Localized suffix array and its application to genome mapping problems for paired-end short reads.
We introduce a new data structure, a localized suffix array, based on which occurrence information is dynamically represented as the combination of global positional information and local lexicographic order information in text search applications. For the search of a pair of words within a given distance, many candidate positions that share a coarse-grained global position can be compactly represented in term of local lexicographic orders as in the conventional suffix array, and they can be simultaneously examined for violation of the distance constraint at the coarse-grained resolution. Trade-off between the positional and lexicographical information is progressively shifted towards finer positional resolution, and the distance constraint is reexamined accordingly. Thus the paired search can be efficiently performed even if there are a large number of occurrences for each word. The localized suffix array itself is in fact a reordering of bits inside the conventional suffix array, and their memory requirements are essentially the same. We demonstrate an application to genome mapping problems for paired-end short reads generated by new-generation DNA sequencers. When paired reads are highly repetitive, it is time-consuming to naïvely calculate, sort, and compare all of the coordinates. For a human genome re-sequencing data of 36 base pairs, more than 10 times speedups over the naïve method were observed in almost half of the cases where the sums of redundancies (number of individual occurrences) of paired reads were greater than 2,000.


Posttraumatic stress disorder-like induction elevates β-amyloid levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses.
Recent studies have found that those who suffer from posttraumatic stress disorder (PTSD) are more likely to experience dementia as they age, most often Alzheimer's disease (AD). These findings suggest that the symptoms of PTSD might have an exacerbating effect on AD progression. AD and PTSD might also share common susceptibility factors such that those who experience trauma-induced disease were already more likely to succumb to dementia with age. Here, we explored these two hypotheses using a mouse model of PTSD in wild-type and AD model animals. We found that expression of human familial AD mutations in amyloid precursor protein and presenilin 1 leads to sensitivity to trauma-induced PTSD-like changes in behavioral and endocrine stress responses. PTSD-like induction, in turn, chronically elevates levels of CSF β-amyloid (Aβ), exacerbating ongoing AD pathogenesis. We show that PTSD-like induction and Aβ elevation are dependent on corticotropin-releasing factor (CRF) receptor 1 signaling and an intact hypothalamic-pituitary-adrenal axis. Furthermore, we show that Aβ species can hyperexcite CRF neurons, providing a mechanism by which Aβ influences stress-related symptoms and PTSD-like phenotypes. Consistent with Aβ causing excitability of the stress circuitry, we attenuate PTSD-like phenotypes in vivo by lowering Aβ levels during PTSD-like trauma exposure. Together, these data demonstrate that exposure to PTSD-like trauma can drive AD pathogenesis, which directly perturbs CRF signaling, thereby enhancing chronic PTSD symptoms while increasing risk for AD-related dementia.


Activation of morphine glucuronidation by fatty acyl-CoAs and its plasticity: a comparative study in humans and rodents including chimeric mice carrying human liver.
The formation of morphine-3-glucuronide (M-3-G, pharmacologically inactive) and morphine-6-glucuronide (M-6-G, active metabolite) by liver microsomes from humans and rodents, including chimeric mice carrying human liver, was evaluated in the presence of fatty acyl-CoAs. Medium- to long-chain fatty acyl-CoAs, including oleoyl-CoAs, at a physiologic level (around 15 microM) markedly enhanced M-3-G formation catalyzed by rat liver microsomes. A separate experiment indicated that 15 microM oleoyl-CoA enhanced (14)C-UDP-glucuronic acid (UDPGA) uptake by microsomes. The activation by acyl-CoAs disappeared or was greatly reduced by either pre-treating microsomes with detergent or freezing/thawing the rat liver before preparation. Many of the microsomes prepared from frozen human livers (N=14) resisted oleoyl-CoA-mediated activation of UDP-glucuronosyltransferase (UGT) activity, including M-6-G formation, which is highly specific to humans. In sharp contrast, the activity of M-6-G and M-3-G formation in freshly-prepared hepatic microsomes from chimeric mice with humanized liver was potently activated by oleoyl-CoA. Thus, acyl-CoAs activate morphine glucuronidation mediated by human as well as rat UGTs. This activation is assumed to be due to the acyl-CoA-facilitated transportation of UDPGA, and microsomes need to maintain the intact conditions required for the activation. The function of UGT appears to be dynamically changed depending on the cellular acyl-CoA level in many species.


Grip on challenging behavior: process evaluation of the implementation of a care program.
The Grip on Challenging Behavior care program for managing challenging behavior was implemented in the dementia special care units of 17 Dutch nursing homes. A process evaluation of the implementation of the care program was performed to determine the quality of the implementation and the lessons to be learned for future implementation. The care program was implemented according to a stepped wedge design. First-order data (data on recruitment, reach, relevance and feasibility) were used to determine the validity of the study, and second-order data (intervention quality and the barriers and facilitators for implementing the care program) were used to describe the implementation process. Two structured questionnaires were administered to care staff and key stakeholders and semi-structured interviews were held in the units. University affiliated and non-affiliated nursing homes from different parts of the Netherlands participated. The resident participation rate was over 95% and the participation rate for the training sessions was 82%. Respondents considered the care program relevant and feasible. The degree of implementation was not optimal. The barriers and facilitators in implementing the care program could be divided into three categories: organizational aspects, culture on the unit and aspects of the care program itself. The recruitment, reach, relevance and feasibility are sufficient to allow for analysis and generalization of the effects of the care program, but the degree of implementation should be taken into account in further analysis. Future projects that involve implementation should consider the specific features of the organization and the cultural orientation of the unit to better adapt to specific needs. The Netherlands National Trial register under number NTR2141 registered on 11 December 2009. Randomization took place in November 2010, and the first intervention group started using the intervention in February 2011.


Face masks: protecting the wearer but neglecting the aquatic environment? - A perspective from Bangladesh.
In Bangladesh, as with many countries, the spread of COVID-19 made the wearing of single-use face masks, a non-pharmaceutical intervention to reduce viral transmission, surge in popularity amongst the general population. Consequently, irresponsible discarding of used masks into the environment, and mismanagement of the waste they produce, is potentially placing a large pollution burden on aquatic ecosystems in the country. Slow degradation of mask-derived polypropylene and polyethylene fibres creates large reservoirs of microplastic pollutants and these have acute and chronic effects on aquatic organism physiology. Using literature reviews, extrapolation of published data, and field observations, we present an emerging issue of pollution from COVID-19 personal protective equipment such as face masks in Bangladesh. We have estimated the volume of waste generated and document the potential consequences of its improper disposal, and subsequent degradation, in aquaculture ponds within country. In a field survey of 30 ponds in the Muktagacha upazilla, 76.7% were found to have plastics in contact with the water, or within 1m of the pond, and there was an average of 63 pieces of macro-plastic pollution per 5m2. This included floating discarded face masks. Bangladesh has a rich freshwater and marine resource which it depends upon for export trade, nutrition of the population, and jobs. To mitigate potential acute and chronic impacts on aquaculture and the environment, recommendations are made that, if adopted, would reduce entry of microplastics into the aquatic environments via face mask waste mismanagement.


Eye movements in patients with Neglect show space-centred attention when fixating rotating objects.
To determine whether attention operates in space-based or object-based coordinates, Neglect patients were confronted with a rotating object. After the object had undergone a 180-degree rotation a stimulus appeared on either side of the object and the reaction times were measured. The results of the present study showed that all patients performed worse on the contralateral side, both in the static as well as in the moving condition. This supports the theory that attention operates in space-centred reference frames. To bring some light into the discussion, the recording of eye movements was included. Our results showed three effects: (1) most eye movements started to the right of the midline; (2) some patients followed the moving object to the mid-line, before they returned to the ipsi-lesional side; (3) some patients followed the complete movement of the barbell. It is argued that patients recovering from Neglect consciously make more eye movements to the left to compensate for the deficit, but attention remains in the ipsi-lesional field.


Mental Images and School Learning: A Longitudinal Study on Children.
Recent literature have underlined the connections between children's reading skills and capacity to create and use mental representations or mental images; furthermore data highlighted the involvement of visuospatial abilities both during math learning and during subsequent developmental phases in performing math tasks. The present research adopted a longitudinal design to assess whether the processes of mental imagery in preschoolers (ages 4-5 years) are predictive of mathematics skills, writing and reading, in the early years of primary school (ages 6-7 years). The research lasted for two school years; in the first phase, the general group of participants consisted of 100 children, and although all participants agreed to be part of the research, in the second phase, there was a mortality rate of 30%. In order to measure school learning and mental imagery processes four batteries of tests were used. The mental imagery battery evaluated mental generation, inspection and transformation processes. Data underlined that the different aspects in which mental imagery processes are articulated are differently implied in some skills that constitute school learning. These findings emphasize the potential usefulness of a screening for mental imagery ability for schoolchildren to adopt effective measures to increase their mental imagery abilities.


Categorizing some early and late transcripts directed by the Autographa californica nuclear polyhedrosis virus.
Using an S1 mapping assay on RNA from Spodoptera frugiperda cells infected by the Autographa californica nuclear polyhedrosis virus in the presence and absence of cycloheximide and aphidicolin, we can distinguish three classes of transcripts. First, there are those whose synthesis is blocked by the DNA synthesis inhibitor aphidicolin and which are therefore late transcripts. These include the late transcript of the 39K gene and a late leftward transcript across the XhoI site in the HindIII-F region. Second, there are those whose synthesis is not blocked by aphidicolin, but whose accumulation is inhibited by the protein synthesis inhibitor cycloheximide and which are therefore presumably delayed early genes. These include the p26 transcript(s), the early 39K transcript and the alpha 2 transcript in the HindIII-K/Q region. Third, there are those whose accumulation is not affected or is enhanced by cycloheximide. These are not necessarily immediate early transcripts, but their response to cycloheximide is clearly different from that of those in the second class. They include the alpha 1 and alpha 3 transcripts in the HindIII-K/Q region and the early leftward transcript across the XhoI site in the HindIII-F region.


