically detected 24 months after MRI-guided VAB. The other three malignancies developed 4 cm or more from the site of MRI-guided VAB: one ductal carcinoma in situ (DCIS) detected on mammography 12 months after MRI-guided VAB, one DCIS detected on MRI 24 months after MRI-guided VAB, and one Paget disease lesion detected at physical examination 32 months after MRI-guided VAB. Breast MRI-guided VAB has a low false omission rate. MRI follow-up of lesions with concordant benign MRI-guided VAB histopathology results may not be warranted.


Highly cited works in neurosurgery. Part I: the 100 top-cited papers in neurosurgical journals.
The number of citations a published article receives is a measure of its impact in the scientific community. This study identifies and characterizes the current 100 top-cited articles in journals specifically dedicated to neurosurgery. Neurosurgical journals were identified using the Institute for Scientific Information Journal Citation Reports. A search was performed using Institute for Scientific Information Web of Science for articles appearing in each of these journals. The 100 top-cited articles were selected and analyzed. The 100 most cited manuscripts in neurosurgical journals appeared in 3 of 13 journals dedicated to neurosurgery. These included 79 in the Journal of Neurosurgery, 11 in the Journal of Neurology, Neurosurgery and Psychiatry, and 10 in Neurosurgery. The individual citation counts for these articles ranged from 287 to 1515. Seventy-seven percent of articles were published between 1976 and 1995. Representation varied widely across neurosurgical disciplines, with cerebrovascular diseases leading (43 articles), followed by trauma (27 articles), stereotactic and functional neurosurgery (13 articles), and neurooncology (12 articles). The study types included 5 randomized trials, 5 cooperative studies, 1 observational cohort study, 69 case series, 8 review articles, and 12 animal studies. Thirty articles dealt with surgical management and 12 with nonsurgical management. There were 15 studies of natural history of disease or outcomes after trauma, 11 classification or grading scales, and 10 studies of human pathophysiology. The most cited articles in neurosurgical journals are trials evaluating surgical or medical therapies, descriptions of novel techniques, or systems for classifying or grading disease. The time of publication, field of study, nature of the work, and the journal in which the work appears are possible determinants of the likelihood of citation and impact.


Development and evaluation of smoke-free or tobacco-free policies in university settings: a systematic scoping review.
We conducted a systematic scoping review to map the available evidence on smoke-free or tobacco-free (SF/TF) university policies globally. We specifically looked at (i) how policies were developed and communicated and (ii) what indicators were used to evaluate their impact. We searched for peer-reviewed literature, published up to January 2020, across 10 multi-disciplinary databases. We followed a duplicate, independent data selection, and charting process. We inductively categorized the studies according to the research design and objective of 'process' and 'impact evaluation'. We identified 75 unique studies across 23 countries conducted between 1993 and 2019. Most studies were conducted in the United States (46/75, 61.3%), were based on quantitative research design and focused on impact evaluations; a third (n = 28) reported both process and impact evaluations (37.3%). Community engagement and multi-channel communication strategies were mostly used to disseminate SF/TF policies. The impact was determined by a wide range of indicators for knowledge, attitudes and behaviors related to policies. There is a mature, relevant body of literature describing the development and evaluation of SF/TF policies in universities. Future reviews could quantify the impact of the bans and may consider process indicators as moderating factors to explain the potential heterogeneity of results.


Influenza A virus neuraminidase enhances meningococcal adhesion to epithelial cells through interaction with sialic acid-containing meningococcal capsules.
The underlying mechanisms of the epidemiological association between influenza virus infections and Neisseria meningitidis invasive infections are not fully understood. Here we report that adhesion of N. meningitidis to human Hec-1-B epithelial cells is enhanced by influenza A virus (IAV) infection. A potential role of the viral neuraminidase (NA) in facilitating meningococcal adhesion to influenza virus-infected epithelial cells was examined. Expression of a recombinant IAV NA in Hec-1-B human epithelial cells increased the adhesion of strains of N. meningitidis belonging to the sialic acid-containing capsular serogroups B, C, and W135 but not to the mannosamine phosphate-containing capsular serogroup A. Adhesion enhancement was not observed with an inactive NA mutant or in the presence of an NA inhibitor (zanamivir). Furthermore, purified IAV NA was shown to cleave sialic acid-containing capsular polysaccharides of N. meningitidis. On the whole, our findings suggest that a direct interaction between the NA of IAV and the capsule of N. meningitidis enhances bacterial adhesion to cultured epithelial cells, most likely through cleavage of capsular sialic acid-containing polysaccharides. A better understanding of the association between IAV and invasive meningococcal infections should help to set up improved control strategies against these seasonal dual viral-bacterial infections.


Measurement of Accumulation of Antibiotics to Staphylococcus aureus in Phagosomes of Live Macrophages.
Staphylococcus aureus ( S. aureus ) has evolved the ability to persist after uptake into host immune cells. This intracellular niche enables S. aureus to potentially escape host immune responses and survive the lethal actions of antibiotics. While the elevated tolerance of S. aureus to small-molecule antibiotics is likely to be multifactorial, we pose that there may be contributions related to permeation of antibiotics into phagocytic vacuoles, which would require translocation across two mammalian bilayers. To empirically test this, we adapted our recently developed permeability assay to determine the accumulation of FDA-approved antibiotics into phagocytic vacuoles of live macrophages. Bioorthogonal reactive handles were metabolically anchored within the surface of S. aureus, and complementary tags were chemically added to antibiotics. Following phagocytosis of tagged S. aureus cells, we were able to specifically analyze the arrival of antibiotics within the phagosomes of infected macrophages. Our findings enabled the determination of permeability differences between extra- and intracellular S. aureus , thus providing a roadmap to dissect the contribution of antibiotic permeability to intracellular pathogens.


Legionellosis associated with ships: 1977 to 1997.
Over one hundred cases of legionnaires' disease have been linked to ships, and ten cases are known to have died. Most of the cases were associated with cruise ships, but a variety of other vessels were also linked to cases. Few vessels were investigated microbiologically, and the cases associated with ferries were exposed to other sources of infection. Cases appear to be less common among crew members than among passengers. To prevent further cases, ship owners, operators, and captains need to be diligent in maintaining the water and air conditioning systems of their vessels. Whirlpool spas need particular care. Ship-associated cases of non-pneumonic legionellosis appear to be rare.


