CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain.
In light of the adverse side-effects of opioids, cannabinoid receptor agonists may provide an effective alternative for the treatment of cancer pain. This study examined the potency and efficacy of synthetic CB1 and CB2 receptor agonists in a murine model of tumor pain. Intraplantar injection of the CB1 receptor agonist arachidonylcyclopropylamide (ED(50) of 18.4 μg) reduced tumor-related mechanical hyperalgesia by activation of peripheral CB1 but not CB2 receptors. Similar injection of the CB2 receptor agonist AM1241 (ED50 of 19.5 μg) reduced mechanical hyperalgesia by activation of peripheral CB2 but not CB1 receptors. Both agonists had an efficacy comparable with that of morphine (intraplantar), but their analgesic effects were independent of opioid receptors. Isobolographic analysis of the coinjection of arachidonylcyclopropylamide and AM1241 determined that the CB1 and CB2 receptor agonists interacted synergistically to reduce mechanical hyperalgesia in the tumor-bearing paw. These data extend our previous findings that the peripheral cannabinoid receptors are a promising target for the management of cancer pain and mixed cannabinoid receptor agonists may have a therapeutic advantage over selective agonists.


Financial time series prediction using least squares support vector machines within the evidence framework.
The Bayesian evidence framework is applied in this paper to least squares support vector machine (LS-SVM) regression in order to infer nonlinear models for predicting a financial time series and the related volatility. On the first level of inference, a statistical framework is related to the LS-SVM formulation which allows one to include the time-varying volatility of the market by an appropriate choice of several hyper-parameters. The hyper-parameters of the model are inferred on the second level of inference. The inferred hyper-parameters, related to the volatility, are used to construct a volatility model within the evidence framework. Model comparison is performed on the third level of inference in order to automatically tune the parameters of the kernel function and to select the relevant inputs. The LS-SVM formulation allows one to derive analytic expressions in the feature space and practical expressions are obtained in the dual space replacing the inner product by the related kernel function using Mercer's theorem. The one step ahead prediction performances obtained on the prediction of the weekly 90-day T-bill rate and the daily DAX30 closing prices show that significant out of sample sign predictions can be made with respect to the Pesaran-Timmerman test statistic.


Asthma/COPD drugs reflecting disease prevalence, patient adherence and persistence.
The aim of this review is to discuss the methodological issues involved in using pharmacy-record databases of drug sales in pharmacoepidemiology and to illustrate the usefulness of such data in estimating disease prevalence, patient adherence and persistence to therapy. Recent studies show that asthma/chronic obstructive pulmonary disease (COPD) prevalence increases with age. The volume of acquired asthma/COPD drugs per patient also increases with age and was approximately 2.5-times higher for patients aged 60-69 years compared with patients aged 20-29 years. Despite this, there is a comparatively low interest in asthma/COPD research involving elderly individuals. Published asthma/COPD-prevalence data and drug-treatment-prevalence data correspond reasonably well. Short- as well as long-term studies on drug acquisition indicate that approximately a third of patients have drugs available to cover at least 80% of the prescribed treatment time. Only approximately a tenth of the patients acquired steroids or steroid combinations, corresponding to one daily defined dose per day over a 5-year treatment period. It is probable that asthma/COPD is undertreated in all age groups.


[The antiarrhythmic action of piracetam].
It was found that a drug of the nootropic nature piracetam possessing pronounced antihypoxic properties eliminates calcium chloride-induced disturbances of the cardiac rhythm and significantly raises the threshold of atrial fibrillation during electrical stimulation. The drug's antiarrhythmic effect is followed by a decrease of the rhythm rate and an increase of the contraction amplitude. The animals treated with piracetam in a dose when its antiarrhythmic effects (300 mg/kg) exhibited a decrease of the membrane potential of erythrocytes as compared with control. Similar effects occurred in the animals treated with lidocaine. It can be concluded that in certain types of arrhythmias the use of piracetam restores the normal rhythm of contractions that is perhaps connected with its positive influence on metabolic processes in the myocardium.


Adductor canal block versus femoral nerve block for total knee arthroplasty: a prospective, randomized, controlled trial.
This prospective double-blinded, randomized controlled trial compared adductor canal block (ACB) with femoral nerve block (FNB) in patients undergoing total knee arthroplasty. The authors hypothesized that ACB, compared with FNB, would exhibit less quadriceps weakness and demonstrate noninferior pain score and opioid consumption at 6 to 8 h postanesthesia. Patients received an ACB or FNB as a component of a multimodal analgesic. Quadriceps strength, pain score, and opioid consumption were assessed on both legs preoperatively and at 6 to 8, 24, and 48 h postanesthesia administration. In a joint hypothesis test, noninferiority was first evaluated on the primary outcomes of strength, pain score, and opioid consumption at 6 to 8 h; superiority on each outcome at 6 to 8 h was then assessed only if noninferiority was established. Forty-six patients received ACB; 47 patients received FNB. At 6 to 8 h postanesthesia, ACB patients had significantly higher median dynamometer readings versus FNB patients (median [interquartile range], 6.1 kgf [3.5, 10.9] (ACB) vs. 0 kgf [0.0, 3.9] (FNB); P < 0.0001), but was not inferior to FNB with regard to Numeric Rating Scale pain scores (1.0 [0.0, 3.5] ACB vs. 0.0 [0.0, 1.0] FNB; P = 0.019), or to opioid consumption (32.2 [22.4, 47.5] ACB vs. 26.6 [19.6, 49.0]; P = 0.0115). At 24 and 48 h postanesthesia, there was no significant statistical difference in dynamometer results, pain scores, or opioid use between the two groups. At 6 to 8 h postanesthesia, the ACB, compared with the FNB, exhibited early relative sparing of quadriceps strength and was not inferior in both providing analgesia or opioid intake.


A-kinase-anchoring protein 1 (dAKAP1)-based signaling complexes coordinate local protein synthesis at the mitochondrial surface.
Compartmentalization of macromolecules is a ubiquitous molecular mechanism that drives numerous cellular functions. The appropriate organization of enzymes in space and time enables the precise transmission and integration of intracellular signals. Molecular scaffolds constrain signaling enzymes to influence the regional modulation of these physiological processes. Mitochondrial targeting of protein kinases and protein phosphatases provides a means to locally control the phosphorylation status and action of proteins on the surface of this organelle. Dual-specificity protein kinase A anchoring protein 1 (dAKAP1) is a multivalent binding protein that targets protein kinase A (PKA), RNAs, and other signaling enzymes to the outer mitochondrial membrane. Many AKAPs recruit a diverse set of binding partners that coordinate a broad range of cellular processes. Here, results of MS and biochemical analyses reveal that dAKAP1 anchors additional components, including the ribonucleoprotein granule components La-related protein 4 (LARP4) and polyadenylate-binding protein 1 (PABPC1). Local translation of mRNAs at organelles is a means to spatially control the synthesis of proteins. RNA-Seq data demonstrate that dAKAP1 binds mRNAs encoding proteins required for mitochondrial metabolism, including succinate dehydrogenase. Functional studies suggest that the loss of dAKAP1-RNA interactions reduces mitochondrial electron transport chain activity. Hence, dAKAP1 plays a previously unappreciated role as a molecular interface between second messenger signaling and local protein synthesis machinery.


[Prevention of complications in congenital diaphragmatic defects].
The mortality rate from congenital diaphragmatic hernia is not much better than it was 25 years ago. Most children, who are more than 24 hours of age at operation, survive. On the first day of life postoperative mortality is about 47%. Pediatric surgical problems are stabilization of the diaphragm and abdominal decompression. Some risk patients may be brought out of the fatal zone by high frequency ventilatory support and pharmacologic reversal of the fetal circulation. The most important causes of death are pulmonary hypoplasia with abnormal pulmonary vascular reactivity and persistent fetal circulation, iatrogenic pneumothorax, interstitial emphysema, mediastinal shifting with subsequent pulmonary hypertension and right to left shunting, and associated cardiac malformations.


In situ primary metabolites localization on a rat brain section by chemical mass spectrometry imaging.
We describe here the detection and identification of 13 primary metabolites (AMP, ADP, ATP, UDP-GlcNAc, ...) directly from rat brain sections by chemical mass spectrometry imaging. Matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS) was combined with 9-aminoacridine as a powerful matrix. We also demonstrate that a new robotic sprayer allows us to homogeneously coat the surface with the matrix, enabling the acquisition of chemical images at a 50 microm resolution, leading us to precisely and simultaneously localize each metabolite over the tissue surface. These experiments open a new field of investigation for chemical mass spectrometry imaging and are of great interest for both chemists and biologists.


Food-based Science Curriculum Increases 4th Graders Multidisciplinary Science Knowledge.
Health professionals and policymakers are asking educators to place more emphasis on food and nutrition education. Integrating these topics into science curricula using hand-on, food-based activities may strengthen students' understanding of science concepts. The Food, Math, and Science Teaching Enhancement Resource (FoodMASTER) Initiative is a compilation of programs aimed at using food as a tool to teach mathematics and science. Previous studies have shown that students experiencing the FoodMASTER curriculum were very excited about the activities, became increasingly interested in the subject matter of food, and were able to conduct scientific observations. The purpose of this study was to: 1) assess 4th graders food-related multidisciplinary science knowledge, and 2) compare gains in food-related science knowledge after implementation of an integrated, food-based curriculum. During the 2009-2010 school year, FoodMASTER researchers implemented a hands-on, food-based intermediate curriculum in eighteen 4th grade classrooms in Ohio (n=9) and North Carolina (n=9). Sixteen classrooms in Ohio (n=8) and North Carolina (n=8), following their standard science curricula, served as comparison classrooms. Students completed a researcher-developed science knowledge exam, consisting of 13 multiple-choice questions administered pre- and post-test. Only subjects with pre- and post-test scores were entered into the sample (Intervention n=343; Control n=237). No significant differences were observed between groups at pre-test. At post-test, the intervention group scored (9.95±2.00) significantly higher (p=.000) than the control group (8.84±2.37) on a 13-point scale. These findings suggest the FoodMASTER intermediate curriculum is more effective than a standard science curriculum in increasing students' multidisciplinary science knowledge related to food.