Combination treatment of neuropathic pain: Danish expert recommendations based on a Delphi process.
Current Danish treatment algorithms for pharmacological treatment of neuropathic pain (NeP) are tricyclic antidepressants (TCA), gabapentin and pregabalin as first-line treatment for the most common NeP conditions. Many patients have insufficient pain relief on monotherapy, but combination therapy had not been included in guidelines until recently. Based on clinical empiricism and scientific evidence, a Delphi consensus process provided a consolidated guidance on pharmacological combination treatment of NeP. A two-round virtual internet-based Delphi process with 6 Danish pain specialists was undertaken. In the first round, questions were answered individually and anonymously, whereas in the second round, the panel openly discussed first round's summary of outcomes. Combinations of pharmacological pain treatments, that is, pregabalin/gabapentin, TCAs, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors, opioids, other antiepileptics and cutaneous patches, were assessed based on both scientific and clinical practice experiences. The Centers for Disease Control and Prevention (CDC) grading system was used for evidence rating. Combination of pregabalin/gabapentin with TCA is useful in patients who do not gain sufficient pain relief or tolerate either drug in high doses, or to improve sleep disturbance. Also, combination of pregabalin/gabapentin and SNRIs is reasonably well documented and experienced by some experts to result in sufficient pain relief and fewer side effects than monotherapy. Good evidence on efficacy was found for the combination of pregabalin/gabapentin or TCAs and opioids, which was also frequently used in clinical practice. The evidence for combining TCAs and SNRIs is insufficient, although sometimes used in clinical practice despite the risk of serotonin syndrome. For localized NeP, combination therapy with cutaneous patches should be considered. There was insufficient scientific evidence for any pharmacologic combination therapies with selective serotonin reuptake inhibitors - as well as for other potential combinations. The study revealed that combination therapy is widely used in clinical practice and supported by some scientific evidence. However, further studies are needed.


Better Predictive Value of Cancer Antigen125 (CA125) as Biomarker in Ovary and Breast Tumors and its Correlation with the Histopathological Type/Grade of the Disease.
Both ovarian/breast cancers are the most prevalent hormone-associated gynecological-cancers, where uncontrolled cellular proliferations/genetic-errors are noticed. The cancer-antigen125 (CA125), which we assessed presently is an important biomarker in the early detection/monitoring of this disease-pathogenesis. Serum/tissue CA125 was measured by solid-phase-Enzyme-linked-immunosorbentassay in women with ovarian/breast tumors of different types (epithelial/non-epithelial; benign/ borderline/ malignant)/stages. Breast-tumor tissues were employed for histoarchitecture/DNAstability (comet) assay. Extensive protein-protein(CA125) interactions were studied by the STRING (Search-Tool-for-the-Retrieval-of-Interacting Genes/Proteins) Bioinformatics-software. Serum CA125 levels were <35 U/ml in 94% of benign epithelial-cases, 35-65 U/ml in 100% of borderline-tumors and >100 U/ml in the 41.17% of patients with malignant-tumors. The malignant epithelial tumor showed significantly higher (>100U/ml) CA125 than the non-epithelial malignant-tumor (<35-65 U/ml). Highly enhanced cellularity/histo-architectural impairment/unstable- DNA-materials/CA125 was found in advanced breast-cancers. The CA125 is highly metabolically interactive, especially with mesothelin impairing cell-cell adhesion and enhancing tissue anti-establishment. CA125 is a predictive-marker in ovarian/breast carcinoma depending on disease nature/stages. CA125, in combination with other tests like mesothelin/estradiol can be of great use in the better diagnosis of this disease. Not only as a detection-marker, has the CA125 played an interactive role in the disease processes. The Bioinformatics study revealed an important role of mesothelin and other mucin like proteins. Early detection and proper diagnosis are important determinants for the greater possibility of the relief from the disease like cancers. Selection of suitable biomarker combinations may increase the better diagnosis of the types and severity of this disease. Our present result has an impact on these aspects.


A grid-based protein complex predictor.
Proteins interact among them and different interactions form a very huge number of possible combinations representable as protein to protein interaction (PPI) networks that are mapped into graph structures. The interest in analyzing PPI networks is related to the possibility of predicting PPI properties, starting from a set of known proteins interacting among each other. For example, predicting the configuration of a subset of nodes in a graph (representing a PPI network), allows to study the generation of protein complexes. Nevertheless, due to the huge number of possible configurations of protein interactions, automatic based computation tools are required. Available prediction tools are able to analyze and predict possible combinations of proteins in a PPI network which have biological meanings. Once obtained, the protein interactions are analyzed with respect to biological meanings representing quality measures. Nevertheless, such tools strictly depend on input configuration and require biological validation. In this paper we propose a new grid-based prediction tool that integrate of different prediction results.


Statin utilization improves oncologic and survival outcomes in patients with dyslipidemia and surgically treated renal cell carcinoma.
We evaluated the role of statins in patients who underwent surgery for renal cell carcinoma (RCC) and who had dyslipidemia, as use of statins has been suggested to improve outcomes in RCC. Two-center retrospective study of patients with dyslipidemia who underwent surgery for RCC from 7/1995 to 6/2005. Patients were managed by statins or ezetimibe, fibrate agents, or cholestyramine. Analysis was conducted between patients who received statin therapy versus those that did not. Primary outcome was progression-free survival (PFS). Secondary outcomes were cancer-specific (CSS) and overall survival (OS). Multivariable analysis was performed to identify risk factors associated with disease progression. In this study 283 patients were analyzed (180 statin, 103 non-statin, median follow-up 68 months). There were no significant demographic differences. Median duration of antidyslipidemia therapy was similar (statin 31 months vs. non-statin 28 months, P=0.413). Tumor size (statin 5.4 cm vs. non-statin 5.6 cm, P=0.569), stage distribution (P=0.591), histology (P=0.801), and grade (P=0.807) were similar. Kaplan-Meier analysis demonstrated higher 5-yr PFS (91% vs. 70%, P<0.001), CSS (88% vs. 69%, P<0.001), and OS (71% vs. 67%, P=0.025) in statin vs. non-statin patients. Multivariable analysis for factors associated with disease progression found absence of statin therapy (OR 2.41, P<0.001), higher stage (OR 2.01-3.86 P<0.001), and higher grade tumors (OR 2.07, P=0.006) to be predictive. In RCC patients with dyslipidemia, statin use was associated with improved survival outcomes, and was an independent predictor of PFS. Further investigations are requisite to determine utility of statins in RCC patients.


A typical thymic carcinoid tumour within a thymolipoma: report of a case and review of combined tumours of the thymus.
Thymolipomas are rare tumours located in the anterior mediastinum. Sometimes these tumours may be combined with thymomas or lymphomas. We present a unique case of a thymic carcinoid arising within a thymolipoma. A 68-year-old patient presented with chronic chest and neck pain, which was initially thought to be caused by coronary artery disease. A chest x-ray, exercise tolerance test and coronary angiography were unremarkable. The following CT scan of the neck and chest showed a small tumour in the anterior mediastinum. A robotic-assisted thymectomy was performed and histological examination revealed a neuroendocrine tumour of the thymus within a thymolipoma. The patient was discharged 3 days after surgery in good general condition.


Anomaly classification by inserting prior knowledge into a max-tree based method for divertor hot spot characterization on WEST tokamak.
The divertor of WEST (W Environment in Steady-state Tokamak) is the main component for plasma control and exhaust. It receives high heat fluxes, which can cause damage to plasma facing units above the allowable heat flux. Improving the operation safety on the actively cooled tungsten divertor is being researched in place at WEST, toward providing divertor monitoring solution for ITER. Divertor operation safety relies on detecting, monitoring, and classifying all hot spots on the divertor surface using infrared (IR) cameras. In this paper, a method based on max-tree representation and attributes of IR images is used to classify normal from abnormal strikelines on the divertor. The proposed method requires only high-level prior knowledge of abnormal temperatures and divertor structure but does not require any labeled data, unlike existing methods, such as support vector machines (SVMs) or convolutional neural networks (CNNs). The max-tree classifier method is tested on real IR images from the WEST tokamak and shows that 88% of hot spots are accurately classified with a small enough calculation duration that can be performed between two pulses.


Using encrypted genotypes and phenotypes for collaborative genomic analyses to maintain data confidentiality.
To adhere to and capitalize on the benefits of the FAIR (Findable, Accessible, Interoperable and Reusable) principles in agricultural genome-to-phenome studies, it is crucial to address privacy and intellectual property issues that prevent sharing and reuse of data in research and industry. Direct sharing of genotype and phenotype data is often prohibited due to intellectual property and privacy concerns. Thus there is a pressing need for encryption methods that obscure confidential aspects of the data, without affecting the outcomes of certain statistical analyses. A homomorphic encryption method for genotypes and phenotypes (HEGP) has been proposed for single-marker regression in genome-wide association studies using linear mixed models with Gaussian errors. This methodology permits frequentist likelihood-based parameter estimation and inference. In this paper, we extend HEGP to broader applications in genome-to-phenome analyses. We show that HEGP is suited to commonly used linear mixed models for genetic analyses of quantitative traits including GBLUP and RR-BLUP, as well as Bayesian variable selection methods (e.g., those in Bayesian Alphabet), for genetic parameter estimation, genomic prediction, and genome-wide association studies. By advancing the capabilities of HEGP, we offer researchers and industry professionals a secure and efficient approach for collaborative genomic analyses while preserving data confidentiality.


Translational Sepsis Research: Spanning the Divide.
Our knowledge of the molecular mechanisms of sepsis has attained exponential growth. Yet, the pillars of its care remain antibiotics, fluid resuscitation, and physiologic support of failing organ systems. The inability to bring biologic breakthroughs to the bedside is not for lack of effort. Over 60 clinical trials of novel therapies, each heavily supported by the momentum of biologic data suggesting clinical utility, have been conducted and have failed to identify benefit. This mass of "negative" clinical data abut an equally towering mound of knowledge of sepsis biology, which collectively have led investigators to ask, "what happened?" Review of published scientific literature via MEDLINE searches using key terms related to the article topics. Original articles, review articles, and systematic reviews were considered. Articles were selected for inclusion based upon author consensus. Here, we present a synthetic review of some of the challenges in translating experimental animal models of sepsis to the bedside. We commence with the concept that the heterogeneity in the kinetics of the sepsis response serves as an important, often underappreciated but surmountable, source of translational impedance. Upon this groundwork, we discuss distinctions between animal experimentation and clinical trial design in the elements for hypothesis testing: cohort selection, power and sample size, randomization and blinding, and timing of intervention. From this concept, we develop a contextual framework for advancing the paradigm of animal-based investigations to facilitate science that transitions from molecule to medicine. A persistent divide exists between the laboratory and clinical research arenas, which may be addressable via systematic targeting of identified translational gaps.