Two-Photon Fluorescence Microscopy for Determination of the Riboflavin Concentration in the Anterior Corneal Stroma When Using the Dresden Protocol.
To determine the riboflavin concentration gradient in the anterior corneal stroma when using the Dresden protocol with different dextran solutions. Three different groups of porcine corneas, five each, were compared regarding the riboflavin concentration in the anterior stroma. Before all experiments, stable hydration conditions were established for the corresponding solution. All groups were treated with 0.1% riboflavin in different dextran solutions (15%, 16%, 20%). After imbibition, two-photon microscopy was used to determine fluorescence intensity. For signal attenuation and concentration determination corneas were saturated and measured a second time by two-photon microscopy. Additionally, the distribution was calculated mathematically and compared to the empiric results. Riboflavin concentration is decreasing with depth for all dextran solutions. A nearly constant concentration could be determined over the first 75 μm. Analysis of the fit functions leads to diffusion coefficients of D = 2.97 × 10-7 cm2/s for the 15% dextran solution, D = 2.34 × 10-7 cm2/s for the 16% dextran solution, and D = 1.28 × 10-7 cm2/s for the 20% dextran solution. The riboflavin gradients of the 20% dextran group were statistically significantly different from 15% dextran starting at a depth of 220 μm and deeper (P = 0.047). The 16% dextran group differed statistically at a depth of 250 μm and deeper (P = 0.047). These results show a significant difference to those published previously. With correct settings two-photon microscopy is a precise way to determine the concentration of riboflavin in cornea. The measured gradient is excellently fit by a Gaussian distribution, which comes out as a solution of Fick's second law.


Corticotropin-releasing factor in the rat amygdala differentially influences sensory-discriminative and emotional-like pain response in peripheral neuropathy.
The central nucleus of the amygdala (CeA) is involved in processing and regulation of pain. We determined whether amygdaloid corticotropin-releasing factor (CRF) contributes to pain modulation in the neuropathic rat. Emotional aspect of pain was assessed by an aversive place-conditioning test and sensory aspect of pain by determining monofilament-induced limb-withdrawal threshold. CRF₆₋₃₃ (an inhibitor of CRF-binding protein) or CRF₉₋₄₁, a nonselective CRF receptor antagonist, was microinjected to the left or right CeA or a control site in rats with spared nerve injury (SNI) or sham operation of the left hind limb. In SNI animals, CRF₆₋₃₃ in the left or right CeA, but not in a control site, attenuated emotional painlike behavior and increased sensory pain. In sham controls, CRF₆₋₃₃ in the right but not left CeA increased sensory aspect of pain, without influence on place-avoidance behavior. The effects induced by CRF₆₋₃₃ were reversed by CRF₉₋₄₁. The results indicate that endogenous CRF in the CeA, through action on CRF receptors, may differentially influence emotional and sensory aspects of pain in neuropathy. While the right CeA had a dominant role in modulation of pain-related responses in sham controls, left as well as right CeA contributed to pain modulation in neuropathic animals. An increase in free endogenous corticotropin-releasing factor in the central nucleus of the amygdala was accompanied by increased cutaneous hypersensitivity and decreased emotional painlike behavior in neuropathic animals. This finding indicates that CRF in the amygdala may have differential effects on sensory and emotional aspects of neuropathic pain.


Imaging Biomarkers as Predictors for Breast Cancer Death.
To differentiate the risk of breast cancer death in a longitudinal cohort using imaging biomarkers of tumor extent and biology, specifically, the mammographic appearance, basal phenotype, histologic tumor distribution, and conventional tumor attributes. Using a prospective cohort study design, 498 invasive breast cancer patients diagnosed between 1996 and 1998 were used as the test cohort to assess the independent effects of the imaging biomarkers and other predictors on the risk of breast cancer death. External validation was performed with a cohort of 848 patients diagnosed between 2006 and 2010. Mammographic tumor appearance was an independent predictor of risk of breast cancer death (P=0.0003) when conventional tumor attributes and treatment modalities were controlled. The casting type calcifications and architectural distortion were associated with 3.13-fold and 3.19-fold risks of breast cancer death, respectively. The basal phenotype independently conferred a 2.68-fold risk compared with nonbasal phenotype. The observed deaths did not differ significantly from expected deaths in the validation cohort. The application of imaging biomarkers together with other predictors classified twelve categories of risk for breast cancer death. Combining imaging biomarkers such as the mammographic appearance of the tumor with the histopathologic distribution and basal phenotype, accurately predicted long-term risk of breast cancer death. The information may be relevant for determining the need for molecular testing, planning treatment, and determining the most appropriate clinical surveillance schedule for breast cancer patients.


Real-Time Transferrin-Based PET Detects MYC-Positive Prostate Cancer.
Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether 68Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with 68Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether 68Ga-citrate can detect MYC-positive prostate cancer. Importantly, 68Ga-citrate detected human prostate cancer models in a MYC-dependent fashion. In patients with castration-resistant prostate cancer, analysis of cfDNA revealed that all patients with 68Ga-citrate avid tumors had a gain of at least one MYC copy number. Moreover, biopsy of two PET avid metastases showed molecular or histologic features characteristic of MYC hyperactivity. These data demonstrate that 68Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of 68Ga-citrate for tumors with hyperactive MYC.Implications: Noninvasive measurement of MYC activity with quantitative imaging modalities could substantially increase our understanding of the role of MYC signaling in clinical settings for which invasive techniques are challenging to implement or do not characterize the biology of all tumors in a patient. Moreover, measuring MYC activity noninvasively opens the opportunity to study changes in MYC signaling in patients under targeted therapeutic conditions thought to indirectly inhibit MYC. Mol Cancer Res; 15(9); 1221-9. ©2017 AACR.


Effects of ketamine on neurogenesis, extracellular matrix homeostasis and proliferation in hypoxia-exposed HT22 murine hippocampal neurons.
Ketamine is a widely used drug in pediatric anesthesia, and both neurotoxic and neuroprotective effects have been associated with its use. There are only a few studies to date which have examined the effects of ketamine on neurons under hypoxic conditions, which may lead to severe brain damage and poor neurocognitive outcomes in neonates. In the present study, the effects of ketamine on cellular pathways associated with neurogenesis, extracellular matrix homeostasis and proliferation were examined in vitro in hypoxia-exposed neurons. Differentiated HT22 murine hippocampal neurons were treated with 1, 10 and 20 µM ketamine and cultured under hypoxic or normoxic conditions for 24 h followed by quantitative PCR analysis of relevant candidate genes. Ketamine treatment did not exert any notable effects on the mRNA expression levels of markers of neurogenesis (neuronal growth factor and syndecan 1), extracellular matrix homeostasis (matrix-metalloproteinase 2 and 9, tenascin C and tenascin R) or proliferation markers (Ki67 and proliferating cell nuclear antigen) compared with the respective untreated controls. However, there was a tendency towards downregulation of multiple cellular markers under hypoxic conditions and simultaneous ketamine treatment. No dose-dependent association was found in the ketamine treated groups for genetic markers of neurogenesis, extracellular matrix homeostasis or proliferation. Based on the results, ketamine may have increased the vulnerability of hippocampal neurons in vitro to hypoxia, independent of the dose. The results of the present study contribute to the ongoing discussion on the safety concerns around ketamine use in pediatric clinical practice from a laboratory perspective.


Transcription factor achaete scute-like 2 controls intestinal stem cell fate.
The small intestinal epithelium is the most rapidly self-renewing tissue of mammals. Proliferative cells are confined to crypts, while differentiated cell types predominantly occupy the villi. We recently demonstrated the existence of a long-lived pool of cycling stem cells defined by Lgr5 expression and intermingled with post-mitotic Paneth cells at crypt bottoms. We have now determined a gene signature for these Lgr5 stem cells. One of the genes within this stem cell signature is the Wnt target Achaete scute-like 2 (Ascl2). Transgenic expression of the Ascl2 transcription factor throughout the intestinal epithelium induces crypt hyperplasia and ectopic crypts on villi. Induced deletion of the Ascl2 gene in adult small intestine leads to disappearance of the Lgr5 stem cells within days. The combined results from these gain- and loss-of-function experiments imply that Ascl2 controls intestinal stem cell fate.