Salivary microRNAs in oral cancer.
This study investigated the use of three salivary microRNAs (miRNA-21, miRNA-184, and miRNA-145) as possible markers for malignant transformation in oral mucosal lesions. Salivary whole unstimulated samples were collected from a study group of 100 subjects, consisting of 20 clinically healthy controls, 40 patients with oral potentially malignant disorders (PMDs) [20 with dysplastic lesions and 20 without dysplasia], 20 with biopsy-confirmed oral squamous cell carcinoma (OSCC), and 20 with recurrent aphthous stomatitis (RAS) as disease controls. Total RNA was isolated and purified from saliva samples using the microRNA Isolation Kit (Qiagen, UL). miRNA expression analysis was performed using qRT-PCR (Applied Biosystems). There was a highly significant increase in salivary miRNA-21 and miRNA-184 in OSCC and PMD (with and without dysplasia) when compared to healthy and disease controls (P < 0.001). Conversely, miRNA-145 levels showed a highly significant decrease in OSCC and PMD overall (P < 0.001). RAS cases showed no significant difference from normal controls in any measured miRNA (P > 0.05). The only microRNA to discriminate between OSCC and PMD with dysplasia was miRNA-184. When receiver operating characteristic curves were designed for the three miRNAs, cutoff points delineating the occurrence of malignant change were a fourfold increase in miRNA-21 with specificity 65% and sensitivity 65%, a 0.6 decrease in miRNA-145, with specificity 70% and sensitivity 60%, and a threefold increase of miRNA-184, with specificity 75% and sensitivity 80%. Calculating the area under the curve revealed that miRNA-184 was the only one among the studied miRNAs that provided good diagnostic value. Salivary determination of the miRNAs tested might furnish a noninvasive, rapid adjunctive aid for revealing malignant transformation in oral mucosal lesions, particularly miRNA-184.


Acceptability of financial incentives for health behaviour change to public health policymakers: a qualitative study.
Providing financial incentives contingent on healthy behaviours is one way to encourage healthy behaviours. However, there remains substantial concerns with the acceptability of health promoting financial incentives (HPFI). Previous research has studied acceptability of HPFI to the public, recipients and practitioners. We are not aware of any previous work that has focused particularly on the views of public health policymakers. Our aim was to explore the views of public health policymakers on whether or not HPFI are acceptable; and what, if anything, could be done to maximise acceptability of HPFI. We recruited 21 local, regional and national policymakers working in England via gatekeepers and snowballing. We conducted semi-structured in-depth interviews with participants exploring experiences of, and attitudes towards, HPFI. We analysed data using the Framework approach. Public health policymakers working in England acknowledged that HPFI could be a useful behaviour change tool, but were not overwhelmingly supportive of them. In particular, they raised concerns about effectiveness and cost-effectiveness, potential 'gaming', and whether or not HPFI address the underlying causes of unhealthy behaviours. Shopping voucher rewards, of smaller value, targeted at deprived groups were particularly acceptable to policymakers. Participants were particularly concerned about the response of other stakeholders to HPFI - including the public, potential recipients, politicians and the media. Overall, the interviews reflected three tensions. Firstly, a tension between wanting to trust individuals and promote responsibility; and distrust around the potential for 'gaming the system'. Secondly, a tension between participants' own views about HPFI; and their concerns about the possible views of other stakeholders. Thirdly, a tension between participants' personal distaste of HPFI; and their professional view that they could be a valuable behaviour change tool. There are aspects of design that influence acceptability of financial incentive interventions to public health policymakers. However, it is not clear that even interventions designed to maximise acceptability would be acceptable enough to be recommended for implementation. Further work may be required to help policymakers understand the potential responses of other stakeholder groups to financial incentive interventions.


Bronchial hyperresponsiveness in preschool children with allergic rhinitis.
Nonasthmatic subjects with allergic rhinitis often have bronchial hyperresponsiveness (BHR), characteristic of asthma. The presence and degree of atopy is suggested to be important for BHR in patients with asthma. We aimed to assess BHR to methacholine (direct stimulus) and to adenosine 5'-monophosphate (AMP; indirect stimulus) in preschool children with allergic rhinitis and to investigate their relationship with the degree of atopy. Methacholine and AMP bronchial challenges were performed in preschool children with allergic rhinitis (n = 96), using a modified auscultation method. The end point concentration, resulting in audible wheezing and/or oxygen desaturation, was determined for each challenge. The degree of atopy was assessed using serum total IgE levels, the number of positive skin-prick tests, and atopic scores (sum of graded wheal size). BHR to methacholine (end point concentration, ≤8 mg/mL) and to AMP (end point concentration, ≤200 mg/mL) was observed in 32 (33.3%) and 26 (27.1%) subjects, respectively. No significant relationship was observed between BHR to methacholine and any atopy parameter. In contrast, the atopic scores were higher in the AMP-BHR(+) group compared with the AMP-BHR(-) group, and a significant association was found between the degree of atopic scores and the frequency of BHR to AMP (score for trend, p = 0.006). Such a relationship was not observed for serum total IgE levels and the number of positive SPTs. BHR to methacholine and BHR to AMP were detected in a significant proportion of preschool children with allergic rhinitis. The degree of atopy in terms of atopic scores seems to be an important factor for BHR to AMP but not for BHR to methacholine.


Phylogeny, host use, and diversification in the moth family Momphidae (Lepidoptera: Gelechioidea).
Insect herbivores and their hostplants constitute much of Earth's described biological diversity, but how these often-specialized associations diversify is not fully understood. We combined detailed hostplant data and comparative phylogenetic analyses of the lepidopteran family Momphidae to explore how shifts in the use of hostplant resources, not just hostplant taxon, contribute to the diversification of a phytophagous insect lineage. We inferred two phylogenetic hypotheses emphasizing relationships among species in the nominate genus, Mompha Hübner. A six-gene phylogeny was constructed with reared exemplars and collections from hostplants in the family Onagraceae from western and southwestern USA, and a cytochrome c oxidase subunit 1 (COI) phylogeny was inferred from collections and publicly available accessions in the Barcode of Life Data System. Species delimitation analyses combined with morphological data revealed ca. 56 undescribed species-level taxa, many of which are hostplant specialists on Onagraceae in the southwestern USA. Our phylogenetic reconstructions divided Momphidae into six major clades: 1) an Onagraceae flower- and fruit-boring clade, 2) a Melastomataceae-galling clade, 3) a leafmining clade A, 4) a leafmining clade B, 5) a Zapyrastra Meyrick clade, and 6) a monobasic lineage represented by Mompha eloisella (Clemens). Ancestral trait reconstructions using the COI phylogeny identified leafmining on Onagraceae as the ancestral state for Momphidae. Our study finds that shifts along three hostplant resource axes (plant taxon, plant tissue type, and larval feeding mode) have contributed to the evolutionary success and diversification of momphids.


Increase in malaria cases imported from Pakistan to Germany in 2012.
A significant increase of malaria cases imported to Germany from Pakistan was observed in 2012. As of 14 November, Pakistan was the country of infection in 32 out of 434 malaria cases in 2012, compared to zero to eight annual malaria cases (out of over 500 cases) in previous years. Physicians and public health authorities should consider malaria in febrile patients returning or migrating from Pakistan.


Epidemiology of rheumatoid arthritis in a tertiary care unit, Karachi, Pakistan.
To determine the frequency, demographic characteristics, associated co- morbidities and extraarticular manifestations in patients with rheumatoid arthritis (RA) visiting the rheumatology clinic at a tertiary care hospital, Karachi. A retrospective medical chart review of 4900 patients, who visited the rheumatology clinic at Liaquat National Hospital, from January 2005 to June 2007, was conducted. All patients with RA, of both gender and ages 16 years and above, who fulfilled the 1987 ACR criteria were included. Demographic characteristics, base line co-morbidity and extra-articular manifestations were recorded according to pre-defined criteria. Among 4900 patients, 633 (12.9%) visited the rheumatology clinic with RA, female to male ratio being 4:1. The mean age of onset was 38.5 +/- 12.4 years in females and 44.8 +/- 13.12 years in males. Among the age group 16-29 years females were more affected, whereas greater number of males presented between 50-75 years of age. Co-morbidities were found in 35.38% of RA patients. Cardiovascular disease including hypertension (13.79%) and ischaemic heart disease (6.6%) were the most common co-morbidities. RA factor was positive in 85.05% of the patients with hypertension and 88.09% of the patients with ischaemic heart disease. Extra-articular manifestations were reported in 3.47% of patients. Interstitial lung disease (1.57%) was the most common extra-articular manifestation. Significant proportion of patients with female predominance visited the rheumatology clinic at a tertiary care hospital due to RA. Rheumatoid factor may predict the risk of developing cardiovascular disease in patients with RA. The frequency of extra-articular manifestation was lower than that reported in western population.


Reconstructing Local Profile of Exciton-Emission Wavelengths across a WS2 Bubble beyond the Diffraction Limit.
Air bubbles formed between layers of two-dimensional (2D) materials not only are unavoidable but also emerge as an important means of engineering their excitonic emission properties, especially as controllable quantum light sources. Measuring the actual spatially resolved optical properties across such bubbles is important for understanding excitonic physics and for device applications; however, such a measurement is challenging due to nanoscale features involved which require spatial resolution beyond the diffraction limit. Additional complexity is the involvement of multiple physical effects such as mechanical strain and dielectric environment that are difficult to disentangle. In this paper, we demonstrate an effective approach combining micro-photoluminescence measurement, atomic force microscope profile mapping, and a theoretical strain model. We succeeded in reconstructing the actual spatial profiles of the emission wavelengths beyond the diffraction limit for bubbles formed by a monolayer tungsten disulfide on boron nitride. The agreements and consistency among various approaches established the validity of our approach. In addition, our approach allows us to disentangle the effects of strain and dielectric environment and provides a general and reliable method to determine the true magnitude of wavelength changes due to the individual effects across bubbles. Importantly, we found that micro-optical measurement underestimates the red and blue shifts by almost 5 times. Our results provide important insights into strain and screening-dependent optical properties of 2D materials on the nanometer scale and contribute significantly to our understanding of excitonic emission physics as well as potential applications of bubbles in optoelectronic devices.