The effect of virus infection on the adherence of leukocytes or platelets to endothelial cells.
It has been reported that atherosclerotic lesions contain genomic material belonging to members of the herpes family. This suggests that latent viral infection may be one of the atherogenic triggers. In this study we show that early infection of endothelial cell monolayers with Herpes Simplex virus type 1 (HSV-1) or Cytomegalovirus (CMV) results in an increased monocyte (MC) and polymorphonuclear leukocyte (PMN) adherence, but not in an increased platelet adhesion. Further, is demonstrated that MC and PMN respond differently to virus infected endothelial cell monolayers: PMN adhesion to CMV infected cells is approximately 430% of the control adherence, while the MC adherence is increased to 160%. Also, a difference in virus acting is observed: the adherence of MC or PMN to HSV-1 infected endothelial cells is caused by a secreted adherence promoting factor, while the adherence of MC or PMN to CMV infected endothelial cells seems to be a cell-bound phenomenon. In addition, it was demonstrated that the augmentation of MC or PMN adherence to virus infected endothelial cells is sensitive to tunicamycin, suggesting that both virus infections induce the expression of glycoproteins on the endothelial cell membrane, which is responsible for the MC and PMN adhesion. Thus, HSV-1 and CMV infection of endothelium results in an increased adherence of leukocytes which is suggested, irrespective of the precise nature of the mechanism of virus induced atherosclerosis, to be the earliest event associated with endothelium cell damage.


Does insect netting affect the containment of airborne pollen from (GM-) plants in greenhouses?
Greenhouses are a well-accepted containment strategy to grow and study genetically modified plants (GM) before release into the environment. Various containment levels are requested by national regulations to minimize GM pollen escape. We tested the amount of pollen escaping from a standard greenhouse, which can be used for EU containment classes 1 and 2. More specifically, we investigated the hypothesis whether pollen escape could be minimized by insect-proof netting in front of the roof windows, since the turbulent airflow around the mesh wiring could avoid pollen from escaping. We studied the pollen flow out of greenhouses with and without insect netting of two non-transgenic crops, Ryegrass (Loliummultiflorum) and Corn (Zea Mays). Pollen flow was assessed with Rotorod(®) pollen samplers positioned inside and outside the greenhouse' roof windows. A significant proportion of airborne pollen inside the greenhouse leaves through roof windows. Moreover, the lighter pollen of Lolium escaped more readily than the heavier pollen of Maize. In contrast to our expectations, we did not identify any reduction in pollen flow with insect netting in front of open windows, even under induced airflow conditions. We conclude that insect netting, often present by default in greenhouses, is not effective in preventing pollen escape from greenhouses of wind-pollinated plants for containment classes 1 or 2. Further research would be needed to investigate whether other alternative strategies, including biotic ones, are more effective. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10453-011-9237-8) contains supplementary material, which is available to authorized users.


A viral microRNA downregulates metastasis suppressor CD82 and induces cell invasion and angiogenesis by activating the c-Met signaling.
Kaposi's sarcoma (KS) as the most common AIDS-associated malignancy is etiologically caused by KS-associated herpesvirus (KSHV). KS is a highly disseminated and vascularized tumor. KSHV encodes 12 pre-microRNAs that yield 25 mature microRNAs (miRNAs), but their roles in KSHV-induced tumor metastasis and angiogenesis remain largely unclear. KSHV-encoded miR-K12-6 (miR-K6) can generate two mature miRNAs, miR-K6-5p and miR-K6-3p. Recently, we have shown that miR-K6-3p induced cell migration and angiogenesis via directly targeting SH3 domain binding glutamate-rich protein (SH3BGR). Here, by using mass spectrometry, bioinformatics analysis and luciferase reporter assay, we showed that miR-K6-5p directly targeted the coding sequence of CD82 molecule (CD82), a metastasis suppressor. Ectopic expression of miR-K6-5p specifically inhibited the expression of endogenous CD82 and strongly promoted endothelial cells invasion and angiogenesis. Overexpression of CD82 significantly inhibited cell invasion and angiogenesis induced by miR-K6-5p. Mechanistically, CD82 directly interacted with c-Met to inhibit its activation. MiR-K6-5p directly repressed CD82, relieving its inhibition on c-Met activation and inducing cell invasion and angiogenesis. Lack of miR-K6 abrogated KSHV suppression of CD82 resulting in compromised KSHV activation of c-Met pathway, and KSHV induction of cell invasion and angiogenesis. In conclusion, our data show that by reducing CD82, KSHV miR-K6-5p expedites cell invasion and angiogenesis by activating the c-Met pathway. Our findings illustrate that KSHV miRNAs may be critical for the dissemination and angiogenesis of KSHV-induced malignant tumors.


Hypoxia inducible factor-1α-dependent epithelial to mesenchymal transition under hypoxic conditions in prostate cancer cells.
Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer death. Hypoxia is an environmental stimulus that plays an important role in the development and cancer progression especially for solid tumors. The key regulator under hypoxic conditions is stabilized hypoxia-inducible factor (HIF)-1α. In the present study, immune-fluorescent staining, siRNAs, qRT-PC, immunoblotting, cell migration and invasion assays were carried out to test typical epithelial to mesenchymal transition under hypoxia and the key regulators of this process in PC3, a human prostate cancer cell line. Our data demonstrated that hypoxia induces diverse molecular, phenotypic and functional changes in prostate cancer cells that are consistent with EMT. We also showed that a cell signal factor such as HIF-1α, which might be stabilized under hypoxic environment, is involved in EMT and cancer cell invasive potency. The induced hypoxia could be blocked by HIF-1α gene silencing and reoxygenation of EMT in prostate cancer cells, hypoxia partially reversed accompanied by a process of mesenchymal-epithelial reverting transition (MErT). EMT might be induced by activation of HIF-1α-dependent cell signaling in hypoxic prostate cancer cells.


Control of 5-aminolaevulinate synthetase activity in Rhodopseudomonas spheroides. The involvement of sulphur metabolism.
1. The ;initial' 5-aminolaevulinate synthetase activity, that is the activity observed immediately after cell disruption, in extracts prepared from unharvested semianaerobically grown Rhodopseudomonas spheroides, was twice that observed under the same assay conditions in extracts prepared from harvested cells. 2. The effect of oxygenation of a culture on the ;maximum' aminolaevulinate synthetase activity, that is the activity observed 1h after disruption of harvested cells, is markedly influenced by the contents of the growth medium. Oxygenation of organisms for 1h in the medium in which they have grown produces an 80-90% decrease in maximum activity, whereas similar treatment of organisms resuspended in fresh medium produces less than a 40% decrease. 3. This protective effect of fresh medium is absolutely dependent on the presence of sulphate. When cells are suspended in sulphate-deficient fresh medium, the maximum activity falls by 65-75% even without oxygenation. A high maximum activity is regenerated when sulphate is resupplied. 4. When organisms are oxygenated in the medium in which they have grown, the cellular contents of GSH+GSSG and cysteine+cystine fall very markedly and homolanthionine is formed. Both the fall in aminolaevulinate synthetase activity and the changes in sulphur metabolism are largely prevented by the addition of compounds which stimulate synthesis of cysteine de novo or inhibit the conversion of cysteine S into homocysteine S. 5. The maximum aminolaevulinate synthetase activity was directly proportional to the GSH+GSSG content of all cell preparations. In glutathione-depleted extracts the ;low'-activity enzyme could be re-activated in vitro by the addition of GSH, GSSG, cysteine or cystine, whereas in extracts with a high glutathione content the ;high'-activity enzyme was unaffected by these sulphur compounds. 6. The activation of low-activity enzyme with exogenous sulphur compounds was prevented by excluding air or by adding NADH. Studies with purified enzyme indicate that sulphur compounds do not interact directly with the enzyme, but that their effect is mediated by a number of other endogenous factors.


Metabolic anatomy of focal motor seizures.
Contralateral focal seizures occurred in rats following the intracortical injection of penicillin into the anterior motor cortex. The anatomic dimensions of the metabolic response in the focus as well as the spread of increased activity through the brain were studied by autoradiography following intravenous injection of carbon 14-labeled 2-deoxyglucose. Injections of 25 to 200 units of penicillin resulted in mild to severe contralateral motor jerks coincident with repetitive single spike discharges on the electroencephalogram. Concurrent autoradiography revealed a 1.3- to 2.5-fold increase in metabolic activity in discrete areas in ipsilateral cortex, basal ganglia, thalamus, and contralateral cerebellum. Intracortical injections of over 300 units resulted in the development of recurrent contralateral tonic-clonic seizures, with 20% becoming bilateral. In brains of these animals there was activation of bilateral medial frontal cortex, bilateral extrapyramidal system, thalamus, cerebellum, and limbic structures.


The Association between Membership in the Sandwich Generation and Health Behaviors: A Longitudinal Study.
The current study examined the association between membership in the sandwich generation, defined as providing care to both children and parents or in-laws, and five health behaviors: checking the food label for health value when buying foods, using a seat belt, choosing foods based on health value, exercising regularly, and cigarette smoking. Participants (N=4943) were from a longitudinal study of a midwestern community-based sample. Regression analyses tested the unique effect of sandwich generation membership on health behaviors above and beyond demographic factors and prior levels of the same behavior. Compared to other caregivers and noncaregivers, multigenerational caregivers were less likely to check food labels and to choose foods based on health values. Multigenerational caregivers were less likely than noncaregivers and those who cared for children only to use seat belts, and they smoked marginally more cigarettes per day than those groups. Multigenerational caregivers were less likely than noncaregivers and those who cared for parents/in-laws only to exercise regularly. Thus, in general, healthy behaviors were diminished for multigenerational caregivers.