Mechanisms and genes involved in enhancement of HIV infectivity by tobacco smoke.
HIV infection is more common among smokers than nonsmokers, and, remarkably, HIV-infected individuals are about 3 times more likely to smoke than the uninfected general population. However, the relationship between tobacco smoking and HIV/AIDS disease progression remains controversial. In this study, we demonstrate a potent enhancing effect of aqueous tobacco smoke extract (TSE) on HIV infectivity that is nicotine-independent. This increased infectivity is neither NF-κB mediated nor a direct result of oxidative stress, as it cannot be blocked by antioxidants. On the contrary, TSE itself was found to possess significant antioxidant potential, enabling it to protect the viability of both infected cells and HIV virions in the presence of peroxide. Assessment of TSE-induced alterations in cellular gene expression that may be involved in increasing HIV infectivity in T cells showed that TSE up-regulates some genes known to be capable of enhancing HIV and HCV infection, or protecting HIV, but down-regulates several genes involved in cellular defense and antigen presentation. These results demonstrate that tobacco smoke can enhance HIV infectivity, possibly by a combination of direct (antioxidant) and indirect (gene-based) mechanisms. This raises the concern that smoking may thereby increase the risk of acquisition or progression of HIV infection.


Stereoselective pH Responsive Peptide Dendrimers for siRNA Transfection.
Transfecting nucleic acids into cells is an essential procedure in biological research usually performed using nonviral transfection reagents. Unfortunately, most transfection reagents have polymeric or undisclosed structures and require nonstandard synthetic procedures. Herein we report peptide dendrimers accessible as pure products from standard building blocks by solid-phase peptide synthesis and acting as nontoxic single component siRNA transfection reagents for a variety of cell lines with equal or better performance than the gold standard lipofectamine L2000. Structure-activity relationships and mechanistic studies illuminate their transfection mechanism in unprecedented detail. Stereoselective dendrimer aggregation via intermolecular β-sheets at neutral pH enables siRNA complexation to form nanoparticles which enter cells by endocytosis. Endosome acidification triggers protonation of amino termini and rearrangement to an α-helical conformation forming smaller dendrimer/siRNA nanoparticles, which escape the endosome and release their siRNA cargo in the cytosol. Two particularly efficient d-enantiomeric dendrimers are proposed as new reference reagents for siRNA transfection.


B cells moderate inflammatory progression and enhance bacterial containment upon pulmonary challenge with Mycobacterium tuberculosis.
Though much is known about the function of T lymphocytes in the adaptive immune response against Mycobacterium tuberculosis, comparably little is understood regarding the corresponding role of B lymphocytes. Indicating B cells as components of lymphoid neogenesis during pulmonary tuberculosis, we have identified ectopic germinal centers (GCs) in the lungs of infected mice. B cells in these pulmonary lymphoid aggregates express peanut agglutinin and GL7, two markers of GC B cells, as well as CXCR5, and migrate in response to the lymphoid-associated chemokine CXCL13 ex vivo. CXCL13 is negatively regulated by the presence of B cells, as its production is elevated in lungs of B cell-deficient (B cell(-/-)) mice. Upon aerosol with 100 CFU of M. tuberculosis Erdman, B cell(-/-) mice have exacerbated immunopathology corresponding with elevated pulmonary recruitment of neutrophils. Infected B cell(-/-) mice show increased production of IL-10 in the lungs, whereas IFN-gamma, TNF-alpha, and IL-10R remain unchanged from wild type. B cell(-/-) mice have enhanced susceptibility to infection when aerogenically challenged with 300 CFU of M. tuberculosis corresponding with elevated bacterial burden in the lungs but not in the spleen or liver. Adoptive transfer of B cells complements the phenotypes of B cell(-/-) mice, confirming a role for B cells in both modulation of the host response and optimal containment of the tubercle bacillus. As components of ectopic GCs, moderators of inflammatory progression, and enhancers of local immunity against bacterial challenge, B cells may have a greater role in the host defense against M. tuberculosis than previously thought.


The impact of gaps in health insurance coverage on immunization status for young children.
To examine the impact of full-year versus intermittent public and private health insurance coverage on the immunization status of children aged 19-35 months. 2001 State and Local Area Integrated Telephone Survey's National Survey of Children with Special Health Care Needs (NS-CSHCN) and the 2000-2002 National Immunization Survey (NIS). Linked health insurance data from 2001 NS-CSHCN with verified immunization status from the 2000-2002 NIS for a nationally representative sample of 8,861 nonspecial health care needs children. Estimated adjusted rates of up-to-date (UTD) immunization status using multivariate logistic regressions for seven recommended immunizations and three series. Children with public full-year coverage were significantly more likely to be UTD for two series of recommended vaccines, (4:3:1:3) and (4:3:1:3:3), compared with children with private full-year coverage. For three out of 10 immunizations and series tested, children with private part-year coverage were significantly less likely to be UTD than children with private full-year coverage. Our findings raise concerns about access to needed immunizations for children with gaps in private health insurance coverage and challenge the prevailing belief that private health insurance represents the gold standard with regard to UTD status for young children.


Functional heartburn: clinical characteristics and outcome.
Patients with heartburn and normal upper gastrointestinal endoscopy, normal oesophageal acid exposure, no symptom-reflux association and who fail to respond to a proton-pump inhibitor are classified as having functional heartburn (FH). This study aimed (i) to characterize the symptoms and functional abnormalities of patients with FH and (ii) to describe their clinical outcome. Among all patients referred for 24 h multichannel intraluminal impedance-pH (MII-pH), patients with FH were identified. The clinical characteristics and high-resolution oesophageal pressure topography recordings of FH patients were analyzed at the time of the 24-h MII-pH test. A symptom-related and health-related quality-of-life questionnaire was then sent to FH patients to assess the long-term outcome. Forty patients fulfilled the criteria for FH, representing 8.5% of the referred population. Twenty-two months after initial testing, 66% of patients still suffered from heartburn. The rate of mixed reflux (liquid/gas) was higher in patients with persisting heartburn at the final evaluation (63 vs. 50%, P=0.04). Sixty-six per cent of patients had one or more manometric abnormalities. Acid clearance time in MII-pH was significantly higher in patients with weak peristalsis than patients with normal peristalsis (60 ± 45 vs. 31 ± 19 s, P=0.03). A high rate of mixed reflux and/or a manometric abnormality were associated with a higher risk of persistent heartburn. FH is a chronic disorder with persisting symptoms in two-thirds of patients. An increased rate of mixed reflux and/or the presence of manometric abnormalities are associated with a higher risk of persisting symptoms and may help to identify the population with unmet therapeutic needs.