E-psychiatry: uses and limitations.
The importance of using e-mail as a mode of communication between physicians and patients is becoming more common and popular because of its speed and effectiveness. Though little research has been done on the use and impact of e-mail in psychiatry but evidence is available about its frequent use both by the patients and the psychiatrists. This review paper attempts to examine the importance of this mode of communication, with its risks and threats. The inherent limitations of the message transfer method and the magnitude of its usage with benefits and hazards, both for the doctors and patients, will also be analyzed. The recommended guidelines concerning its usage are also present. It is concluded that though e-mail communication is fast gaining popularity, its impact on psychiatry is yet to be seen keeping in view the importance of direct communication with patients in the practice of psychiatry. It appears that with the development of future technologies, e-psychiatry will become relatively risk free and a source of help for the general health care system.


Transcriptional analysis of avian embryonic tissues following infection with avian infectious bronchitis virus.
Avian infectious bronchitis virus (IBV) infection is one of the major viral respiratory diseases of chickens. Better understanding of the molecular basis of viral pathogenesis should contribute significantly towards the development of improved prophylactic, therapeutic and diagnostic reagents to control infections. In the present investigation, transcriptional profiles were analyzed by using RNA recovered from the lung tissue of IBV infected 18-day-old chicken embryos at 6, 24, 48 and 72 h post IBV infection. This microarray analysis was completed using avian cDNA arrays comprised of fragments of 1191 unique chicken and turkey gene transcripts. These arrays were generated from normalized cDNA subtraction libraries that were derived from avian pneumovirus (APV) infected chicken embryo fibroblast (CEF) cultures and tissues obtained from APV infected turkeys subtracted with their respective uninfected cultures and tissues. Of the 1191 unique genes represented on the array, the expression of a total of 327 genes (27% of total) were altered by two-fold or more from 6 through 72 h post-infection. A comparative analysis of IBV regulated genes with genes previously reported to change in expression following infection with other avian respiratory viruses revealed both conserved and unique changes. Real-time qRT-PCR was used to confirm the regulated expression of genes related to several functional classes including kinases, interferon induced genes, chemokines and adhesion molecules, vesicular trafficking and fusion protein genes, extracellular matrix protein genes, cell cycle, metabolism, cell physiology and development, translation, RNA binding, lysosomal, protein degradation and ubiquitination related genes. Microarray analysis served as an efficient tool in facilitating a comparative analysis of avian respiratory viral infections and provided insight into host transcriptional changes that were conserved as well as those which were unique to individual pathogens.


Interactions of plant growth-promoting rhizobacteria and soil factors in two leguminous plants.
Although the rhizomicrobiome has been extensively studied, little is known about the interactions between soil properties and the assemblage of plant growth-promoting microbes in the rhizosphere. Herein, we analysed the composition and structure of rhizomicrobiomes associated with soybean and alfalfa plants growing in different soil types using deep Illumina 16S rRNA sequencing. Soil pH, P and K significantly affected the composition of the soybean rhizomicrobiome, whereas soil pH and N had a significant effect on the alfalfa rhizomicrobiome. Plant biomass was influenced by plant species, the composition of the rhizomicrobiome, soil pH, N, P and plant growth stage. The beta diversity of the rhizomicrobiome was the second most influential factor on plant growth (biomass). Rhizomicrobes associated with plant biomass were identified and divided into four groups: (1) positively associated with soybean biomass; (2) negatively associated with soybean biomass; (3) positively associated with alfalfa biomass; and (4) negatively associated with alfalfa biomass. Genera assemblages among the four groups differentially responded to soil properties; Group 1 and Group 2 were significantly correlated with soil pH and P, whereas Group 3 and Group 4 were significantly correlated with soil N, K and C. The influence of soil properties on the relative abundance of plant biomass-associated rhizomicrobes differed between soybean and alfalfa. The results suggest the rhizomicrobiome has a pronounced influence on plant growth, and the rhizomicrobiome assemblage and plant growth-associated microbes are differentially structured by soil properties and leguminous plant species.


[Progressive respiratory insufficiency secondary to pulmonary fibrosis in childhood. Report of one case].
Interstitial lung diseases are uncommon in children, and can be idiopathic or secondary to known causes, sharing common pathological findings. We report a girl with progressive respiratory insufficiency secondary to interstitial pneumonia and pulmonary fibrosis, with risk factors such as bronchopulmonary dysplasia and respiratory infections (respiratory syncytial virus and suspected Mycoplasma pneumoniae), that may have had an additive effect. Nasal bi-level Positive Airway Pressure was used in the last period of her disease. She died due to global respiratory failure at the age of 14 years.


The pattern of plant annexin gene expression.
Peptide sequence data derived from a plant annexin, P34 [Smallwood, Keen & Bowles (1990) Biochem. J. 270, 157-161] was used to design amplimers for PCR. A unique fragment of 95 bp, amplified from tomato (Lycopersicon esculertum) genomic DNA, was used in Northern analyses and demonstrated a differential pattern of expression in vegetative tissues of tomato, potato (Solanum tuberosum) and barley (Hordeum vulgare). The tissue-specific abundance of the annexin transcript was found to correlate closely with abundance of annexin protein as revealed by their partial purification and analysis with antisera specific for annexins isolated from tomato suspension-culture cells.


[Sudden tetraplegia caused by hemorrhage in a central-medullary astrocytoma].
A case is reported of central-medullary cervical astrocytoma, which without any previous history is shown by a sudden pattern of tetraplegia and breathing insufficiency. The myelography suggested the existence of an expansive intramedullary process, carrying out an urgent surgical decompression and evacuating a central-medullary hematoma in relation to a glial benign type. Various aspects of the sudden tetraplegia are discussed.


Murine gammaherpesvirus 68 ORF52 encodes a tegument protein required for virion morphogenesis in the cytoplasm.
The tegument, a semiordered matrix of proteins overlying the nucleocapsid and underlying the virion envelope, in viruses in the gamma subfamily of Herpesviridae is poorly understood. Murine gammaherpesvirus 68 (MHV-68) is a robust model for studying gammaherpesvirus virion structure, assembly, and composition, as MHV-68 efficiently completes the lytic phase and productively infects cultured cells. We have found that MHV-68 ORF52 encodes an abundant tegument protein conserved among gammaherpesviruses. Detergent sensitivity experiments revealed that the MHV-68 ORF52 protein is more tightly bound to the virion nucleocapsid than the ORF45 tegument protein but could be dissociated from particles that retained the ORF65 small capsomer protein. ORF52, tagged with enhanced green fluorescent protein or FLAG epitope, localized to the cytoplasm. A recombinant MHV-68 bacterial artificial chromosome mutant with a nonsense mutation incorporated into ORF52 exhibited viral DNA replication, expression of late lytic genes, and capsid assembly and packaging at levels near those of the wild type. However, the MHV-68 ORF52-null virus was deficient in the assembly and release of infectious virion particles. Instead, partially tegumented capsids produced by the ORF52-null mutant accumulated in the cytoplasm, containing conserved capsid proteins, the ORF64 and ORF67 tegument proteins, but virtually no ORF45 tegument protein. Thus, ORF52 is essential for the tegumentation and egress of infectious MHV-68 particles in the cytoplasm, suggesting an important conserved function in gammaherpesvirus virion morphogenesis.


A Virulent Babesia bovis Strain Failed to Infect White-Tailed Deer (Odocoileus virginianus).
Wildlife are an important component in the vector-host-pathogen triangle of livestock diseases, as they maintain biological vectors that transmit pathogens and can serve as reservoirs for such infectious pathogens. Babesia bovis is a tick-borne pathogen, vectored by cattle fever ticks, Rhipicephalus spp., that can cause up to 90% mortality in naive adult cattle. While cattle are the primary host for cattle fever ticks, wild and exotic ungulates, including white-tailed deer (WTD), are known to be viable alternative hosts. The presence of cattle fever tick populations resistant to acaricides raises concerns regarding the possibility of these alternative hosts introducing tick-borne babesial parasites into areas free of infection. Understanding the B. bovis reservoir competence of these alternative hosts is critical to mitigating the risk of introduction. In this study, we tested the hypothesis that WTD are susceptible to infection with a B. bovis strain lethal to cattle. Two groups of deer were inoculated intravenously with either B. bovis blood stabilate or a larval extract supernatant containing sporozoites from infected R. microplus larvae. The collective data demonstrated that WTD are neither a transient host nor reservoir of B. bovis. This conclusion is supported by the failure of B. bovis to establish an infection in deer regardless of inoculum. Although specific antibody was detected for a short period in the WTD, the PCR results were consistently negative at multiple time points throughout the experiment and blood from WTD that had been exposed to parasite, transferred into naïve recipient susceptible calves, failed to establish infection. In contrast, naïve steers inoculated intravenously with either B. bovis blood stabilate or the larval extract supernatant containing sporozoites rapidly succumbed to disease. These findings provide evidence that WTD are not an epidemiological component in the maintenance of B. bovis infectivity to livestock.


[Use of 99mTc-tetrofosmin scintigraphy in the diagnosis of patients with hyperparathyroidism].
The aim of the work was to study the diagnostic value of 99mTc-tetrofosmin to localize anomalous parathyroid glands in patients with hyperparathyroidism. We have studied 33 patients: 12 with primary and 21 with secondary hyperparathyroidism, 9 of them renal graft recipients. Sixteen patients underwent surgery, 12 with primary and 4 with secondary hyperparathyroidism. All patients were injected with 740 MBq of 99mTc-tetrofosmin. Subsequently at 15, 30 and 60 minutes images were acquired for 300 seconds using a pin-hole collimator. A pertechnetate thyroid scintigraphy was obtained in 7 cases (24-48 h later) when the thyroid activity made difficult the identification of parathyroid glands. In the group of patients with primary hyperparathyroidism, all cases showed a focal uptake in lower right localization. In the secondary hyperparathyroidism group, 12 patients showed diffuse tracer uptake in two or more glands and histology confirmed hyperplasia in four of them. Seven cases showed a greater focal uptake in a gland: two of them were renal graft recipients and three were chronic renal failure cases in haemodyalisis, and two were evaluated postsurgery showing uptake in the remnant parathyroid gland. The two remaining patients had a normal scintigraphy and corresponded to two false negative cases. In conclusion, our results suggest that 99Tc-tetrofosmin may be used as a suitable tracer for preoperative detection and screening of anomalous parathyroid glands.