A 3D integral imaging optical see-through head-mounted display.
An optical see-through head-mounted display (OST-HMD), which enables optical superposition of digital information onto the direct view of the physical world and maintains see-through vision to the real world, is a vital component in an augmented reality (AR) system. A key limitation of the state-of-the-art OST-HMD technology is the well-known accommodation-convergence mismatch problem caused by the fact that the image source in most of the existing AR displays is a 2D flat surface located at a fixed distance from the eye. In this paper, we present an innovative approach to OST-HMD designs by combining the recent advancement of freeform optical technology and microscopic integral imaging (micro-InI) method. A micro-InI unit creates a 3D image source for HMD viewing optics, instead of a typical 2D display surface, by reconstructing a miniature 3D scene from a large number of perspective images of the scene. By taking advantage of the emerging freeform optical technology, our approach will result in compact, lightweight, goggle-style AR display that is potentially less vulnerable to the accommodation-convergence discrepancy problem and visual fatigue. A proof-of-concept prototype system is demonstrated, which offers a goggle-like compact form factor, non-obstructive see-through field of view, and true 3D virtual display.


The ultrastructure of membranes in sympathetic ganglia.
This review presents some recent observations made on membranes in the mammalian sympathetic ganglia after application of freeze-fracturing and histochemistry. After freeze-fracture clear differences have been found between the neuronal and the satellite cell plasmalemma. The satellite cell plasma membrane exhibits specialized intramembrane particles not found in the neuronal membrane. Freeze-fracture cytochemistry reveals a further difference between the neurons and satellite cells i.e., a higher density of beta-hydroxysterols is present in the satellite cell membrane than in the neuronal membrane. Histochemical methods to localize 5'-nucleotidase, Ca2+-ATPase and Na+/K+-ATPase in the membranes have been utilized. The cytochemical reaction products of 5'-nucleotidase and Ca2+-ATPase were found on the external aspect of the plasma membranes. The Na+/K+-ATPase reaction product was located on the cytoplasmic aspect of the membranes, with most activity seen in the satellite cell membrane. With respect to the intercellular junctions, the presynaptic membranes have been analyzed with the freeze-fracture technique under stimulated and unstimulated conditions and ultrastructural differences have been observed which might be correlated to neurotransmission. Furthermore, gap junctions and tight junctional elements occur between the satellite cells surrounding the neuronal perikarya and their processes.


Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8α+ dendritic cells.
The class III PI3K Vacuolar protein sorting 34 (Vps34) plays a role in both canonical and noncanonical autophagy, key processes that control the presentation of antigens by dendritic cells (DCs) to naive T lymphocytes. We generated DC-specific Vps34-deficient mice to assess the contribution of Vps34 to DC functions. We found that DCs from these animals have a partially activated phenotype, spontaneously produce cytokines, and exhibit enhanced activity of the classic MHC class I and class II antigen-presentation pathways. Surprisingly, these animals displayed a defect in the homeostatic maintenance of splenic CD8α+ DCs and in the capacity of these cells to cross-present cell corpse-associated antigens to MHC class I-restricted T cells, a property that was associated with defective expression of the T-cell Ig mucin (TIM)-4 receptor. Importantly, mice deficient in the Vps34-associated protein Rubicon, which is critical for a noncanonical form of autophagy called "Light-chain 3 (LC3)-associated phagocytosis" (LAP), lacked such defects. Finally, consistent with their defect in the cross-presentation of apoptotic cells, DC-specific Vps34-deficient animals developed increased metastases in response to challenge with B16 melanoma cells. Collectively, our studies have revealed a critical role of Vps34 in the regulation of CD8α+ DC homeostasis and in the capacity of these cells to process and present antigens associated with apoptotic cells to MHC class I-restricted T cells. Our findings also have important implications for the development of small-molecule inhibitors of Vps34 for therapeutic purposes.


Emergence of T cell progenitors without B cell or myeloid differentiation potential at the earliest stage of hematopoiesis in the murine fetal liver.
It has been unclear whether the progenitors colonizing the thymus are multipotent or T cell lineage restricted. We investigated the developmental potential of hematopoietic progenitors in various populations of liver and blood cells from day 12 fetuses using the recently established in vitro experimental system effective in determining the capability of individual progenitors to generate T, B, and myeloid cells. Multipotent progenitors (p-Multi) were exclusively found in the Sca-1 high-positive (Sca-1high) subpopulation of lineage marker (Lin)-c-kit+CD45+ fetal liver cells. Restriction of developmental capacity begins at the Sca-1high stage, and a large majority of progenitors in the Sca-1low or Sca-1- population are restricted to generate T, B, or myeloid cells. Such a lineage commitment or restriction taking place in the fetal liver is independent of the thymus, because no difference in the proportion of different types of progenitors were seen between nu/nu and nu/+ fetuses. T cell lineage-restricted progenitors (p-T) were abundant in the blood of day 12 fetuses, whereas p-Multi were undetectable. It was further shown that the p-Multi generated a large number of B and myeloid cells in the thymic lobe. These results strongly suggest that it is p-T but not p-Multi that migrate into the thymus.


One-pot highly efficient synthesis of substituted pyrroles and N-bridgehead pyrroles by zinc-catalyzed multicomponent reaction.
A convenient zinc(II) chloride-catalyzed regioselective propargylation/amination/cycloisomerization process has been developed for the synthesis of substituted pyrrole derivatives from propargylic acetates, enoxysilanes and primary amines. Various aromatic and aliphatic propargylic acetates participate well in the reaction, providing the propargylation/amination/cycloisomerization products in good yields with complete regioselectivity. The one-pot multicomponent coupling reaction furnishes substituted pyrroles in high yields by circumventing the intermediates' isolation. Zinc(II) chloride acts as a multifunctional catalyst and catalyzes three mechanistically distinct processes in a single-pot. The protocol developed has been extended to the synthesis of N-bridgehead pyrroles containing polycyclic fragments.


Polyfunctional T cells accumulate in large human cytomegalovirus-specific T cell responses.
Large cytomegalovirus (CMV)-specific CD8 T-cell responses are observed in both young and, somewhat more often, old people. Frequent CMV reactivation is thought to exhaust these cells and render them dysfunctional so that larger numbers of them are needed to control CMV. Expansions of CMV-specific CD4 T cells are also seen but are less well studied. In this study, we examined the T-cell response to the dominant CMV pp65 and IE-1 antigens in healthy CMV-infected people across a wide age range (20 to 84 years) by using multicolor flow cytometry. CMV-specific T cells were characterized by the activation markers CD40 ligand (CD40L), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) and the memory markers CD27 and CD45RA. The proportions of effector memory T cells increased in large responses, as did the proportions of polyfunctional CD8 (IFN-γ(+) IL-2(+/-) TNF-α(+)) and CD4 (CD40L(+/-) IFN-γ(+) IL-2(+) TNF-α(+)) T-cell subsets, while the proportion of naïve T cells decreased. The bigger the CD4 or CD8 T-cell response to pp65, the larger was the proportion of T cells with an advanced memory phenotype in the entire (including non-CMV-specific) T-cell compartment. In addition, the number of activation markers per cell correlated with the degree of T-cell receptor downregulation, suggesting increased antigen sensitivity in polyfunctional cells. In summary, our findings show that polyfunctional CMV-specific T cells were not superseded by dysfunctional cells, even in very large responses. At the same time, however, the memory subset composition of the entire T-cell compartment correlated with the size of the T-cell response to CMV pp65, confirming a strong effect of CMV infection on the immune systems of some, but not all, infected people.


Rational Sentence Interpretation in Mandarin Chinese.
Previous work has shown that English native speakers interpret sentences as predicted by a noisy-channel model: They integrate both the real-world plausibility of the meaning-the prior-and the likelihood that the intended sentence may be corrupted into the perceived sentence. In this study, we test the noisy-channel model in Mandarin Chinese, a language taxonomically different from English. We present native Mandarin speakers sentences in a written modality (Experiment 1) and an auditory modality (Experiment 2) in three pairs of syntactic alternations. The critical materials are literally implausible but require differing numbers and types of edits in order to form more plausible sentences. Each sentence is followed by a comprehension question that allows us to infer whether the speakers interpreted the item literally, or made an inference toward a more likely meaning. Similar to previous research on related English constructions, Mandarin participants made the most inferences for implausible materials that could be inferred as plausible by deleting a single morpheme or inserting a single morpheme. Participants were less likely to infer a plausible meaning for materials that could be inferred as plausible by making an exchange across a preposition. And participants were least likely to infer a plausible meaning for materials that could be inferred as plausible by making an exchange across a main verb. Moreover, we found more inferences in written materials than spoken materials, possibly a result of a lack of word boundaries in written Chinese. Overall, the fact that the results were so similar to those found in related constructions in English suggests that the noisy-channel proposal is robust.


Tobacco calcium-dependent protein kinases are differentially phosphorylated in vivo as part of a kinase cascade that regulates stress response.
In vivo phosphorylation sites of the tobacco calcium-dependent protein kinases NtCDPK2 and NtCDPK3 were determined in response to biotic or abiotic stress. Stress-inducible phosphorylation was exclusively located in the variable N termini, where both kinases were phosphorylated differentially despite 91% overall sequence identity. In NtCDPK2, serine 40 and threonine 65 were phosphorylated within 2 min after stress. Whereas Thr(65) is subjected to intra-molecular in vivo autophosphorylation, Ser(40) represents a target for a regulatory upstream protein kinase, and correct NtCDPK2 membrane localization is required for Ser(40) phosphorylation. NtCDPK3 is phosphorylated at least at two sites in the N terminus by upstream kinase(s) upon stress stimulus, first at Ser(54), a site not present in NtCDPK2, and also at a second undetermined site not identical to Ser(40). Domain swap experiments established that differential phosphorylation of both kinases is exclusively determined by the respective N termini. A cell death-inducing response was only observed upon expression of a truncated variant lacking the junction and calcium-binding domain of NtCDPK2 (VK2). This response required protein kinase activity and was reduced when subcellular membrane localization was disturbed by a mutation in the myristoylation and palmitoylation site. Our data indicate that CDPKs are integrated in stress-dependent protein kinase signaling cascades, and regulation of CDPK function in response to in vivo stimulation is dependent on its membrane localization.