Randomized trial of the effect of research design and publication characteristics on physician change.
The primary barrier to translation of research into practice relates to physician use of research. If we are to succeed at translating research into practice, we must understand to which research characteristics and publication formats practitioners attend. To determine which characteristics of research design (sample characteristics, study design) and publication (type of publication) are most influential on the acquisition of knowledge and change in behavior of family practitioners. This randomized clinical trial was conducted in family practice offices on the 305 family physicians who scored lowest on a survey of knowledge about management of major depressive disorder (MDD), panic disorder, and generalized anxiety disorder (GAD). Subjects were randomly assigned to receive 1 of 3 MDD abstracts differing in study site, 1 of 3 panic disorder abstracts differing in study design, and 1 of 3 GAD communications differing in format. The main outcome measures (knowledge and management strategies) were assessed immediately following the intervention and again 6 months later. Data for the intervention survey were gathered in November 2002. This study found significant increases in knowledge level and use of first-line agents with all interventions; however, knowledge declined again after 6 months for both panic disorder and GAD. The only statistically significant interoption difference was that the POEM (patient-oriented evidence that matters) was associated with better retention of knowledge of the treatment of GAD. In conclusion, all interventions were associated with immediate increases in knowledge and use of first-line treatments. However, such gains were not retained for panic disorder and GAD. Except for better knowledge retention associated with POEM use, no consistent differences between intervention options were noted.


Correlation between flow-mediated vasodilatation of the brachial artery and intima-media thickness in the carotid artery in men.
Endothelial dysfunction has been reported to be the initial step in atherosclerosis. A noninvasive technique that uses ultrasound to measure the intima-media thickness of the carotid artery has been applied to evaluate localized atherosclerosis. This study was undertaken to elucidate whether endothelial dysfunction in the brachial artery is related to the intima-media thickness of the carotid artery. Thirty-four men with atherosclerosis (mean+/-SE age 61+/-2 years) and 33 age-matched men without clinical atherosclerosis were examined. The intima-media thickness and plaque formation of the common carotid artery were assessed by B-mode ultrasonography. We also noninvasively measured brachial artery diameter by the same ultrasound machine when the subjects were at rest, during reactive hyperemia, which causes endothelium-dependent vasodilatation, and after sublingual administration of nitroglycerin, which causes endothelium-independent vasodilatation. The atherosclerosis group had a significantly greater intima-media thickness of the common carotid artery than did the control group (1. 02+/-0.04 versus 0.91+/-0.03 mm, P<0.05). The flow-mediated diameter (FMD) increase (percent FMD=DeltaD/D x 100) in the atherosclerosis group was significantly smaller than that in the control group (2. 8+/-0.4% versus 5.1+/-0.6%, P<0.01). A significant negative correlation between the intima-media thickness of the carotid artery and percent FMD was found in all of the subjects. On multiple regression analysis, percent FMD showed a significant negative correlation with the intima-media thickness of the common carotid artery. These findings support the concept that endothelial dysfunction is significantly related to atherogenesis.


Natal foraging philopatry in eastern Pacific hawksbill turtles.
The complex processes involved with animal migration have long been a subject of biological interest, and broad-scale movement patterns of many marine turtle populations still remain unresolved. While it is widely accepted that once marine turtles reach sexual maturity they home to natal areas for nesting or reproduction, the role of philopatry to natal areas during other life stages has received less scrutiny, despite widespread evidence across the taxa. Here we report on genetic research that indicates that juvenile hawksbill turtles (Eretmochelys imbricata) in the eastern Pacific Ocean use foraging grounds in the region of their natal beaches, a pattern we term natal foraging philopatry. Our findings confirm that traditional views of natal homing solely for reproduction are incomplete and that many marine turtle species exhibit philopatry to natal areas to forage. Our results have important implications for life-history research and conservation of marine turtles and may extend to other wide-ranging marine vertebrates that demonstrate natal philopatry.


Smoking is associated with progressive disease course and increased progression in clinical disability in a prospective cohort of people with multiple sclerosis.
Multiple sclerosis has a variable disease course. The contribution of modifiable lifestyle factors to disease course has not been well studied, although one cohort has reported that smoking is associated with conversion to secondary progressive MS course and another that smoking is not. We conducted a prospective cohort study of people with MS in Southern Tasmania from 2002 to 2004 with 78% (203/259) of eligible participating and 198 with one or more reviews and confirmed MS. The cohort had a high retention rate (90% (183/203)). The median follow-up time was 909 days. Smoking data were collected at baseline and six-monthly reviews. Clinical disability assessments were conducted annually in conjunction with a real time clinical notification system for relapses. A repeated measures analysis and other statistical methods were used. Cumulative pack-years (p-y) smoked after cohort entry was associated with an increase in longitudinal MSSS (p < 0.001). Relative to the 0 pack years (p-y) category (in the year prior to the MSSS measure) those in the 0 to 1 p-y category had an adjusted mean difference in MSSS of 0.34 (95% CI 0.28, 0.66); those in the 1 to 2 p-y category had a 0.41 (95% CI -0.03, 0.85) increase; and those in the 2 or more p-y category had a 0.99 (95% CI 0.41, 1.58) increase in MSSS. Similar results were found using a variety of statistical approaches or EDSS as a clinical outcome. Smoking during the cohort period was not associated with relapse (cumulative pack years smoked after cohort entry, HR 0.94 (0.69, 1.26) per pack year). A better understanding of the mechanisms underlying smoking and multiple sclerosis, particularly progressive forms of the disease, may provide new insights for the eventual goal of better treatment and prevention of multiple sclerosis.


Cost-effectiveness of translocation options for a threatened waterbird.
Reintroduction of captive-reared animals has become increasingly popular in recent decades as a conservation technique, but little is known of how demographic factors affect the success of reintroductions. We believe whether the increase in population persistence associated with reintroduction is sufficient to warrant the cost of rearing and relocating individuals should be considered as well. We examined the trade-off between population persistence and financial cost of a reintroduction program for Crested Coots (Fulica cristata). This species was nearly extirpated from southern Europe due to unsustainable levels of hunting and reduction in amount and quality of habitat. We used a stochastic, stage-based, single-sex, metapopulation model with site-specific parameters to examine the demographic effects of releasing juveniles or adults in each population for a range of durations. We parameterized the model with data from an unsuccessful reintroduction program in which juvenile captive-bred Crested Coots were released between 2000 and 2009. Using economic data from the captive-breeding program, we also determined whether the strategy that maximized abundance coincided with the least expensive strategy. Releasing adults resulted in slightly larger final abundance than the release of nonreproductive juveniles. Both strategies were equally poor in achieving a viable metapopulation, but releasing adults was 2-4 times more expensive than releasing juveniles. To obtain a metapopulation that would be viable for 30 years, fecundity in the wild would need to increase to the values observed in captivity and juvenile survival would need to increase to almost unity. We suggest that the most likely way to increase these vital rates is by increasing habitat quality at release sites.