Spatial Variation in the Inflammatory Response of House Sparrows in their Native Range.
Characterizing spatial differences in wildlife immunity is the first step to identify environmental drivers of host defense and disease risks. The house sparrow (Passer domesticus) is a model system for ecoimmunology, but spatial differences in immunity have been largely restricted to the invasive range of this global species. We provide an initial test of spatial variation in immune response to phytohemagglutinin in the native range, finding that birds from Romania have greater inflammatory responses than birds from Egypt. Future broad surveys across the house sparrow native range could contextualize these differences and determine underlying drivers.


How Americans Make Sense of Two Novel Pandemics.
Using Galileo theory and method of multidimensional scaling (MDS), we compared the psychological distances between concepts related to two pandemic viruses, Zika and COVID-19. Surveys (Zika, N = 410; COVID-19, N = 291) were used to investigate the role of media use and interpersonal communication on the relationship between 10 concepts in multidimensional spaces. We asked these four research questions: Do the two spaces represent the two pandemics similarly? What is the relationship of me and of people to each pandemic? What is the effect of virus-related media use and interpersonal talk on the pandemic space? What are optimal messages for moving me closer to Zika and to COVID-19? Media use influenced the distances for both pandemics: With greater media use, the concepts were closer in the Zika space and further apart in the COVID-19 space. Interpersonal communication was associated with few differences in the spaces. Based on the psychological distances between concepts, optimal messages were identified: For Zika, a message with two concepts, people and women, is predicted to be most effective to move Zika to the concept me, whereas for COVID-19, a message with people is predicted to be most effective to move COVID-19 to me.


Effects of tumour necrosis factor-alpha on human sperm motility and apoptosis.
The aim of this study was to evaluate the effects of tumour necrosis factor-alpha (TNF-alpha) on sperm motility, mitochondrial membrane potential (DeltaPsi), phosphatidylserine (PS) externalization, sperm chromatin packaging quality, and DNA fragmentation. Motile spermatozoa, obtained from 10 normozoospermic men, were incubated with increasing concentrations of TNF-alpha and analyzed 1, 3, 6, and 24 h after incubation by flow cytometry. TNF-alpha decreased total motility 24 h after incubation at 10 ng/mL and progressive motility 3 h after incubation. Accordingly, TNF-alpha reduced sperm DeltaPsi in a concentration- and time-dependent manner. TNF-alpha increased the percentage of spermatozoa with PS externalization from the concentration of 1 ng/mL 1 h after incubation. TNF-alpha produced sperm chromatin and DNA damage in a concentration- and time-dependent manner. In conclusion, these findings may explain the reduction of fertility, secondary to upregulated production of TNF-alpha, in men with urogenital infections.


The effect of removing potentially infectious dogs on the numbers of canine Leishmania infantum infections in an endemic area with high transmission rates.
To assess the effect of the rapid removal of potentially infectious dogs on the prevalence and incidence of canine infections, a prospective study was undertaken in an area endemic for Leishmania infantum. We used serological testing based on the rapid DPP rK28 fusion protein chromatographic immunoassay for this dog screening-and-culling intervention trial. The outcome was evaluated by measuring seropositivity and sero-conversion/-reversion rates for canine infection. Our estimates indicated that concomitant detection and elimination of seropositive dogs with active disease may affect the numbers of canine infections and disease burden temporarily, although it is insufficient as a measure to interrupt the zoonotic L. infantum transmission. However, most of the asymptomatic, seropositive dogs continuously exhibit low levels of antibodies and/or reverted, remaining seronegative thereafter. In the process of waiting for an effective vaccine, one option for canine reservoir control may be to identify these possibly genetically resistant animals and promote their expansion in the population.


Hydrogen Transfer in Energetic Materials from ReaxFF and DFT Calculations.
Energetic materials are characterized by fast and complex chemical reactions. It makes them hardly available for kinetic experiments in relevant conditions and a good target for reactive molecular dynamics simulations. In this work, unimolecular and condensed-phase thermal decomposition of pentaerythritol tetranitrate (PETN) are investigated by ReaxFF molecular dynamics. It is shown that the decomposition kinetics in condensed phase may be described with the activation barrier lower by a factor of 2 than that for isolated molecules. The effect of the intermolecular hydrogen transfer is revealed in condensed phase. Energetic barriers for hydrogen transfer in two energetic materials (methyl nitrate, which is a nitroester as well as PETN, and o-nitrotoluene) are studied with ReaxFF and DFT using nudged elastic band technique. The results indicate that ReaxFF gives significantly lower activation energy for intermolecular hydrogen transfer in nitroesters than different DFT approximations, which explains the molecular dynamics results for PETN.


Striving towards integrated people-centred health services: reflections on the Australian experience.
Health systems around the world are under continuing pressure for reform. Health system reform involves both content and process. Content deals with changes to the structures of the health system; process deals with the strategies of change. In this paper, we reflect on the development of the Australian healthcare system and draw out lessons regarding both structural and developmental principles. We review the historical development and functional performance of a range of 'programmes' which comprise the Australian health system. We use WHO's 2016 'framework on integrated people-centred health services' as a standard against which to evaluate the performance of the different programmes. A model of health system development featuring incremental change, windows of opportunity and policy coherence is used to frame some lessons from the Australian experience regarding reform strategy. Several of the programmes reviewed can be shown to have contributed positively to integrated and people-centred services. However, there have also been significant shortfalls in performance. The successes and the shortfalls of the programmes reviewed reflect both their histories and their contemporary context. Structural principles emerging from this review include the policy leverage available under single payer purchasing and on the other hand the fragmenting effects of privatisation and marketisation. Lessons regarding strategies of reform include cultivating 'reform readiness' across all of the locations and levels where opportunities for change may emerge while cultivating system wide coherence through a shared vision of how the system as a whole should develop.


Hepatic hemangioma in celiac patients: data from a large consecutive series.
Background and Aims. Hepatic hemangioma (HH) has a widely ranging prevalence. The etiology is unclear; however, associations with autoimmune disorders have been described. We aimed at evaluating the prevalence of HH in celiac disease. Methods. Ninety-seven consecutive patients with celiac disease (18 M, 79 F, median age 41, and range 17-84 years) underwent liver ultrasound between January 2011 and 2012. The findings were compared with those of 1352 nonceliac patients (581 M, 771 F, median age 50, and range 16-94 years), without liver disease or previously detected HH, who underwent US in the same period. Results. Ultrasonographic findings consistent with HH were observed in 14 celiac patients (14.4%), a prevalence significantly higher than in controls (69 cases, 5.1%) (P = 0.0006). Subgroup analysis showed that, among women, the prevalence of HH was 16.4% in the celiac disease group (13/79) compared with 5.9% in controls (46/771) (P = 0.002). In celiac setting, HH had a median diameter of 1.3 cm and presented as a single lesion in 12 cases (86%). Conclusions. Our findings are consistent with a significantly higher prevalence of HH in celiac patients. Although mechanisms underlying this association remain unclear, autoimmune and metabolic processes, as well as alterations of gut-liver axis equilibrium, could play a role.


Progress in development of immunocontraceptive vaccines for permanent non-surgical sterilization of cats and dogs.
Each year, millions of cats and dogs are euthanized worldwide. There are insufficient resources to control shelter animals in developed countries, as well as feral cat and wild dog population levels, with current surgical sterilization techniques. Thus, population control of these animals will likely depend on the development of new non-surgical methods for cat and dog sterilization. One promising area of research is the development of contraceptive vaccines, or immunocontraceptives. In this article, previous approaches aimed at developing contraceptive vaccines will be reviewed, with a focus on those most related to sterilization of cats and dogs. There are a number of steps in reproduction that have been, or could be, targeted by the immune system, and the advantages and obstacles for inducing immunity to each of these will be discussed. Our current understanding of how these vaccines cause sterility, and our current ability to dissect these mechanisms in cats and dogs, also will be discussed.


The Inhibitory Effect of Sulforaphane on Bladder Cancer Cell Depends on GSH Depletion-Induced by Nrf2 Translocation.
Sulforaphane (SFN), an isothiocyanate (ITCs) derived from glucosinolate that is found in cruciferous vegetables, has been reported to exert a promising anticancer effect in a substantial amount of scientific research. However, epidemical studies showed inconsistencies between cruciferous vegetable intake and bladder cancer risk. In this study, human bladder cancer T24 cells were used as in vitro model for revealing the inhibitory effect and its potential mechanism of SFN on cell growth. Here, a low dose of SFN (2.5 µM) was shown to promote cell proliferation (5.18-11.84%) and migration in T24 cells, whilst high doses of SFN (>10 µM) inhibited cell growth significantly. The induction effect of SFN on nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression at both low (2.5 µM) and high dose (10 µM) was characterized by a bell-shaped curve. Nrf2 and glutathione (GSH) might be the underlying mechanism in the effect of SFN on T24 cell growth since Nrf2 siRNA and GSH-depleting agent L-Buthionine-sulfoximine abolished the effect of SFN on cell proliferation. In summary, the inhibitory effect of SFN on bladder cancer cell growth and migration is highly dependent on Nrf2-mediated GSH depletion and following production. These findings suggested that a higher dose of SFN is required for the prevention and treatment of bladder cancer.


Association Between Lymphatic Malformations of the Mediastinum and Congenital Venous Ectasia: Is It Just Coincidental?
The association between lymphatic malformations and congenital venous ectasia is extremely rare, and the relative rarity of both entities makes it difficult to determine the relationship between the two. Here we present four new cases and review the current literature. We hypothesize that there might be a strong association between mediastinal lymphatic malformations and segmental phlebectasia; furthermore, there is a molecular background that may justify the association between these two entities.


Gene transfer into mouse prepancreatic endoderm by whole embryo electroporation.
Understanding gene function in the developing pancreas is a major issue for pancreatic cell therapy. The in vivo analysis of gene function has essentially been performed by modulating gene expression in transgenesis. A faster and easier method is electroporation of mouse embryos. This technique, coupled with whole embryo culture, enables one to deliver genes and analyze their effects in a spatially and temporally regulated manner. We wanted to adapt the electroporation technique for gene transfer of whole e8.5 mouse embryos into the endoderm to allow expression of transgenes in the pancreas or liver. Using two platinum plate electrodes, low voltage and a precise positioning of the embryo in the electroporation cuvette we could target and express DNA constructs in the prepancreatic or prehepatic territories, identified with cell markers. We also demonstrated that this technique is a valuable tool in the study of transcriptional regulation in the developing endoderm. Targeted electroporation of whole embryos is a useful method of characterizing the gene network which controls pancreatic development.