Predictive Factors in Identifying Pediatric Patients at Risk of Diagnostically Limited Videofluoroscopic Swallow Studies.
Objective: Videofluoroscopic swallow studies (VFSS) are highly effective in characterizing pediatric dysphagia, but they are time- and resource-intensive, and necessitate the use of radiation. Identifying patients unlikely to benefit from VFSS is crucial to improving patient safety and resource allocation. The purpose of this study was to assess whether the ability of a patient to consume at least 0.5 oz by mouth is a reliable indicator of their ability to produce a diagnostically useful VFSS. Study Design: Retrospective chart review. Methods: Clinical data of pediatric patients aged 0 to 18 years, who underwent VFSS at a tertiary academic medical center from 2014 to 2021 were analyzed. Results: Regardless of whether due to mechanical dysphagia or oral aversion, an inability to consume at least 0.5 oz of any texture by mouth at home was not found to be associated with nondiagnostic VFSS. Age was found to have an effect on VFSS utility with toddlers having higher odds of nondiagnostic VFSS compared to children and adolescents. Overall, there was no significant interaction between the ability to take at least 0.5 oz and age group. Gastrointestinal (GI) and neuromuscular comorbidities were also associated with clinically useful swallow studies. Conclusions and Relevance: Clinicians should consider several factors, including age, at-home intake by mouth, and comorbidities such as neuromuscular and GI disorders, as they decide whether to order a VFSS.


LC3-associated phagocytosis.
A recent report from our group has described that upon engulfment of pathogens, a subset of phagosomes is formed to preserve antigens for prolonged presentation on MHC class II molecules. The distinctive feature of these particular vesicles is their coating with LC3/Atg8, a key component of the autophagy machinery. Here we discuss the possible outcomes of LC3-associated phagocytosis and its implications in the context of immunity.


Induction of lymphoid leukosis transplant able tumours and the establishment of lymphoblastoid cell lines.
Primary lymphoid tumours induced by the subgroup A, B, C and D lymphoid leukosis viruses RAV-1, RAV-2, RAV-49 and RAV-50, respectively, have been developed as transplantable "B-cell" lymphoid tumours and designated LSCT-RP5, LSCT-RP6, LSCT-RP7 and LSCT-RP8, respectively. There seems little doubt that these are indeed transplants because all produce tumours and death of the inoculated chicks in a very short time (median days to death =5-10 days), and chromosome analyses reveal that the sex of the tumour cells remains unchanged when passaged in chicks of the opposite sex. We have established 2 in vitro lymphoblastoid lines (LSCC-RP9 and LSCC-RP12) from the RAV-2 transplantable tumour (LSCT-RP6), but were unsuccessful after numerous attempts with RAV-1 transplantable tumours (LSCT-RP5). The LSCC-RP9 and LSCC-RP12 lymphoblastoid cell lines grow rapidly and produce large amounts of virus. These transplantable tumours and lymphoblastoid cell lines should provide valuable materials for studies on virus-host and tumour cell-host interrelationships.


Block vs. Traditional Periodization of HIT: Two Different Paths to Success for the World's Best Cross-Country Skier.
In short-term studies, block periodization of high-intensity training (HIT) has been shown to be an effective strategy that enhances performance and related physiological factors. However, long-term studies and detailed investigations of macro, meso, and micro-periodization of HIT blocks in world-class endurance athletes are currently lacking. In a recent study, we showed that the world's most successful cross-country (XC) skier used two different periodization models with success throughout her career. One including extensive use of HIT blocks, namely BP, and one using a traditional method namely TRAD. In this study, we compare BP with TRAD in two comparable successful seasons and provide a detailed description of the annual use of HIT blocks in BP. The participant is the most-decorated winter Olympian, with 8 Olympic gold medals, 18 world championship titles, and 114 world cup victories. Training data was categorized by training form (endurance, strength, and speed), intensity [low (LIT), moderate (MIT), and HIT], and mode (running, cycling, and skiing/roller skiing). No significant difference was found in the total endurance training load between BP and TRAD. However, training volume in BP was lower compared to TRAD (15 ± 6 vs. 18 ± 7 h/wk, P = 0.001), mainly explained by less LIT (13 ± 5 vs. 15 ± 5 h/wk, P = 0.004). Lower volume of MIT was also performed in BP compared to TRAD (13 vs. 38 sessions/year), whereas the amount of HIT was higher in BP (157 vs. 77 sessions/year). While BP included high amounts of HIT already from the first preparation period, followed by a reduction toward the competition period, TRAD had a progressive increase in HIT toward the competition period. In BP, the athlete performed seven HIT blocks, varying from 7 to 11 days, each including 8-13 HIT sessions. This study provides novel insights into successful utilization of two different periodization models in the worlds best XC skier, and illustrates the macro, meso and micro- periodization of HIT blocks to increase the overall amount of HIT.


Randomized, multicenter, warfarin-controlled phase II study of edoxaban in Japanese patients with non-valvular atrial fibrillation.
Edoxaban is a once-daily (QD) oral, direct factor Xa inhibitor in clinical development for the prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to evaluate the safety of edoxaban in Japanese patients with NVAF. A total of 536 NVAF patients (CHADS2 ≥1) were randomized to receive double-blinded edoxaban 30, 45, or 60 mg QD or open-label warfarin (international normalized ratio [INR] 2.0-3.0 for age <70 years; 1.6-2.6 for age ≥70 years) for 12 weeks. The primary endpoint was the incidence of all bleeding events (major, clinically relevant non-major, and minor bleeds). Patients underwent CT and/or MRI to assess asymptomatic intracranial hemorrhage (ICH). Secondary endpoints included thromboembolic events and pharmacodynamic indices. The mean incidence of all bleeding events for edoxaban 30, 45, and 60mg, and warfarin was 18.5%, 22.4%, 27.7%, and 20.0%, respectively. There were no statistically significant differences among the edoxaban groups and no significant differences from the warfarin group. There were no asymptomatic ICH events in any group. One episode of cerebral infarction was observed in the edoxaban 45-mg group. Subgroup analysis suggested low body weight (≤60kg) was associated with higher bleeding risk. Edoxaban 30, 45, and 60mg QD in patients with NVAF was associated with a numerical increase in all bleeding across the dose range, but this was not statistically significant, nor was any dose compared with warfarin.


Self-responsive co-delivery system for remodeling tumor intracellular microenvironment to promote PTEN-mediated anti-tumor therapy.
Delivering the pten gene into tumor cells to reacquire PTEN functionality is considered to be an attractive method for cancer treatment. However, the inhibition effect of the tumor intracellular microenvironment (TIME), especially at the high reactive oxygen species (ROS) level, on pten expression and PTEN protein functionality was nearly overlooked. Herein, the development of a potential strategy is described, which enhances PTEN-mediated anti-tumor capability by exhausting the intracellular ROS in TIME. To achieve this, poly(ethyleneimine) (PEI)-modified DSPE was introduced to protect the pten plasmid, and form liposomes for encapsulating the "scavenger" of oxidation homeostasis, epigallocatechin-3-gallate (EGCG). Notably, this was a simple system with improved safety compared which when compared with the use of PEI could accomplish efficient pten transfection and simultaneous disintegration to cause transient release of EGCG responding to the endosome environment through the "proton sponge effect". In the cytoplasm, EGCG depleted ROS and promoted the expression of the pten gene as well as restoring protein functionality, thus negatively regulating the PI3K-AKT signaling pathway. In vitro and in vivo results revealed that this system significantly inhibited tumor growth via remodeling of the TIME, and provided a promising way to control malignant tumors.


Characterization and Validation of an "Acute Aerobic Exercise Load" as a Tool to Assess Antioxidative and Anti-inflammatory Nutrition in Healthy Subjects Using a Statistically Integrated Approach in a Comprehensive Clinical Trial.
The homeostatic challenge may provide unique opportunities for quantitative assessment of the health-promoting effects of nutritional interventions in healthy individuals. Objective. The present study is aimed at characterizing and validating the use of acute aerobic exercise (AAE) on a treadmill at 60% of VO2max for 30 min, in assessing the antioxidative and anti-inflammatory effects of a nutritional intervention. In a controlled, randomized, parallel trial of Korean black raspberry (KBR) (n = 24/group), fasting blood and urine samples collected before and following the AAE load at either baseline or 4-week follow-up were analyzed for biochemical markers, 1H-NMR metabolomics, and transcriptomics. The AAE was characterized using the placebo data only, and either the placebo or the treatment data were used in the validation. The AAE load generated a total of 50 correlations of 44 selected markers, based on Pearson's correlation coefficient analysis of 105 differential markers. Subsequent mapping of selected markers onto the KEGG pathway dataset showed 127 pathways relevant to the AAE load. Of these, 54 pathways involving 18 key targets were annotated to be related to oxidative stress and inflammation. The biochemical responses were amplified with the AAE load as compared to those with no load, whereas, the metabolomic and transcriptomic responses were downgraded. Furthermore, target-pathway network analysis revealed that the AAE load provided more explanations on how KBR exerted antioxidant effects in healthy subjects (29 pathways involving 12 key targets with AAE vs. 12 pathways involving 2 key targets without AAE). This study provides considerable insight into the molecular changes incurred by AAE and furthers our understanding that AAE-induced homeostatic perturbation could magnify oxidative and inflammatory responses, thereby providing a unique opportunity to test functional foods for antioxidant and anti-inflammatory purposes in clinical settings with healthy subjects.


Lumbar Puncture: Creation and Resident Acceptance of a Low-Cost, Durable, Reusable Fluoroscopic Phantom with a Fluid-Filled Spinal Canal for Training at an Academic Program.
Simulation-based medical training provides learners a method to develop technical skills without exposing patients to harm. Although fluoroscopic phantoms are already adopted in some areas of radiology, this has historically not been for lumbar puncture. Commercially available phantoms are expensive. We report a cost-effective, accessible solution by creation of an inexpensive phantom for resident training to perform fluoroscopically guided lumbar puncture, as well as instructions on how to make a phantom for residency education. An anthropomorphic ballistics-gel phantom that contains a plastic lumbar vertebral column and simulated CSF space was created. Radiology residents with minimum or no experience with fluoroscopically guided lumbar punctures were given a brief education and practiced fluoroscopically guided lumbar punctures on the phantom. A survey from the residents was then done. The phantom was qualitatively quite durable and deemed adequate for educational purposes. All the residents surveyed expressed the desire to have this phantom available and it increased comfort, knowledge, and perceived likelihood of success. Few articles have been published that focused on low-cost phantom creation for fluoroscopic-procedure training. This study supports the benefits of using phantoms for fluoroscopic training as well as step-by-step instructions for creation of this phantom. The residents responded positively and felt more confident in their fluoroscopically guided techniques. The ability to make a long-term training device for resident education would be inexpensive and relatively easy to implement in academic programs.