The neuroethology of acoustic startle and escape in flying insects.
The acoustic startle/escape response is a phylogenetically widespread behavioral act, provoked by an intense, unexpected sound. At least six orders of insects have evolved tympanate ears that serve acoustic behavior that ranges from sexual communication to predator detection. Insects that fly at night are vulnerable to predation by insectivorous bats that detect and locate their prey by using biosonar signals. Of the six orders of insects that possess tympanate hearing organs, four contain species that fly at night and, in these, hearing is sensitive to a range of ultrasonic frequencies found in the biosonar signals of bats. Laboratory and field studies have shown that these insects (including some orthopterans, lepidopterans, neuropterans and dictyopterans), when engaged in flight behavior, respond to ultrasound by suddenly altering their flight, showing acoustic startle or negative phonotaxis, which serve as bat-avoidance behavior. A neural analysis of ultrasound-mediated escape behavior was undertaken in the field cricket Telegryllus oceanicus. An identified thoracic interneuron, int-1, was shown to trigger the escape response, but only when the cell was driven (synaptically or electrically) at high spike rates, and only when the insect was performing flight behavior; avoidance steering only occurs in the appropriate behavioral context: flight. Thus, significant constraints operate upon the ability of int-1 to trigger the escape response. The integration of auditory input and flight central pattern generator output occurs in the brain. It is found that neural activity descending from the brain in response to stimulation by ultrasound is increased when the insect is flying compared to when it is not. Although the behavioral act of avoidance steering may appear to be a simple reflex act, further analysis shows it to be anything but simple.


Infiltration between the popliteal artery and the capsule of the knee (IPACK) block in knee surgery: a narrative review.
The infiltration between the popliteal artery and the capsule of the knee (IPACK) block has been described as an alternative analgesic strategy for knee pain. Our aim was to perform a narrative review to examine the place and value that the IPACK block has in comparison to and in conjunction with other regional anesthesia modalities. Following an extensive search of electronic databases, we included anatomical studies, letters, comparative observational studies, and non-randomized and randomized controlled trials that examined the IPACK block in relation to surgery on the knee under general or neuraxial anesthesia. In all, 35 articles were included. Cadaveric studies demonstrated the potential for injected dye to spread to the nerves responsible for the innervation of the posterior as well as anteromedial and anterolateral aspects of the knee. Of the comparative observational studies (n=15) and non-randomized (n=1) and randomized controlled trials (n=13), 2 and 27 were conducted in the context of anterior cruciate ligament reconstruction and knee replacement surgery, respectively. The role of the IPACK block with each different permutation of regional anesthesia techniques was investigated by a small number of studies. Clinical studies, in the setting of knee replacement surgery, revealed variation in the manner in which the IPACK block was performed, and indicated the possible superiority of distal injection at the level of the femoral condyles for the management of posterior knee pain. Evidence suggested the following: the IPACK block in combination with single shot adductor canal block (ACB) may be beneficial for analgesic and functional outcomes; in conjunction with single shot or continuous ACB, the IPACK block might be superior to local infiltration analgesia (LIA); and functional outcomes may be improved with the supplementation of continuous ACB and LIA with the IPACK block. The IPACK block did not commonly result in the occurrence of foot drop. Relative to tibial nerve block (TNB), the IPACK block reduced the occurrence of foot drop and increased the proportion of patients who were able to be discharged on the third postoperative day. The IPACK block was potentially complementary to the ACB and might be preferable to the TNB as a motor-sparing regional anesthesia technique in knee surgery. Definitive recommendations were not reached in the presence of the heterogeneous and limited evidence base.


Tumour-specific HMG-CoAR is an independent predictor of recurrence free survival in epithelial ovarian cancer.
Our group previously reported that tumour-specific expression of the rate-limiting enzyme in the mevalonate pathway, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) is associated with more favourable tumour parameters and a good prognosis in breast cancer. In the present study, the prognostic value of HMG-CoAR expression was examined in tumours from a cohort of patients with primary epithelial ovarian cancer. HMG-CoAR expression was assessed using immunohistochemistry (IHC) on tissue microarrays (TMA) consisting of 76 ovarian cancer cases, analysed using automated algorithms to develop a quantitative scoring model. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the risk of recurrence free survival (RFS). Seventy-two tumours were suitable for analysis. Cytoplasmic HMG-CoAR expression was present in 65% (n = 46) of tumours. No relationship was seen between HMG-CoAR and age, histological subtype, grade, disease stage, estrogen receptor or Ki-67 status. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS (p = 0.012). Multivariate Cox regression analysis revealed that HMG-CoAR expression was an independent predictor of improved RFS (RR = 0.49, 95% CI (0.25-0.93); p = 0.03) when adjusted for established prognostic factors such as residual disease, tumour stage and grade. HMG-CoAR expression is an independent predictor of prolonged RFS in primary ovarian cancer. As HMG-CoAR inhibitors, also known as statins, have demonstrated anti-neoplastic effects in vitro, further studies are required to evaluate HMG-CoAR expression as a surrogate marker of response to statin treatment, especially in conjunction with current chemotherapeutic regimens.


Preferences of healthy men for two different endocrine treatment options offered for locally advanced prostate cancer.
The aim of this study was to determine whether healthy men would prefer either luteinizing hormone releasing hormone analogues (LHRHa) or non-steroidal anti-androgen therapy (NSAA) should they hypothetically develop locally advanced prostate cancer. A representative sample of 180 men without prostate cancer (68% over 65 years of age, range 50-90 years), read two scenarios describing LHRHa or NSAA treatments for locally advanced prostate cancer. Participants chose which drug treatment they hypothetically would prefer, gave a reason for their choice and indicated the degree to which they wanted to avoid side effects specific to each drug. Eighty-six per cent (156/180) of the men chose NSAA therapy, 7% (12/180) chose LHRHa therapy and 7% (12/180) could not decide. The main reason men chose LHRHa therapy was because of the method of administration (9/12) whereas those who chose NSAA therapy cited avoidance of the side effects associated with LHRHa treatment (115/156). The side effects, ranked in order of importance, that men who chose NSAA therapy most wanted to avoid included risk of potential fractures (85%), reduced physical strength (76%), decreased sexual interest (56%), impotence (51%), hot flushes (49%), breast enlargement (17%) and breast tenderness (13%). Although this project was a hypothetical study, several important issues emerged from the data that are relevant to patient choice. Men should be fully informed about the side-effect profiles of different endocrine treatments, involved in decision making and allowed to choose therapies less likely to cause side effects they would prefer to avoid.


Developing a model to estimate the potential impact of municipal investment on city health.
This article summarizes a process which exemplifies the potential impact of municipal investment on the burden of cardiovascular disease (CVD) in city populations. We report on Developing an evidence-based approach to city public health planning and investment in Europe (DECiPHEr), a project part funded by the European Union. It had twin objectives: first, to develop and validate a vocational educational training package for policy makers and political decision takers; second, to use this opportunity to iterate a robust and user-friendly investment tool for maximizing the public health impact of 'mainstream' municipal policies, programs and investments. There were seven stages in the development process shared by an academic team from Sheffield Hallam University and partners from four cities drawn from the WHO European Healthy Cities Network. There were five iterations of the model resulting from this process. The initial focus was CVD as the biggest cause of death and disability in Europe. Our original prototype 'cost offset' model was confined to proximal determinants of CVD, utilizing modified 'Framingham' equations to estimate the impact of population level cardiovascular risk factor reduction on future demand for acute hospital admissions. The DECiPHEr iterations first extended the scope of the model to distal determinants and then focused progressively on practical interventions. Six key domains of local influence on population health were introduced into the model by the development process: education, housing, environment, public health, economy and security. Deploying a realist synthesis methodology, the model then connected distal with proximal determinants of CVD. Existing scientific evidence and cities' experiential knowledge were 'plugged-in' or 'triangulated' to elaborate the causal pathways from domain interventions to public health impacts. A key product is an enhanced version of the cost offset model, named Sheffield Health Effectiveness Framework Tool, incorporating both proximal and distal determinants in estimating the cost benefits of domain interventions. A key message is that the insights of the policy community are essential in developing and then utilising such a predictive tool.