A new technique of fixation of radial head fractures using a modified tubular plate.
Radial head fractures are fairly common, occurring in 17-44% of all elbow injuries. Mason Type 2 fractures may be fixed using mini fragment screws, this fixation often needing augmentation with a plate to make the construct rotationally stable. However, the drill holes needed to fix the plate to the radial head, carry the risk of inflicting more injury to the fractured fragments. In our case, the radial head fracture was fixed with a modified one-third tubular plate. The plate was cut through the distal hole and the two cut ends were bent into hooks. These two hooks were engaged into two breaches made on the margin of the radial head and this provided rotational stability to the head without causing further damage. The fracture healed well and the patient regained full movement in the elbow. We conclude that this method may be used to fix fractures of the radial head, which require additional support with a plate.


Synthesis of a novel photopolymerized nanocomposite hydrogel for treatment of acute mechanical damage to cartilage.
Intra-articular fractures initiate a cascade of pathobiological and pathomechanical events that culminate in post-traumatic osteoarthritis (PTOA). Hallmark features of PTOA include destruction of the cartilage matrix in combination with loss of chondrocytes and acute mechanical damage (AMD). Currently, treatment of intra-articular fractures essentially focuses completely on restoration of the macroanatomy of the joint. However, current treatment ignores AMD sustained by cartilage at the time of injury. We are exploring aggressive biomaterial-based interventions designed to treat the primary pathological components of AMD. This study describes the development of a novel injectable co-polymer solution that forms a gel at physiological temperatures that can be photocrosslinked, and can form a nanocomposite gel in situ through mineralization. The injectable co-polymer solution will allow the material to fill cracks in the cartilage after trauma. The mechanical properties of the nanocomposite are similar to those of native cartilage, as measured by compressive and shear testing. It thereby has the potential to mechanically stabilize and restore local structural integrity to acutely injured cartilage. Additionally, in situ mineralization ensures good adhesion between the biomaterial and cartilage at the interface, as measured through tensile and shear testing. Thus we have successfully developed a new injectable co-polymer which forms a nanocomposite in situ with mechanical properties similar to those of native cartilage, and which can bond well to native cartilage. This material has the potential to stabilize injured cartilage and prevent PTOA.


[Comparison of formulas for intraocular lens power calculation after corneal refractive surgery].
Objective: To evaluate the accuracy of five intraocular lens (IOL) power calculation formulas for calculating IOL power in patients with previous myopia-corrected corneal refractive surgery. Methods: In this case series study, a total of 30 eyes of 30 patients who had excimer laser corneal refractive surgery for myopia and subsequent cataract surgery in Qingdao Eye Hospital from April 2020 to October 2022 were included. The Pentacam anterior segment analysis system and IOLMaster were used to measure ocular parameters, including axial length, anterior chamber depth, keratometry, lens thickness, and mean true net power (mTNP). Five formulas were used for IOL power calculation: Shammas formula, Olsen formula, SRK/T (mTNP) formula, Haigis-L formula, and Barrett True-K formula. After cataract extraction, we obtained the actual postoperative refraction by measuring the objective refraction. The prediction error was determined as the difference between the actual postoperative refraction and the predicted refraction, and the absolute value of the prediction error was the absolute error. The differences in the calculation errors of the 5 formulas were compared. Results: Regarding the prediction errors, the results of the SRK/T (mTNP) and Olsen formulas were better than those of Shammas and Haigis-L, and the differences were statistically significant (all P<0.05). The proportion of eyes with an absolute error of 0.50 D for Barrett True-K was highest (70%, 21/30), followed by the SRK/T (mTNP) formula (67%, 20/30). The proportions of eyes with an absolute error within 1.00 D for Barrett True-K, SRK/T (mTNP), and Olsen were all over 80%, with 24 eyes, 24 eyes, and 25 eyes, respectively. Conclusions: The Barrett True-K formula showed high accuracy in predicting the refraction after cataract extraction in patients with a history of corneal refractive surgery for myopia. The calculation result of the Haigis-L formula was highly unstable.


Safety Monitoring of the Janssen (Johnson & Johnson) COVID-19 Vaccine - United States, March-April 2021.
On February 27, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Janssen (Ad.26.COV2.S) COVID-19 vaccine (Janssen Biotech, Inc., a Janssen Pharmaceutical company, Johnson & Johnson) (1). The Janssen COVID-19 vaccine, the third COVID-19 vaccine authorized for use in the United States, uses a replication-incompetent human adenoviral type 26 vector platform* (2) and is administered as a single intramuscular dose, whereas the first two authorized vaccines use an mRNA platform and require 2 doses. On February 28, 2021, the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for use of Janssen COVID-19 vaccine among persons aged ≥18 years (3). During April 13-23, CDC and FDA recommended a pause in use of Janssen vaccine after reports of six cases of cerebral venous sinus thrombosis (CVST) with thrombocytopenia (platelet count <150,000/μL of blood) among Janssen vaccine recipients (4). Similar thrombotic events, primarily among women aged <60 years, have been described in Europe after receipt of the AstraZeneca COVID-19 vaccine, which uses a replication-incompetent chimpanzee adenoviral vector (5-7). The U.S. CVST cases that prompted the pause in Janssen vaccination, as well as subsequently detected CVST cases, are described elsewhere (8). This report summarizes adverse events among Janssen vaccine recipients, including non-CVST cases of thrombosis with thrombocytopenia syndrome (TTS), reported to the Vaccine Adverse Events Reporting System (VAERS), a passive surveillance system, and through v-safe, an active monitoring system. As of April 21, 2021, 7.98 million doses of the Janssen COVID-19 vaccine had been administered. Among 13,725 VAERS reports reviewed, 97% were classified as nonserious and 3% as serious,† including three reports among women of cases of thrombosis in large arteries or veins accompanied by thrombocytopenia during the second week after vaccination. These three cases and the previously detected CVST cases are consistent with 17 cases of TTS,§ a newly defined condition. Approximately 338,700 Janssen COVID-19 vaccine recipients completed at least one v-safe survey during the week after vaccination; 76% reported a systemic reaction, 61% reported a local reaction, and 34% reported a health impact.¶ Fatigue and pain were commonly reported symptoms in both VAERS and v-safe. The overall safety profile is consistent with preauthorization clinical trials data. Prompt review of U.S. vaccine safety data detected three additional cases of non-CVST TTS, in addition to the previously recognized CVST cases that initiated the pause in use of the Janssen COVID-19 vaccine. Ongoing monitoring of adverse events after COVID-19 vaccination, including vaccination with the Janssen single-dose vaccine, is essential for evaluating the risks and benefits of each vaccine.


The psychosis susceptibility gene ZNF804A: associations, functions, and phenotypes.
As the first gene to have achieved genome-wide significance for psychosis, ZNF804A has predictably been a subject of intense research activity. We review the evidence to date for the association between schizophrenia and the original risk variant rs1344706 identified as well as additional common and rare variants at this locus. We describe the still scant literature on the biological function of ZNF804A and discuss the efforts being made to characterize and refine the associated phenotype using imaging and neuropsychological approaches. We conclude that ZNF804A is robustly, if modestly, associated with schizophrenia risk, with much work still remaining to elucidate its role in schizophrenia biology.


Role of thymic stromal lymphopoietin in the pathogenesis of lumbar disc degeneration.
This study aims to investigate the role of thymic stromal lymphopoietin (TSLP) in the pathogenesis of lumbar disc degeneration (LDD). Nucleus pulposus tissues were collected from 77 LDD patients (the case group), in addition, normal tissues were extracted from 21 patients suffering from lumbar fractures (the control group). Immunohistochemistry was applied in order to detect TSLP positive expression. In accordance with varying transfection, the cells were divided into TSLP-siRNA, TSLP-siRNA + TSLPR-siRNA, control, blank, anti-TSLPR, and IgG groups. Western blotting was used in order to detect TSLP expression in tissues, and TSLP and type II collagen (COL2AL) in cell culture media were detected using enzyme linked immunosorbent assay (ELISA). Cell viability was measured using a MTT assay. Aggrecan levels were detected using antonopulos, and cell apoptosis was determined using flow cytometry. TSLP-positive expression was found to be significantly higher in the case group compared with the control group. LDD patients' Pfirrmann grades and preoperative visual analogue scale (VAS) scores were associated with TSLP-positive rate. Cells transfected with TSLP-siRNA and TSLPR-siRNA plasmids exhibited lower TSLP and thymic stromal lymphopoietin receptor (TSLPR) protein expression compared with the control and blank groups. Compared with the control and blank groups, there was significantly higher cell viability, lower cell apoptosis, and higher COL2AL and Aggrecan levels in the TSLP-siRNA, anti-TSLPR, and TSLP-siRNA+TSLPR-siRNA groups; there were significant differences between the TSLP-siRNA, anti-TSLPR, and TSLP-siRNA+TSLPR-siRNA groups and IgG group (all P < .05) CONCLUSION:: Our study provides evidence for the hypothesis that TSLP could reflect the histological severity of LDD, and TSLP-siRNA and, TSLPR-siRNA could inhibit apoptosis of nucleus pulposus cells. The evident information obtained from the investigation could lead the way for new therapeutic approaches regarding LDD treatment.