The Effect of a Standardized Triage Process on Efficiency and Productivity of an Inpatient Palliative Care Team.
Studies have shown that palliative care involvement delivers a multitude of benefits to patients and caregivers. The existing palliative care workforce is inadequate to meet growing demand. Innovative strategies to triage inpatient consults are necessary. To describe the implementation of a new palliative care triage process and to demonstrate its impact on efficiency, teamwork, and patient care. A quasi-experimental study design, comparing clinical consult data from a 6-month period before and a 6-month period after implementation of the novel consult triage model. Across the 2 study periods, consult demand increased by 44% while the physician staffing (full time equivalent [FTE]) decreased by 38%. Penetration rate per clinical FTE increased (from 1.9%-2.4%; P = .004). Monthly physician work relative value units (RVUs) per FTE increased from 909 to 1678. Physician encounters with hospitalized patients increased from 284 to 353, and total team visits increased from 596 to 891 (P < .001). Average time to consult decreased by 2.4 hours (P = .54). An efficient and streamlined consult triage process had a positive impact on our palliative care team's ability to reach patients. We were able to generate more physician visits and RVUs despite a decrease in physician clinical time, and our penetration rate per physician clinical FTE improved. Our findings highlight the importance of thoughtful and appropriate triage, not to mention teamwork, in helping to augment patient access to palliative care.


[Gastrostomy as a stage of esophagoplasty].
The description of a modified technique of gastrostoma formation on small flexure is presented. Indications for this operation in patients with tumor and cicatrical esophageal strictures, planned for gastric esophagoplasty are formulated. The are authors regard a correctly created gastrostoma as the first stage of esophagoplasty. The main mistakes in gastrostoma creation that donTt permit to use the stomach for esophagus replacement are noted. The main principles and techniques of stoma creation on small flexure are described. The presented method is recommended for use in specialized esophageal departments and in general surgical hospitals.


Development and validation of a high performance liquid chromatography-tandem mass spectrometry method for the absolute analysis of 17 α D-amino acids in cooked meals.
In the nutrition field, there is a lack of understanding about the impact that dietary chiral composition may have on health, especially regarding cooked meals. Chiral amino acids (AAs) are naturally present in food and their proportion may vary quite a lot. Besides, the D-amino acids (D-AAs) are present in very low concentration compared to L-AAs, so very sensitive methods are required for their accurate quantitation. Moreover, some of them have been described as indicators of quality and different food processes. In this research, we propose a robust method for the absolute quantitation and enantiomeric ratio of 17 D-AAs in cooked meals. The AAs were extracted from 1 g of the homogenised meal with methanol, derivatised with (S)-N-(4-nitrophenoxycarbonyl) phenylalanine methoxyethyl ester ((S)-NIFE) and analysed by RP-LC-MS/MS. The separation was carried out with an Acquity BEH C18 (100 mm x 2.1 mm, 1.7 µm) column at 70 ºC, with 10 mmol/L ammonium bicarbonate in water as eluent A and acetonitrile as eluent B at a 0.3 mL/min flow rate in gradient elution. The MS operated in positive electrospray ionisation method in multiple reaction monitoring (MRM) mode. Isotopically labelled AAs were used as internal standards for the quantitation. The method was validated for 17 D-AAs in the cooked food samples in terms of specificity, linearity, precision, accuracy, matrix effect and stability. LLOQ are 2.0 ng/mL for most of them. Additionally, linearity was also studied for L-AAs. After optimization and validation, the method was applied to real breakfast, lunch and dinner samples of cooked meals (n = 18) that were part of a diet with a very high concordance with WHO dietary guidelines. Level of concentration of major and minor D-AAs have been described per total daily intake and within each of the three main meals. This method can be used for quality control purposes as well as to investigate the role of chiral composition in food and clinical outcomes.


A general strategy for site-directed enzyme immobilization by using NiO nanoparticle decorated mesoporous silica.
Mesoporous materials have recently gained much attention owing to their large surface area, narrow pore size distribution, and superior pore structure. These materials have been demonstrated as excellent solid supports for immobilization of a variety of proteins and enzymes for their potential applications as biocatalysts in the chemical and pharmaceutical industries. However, the lack of efficient and reproducible methods for immobilization has limited the activity and recyclability of these biocatalysts. Furthermore, the biocatalysts are usually not robust owing to their rapid denaturation in bulk solvents. To solve these problems, we designed a novel hybrid material system, mesoporous silica immobilized with NiO nanoparticles (SBA-NiO), wherein enzyme immobilization is directed to specific sites on the pore surface of the material. This yielded the biocatalytic species with higher activity than free enzyme in solution. These biocatalytic species are recyclable with minimal loss of activity after several cycles, demonstrating an advantage over free enzymes.


When More Means Less: The Prognosis of Recurrent Acute Myocardial Infarctions.
Recurrent acute myocardial infarctions (AMI) are common and associated with dismal outcomes. We evaluated the clinical characteristics and the prognosis of AMI survivors according to the number of recurrent AMIs (ReAMI) and the time interval of events (TI). A retrospective analysis of patients who survived following hospitalization with an AMI throughout 2002-2017 was conducted. The number of ReAMIs for each patient during the study period was recorded and classified based on following: 0 (no ReAMIs), 1, 2, ≥3. Primary outcome: all-cause mortality up to 10 years post-discharge from the last AMI. A total of 12,297 patients (15,697 AMI admissions) were analyzed (age: 66.1 ± 14.1 years, 68% males). The mean number of AMIs per patient was 1.28 ± 0.7; the rates of 0, 1, 2, ≥3 ReAMIs were 81%, 13.4%, 3.6% and 1.9%, respectively. The risk of mortality increased in patients with greater number of AMIs, HR = 1.666 (95% CI: 1.603-1.720, p < 0.001) for each additional event (study group), attenuated following adjustment for potential confounders, AdjHR = 1.135 (95% CI: 1.091-1.181, p < 0.001). Increased risk of mortality was found with short TI (<6-months), AdjHR = 2.205 (95% CI: 1.418-3.429, p < 0.001). The risk of mortality following AMI increased as the number of ReAMIs increased, and the TI between the events shortened. These findings should guide improved surveillance and management of this high-risk group of patients (i.e., ReAMI).


Archeological traces of early hominid activities, East of lake Rudolf, kenya.
Excavations have demonstrated that stone artifacts occur stratified within beds of Lower Pleistocene (or end Pliocene) age. At one site a low-density scatter of worked stone objects occurs together with small but significant quantities of broken-up bones. Potassium-argon dates indicate an age greater than 2 million years; thus, this may be the oldest known hominid occupation site. More than 20 hominid fossils have been recovered from various sedimentary formations in the area.


Remineralization of deep enamel dentine caries lesions.
Enamel remineralization is generally studied in superficial (up to 100 mum) lesions, but in vivo caries lesions may be tenfold deeper. This article addresses the question whether deep lesions, and extending into dentine, can be remineralized under optimal conditions and if this process is influenced by agents affecting calcium phosphate precipitation and dissolution. Lesions through enamel into dentine were first formed in thin sections and then continuously remineralized for periods up to 200 days. With longitudinal assessment by transversal microradiography it was showed that remineralization throughout the depth of the lesion and into the dentine was possible, although this process is very slow. Fluoride and bisphosphonate treatments affected mainly the deposition in the outer enamel. Although it was assumed that this would affect the diffusion of ions to deeper layers, the treatments had no impact on remineralization in the inner enamel or dentinal parts of the lesions. These findings are discussed with relevant theoretical considerations, and in their possible clinical implications.


Activity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae Isolates Collected from Respiratory Tract Specimens of Hospitalized Patients in the United States during 2013 to 2015.
The activities of ceftolozane-tazobactam and comparator agents against organisms deemed to be the cause of pneumonia among patients hospitalized in the United States during 2013 to 2015 were evaluated. Organisms included 1,576 Pseudomonas aeruginosa and 2,362 Enterobacteriaceae isolates susceptibility tested using reference broth microdilution methods. Ceftolozane-tazobactam, cefepime, ceftazidime, meropenem, and piperacillin-tazobactam inhibited 96.3%, 84.8%, 83.5%, 80.0%, and 78.6%, respectively, of the P. aeruginosa isolates. Ceftolozane-tazobactam inhibited 77.5 to 85.1% of isolates nonsusceptible to antipseudomonal β-lactams and 86.6% and 71.0% of the 372 (23.6% overall) multidrug- and 155 (9.8%) extensively drug-resistant isolates tested. The activity of this combination was greater than those of other β-lactams evaluated against P. aeruginosa groups across all U.S. census divisions. Ceftolozane-tazobactam was active against 90.6% of the Enterobacteriaceae, being less active than only meropenem (95.6% susceptible) among the β-lactams evaluated. Against 145 Escherichia coli and Klebsiella pneumoniae isolates carrying extended-spectrum-β-lactamase (ESBL)-encoding genes without carbapenemases, ceftolozane-tazobactam inhibited 82.8% of these isolates and was more active than cefepime and piperacillin-tazobactam (15.2% and 74.3% susceptible, respectively). ESBL genes included in this analysis were mainly blaCTX-M-15-like (89 isolates) and blaCTX-M-14-like (22) genes but also blaSHV (31) and blaTEM (3). Ceftolozane-tazobactam also displayed activity (84.6% susceptible) against 13 isolates harboring acquired AmpC genes. All β-lactams displayed limited activity against blaKPC-carrying isolates. Ceftolozane-tazobactam was the most active β-lactam tested against P. aeruginosa isolates from isolates that were the probable cause of pneumonia and displayed in vitro activity against Enterobacteriaceae, including isolates resistant to cephalosporins and carrying ESBL genes.


Developmental screening tools: feasibility of use at primary healthcare level in low- and middle-income settings.
An estimated 150 million children have a disability. Early identification of developmental disabilities is a high priority for the World Health Organization to allow action to reduce impairments through Gap Action Program on mental health. The study identified the feasibility of using the developmental screening and monitoring tools for children aged 0-3 year(s) by non-specialist primary healthcare providers in low-resource settings. A systematic review of the literature was conducted to identify the tools, assess their psychometric properties, and feasibility of use in low- and middle-income countries (LMICs). Key indicators to examine feasibility in LMICs were derived from a consultation with 23 international experts. We identified 426 studies from which 14 tools used in LMICs were extracted for further examination. Three tools reported adequate psychometric properties and met most of the feasibility criteria. Three tools appear promising for use in identifying and monitoring young children with disabilities at primary healthcare level in LMICs. Further research and development are needed to optimize these tools.