Oxytocin and the biopsychology of performance in team sports.
Little is known about the biopsychological underpinnings of expert performance in team sports. In this paper we show that there is a vast support for oxytocin as a neuropeptide involved in the encouragement of important processes linked to greater team performance in sport. We argue that oxytocin is related to biopsychological processes aimed at convergence of emotions and moods between people, and in doing so it is a critical neuropeptide involved in the shaping of important team processes in sport such as trust, generosity, altruism, cohesion, cooperation, and social motivation, and also envy and gloating. Future research should examine the role of oxytocin in these essential components of sport performance. In particular, the link between oxytocin, emotional contagion and the cultivation of experiences of positive emotions is a worthwhile line of investigation for sport participation and development as well as high performance in sport.


Measuring nanoparticle size using optical surface profilers.
Optical surface profilers are state-of-the-art instruments for measuring surface height profiles. They are not conventionally applied to nanoparticle measurements due to the presence of diffraction artifacts. Here we use a theoretical model based on wave-optics to account for diffraction-based artifacts in optical surface profilers. This then enables accurate measurement of nanoparticles size of a known geometry. The model is developed for both phase shifting interferometry and vertical scanning interferometry modes of operation. It is demonstrated that nanosphere radii as small as 12 nm, and nano-cylinder radii as small as 10-15 nm can be measured from a standard profile measurement using phase shifted interferometry interpreted using the wave-optics approach.


Teaching communication with ethnic minority patients: ten recommendations.
Culturally competent communication is indispensable for medical practice in an ethnically diverse society. This article offers recommendations to teach such communication skills based on the experiences of members of a Dutch NMVO Special Interest Group on 'Diversity'. A questionnaire with three open-ended questions on recommendations for training in culturally competent communication was sent to all members (n = 35). Returned questionnaires (n = 23) were analysed qualitatively with a thematic coding framework based on educational themes emerging from the data. All students need to be educated in culturally competent communication. Teachers should stimulate awareness of personal biases and an open attitude. Teach the three core communication skills, listening, exploring and checking, and offer practice with a professional interpreter. Knowledge content should focus on mechanisms relevant to various ethnic groups. Offer students a variety of experiences in a safe environment. All involved should be aware that stereotyping is a pitfall. Training in communication skills for consultation with ethnic minority patients cannot be separated from teaching issues of awareness and knowledge. The shared views on the content of these communication trainings are in line with general patient-centred approaches. The development of proper training in this field demands specific efforts of those involved.


Potential Curative Role of Hypericum Perforatum in an Experimental Rat Model of Tympanic Membrane Perforation.
Our aim was to investigate the curative role of topical Hypericum perforatum (HP) in a rat model of tympanic membrane perforation in a histopathological manner. This study was conducted on 30 female Sprague-Dawley rats. An HP extract was prepared as a suspension in pure olive oil. In all rats, the right and left tympanic membranes were perforated by a fine puncture under a microscope. Rats were randomly assigned to three groups. The HP extract was given as drops on a daily basis in Group 1, while olive oil alone was given on a daily basis in Group 2. In Group 3, the rats were allowed spontaneous recovery without any intervention. Three rats from each group were sacrificed on days 7, 14, and 21. Temporal bullae were removed for histopathological examination to evaluate fibroblast proliferation, leukocyte infiltration, neovascularization, and subepithelial thickness and to compare these among the groups. In histopathological examination of the rats from each group on days 7, 14, and 21, there were significant differences in leukocyte infiltration, fibroblast proliferation, and subepithelial thickness. No significant difference was observed in neovascularization among the groups. Compared with the spontaneous recovery group, HP was found to be more effective in a wound-healing model of the tympanic membrane. HP may be applied in clinical practice if it is shown to be safe with regard to ototoxicity.


Functional study of hepatitis delta virus large antigen in packaging and replication inhibition: role of the amino-terminal leucine zipper.
The large hepatitis delta antigen (HDAg) has been found to be essential for the assembly of the hepatitis delta virion. Furthermore, in a cotransfection experiment, the large HDAg itself, without the hepatitis delta virus (HDV) genome and small HDAg, could be packaged into hepatitis B surface antigen (HBsAg) particles. By deletion analysis, it was shown that the amino-terminal leucine zipper domain was dispensable for packaging. The large HDAg could also help in copackaging of the small HDAg into HBsAg particles without the need for HDV RNA. This process was probably mediated through direct interaction of the two HDAgs as a mutated large HDAg whose leucine zipper domain was deleted such that it could not help in copackaging of the small HDAg. This mutated large HDAg did not suppress HDV replication, suggesting that this effect is probably also via protein interaction. These results indicated that functional domains of the large HDAg responsible for packaging with HBsAg particles and for the trans-negative effect on HDV replication can be separated.


Evaluation of Aerosol Delivery of Nanosuspension for Pre-clinical Pulmonary Drug Delivery.
Asthma and chronic obstructive pulmonary disease (COPD) are pulmonary diseases that are characterized by inflammatory cell infiltration, cytokine production, and airway hyper-reactivity. Most of the effector cells responsible for these pathologies reside in the lungs. One of the most direct ways to deliver drugs to the target cells is via the trachea. In a pre-clinical setting, this can be achieved via intratracheal (IT), intranasal (IN), or aerosol delivery in the desired animal model. In this study, we pioneered the aerosol delivery of a nanosuspension formulation in a rodent model. The efficiency of different dosing techniques and formulations to target the lungs were compared, and fluticasone was used as the model compound. For the aerosol particle size determination, a ten-stage cascade impactor was used. The mass median aerodynamic diameter (MMAD) was calculated based on the percent cumulative accumulation at each stage. Formulations with different particle size of fluticasone were made for evaluation. The compatibility of regular fluticasone suspension and nanosuspension for aerosol delivery was also investigated. The in vivo studies were conducted on mice with optimized setting. It was found that the aerosol delivery of fluticasone with nanosuspension was as efficient as intranasal (IN) dosing, and was able to achieve dose dependent lung deposition.