The Prenatal Origin of Childhood Leukemia: Potential Applications for Epidemiology and Newborn Screening.
Childhood leukemias are heterogeneous diseases with widely differing incident rates worldwide. As circulating tumors, childhood acute leukemias are uniquely accessible, and their natural history has been described in greater detail than for solid tumors. For several decades, it has been apparent that most cases of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) initiate in utero. Circumstantial evidence in support of this contention includes the young age of onset and high rate of concordance among identical twins. "Backtracking" of leukemic somatic mutations, particularly gene translocations, to cord blood and dried blood spots collected during the perinatal period has provided molecular proof of prenatal leukemogenesis. Detection of a patient's leukemia translocation in easily accessible birth samples, such as dried blood spots, is straightforward with the knowledge of their idiosyncratic breakpoints. However, to translate these findings into population-based screening and leukemia prevention requires novel methods able to detect translocations at all possible breakpoints when present in a low frequency of cells. Several studies have attempted to screen for leukemic translocations, mainly the common ETV6-RUNX1 translocation, in cord blood samples from healthy children. Most studies have reported finding translocations in healthy children, but estimates of prevalence have varied widely and greatly exceed the incidence of leukemia, leading to concerns that technical artifact or contamination produced an artificially inflated estimate of translocation prevalence at birth. New generation techniques that capture the presence of these translocations at birth have the potential to vastly increase our understanding of the epidemiology of acute leukemias. For instance, if leukemic translocations are present at birth in a far higher proportion of children than eventually develop acute leukemia, what are the exposures and somatic molecular events that lead to disease? And could children with translocations present at birth be targeted for prevention of disease? These questions must be answered before large-scale newborn screening for leukemia can occur as a public health initiative. Here, we review the literature regarding backtracking of acute leukemias and the prevalence of leukemic translocations at birth. We further suggest an agenda for epidemiologic research using new tools for population screening of leukemic translocations.


Cost-effectiveness analysis of treatment of venous thromboembolism with rivaroxaban compared with combined low molecular weight heparin/vitamin K antagonist.
Venous thromboembolism (VTE) is a burden on healthcare systems. Standard treatment involves parenteral anticoagulation overlapping with a vitamin K antagonist, an approach that is effective but associated with limitations including the need for frequent coagulation monitoring. The direct oral anticoagulant rivaroxaban is similarly effective to standard therapy as a single-drug treatment for VTE and does not require routine coagulation monitoring. The objective of this economic evaluation was to estimate the cost-effectiveness of rivaroxaban compared with standard VTE treatment from a UK perspective. A Markov model was constructed using data and probabilities derived from the EINSTEIN DVT and EINSTEIN PE studies of rivaroxaban and other published sources. Health outcomes included VTE rates, bleeding events avoided, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). There was greater discounted quality-adjusted life expectancy with rivaroxaban than with standard therapy, irrespective of indication and treatment duration. Rivaroxaban was associated with per-patient cost savings for each treatment duration modelled (3, 6 and 12 months), and these were greatest with shorter durations. Rivaroxaban was found to be dominant (cheaper and more effective) and, therefore, cost-effective, in both patients with deep vein thrombosis and pulmonary embolism in all three treatment duration groups, and was also cost-effective in patients requiring lifelong anticoagulation (ICERs: £8677 per QALY and £7072 per QALY in patients with index deep vein thrombosis and pulmonary embolism, respectively). The cost-effectiveness of rivaroxaban was largely insensitive to variations in one-way sensitivity analysis. Probabilistic sensitivity analysis demonstrated that at a threshold of £20,000 per QALY, rivaroxaban had a consistent probability of being cost-effective, compared with LMWH/VKA treatment, of around 80% regardless of index VTE or duration of anticoagulation therapy (3, 6, 12 months or lifelong). This analysis suggests that rivaroxaban represents a cost-effective choice for acute treatment of deep vein thrombosis and pulmonary embolism and secondary prevention of VTE in the UK, compared with LMWH/VKA treatment, regardless of the required treatment duration.


The temporal impulse response function in infantile nystagmus.
Despite rapid to-and-fro motion of the retinal image that results from their incessant involuntary eye movements, persons with infantile nystagmus (IN) rarely report the perception of motion smear. We performed two experiments to determine if the reduction of perceived motion smear in persons with IN is associated with an increase in the speed of the temporal impulse response. In Experiment 1, increment thresholds were determined for pairs of successively presented flashes of a long horizontal line, presented on a 65-cd/m2 background field. The stimulus-onset asynchrony (SOA) between the first and second flash varied from 5.9 to 234 ms. In experiment 2, temporal contrast sensitivity functions were determined for a 3-cpd horizontal square-wave grating that underwent counterphase flicker at temporal frequencies between 1 and 40 Hz. Data were obtained for 2 subjects with predominantly pendular IN and 8 normal observers in Experiment 1 and for 3 subjects with IN and 4 normal observers in Experiment 2. Temporal impulse response functions (TIRFs) were estimated as the impulse response of a linear second-order system that provided the best fit to the increment threshold data in Experiment 1 and to the temporal contrast sensitivity functions in Experiment 2. Estimated TIRFs of the subjects with pendular IN have natural temporal frequencies that are significantly faster than those of normal observers (ca. 13 vs. 9 Hz), indicating an accelerated temporal response to visual stimuli. This increase in response speed is too small to account by itself for the virtual absence of perceived motion smear in subjects with IN, and additional neural mechanisms are considered.


Performance in decoding and writing of children with Developmental Language Disorder: preliminary data.
to verify the performance of children with Developmental Language Disorder in decoding and writing tests in order to better understand their manifestations and the process of acquiring written language skills. The study subjects were 80 children. The Research Group consisted of 16 children diagnosed with Developmental Language Disorder, 13 males and 3 females, mean age of 7.3. The Control Group counted on 64 subjects paired in gender, age, education and socioeconomic level with the Control Group in a 4:1 ratio. The ability to decode words and pseudowords of both groups was evaluated, measuring the time spent to correctly read words and the percentage of correct answers, also considering the length of the word/pseudoword. The writing evaluation was carried out in the control group, which had its spelling errors analyzed and categorized. All data underwent descriptive and inferential statistical analysis. The data indicated a longer decoding time and a lower percentage of correct answers for the children from the Research Group. Regarding spelling errors, there was a predominance of arbitrary spelling errors. The data showed that children with Developmental Language Disorder tend to have a longer decoding time, greater percentage of errors than their peers and tend to present spelling errors more concentrated in natural orthography.


Biased placement of Mitochondria fission facilitates asymmetric inheritance of protein aggregates during yeast cell division.
Mitochondria are essential and dynamic eukaryotic organelles that must be inherited during cell division. In yeast, mitochondria are inherited asymmetrically based on quality, which is thought to be vital for maintaining a rejuvenated cell population; however, the mechanisms underlying mitochondrial remodeling and segregation during this process are not understood. We used high spatiotemporal imaging to quantify the key aspects of mitochondrial dynamics, including motility, fission, and fusion characteristics, upon aggregation of misfolded proteins in the mitochondrial matrix. Using these measured parameters, we developed an agent-based stochastic model of dynamics of mitochondrial inheritance. Our model predicts that biased mitochondrial fission near the protein aggregates facilitates the clustering of protein aggregates in the mitochondrial matrix, and this process underlies asymmetric mitochondria inheritance. These predictions are supported by live-cell imaging experiments where mitochondrial fission was perturbed. Our findings therefore uncover an unexpected role of mitochondrial dynamics in asymmetric mitochondrial inheritance.


Quantitative Bioluminescence Tomography-Guided Conformal Irradiation for Preclinical Radiation Research.
Widely used cone beam computed tomography (CBCT)-guided irradiators in preclinical radiation research are limited to localize soft tissue target because of low imaging contrast. Knowledge of target volume is a fundamental need for radiation therapy (RT). Without such information to guide radiation, normal tissue can be overirradiated, introducing experimental uncertainties. This led us to develop high-contrast quantitative bioluminescence tomography (QBLT) for guidance. The use of a 3-dimensional bioluminescence signal, related to cell viability, for preclinical radiation research is one step toward biology-guided RT. Our QBLT system enables multiprojection and multispectral bioluminescence imaging to maximize input data for the tomographic reconstruction. Accurate quantification of spectrum and dynamic change of in vivo signal were also accounted for the QBLT. A spectral-derivative method was implemented to eliminate the modeling of the light propagation from animal surface to detector. We demonstrated the QBLT capability of guiding conformal RT using a bioluminescent glioblastoma (GBM) model in vivo. A threshold was determined to delineate QBLT reconstructed gross target volume (GTVQBLT), which provides the best overlap between the GTVQBLT and CBCT contrast labeled GBM (GTV), used as the ground truth for GBM volume. To account for the uncertainty of GTVQBLT in target positioning and volume delineation, a margin was determined and added to the GTVQBLT to form a QBLT planning target volume (PTVQBLT) for guidance. The QBLT can reconstruct in vivo GBM with localization accuracy within 1 mm. A 0.5-mm margin was determined and added to GTVQBLT to form PTVQBLT, largely improving tumor coverage from 75.0% (0 mm margin) to 97.9% in average, while minimizing normal tissue toxicity. With the goal of prescribed dose 5 Gy covering 95% of PTVQBLT, QBLT-guided 7-field conformal RT can effectively irradiate 99.4 ± 1.0% of GTV. The QBLT provides a unique opportunity for investigators to use biologic information for target delineation, guiding conformal irradiation, and reducing normal tissue involvement, which is expected to increase reproducibility of scientific discovery.


Immunomodulation of voltage-dependent K+ channels in macrophages: molecular and biophysical consequences.
Voltage-dependent potassium (K(v)) channels play a pivotal role in the modulation of macrophage physiology. Macrophages are professional antigen-presenting cells and produce inflammatory and immunoactive substances that modulate the immune response. Blockage of K(v) channels by specific antagonists decreases macrophage cytokine production and inhibits proliferation. Numerous pharmacological agents exert their effects on specific target cells by modifying the activity of their plasma membrane ion channels. Investigation of the mechanisms involved in the regulation of potassium ion conduction is, therefore, essential to the understanding of potassium channel functions in the immune response to infection and inflammation. Here, we demonstrate that the biophysical properties of voltage-dependent K(+) currents are modified upon activation or immunosuppression in macrophages. This regulation is in accordance with changes in the molecular characteristics of the heterotetrameric K(v)1.3/K(v)1.5 channels, which generate the main K(v) in macrophages. An increase in K(+) current amplitude in lipopolysaccharide-activated macrophages is characterized by a faster C-type inactivation, a greater percentage of cumulative inactivation, and a more effective margatoxin (MgTx) inhibition than control cells. These biophysical parameters are related to an increase in K(v)1.3 subunits in the K(v)1.3/K(v)1.5 hybrid channel. In contrast, dexamethasone decreased the C-type inactivation, the cumulative inactivation, and the sensitivity to MgTx concomitantly with a decrease in K(v)1.3 expression. Neither of these treatments apparently altered the expression of K(v)1.5. Our results demonstrate that the immunomodulation of macrophages triggers molecular and biophysical consequences in K(v)1.3/K(v)1.5 hybrid channels by altering the subunit stoichiometry.