Biosensors in flow-injection systems for biomedical analysis, process and environmental monitoring.
This paper presents the construction of various biosensors using thin-film layers incorporated in flow injection devices, providing automated systems for biomedical analysis, process and environmental monitoring. A urease sensor has been developed in conjunction with a flow injection system for the automatic determination of urea. Use of the spraying immobilization technique gives rise to a response time of a few seconds, which allows sample throughputs up to 200 h-1. With a penicillin biosensor adapted in an appropriate cell detection, on-line measurements of penicillin V in the fermentation broth are achieved during the whole fermentation process; the results are compared with the HPLC method. Linearity, sensitivity and reproducibility of the biosensor are studied with regards to sample dilution in a stirred flow detection cell to provide optimal operating conditions. Measurements without any change in parameters are obtained during the whole fermentation process. Acetylcholinesterase sensors have been used in batch systems for the determination of pesticides, but they require large amounts of substrate. When those enzyme sensors are combined with flow injection systems, only small volumes (100 microliters) of substrate are injected into the carrier stream and an automated system can be obtained for continuous control of water quality.


Outer cell envelope glycoprotein from two strains of Serratia marcescens.
Cell envelope glycoproteins were extracted with sodium dodecyl sulfate from isolated cell walls of two strains of Serratia marcescens and purified by gel filtration column chromatography on Sepharose 4B. There was no significant difference in the chemical composition. Both fractions contained approximately 50% proteins and 10% carbohydrates. Glucosamine and glucose were identified as the only sugar components in the carbohydrate moiety. Immunochemically they shared at least one common antigenic component with each other and possibly with their corresponding lipopolysaccharide fractions.


[Effect of rhythmic photic interference on the working electroencephalogram and efficiency of human movements].
The effect of rhythmic light flashes on the space-time pattern of brain biopotentials during motor functions and biomechanical efficiency of man's actions was investigated. As the motor model we used the ability to maintain equilibrium when standing on the toes of one foot. Electroencephalography (EEG) from 12 neocortical areas and oscillations of the body mass center (stabilography) were recorded in 20 men who performed the exercise under normal conditions and during light flashes of 12 Hz. The resultant EEG and stabilograms were exposed to correlations-spectral and coherent analysis with the aid of an EC-1035 computer. Light flashes induced a change in the EEG peaks and flicker fusion frequency, a significant increase (by 23-108%, P less than 0.05) of the density of biopotentials corresponding to the light stimulation frequency, and a redistribution of the number of high intercentral correlations between neocortical motor centers. When the light flashes were presented, 75-85% test subjects showed a 0.19-0.26 increase in the biopotential coherence of the premotor, motor and sensomotor areas. They also exhibited a significant decrease in the body stability (P less than 0.01) and an increase in the stabilographic amplitude and frequency (P less than 0.01). It is suggested that the decline of biomechanical efficiency is associated with the disorders of the space-time integration between neocortical centers involved in the motor control system that are responsible for the execution of motor acts.


[A package of applied programs for pharmacological and biochemical calculations].
Thirty-three programs from the "Manual of Pharmacologic Calculations" by R. J. Tallarida and R. B. Murray were adapted for the Soviet microcomputer "Elektronika D3-28" using the "BASIC D3-28, variant 3a" language. The original ideology was fully preserved despite the change of operators and syntactical expressions. In the modified form the package of programs may be used for the Soviet microcomputers "Elektronika-60", "Iskra-226", "DVK-2M".


A Novel Subcutaneous Site of Islet Transplantation Superior to the Liver.
Islet transplantation is an attractive treatment for patients with insulin-dependent diabetes mellitus, and currently, the liver is the favored transplantation site. However, an alternative site is desirable because of the low efficiency of hepatic transplantation, requiring 2 to 3 donors for a single recipient, and because the transplanted islets cannot be accessed or retrieved. We developed a novel procedure of islet transplantation to the inguinal subcutaneous white adipose tissue (ISWAT) of mice and described functional and morphological characteristics of transplanted syngeneic islets. Also, it was determined whether islet allograft rejection in the ISWAT can be prevented by immunosuppressive agents. Furthermore, it was examined whether human islets function when grafted in this particular site of immune-deficient mice. In this site, transplanted islets are engrafted as clusters and function to reverse streptozotocin-induced diabetes in mice. Importantly, transplanted islets can be visualized by computed tomography and are easily retrievable, and allograft rejection is preventable by blockade of costimulatory signals. Of much importance, the efficiency of islet transplantation in this site is superior to the liver, in which hyperglycemia of diabetic recipient mice is ameliorated after transplantation of 200 syngeneic islets (the islet number yielded from 1 mouse pancreas) to the ISWAT but not to the liver. Furthermore, human islets transplanted in this particular site function to reverse diabetes in immune-deficient mice. Thus, the ISWAT is superior to the liver as the site of islet transplantation, which may lead to improved outcome of clinical islet transplantation.


Deidentification of facial images using composites.
Maxillofacial surgeons rely on photography for education and documentation. Photographs of the face, unlike those of other body regions, are readily identifiable. Traditional methods of facial image deidentification decrease educational quality or fail to adequately conceal identity. In the present study, a method that uses blended facial composites to deidentify original facial images was developed. This method allows significant components of the original face to be visualized while concealing its identity. The method was used to develop 20 different composite facial images that were viewed by student subjects. Ten of these images contained at least one third of a face that was familiar to the subjects. Subjects viewed the composite faces twice--first unaware that the faces were composites, and then primed to the presence of composites. Subjects later rated the efficacy of this method for image deidentification. When unaware that they were viewing composite images, no subjects recognized the familiar faces within the composites or rated them as familiar (0/120 total views, 0%). When later primed to the potential presence of familiar faces within composites, the identification rate increased significantly (74/120, 62%; P < .001). Results were similar no matter which portion of the familiar face (upper, 67%; mid, 54%; lower, 67%) was present. Subjects rated all composites as clinically realistic patient images. They also rated composites as more effective at deidentification than traditional methods. The use of composites appears to be a promising concept for facial image deidentification. Further larger-scale studies are needed to validate these findings.


Negative regulation of the human polyomavirus BK enhancer involves cell-specific interaction with a nuclear repressor.
We have examined the cell type-specific regulation of the human BK virus (BKV) enhancer. This enhancer functions efficiently in cis to activate expression from the adenovirus major late promoter in the human kidney cell line, 293, and in a monkey kidney cell line, MK2, but not in the HeLa cell line. In gel retardation migration assays, specific BKV enhancer-protein complexes could be observed by using nuclear extracts prepared from each cell line. Moreover, a unique DNA-protein complex was observed by using the HeLa cell nuclear extracts. By DNase footprint analysis, four binding regions for HeLa cell nuclear proteins were defined within the BKV enhancer repeat region. Two of the protected regions encompassed nuclear factor 1 or CCAAT transcription factor binding sites. These nuclear factor 1 sites also were protected by nuclear proteins from the 293 and MK2 cell lines. The other two protected sites encompassed a region of symmetry which included a sequence similar to the simian virus 40 TC enhancer motif and to a conserved sequence present upstream or within the introns of several cellular genes. These two sites were not protected by either the 293 or MK2 nuclear proteins. Competition studies in transfected cells indicated that the reduced activity of the BKV enhancer in the HeLa cell line was due to negative regulation. Further, we have demonstrated that binding of a nuclear factor(s) to the HeLa cell-specific site is involved in the repression of enhancer activity.


A very-low-fat vegan diet increases intake of protective dietary factors and decreases intake of pathogenic dietary factors.
There is increasing evidence that dietary factors in plant-based diets are important in the prevention of chronic disease. This study examined protective (eg, antioxidant vitamins, carotenoids, and fiber) and pathogenic (eg, saturated fatty acids and cholesterol) dietary factors in a very-low-fat vegan diet. Ninety-three early-stage prostate cancer patients participated in a randomized controlled trial and were assigned to a very-low-fat (10% fat) vegan diet supplemented with soy protein and lifestyle changes or to usual care. Three-day food records were collected at baseline (n=42 intervention, n=43 control) and after 1 year (n=37 in each group). Analyses of changes in dietary intake of macronutrients, vitamins, minerals, carotenoids, and isoflavones from baseline to 1 year showed significantly increased intake of most protective dietary factors (eg, fiber increased from a mean of 31 to 59 g/day, lycopene increased from 8,693 to 34,464 mug/day) and significantly decreased intake of most pathogenic dietary factors (eg, saturated fatty acids decreased from 20 to 5 g/day, cholesterol decreased from 200 to 10 mg/day) in the intervention group compared to controls. These results suggest that a very-low-fat vegan diet can be useful in increasing intake of protective nutrients and phytochemicals and minimizing intake of dietary factors implicated in several chronic diseases.


An ipsilateral comparison of acceleromyography and electromyography during recovery from nondepolarizing neuromuscular block under general anesthesia in humans.
Residual neuromuscular block is defined as a mechanomyography (MMG) or electromyography (EMG) train-of-four (TOF) ratio <0.90, and is common in patients receiving neuromuscular blocking drugs. Objective neuromuscular monitoring is the only reliable way to detect and exclude residual neuromuscular block. Acceleromyography (AMG) is commercially available and easy to use in the clinical setting. However, AMG is not interchangeable with MMG or EMG. Currently, it is unclear what value must be reached by AMG TOF ratio to reliably exclude residual neuromuscular block. During spontaneous recovery from neuromuscular block, we monitored TOF ratio on the same arm using AMG at the adductor pollicis and EMG at the first dorsal interosseus. AMG and EMG TOF ratios were compared by the Bland-Altman analysis for repeated measurements. The precision of each device was assessed by the repeatability coefficient. A small repeatability coefficient indicates high precision of the device. The agreement between the devices was assessed by the bias and the 95% limits of agreement. Small bias and narrow limits of agreement indicate strong agreement. We defined clinically acceptable agreement between AMG and EMG as a bias <0.025 and limits of agreement within -0.050 to 0.050, provided that the control comparison between EMG and itself can fulfill these criteria. In 26 patients, 261 comparisons between AMG and EMG were made. The repeatability coefficient of AMG and EMG were 0.094 (95% confidence interval [CI], 0.088-0.100) and 0.051 (95% CI, 0.048-0.055), respectively. The bias between AMG and EMG TOF ratio was 0.176 (95% CI, 0.162-0.190), with limits of agreement -0.045 to 0.396 (95% CI, -0.067 to 0.419). AMG is less precise than EMG and overestimates EMG TOF ratio by at least 0.15. The lack of agreement cannot be attributed to instrumental imprecision or the baseline difference between successive measurements during spontaneous recovery of neuromuscular function. Residual neuromuscular block cannot be excluded on reaching an AMG TOF ratio of 1.00.