The effect of intravenous amino acids on plasma amino acid concentration during total parenteral nutrition in infants with necrotizing enterocolitis.
Plasma aminograms of infants receiving total parenteral nutrition as part of the treatment for necrotizing enterocolitis were studied. Their ages varied from 2 to 60 days and their mean birth mass was 1 621 g (range 760-2 550 g). The intravenous administration of amino acids produced changes in plasma amino acid levels corresponding to the concentration of individual amino acid levels in the solution employed: higher levels of amino acids in the infusate produced increased plasma levels, whereas low plasma levels were obtained for amino acids not present or present in small amounts according to the solution used. The infants did not appear to suffer in any way, but the long-term effects still have to be evaluated. Pending further knowledge in this regard it is suggested that plasma amino acid levels should be maintained as near to normal values as possible. This could probably be achieved by the use of amino acid solutions specially formulated according to the amino acid profile of breast milk or the plasma amino acid profile of normal infants.


Metabolic Profiling in Formalin-Fixed and Paraffin-Embedded Prostate Cancer Tissues.
Metabolite profiling has significantly contributed to a deeper understanding of the biochemical metabolic networks and pathways in cancer cells. Metabolomics-based biomarker discovery would greatly benefit from the ability to interrogate retrospective annotated clinical specimens archived as formalin-fixed, paraffin-embedded (FFPE) material. Mass spectrometry-based metabolomic analysis was performed in matched frozen and FFPE human prostate cancers as well as isogenic prostate cancer cell lines. A total of 352 and 460 metabolites were profiled in human tissues and cell lines, respectively. Classes and physical-chemical characteristics of the metabolites preserved in FFPE material were characterized and related to their preservation or loss following fixation and embedding. Metabolite classes were differentially preserved in archival FFPE tissues, regardless of the age of the block, compared with matched frozen specimen, ranging from maximal preservation of fatty acids (78%) to loss of the majority of peptides and steroids. Generally, FFPE samples showed a decrease of metabolites with functional groups, such as carboxamide. As an adjunct technique, metabolic profiles were also obtained in situ from FFPE tissue sections where metabolites were extracted in a manner that preserves tissue architecture. Despite the fact that selected metabolites were not retained after processing, global metabolic profiles obtained from FFPE can be used to predict biologic states and study biologic pathways. These results pave the way for metabolomics-based biomarker discovery/validation utilizing retrospective and clinically annotated FFPE collections.Implications: Metabolic profiles can be performed in archival tissue and may be used to complement other profiling methods such as gene expression for biomarker discovery or pathway analysis in the assessment of biologic states. Mol Cancer Res; 15(4); 439-47. ©2017 AACR.


Whole-body live mouse imaging by hybrid reflection-mode ultrasound and optoacoustic tomography.
We present a hybrid preclinical imaging scanner that optimally supports image acquisition in both reflection-mode ultrasonography and optoacoustic (OA) tomography modes. The system comprises a quasi-full-ring tomographic geometry capable of the simultaneous dual-mode imaging through entire cross sections of mice with in-plane spatial resolution in the range of 150 and 350 μm in the respective OA and ultrasound (US) imaging modes with an imaging speed of up to 10 two-dimensional frames per second. Three-dimensional whole-body data is subsequently rendered by rapid scanning of the imaged plane. The system further incorporates rapid laser wavelength tuning for real-time acquisition of multispectral OA data, which enables studies of longitudinal dynamics as well as fast kinetics and biodistribution of contrast agents. In vivo imaging performance is demonstrated by label-free hybrid anatomical scans through living mice, as well as real-time visualization of optical contrast agent perfusion. By setting new standards for whole-body tomographic imaging performance in both the OA and pulse-echo US modes, the developed hybrid imaging approach is expected to benefit numerous applications where the availability of high-quality structural information provided by the tomographic reflection-mode US can ease interpretation of the functional and molecular imaging results attained by the OA modality.


The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein-protein interaction in glioblastoma.
Targeted approaches for inhibiting epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in glioblastoma (GBM) have led to therapeutic resistance and little clinical benefit, raising the need for the development of alternative strategies. Endogenous LRIG1 (Leucine-rich Repeats and ImmunoGlobulin-like domains protein 1) is an RTK inhibitory protein required for stem cell maintenance, and we previously demonstrated the soluble ectodomain of LRIG1 (sLRIG1) to potently inhibit GBM growth in vitro and in vivo. Here, we generated a recombinant protein of the ectodomain of LRIG1 (sLRIG1) and determined its activity in various cellular GBM models including patient-derived stem-like cells and patient organoids. We used proliferation, adhesion, and invasion assays, and performed gene and protein expression studies. Proximity ligation assay and NanoBiT complementation technology were applied to assess protein-protein interactions. We show that recombinant sLRIG1 downregulates EGFRvIII but not EGFR, and reduces proliferation in GBM cells, irrespective of their EGFR expression status. We find that sLRIG1 targets and downregulates a wide range of RTKs, including AXL, and alters GBM cell adhesion. Mechanistically, we demonstrate that LRIG1 interferes with AXL but not with EGFR dimerization. These results identify AXL as a novel sLRIG1 target and show that LRIG1-mediated RTK downregulation depends on direct protein interaction. The pan-RTK inhibitory activity of sLRIG1 warrants further investigation for new GBM treatment approaches.


Poly-cytosine-mediated nanotags for SERS detection of Hg2.
Highly sensitive and selective detection of heavy metal ions, such as Hg2+, is of great importance because the contamination of heavy metal ions has been a serious threat to human health. Herein, we have developed poly-cytosine (polyC)-mediated surface-enhanced Raman scattering (SERS) nanotags as a sensor system for rapid, selective, and sensitive detection of Hg2+ based on thymidine-Hg2+-thymidine (T-Hg2+-T) coordination and polyC-mediated Raman activity. The SERS nanotags exploit the mismatched T-T base pairs to capture Hg2+ form T-Hg2+-T bridges, which induce the aggregation of nanotags giving rise to the drastic amplification in the SERS signals. Moreover, this polyC not only provides the anchoring function to induce the formation of intrinsic silver-cytosine coordination but also engineers the Raman-activity of SERS nanotags by mediating its length. As a result, the polyC-mediated SERS nanotags show an excellent response for Hg2+ in the concentration range from 0.1 to 1000 nM and good selectivity over other metal ions. Given its simple principle and easy operation, the polyC-mediated SERS nanotags, therefore, could serve as a promising sensor for practical use.


The effect of levodopa on saccades - Oxford Quantification in Parkinsonism study.
The evaluation of novel disease modifying drugs requires biomarkers that are simultaneously sensitive to disease state but resistant to the effects of background symptomatic treatment. Saccadic eye movement parameters have been proposed as a neurophysiological biomarker for Parkinson's disease (PD) and so it is important to know how they are affected by dopaminergic medication. Studies to date are conflicting: some have concluded that medication prolongs saccadic latencies while others suggest they are shortened. We aimed to characterise the effects of antiparkinsonian medication on prosaccadic and antisaccadic parameters in a large cohort of PD patients and age matched healthy controls and to survey the current literature in comparison to the study findings. We studied saccades both off and on medication in 38 PD patients and 34 healthy controls (HC). Latencies, amplitudes, velocities, and directional errors were evaluated, using a published standardised protocol. We then combined this study and previously published literature in a meta-analysis of the effects of antiparkinsonian medication on prosaccadic latency (PSL). PSL is significantly prolonged by dopaminergic medication in PD, from a mean of 222.7 ms in the OFF medication state to a mean of 236.0 ms in the ON medication state (p = 0.028). This effect size is comparable to the difference between PD OFF medication and healthy control values. There was no statistically significant change in any other saccadic parameter with medication. Of particular note, antisaccadic latency was almost exactly the same on and off medication (means of 414.9 ms and 417.2 ms respectively, p = 0.97), while being almost 20% longer in PD patients compared to healthy controls (HC mean 357.2 ms; PD ON vs HC p = 0.015; PD OFF vs HC p = 0.0066). PSL is significantly affected by dopaminergic medication which may complicate its use as a biomarker in drug trials. Antisaccadic latency is particularly interesting in this regard because it shows a large disease effect with no medication effect.