The role of the DSM-5 personality trait model in moving toward a quantitative and empirically based approach to classifying personality and psychopathology.
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) represents a watershed moment in the history of official psychopathology classification systems because it is the first DSM to feature an empirically based model of maladaptive personality traits. Attributes of patients with personality disorders were discussed by the DSM-5 Personality and Personality Disorders Work Group and then operationalized and refined in the course of an empirical project that eventuated in the construction of the Personality Inventory for DSM-5 (PID-5). We review research to date on the DSM-5 trait model, with a primary aim of discussing how this kind of research could serve to better tether the DSM to data as it continues to evolve. For example, studies to date suggest that the DSM-5 trait model provides reasonable coverage of personality pathology but also suggest areas for continued refinement. This kind of research provides a way of evolving psychopathology classification on the basis of research evidence as opposed to clinical authority.


Impact of DRGs on home health nursing.
Home health care agencies probably will see and care for Medicare patients who need different and more intensive services than in the past because of the impact of the DRG-based system of reimbursement. Therefore, coordination between health care providers is even more critical than before. Providers must examine their clients and modify their delivery system to efficiently and effectively ensure quality health care.


Nutrition component in a comprehensive child development program. II. Nutrient intakes of low-income, pregnant women and the outcome of pregnancy.
Twenty-four-hr. food recall records taken by home visitors in an intervention program for disadvantaged families yielded data similar to three-day records and 24-hr. recalls taken by nutritionists. The young, urban, low-income expectant mothers studied had intakes below the recommended allowances for all nutrients studied except ascorbic acid. Energy, calcium, and iron were particularly low. The use of energy- and/or sodium-restricted diets during pregnancy was associated with lower intakes of other nutrients. Recent studies showed that low energy intake appears common among low-income, young, pregnant women.


Gonadotrophic control of follicular development and function during the oestrous cycle of the ewe.
In the adult non-pregnant ewe the secretion of FSH is sufficient to ensure a continuous growth and development of antral follicles to 3-5 mm size at all times. Further development and increased secretion of oestradiol through the final 72 h to ovulation depends on adequate stimulation by LH. During anoestrus and the luteal phase of the cycle LH pulses occur too infrequently to stimulate sufficient oestradiol to evoke an LH surge. Moreover, during the luteal phase progesterone secreted by the corpus luteum not only reduces the frequency of LH pulses but also inhibits the ability of oestrogen to evoke an LH surge. At the time of luteal regression the frequency of LH pulses increases to at least one per hour due to the fall in progesterone secretion. This change in pulse frequency of LH is associated with a decrease in the secretion of FSH, probably because of a direct inhibitory action of oestrogen on the anterior pituitary gland. The dominant follicle is probably relatively independent of circulating levels of FSH due to the high concentration of oestradiol and FSH within the microenvironment of the follicular cavity. Once the oestrogen secretion achieves a certain level a preovulatory surge of LH (and FSH) occurs. Increased sensitivity of the anterior pituitary to LH-RH and increased secretion of LH-RH from the hypothalamus both play a part in producing the LH surge. The rise in prolactin at this time probably reflects a decrease in hypothalamic dopamine turnover which is necessary for maximum release of LH-RH. The preovulatory LH surge initially stimulates and then totally inhibits further secretion of oestrogen and androgen from the ovulatory follicle. This suppression of steroid secretion is accompanied by a second peak of FSH at about the time of ovulation. The function of this second peak of FSH remains unknown although it may be responsible for the development of the large antral follicles which occur on Days 3 and 4. It is probably more important in those mammals like the rat and hamster which only form a functional corpus luteum if pregnancy occurs and in which oestrogen is necessary for implantation.


Cerebral edema associated with craniectomy and arterial hypertension.
The present studies were performed to determine whether cerebral edema will develop as a consequence of arterial hypertension and/or craniectomy. Arterial hypertension was induced for 30 minutes by inflation of a balloon catheter situated in the descending aorta, and a parietal craniectomy was performed. The cerebral edema noticed was evaluated by macroscopic and microscopic observations, BBB permeability of HRP and Evans blue and water content. In addition, ICP was measured in the cisterna magna and ICPP by a catheter-tip transducer. In arterial hypertension or craniectomy alone, some small areas of Evans blue extravasation with increased water content were seen in the cortex, which corresponded to the occipito-parietal parts of the arterial boundary zones. In contrast, when arterial hypertension was combined with craniectomy, these lesions extended further into underlying white matter with increased water content. Forty-eight hours later, extensive brain edema with a shift of midline structures developed on the side of craniectomy which differed from that in arterial hypertension or craniectomy alone. It is suggested that some hydrostatic pressure gradients, particularly between blood vessel and surrounding extracellular space and among different areas within the brain parenchyma, may play an important role in the development of brain edema.


Detrimental impact of the Geobacter metallireducens type VI secretion system on direct interspecies electron transfer.
Direct interspecies electron transfer (DIET) is important in anaerobic communities of environmental and practical significance. Other than the need for close physical contact for electrical connections, the interactions of DIET partners are poorly understood. Type VI secretion systems (T6SSs) typically kill competitive microbes. Surprisingly, Geobacter metallireducens highly expressed T6SS genes when DIET-based co-cultures were initiated with Geobacter sulfurreducens. T6SS gene expression was lower when the electron shuttle anthraquinone-2,6-disulfonate was added to alleviate the need for interspecies contact. Disruption of hcp, the G. metallireducens gene for the main T6SS needle-tube protein subunit, and the most highly upregulated gene in DIET-grown cells eliminated the long lag periods required for the initiation of DIET. The mutation did not aid DIET in the presence of granular-activated carbon (GAC), consistent with the fact that DIET partners do not make physical contact when electrically connected through conductive materials. The hcp-deficient mutant also established DIET quicker with Methanosarcina barkeri. However, the mutant also reduced Fe(III) oxide faster than the wild-type strain, a phenotype not expected from the loss of the T6SS. Quantitative PCR revealed greater gene transcript abundance for key components of extracellular electron transfer in the hcp-deficient mutant versus the wild-type strain, potentially accounting for the faster Fe(III) oxide reduction and impact on DIET. The results highlight that interspecies interactions beyond electrical connections may influence DIET effectiveness. The unexpected increase in the expression of genes for extracellular electron transport components when hcp was deleted emphasizes the complexities in evaluating the electromicrobiology of highly adaptable Geobacter species. IMPORTANCE Direct interspecies electron transfer is an alternative to the much more intensively studied process of interspecies H2 transfer as a mechanism for microbes to share electrons during the cooperative metabolism of energy sources. DIET is an important process in anaerobic soils and sediments generating methane, a significant greenhouse gas. Facilitating DIET can accelerate and stabilize the conversion of organic wastes to methane biofuel in anaerobic digesters. Therefore, a better understanding of the factors controlling how fast DIET partnerships are established is expected to lead to new strategies for promoting this bioenergy process. The finding that when co-cultured with G. sulfurreducens, G. metallireducens initially expressed a type VI secretion system, a behavior not conducive to interspecies cooperation, illustrates the complexity of establishing syntrophic relationships.


The Finnish Family Competence Study: knowledge of childbirth of nulliparous women seen at maternity health care clinics.
To determine the level of knowledge about pregnancy and childbirth in nulliparous pregnant women. Survey using stratified randomised cluster sampling and confidential questionnaire analysis. Maternity health care clinics. Of a total eligible population of 1713 nulliparous pregnant women from a Finnish province, 1443 took part. Of the remainder, 131 were not informed of the study and 139 (8.8%) refused to participate. The distribution of occupation of the refusers was similar to the participants. Participants were questioned about their sociodemographic characteristics and about their knowledge of pregnancy and childbirth and psychomotor development in the infant, using 28 question sets (118 items). Results showed that, although social differences in the Finnish population are relatively small, there were still distinct differences in knowledge about childbearing in the different strata. The largest knowledge gaps were about health behaviour, particularly about alcohol intake and nutritional aspects of pregnancy and lactation, while knowledge of normal and abnormal delivery was relatively complete. When responses were divided into two groups with the median correct response rate as the cut off point, those with scores at or below the median were significantly more likely to have had modest education, to work in lower level employment, or to be very young or unemployed. Differences still occur in knowledge levels among nulliparous pregnant women and particular guidance and care is needed for less advantaged mothers to ensure that they deliver healthy full term babies.


[Treatment of amyloidosis].
Treatment of amyloidosis is a substantial challenge. Various types of amyloidosis are associated with a broad spectrum of organ manifestations and considerable morbidity and mortality. The present paper is based on a review of international literature, retrieved through a PubMed search on amyloidosis, and the author's clinical experience. Current treatment of amyloidosis is first and foremost aimed at reducing the level of amyloid precursor proteins; e.g. immunosuppression in AA amyloidosis, chemotherapy in AL amyloidosis and supportive treatment of diminished or lost organ function. Aggressive immunomodulating treatment increases survival in AA amyloidosis associated with rheumatic disease, and high-dose melphalan with autologous stem-cell transplantation (HMAS) has in selected studies shown increased survival in AL amyloidosis. More recent knowledge on mechanisms of amyloid formation has given rise to novel therapeutic targets that may be useful for all amyloidoses. Examples of this are immunotherapy and inhibition of the interaction of extrafibrillary components, which have shown benefit in animal models for AA, AL and Abeta amyloidosis as well as in the first human studies. More studies are needed to define their place in treatment of amyloidosis.


A new species, Phialophora europaea, causing superficial infections in humans.
A new species, Phialophora europaea, member of the P. verrucosa complex, is introduced. It is distinguished from existing species by reduced, flaring phialidic collarettes and inability to assimilate melibiose as sole source of carbon. Analysis of ITS1 and 2 rDNA of six strains attributed to the species show it to be clearly individualized. All strains originated from cutaneous and nail infections of humans in North-western Europe. A key to morphologically similar taxa is provided.