Non-fermenters in urinary tract infection.
Sixty four (4.4%) strains of non-fermenting gram negative bacteria (NFGNB) were isolated out of 1,380 bacterial isolates from 7,784 urine samples, of which 43 were isolated from male patients and 21 from female patients. P. aeruginosa was found to be the commonest (67.2%) followed by A. lwoffi (7.8%), A. anitratus and P. acidovorans testosterani (6.2% each), P. maltophilia and P. denitrificans (4.8% each), P. putida and P. vesiculare (1.5% each). Forty two(65.6%) of these isolates were isolated as pure cultures and 22(34.4%) as predominant organisms. Most of these isolates i.e. 50-88.8% were sensitive to Norfloxacin and Ofloxacin and 22.2% to 66.6% of these isolates were sensitive to Gentamycin and Cephalexin whereas 11.1% of these isolates were sensitive to Co-trimoxazole and Ampicillin. All of these isolates were resistant to Penicillin and Tetracycline.


Prognostic value of 1p/19q chromosomal codeletion in patients with oligodendroglioma.
Oligodendrogliomas are common intra-axial primary brain tumours, and carry special significance due to several key features, which when present provide better prognosis compared to other intra-axial tumours. One of these features is presence of 1p/19q chromosomal codeletion that seems to not only be a marker of better prognosis but also signifies better response to chemotherapy. Herein the authors review the literature for evidence of the prognostic value of 1p/19q codeletion in OD.


Toward a better understanding of patient-reported outcomes in clinical practice.
Current shifts toward patient-centered healthcare and accountable payment options point to the more personalized production of better health, not just healthcare, as a next organizational paradigm. Transformation to a system geared toward promoting health requires us to think broadly about what it means to engage patients meaningfully, to give them a voice in their health and care, and to capture more of their varied experience and attitudes beyond the provider visit. The collection and use of patient-reported outcome data into electronic health records represents an important step forward for the transition to a more patient-centered health system. We set out an agenda for better understanding how and when patient-reported outcomes may improve patient health and care experience.


A novel magnetically guided, oxygen propelled CoPt/Au nanosheet motor in conjugation with a multilayer hollow microcapsule for effective drug delivery and light triggered drug release.
In recent years, nanomotors have been developed and attracted extensive attention in biomedical applications. In this work, a magnetically-guided oxygen-propelled CoPt/gold nanosheet motor (NSM) was prepared and used as an active self-propelled platform that can load, transfer and control the release of drug carrier to cancer cells. As a drug carrier, the microcapsules were constructed by the layer-by-layer (LbL) coating of chitosan and carboxymethyl cellulose layers, followed by incorporation of gold and magnetite nanoparticles. Doxorubicin (DOX) as an anti-cancer drug was loaded onto the synthesized microcapsules with a loading efficiency of 77%. The prepared NSMs can deliver the DOX loaded magnetic multilayer microcapsule to the target cancer cell based on the catalytic decomposition of H2O2 solution (1% v/v) via guidance from an external magnetic force. The velocity of NSM was determined to be 25.1 μm s-1 in 1% H2O2. Under near-infrared irradiation, and due to the photothermal effect of the gold nanoparticles, the proposed system was found to rapidly release more drugs compared to that of an internal stimulus diffusion process. Moreover, the investigation of cytotoxicity of NSMs and multilayer microcapsules clearly revealed that they have negligible side effects over all the concentrations tested.


Newly designed compliant hierarchic hybrid vascular grafts wrapped with a microprocessed elastomeric film--I: Fabrication procedure and compliance matching.
The object of this study was to develop a compliant hybrid vascular graft minimally supported by an elastomeric scaffold for arterial replacement. The hybrid vascular grafts designed were composed of three layers: an inner surface lined with endothelial cells (ECs); a hybrid medial tissue composed of a collagenous gel embedded with smooth muscle cells (SMCs); and an outer layer made of a laser-processed micropored segmented polyurethane (SPU) film with the circular pore size (diameter 150 microm) but different film thickness (50-200 microm) and different pore-to-pore distances (1 or 4 mm). The approximate dimensions of the hybrid vascular graft without the SPU film were as follows: inner diameter, 5 mm; length, 5 cm; thickness, 50 microm. The intraluminal pressure-external diameter relationship was measured by infusion of a phosphate buffer solution into the hybrid vascular graft. Canine carotid arteries and commercially available ePTFE grafts served as controls. Decrease in the thickness of the SPU film and increase in the pore density of the SPU film increased the pressure-dependent distensibility of the hybrid vascular grafts. The thinner the film and higher the pore density, the more compliant was the hybrid graft. The pressure-induced distensibility of the designed hybrid graft was found to be close to that of native carotid arteries.


Influence of plasma A esterase on anthelmintic action of haloxon in sheep.
Controlled trials were conducted to evaluate the anthelmintic action of haloxon in 2 phenotypes of lambs, 1 having an A esterase in plasma which rapidly hydrolyzes di-(2-chloroethyl)aryl phosphates and the other without this enzyme. A total of 116 lambs, 57 with and 59 without the plasma A esterase, 6 to 9 months old, harboring naturally acquired nematode infections were used in 3 trials. Haloxon was administered orally at 20, 25, and 35 mg/kg of body weight. Nematodes against which haloxon was evaluated in the abomasum were Ostertagia circumcincta and Trichostrongylus axei and in the small intestine were T vitrinus, T colubriformis, Nematodirus spathiger, and N filicollis. The anthelmintic efficiency of haloxon did not differ in the 2 phenotypes of sheep.


State Variation in the Receipt of a Contralateral Prophylactic Mastectomy Among Women Who Received a Diagnosis of Invasive Unilateral Early-Stage Breast Cancer in the United States, 2004-2012.
The use of contralateral prophylactic mastectomies (CPMs) among patients with invasive unilateral breast cancer has increased substantially during the past decade in the United States despite the lack of evidence for survival benefit. However, whether this trend varies by state or whether it is correlated with changes in proportions of reconstructive surgery among these patients is unclear. To determine state variation in the temporal trend and in the proportion of CPMs among women with early-stage unilateral breast cancer treated with surgery. A retrospective cohort study of 1.2 million women 20 years of age or older diagnosed with invasive unilateral early-stage breast cancer and treated with surgery from January 1, 2004, through December 31, 2012, in 45 states and the District of Columbia as compiled by the North American Association of Central Cancer Registries. Data analysis was performed from August 1, 2015, to August 31, 2016. Contralateral prophylactic mastectomy. Temporal changes in the proportion of CPMs among women with early-stage unilateral breast cancer treated with surgery by age and state, overall and in relation to changes in the proportions of those who underwent reconstructive surgery. Among the 1 224 947 women with early-stage breast cancer treated with surgery, the proportion who underwent a CPM nationally increased between 2004 and 2012 from 3.6% (4013 of 113 001) to 10.4% (12 890 of 124 231) for those 45 years or older and from 10.5% (1879 of 17 862) to 33.3% (5237 of 15 745) for those aged 20 to 44 years. The increase was evident in all states, although the magnitude of the increase varied substantially across states. For example, among women 20 to 44 years of age, the proportion who underwent a CPM from 2004-2006 to 2010-2012 increased from 14.9% (317 of 2121) to 24.8% (436 of 1755) (prevalence ratio [PR], 1.66; 95% CI, 1.46-1.89) in New Jersey compared with an increase from 9.8% (162 of 1657) to 32.2% (495 of 1538) (PR, 3.29; 95% CI, 2.80-3.88) in Virginia. In this age group, CPM proportions for the period from 2010 to 2012 were over 42% in the contiguous states of Nebraska, Missouri, Colorado, Iowa, and South Dakota. From 2004 to 2012, the proportion of reconstructive surgical procedures among women aged 20 to 44 years who were diagnosed with early-stage breast cancer and received a CPM increased in many states; however, it did not correlate with the proportion of women who received a CPM. The increase in the proportion of CPMs among women with early-stage unilateral breast cancer treated with surgery varied substantially across states. Notably, in 5 contiguous Midwest states, nearly half of young women with invasive early-stage breast cancer underwent a CPM from 2010 to 2012. Future studies should examine the reasons for the geographic variation and increasing trend in the use of CPMs.


[A cryo-irrigator].
A stomatological cryoirrigator intended for the treatment of precancerous affections of the oral mucosa and dental pulp through reproduction of local cryonecrosis is described. The cryoprobe helps obtain an oriented capillary jet of a liquid cooling agent. The design of the cryoirrigator ensures a graded delivery of the cooling agent and also the possibility of controlling its supply. It is liquid nitrogen that is used as a cooling agent.


First Experiences with Online Last Aid Courses for Public Palliative Care Education during the COVID-19 Pandemic.
The Last Aid course aims to teach public palliative care by increasing public awareness and empowering people about the role of the individual in the death of loved ones. The Covid-19 pandemic, however, has altered educational methods prohibiting classroom settings. Therefore, an online course was created to enable continued and safe public palliative care education. A mixed-methods study was performed to examine the feasibility of delivering the Last Aid course online. Data collection included participant questionnaires with qualitative and quantitative data, observations and a focus group discussion. Data were analyzed using descriptive analysis and qualitative description. In total, 15 online Last Aid courses were held, 174 participants took part in the study and 92 completed questionnaires were included. Findings revealed overall course satisfaction for the online courses in line with previous findings for classroom teaching. The online platform enabled course participation from people previously unable or unwilling to attend, namely caregivers to dying relatives and younger people. Instructors displayed an ability to teach online. However, some instructors expressed frustration over reduced interaction and technical challenges, which was echoed by participant ratings showing that many lacked social networking with fellow participants. Nonetheless, this pilot study demonstrates the feasibility of the online Last Aid course. Attention must be given to increasing both participant-to-participant and instructor-to-participant interaction. More research on the long-term effects of Last Aid courses is needed.