Resveratrol, a natural red wine polyphenol, reduces ischemia-reperfusion-induced spinal cord injury.
Severe neurologic injury still represents one of the most devastating complications after surgical repair of thoracoabdominal aneurysms. We therefore aimed to investigate the protective effect of resveratrol, a natural polyphenol antioxidant present in grapes and wine, in an experimental model of spinal cord ischemia-reperfusion injury. Sixteen rabbits were assigned either to group A (n = 8; receiving resveratrol, treated group) or group B (n = 8; control group, nontreated group) and underwent a 30-minutes period of spinal cord ischemia by clamping the abdominal aorta between the left renal artery and the aortic bifurcation. Fifteen minutes before clamping, rabbits received either intravenous resveratrol (100 microg/kg; group A) or normal saline (group B). Functional assessment with Tarlov score at 8, 16, and 24 hours postoperatively, histopathologic assessment of the spinal cord, measurements of malondialdehyde levels, and myeloperoxidase activity in the spinal cord were performed. Neurologic impairment (Tavlov score for group A = 4.38 +/- 1.19 and for group B = 0.38 +/- 0.74, p < 0.001), malondialdehyde levels (47.71 +/- 7.81 nmol/g versus 86.56 +/- 11.39 nmol/g, p < 0.001), and myeloperoxidase activity (2.13 +/- 0.72 nm/min versus 3.75 +/- 0.78 nm/min, p = 0.002) were significantly lower in the resveratrol-treated animals. Additionally, pathologically assessed outcomes were better in the resveratrol-treated group. The total number of motor neurons in the gray matter was significantly lower in the nontreated group than in the resveratrol-treated group (14.26 +/- 2.94 versus 29.12 +/- 3.64, p = 0.003). Prophylactic use of resveratrol reduced neurologic injury and provided clinical improvement by attenuating the inflammatory milieu in the rabbit spinal cord ischemia/reperfusion model.


Variability and profiles of lipophilic toxins in bivalves from Great Britain during five and a half years of monitoring: azaspiracids and yessotoxins.
Cefas has been responsible for the delivery of official control biotoxin testing of bivalve molluscs from Great Britain for just over a decade. Liquid chromatography tandem mass spectrometric (LC-MS/MS) methodology has been used for the quantitation of lipophilic toxins (LTs) since 2011. The temporal and spatial distribution of okadaic acid group toxins and profiles in bivalves between 2011 and 2016 have been recently reported. Here we present data on the two other groups of regulated lipophilic toxins, azaspiracids (AZAs) and yessotoxins (YTXs), over the same period. The latter group has also been investigated for a potential link with Protoceratium reticulatum and Lingulodinium polyedra, both previously recognised as YTXs producing phytoplankton. On average, AZAs were quantified in 3.2% of all tested samples but notable inter-annual variation in abundance was observed. The majority of all AZA contaminated samples were found between July 2011 and August 2013 in Scotland, while only two, three-month long, AZA events were observed in 2015 and 2016 in the south-west of England. Maximum concentrations were generally reached in late summer or early autumn. Reasons for AZAs persistence during the 2011/2012 and 2012/2013 winters are discussed. Only one toxin profile was identified, represented by both AZA1 and AZA2 toxins at an approximate ratio of 2 : 1, suggesting a single microalgal species was the source of AZAs in British bivalves. Although AZA1 was always the most dominant toxin, its proportion varied between mussels, Pacific oysters and surf clams. The YTXs were the least represented group among regulated LTs. YTXs were found almost exclusively on the south-west coast of Scotland, with the exception of 2013, when the majority of contaminated samples originated from the Shetland Islands. The highest levels were recorded in the summer months and followed a spike in Protoceratium reticulatum cell densities. YTX was the most dominant toxin in shellfish, further strengthening the link to P. reticulatum as the YTX source. Neither homo-YTX, nor 45-OH homo-YTX were detected throughout the monitored period. 45-OH YTX, thought to be a shellfish metabolite associated with YTX elimination, contributed on average 26% in mussels. Although the correlation between 45-OH YTX abundance and the speed of YTX depuration could not be confirmed, we noted the half-life of YTX was more than two-times longer in queen scallops, which contained 100% YTX, than in mussels. No other bivalve species were affected by YTXs. This is the first detailed evaluation of AZAs and YTXs occurrences and their profiles in shellfish from Great Britain over a period of multiple years.


Spin-transfer and exchange torques in ferromagnetic superconductors.
We consider how superconducting correlations influence spin-transfer torques in ferromagnetic superconductors. It is demonstrated that there is a novel torque arising from particle-hole interference that depends on the U(1) phase associated with the superconducting order parameter. We also show that there is an equilibrium exchange torque between two ferromagnetic superconductors in contact via a normal metal mediated by Andreev states. The latter equilibrium magnetic torque is also sensitive to spin-resolved phase differences in the superconducting order parameters as well as to an externally applied phase difference.


Comparison of transforming growth factor-beta and a macrophage- deactivating polypeptide from tumor cells. Differences in antigenicity and mechanism of action.
A factor in medium conditioned by mouse tumor cells was shown previously to suppress the capacity of mouse peritoneal macrophages to undergo a respiratory burst and to kill protozoal pathogens (macrophage deactivation factor, MDF). Recently, pure transforming growth factor-beta (TGF-beta) proved to be a potent macrophage deactivator as well. Two lines of evidence suggest that MDF is not identical with TGF-beta. First, rabbit anti-TGF-beta IgG neutralized the respiratory burst-suppressing activity of TGF-beta without affecting the bioactivity of MDF, even when the latter was treated with acid to activate potentially latent TGF-beta. Second, in contrast to MDF, which decreases the affinity of the NADPH oxidase for NADPH, permeabilized macrophages that had been deactivated with TGF-beta displayed the same Km and Vmax of the oxidase as activated macrophages. As with MDF, TGF-beta had no effect on two other potential control points over the secretion of respiratory burst products, namely, hydrogen peroxide catabolism or glucose uptake. Finally, neither MDF nor TGF-beta affected the extent or affinity of binding of phorbol diesters to macrophages, the activity or cofactor requirements for protein kinase C, or the ability of protein kinase C to translocate quantitatively from cytosol to membrane fractions in response to phorbol diesters. Thus, 1) MDF is not identical with TGF-beta, and 2) in contrast to the activation or deactivation of macrophages by numerous other agents, TGF-beta regulates macrophage respiratory burst capacity at a level other than the apparent affinity of the oxidase for its substrate.