Chemical composition of the fruit mesocarp of three peach palm (Bactris gasipaes) populations grown in central Amazonia, Brazil.
The percent composition, soluble and insoluble food fibers, oil fatty acids and minerals were determined in the mesocarp of fruits of three peach palm (Bactris gasipaes Kunth) populations grown in Central Amazonia, Brazil. Amino acids were also determined in one of the populations. The mean protein levels ranged from 1.8 to 2.7%, lipid levels ranged from 3.5 to 11.1%, the nitrogen free fraction ranged from 24.3 to 35%, food fiber ranged from 5.2% to 8.7%, and energy ranged from 179.1 to 207.4 kcal%. All essential, as well as non-essential, amino acids were present, with tryptophan and methionine presenting the lowest mean concentrations. The mono-unsaturated oleic acid predominated in the oil, ranging from 42.8 to 60.8%, and palmitic acid was the most abundant saturated fatty acid, ranging from 24.1 to 42.3%. Among the essential fatty acids, linoleic acid was the most abundant, with a maximum of 5.4% in Pampa-8. The most important mineral elements were potassium, selenium and chromium, respectively corresponding to 12%, 9% and 9% of daily recommended allowances. Considering the nutritional potential of the fruit, we suggest its more frequent incorporation into the diet of the Amazonian population.


Oxygenation of (3Z)-alkenals to 4-hydroxy-(2E)-alkenals in plant extracts: a nonenzymatic process.
There is large interest in 4-hydroxy-(2E)-alkenals because of their cytotoxicity in mammals. However, the biosynthetic pathway for these compounds has not been elucidated yet. In plants, 4-hydroxy-(2E)-alkenals were supposed to be derived by the subsequent actions of lipoxygenase and a peroxygenase on (3Z)-alkenals. The presence of 9-hydroxy-12-oxo-(10E)-dodecenoic acid (9-hydroxy-traumatin) in incubations of 12-oxo-(9Z)-dodecenoic acid (traumatin) in the absence of lipoxygenase or peroxygenase, has prompted us to reinvestigate its mode of formation. We show here that in vitro 9-hydroxy-traumatin, 4-hydroxy-(2E)-hexenal and 4-hydroxy-(2E)-nonenal, are formed in a nonenzymatic process. Furthermore, a novel product derived from traumatin was observed and identified as 11-hydroxy-12-oxo-(9Z)-dodecenoic acid. The results obtained here strongly suggest that the 4-hydroxy-(2E)-alkenals, observed in crude extracts of plants, are mainly due to autoxidation of (3Z)-hexenal, (3Z)-nonenal and traumatin. This may have implications for the in vivo existence and previously proposed physiological significance of these products in plants.


Risk of recurrent stroke for Asian stroke patients treated with non-vitamin K antagonist oral anticoagulant and warfarin.
The aim of this study was to establish whether non-vitamin K antagonist oral anticoagulants (NOACs) are superior to warfarin in preventing stroke recurrence for atrial fibrillation (AF) patients with an ischemic or hemorrhagic stroke at the baseline. From 1 January 2009 to 31 December 2017, stroke patients with AF treated with oral anticoagulants in the National Health Insurance Research Database in Taiwan were enrolled. The study was retrospective cohort design. Outcome measures were ischemic and hemorrhagic stroke recurrence. The Cox proportional hazard model was used to obtain the hazard ratio (HR). In total, 39,840 stroke patients with AF treated with NOAC and 42,583 treated with warfarin were identified. NOACs were superior to warfarin in preventing all recurrent stroke [adjusted HR: 0.67, 95% confidence interval (CI), 0.63-0.71, p < 0.001]. Results for the ischemic stroke population were the same as that for all types for stroke (adjusted HR: 0.66, 95% CI, 0.62-0.70, p < 0.001). For the hemorrhagic stroke population, NOACs were equivalent to warfarin in preventing ischemic stroke (adjusted HR: 1.11, 95% CI, 0.86-0.43, p < 0.001), but NOACs were superior to warfarin in preventing hemorrhagic stroke (adjusted HR: 0.64, 95% CI, 0.55-0.74, p < 0.001). NOACs were generally superior to warfarin in terms of efficacy and safety in previous stroke patients. The robustness of our findings was verified and should add new information to current recommendations for Asian stroke patients in selecting NOACs.


The role of beta-adrenergic receptors in the cutaneous water evaporation mechanism in the heat-acclimated pigeon (Columba livia).
The effects of selective and non-selective beta-adrenergic agents on cutaneous water evaporation (CWE) were studied in hand-reared rock pigeons (Columba livia). CWE was measured by the vapor diffusive resistance method, using a transient porometer. Intramuscular and subcutaneous injections of a non-selective beta-adrenergic antagonist (propranolol) or a selective beta(2)-adrenergic antagonist (ICI-118551) to heat-acclimated (HAc) pigeons at ambient temperature (T(a)) of 24 degrees C resulted in intensive CWE. The CWE values that were triggered by propranolol and ICI-118551 (18.59+/-0.73 and 16.48+/-0.70 mg cm(-2) h(-1), respectively) were close to those induced by heat exposure (17.62+/-1.40 mg cm(-2) h(-1)). Subcutaneous administration of propranolol produced local response. Intramuscular injection of salbutamol (selective beta(2)-adrenergic agonist) to HAc pigeons drastically diminished CWE induced by either propranolol, metoprolol or heat exposure. Such manipulations also enhanced panting at relatively low T(a)s (42 degrees C). The inhibition of beta(1)-adrenergic receptors by metoprolol increased CWE, while inhibition by atenolol produced no change from basal values. This difference may be attributed to their distinctive nature in penetrating the blood-brain barrier. Our findings indicate a regulatory pathway for CWE consisting of both beta(1)- and beta(2)-adrenergic receptors. We suggest that the beta(1)-adrenergic effect is restricted mainly to the CNS, while the beta(2)-adrenergic effect takes place at the effector level. We postulate this level to be either the cutaneous microvasculature or the epidermal layer.


Cyclosporine A-induced mammary hyperplasia and hyperprolactinemia in New Zealand White rabbits.
To investigate the potential activity of cyclosporin A (CsA) to induce mammary hyperplasia in New Zealand White (NZW) rabbits. Female NZW rabbits were used throughout experiments. To simulate the conditions of immunosuppression, CsA (10 mg/kg of body weight/d) was administered intravenously on a daily basis for 14 days and methylprednisolone (5 mg/kg/d) was administered on the first two days. The CsA (10 mg/kg/d) also was administered without methylprednisolone for 14 days to another cohort of rabbits. Mammary tissue of each rabbit was palpated and serially measured during this treatment period. The CsA was discontinued, and rabbits were monitored for 14 more days during the washout period. Sequential plasma concentrations of prolactin, 17beta-estradiol, and progesterone in each blood sample were determined by use of radioimmunoassay. All NZW rabbits treated with CsA and methylprednisolone for immunosuppression consistently developed striking mammary tissue hyperplasia. At the end of treatment with CsA and methylprednisolone, mammary glands had extensive changes consistent with actively lactating glands. Similar but less extensive hyperplasia developed in response to CsA alone. Plasma concentration of prolactin increased during treatment and decreased during the washout period. Plasma concentration of 17beta-estradiol increased during treatment and continued to increase during the washout period. Plasma progesterone concentration decreased at the end of treatment. On discontinuation of CsA, mammary hyperplasia regressed. Cyclosporine A, with or without methylprednisolone, induces mammary hyperplasia and hyperprolactinemia in NZW rabbits. This rabbit model may be a reliable in vivo system by which to study immunosuppressant-induced structural and functional changes of mammary glands similar to those observed in humans.


On-Demand Degradation of Metal-Organic Framework Based on Photocleavable Dianthracene-Based Ligand.
We have designed a rigid photocleavable dianthracene-based ligand that reacts with ytterbium as coordination metal ion for the creation of a class of tridimensional light-degradable metal-organic framework (MOF). We demonstrated that we can obtain a high level of control on the disassembly of the MOF formed with this ligand which can be triggered either through light irradiation or temperature increase. The reversible 4π-4π photodimerization is the intrinsic chemical mechanism ruling the ligand and MOF cleavage. In the fields of biology and medicine, MOFs have sparked a strong interest as highly porous vehicles for drug release but have only been explored so far through the passive leakage of their payloads. The designed light-degradable MOFs can potentially overcome this limitation and serve as prototypes for drug delivery and corresponding therapeutic applications.


An enhanced Lactobacillus reuteri biofilm formulation that increases protection against experimental necrotizing enterocolitis.
One significant drawback of current probiotic therapy for the prevention of necrotizing enterocolitis (NEC) is the need for at least daily administration because of poor probiotic persistence after enteral administration, increasing the risk of the probiotic bacteria causing bacteremia or sepsis if the intestines are already compromised. We previously showed that the effectiveness of Lactobacillus reuteri ( Lr) in preventing NEC is enhanced when Lr is grown as a biofilm on the surface of dextranomer microspheres (DM). Here we sought to test the efficacy of Lr administration by manipulating the Lr biofilm state with the addition of biofilm-promoting substances (sucrose and maltose) to DM or by mutating the Lr gtfW gene (encoding an enzyme central to biofilm production). Using an animal model of NEC, we determined that Lr adhered to sucrose- or maltose-loaded DM significantly reduced histologic injury, improved host survival, decreased intestinal permeability, reduced intestinal inflammation, and altered the gut microbiome compared with Lr adhered to unloaded DM. These effects were abolished when DM or GtfW were absent from the Lr inoculum. This demonstrates that a single dose of Lr in its biofilm state decreases NEC incidence. Importantly, preloading DM with sucrose or maltose further enhances Lr protection against NEC in a GtfW-dependent fashion, demonstrating the tunability of the approach and the potential to use other cargos to enhance future probiotic formulations. NEW & NOTEWORTHY Previous clinical trials of probiotics to prevent necrotizing enterocolitis have had variable results. In these studies, probiotics were delivered in their planktonic, free-living form. We have developed a novel probiotic delivery system in which Lactobacillus reuteri (Lr) is delivered in its biofilm state. In a model of experimental necrotizing enterocolitis, this formulation significantly reduces intestinal inflammation and permeability, improves survival, and preserves the natural gut microflora compared with the administration of Lr in its free-living form.