Contact call-driven Zenk protein induction and habituation in telencephalic auditory pathways in the Budgerigar (Melopsittacus undulatus): implications for understanding vocal learning processes.
Expression of the immediate early gene protein Zenk (zif 268, egr-1, NGF1A, Krox24) was induced in forebrain auditory nuclei in a vocal learning parrot species, the budgerigar (Melopsittacus undulatus), when the subjects either listened to playbacks of an unfamiliar contact call or to a contact call with which they had been familiarized previously. Auditory nuclei included the Field L complex (L1, L2a, and L3), the neostriatum intermedium pars ventrolateralis (NIVL), the neostriatum adjacent to caudal nucleus basalis (peri-basalis or pBas), an area in the frontal lateral neostriatum (NFl), the supracentral nucleus of the lateral neostriatum (NLs), and the ventromedial hyperstriatum ventrale (HVvm). The latter three nuclei are main sources of auditory input to the vocal system. Two patterns of nuclear staining were induced by contact call stimulation-staining throughout cell nuclei, which was exhibited by at least some neurons in all areas examined except L2a and perinucleolar staining, which was the only kind of staining exhibited in field L2a. The different patterns of Zenk staining indicate that auditory stimulation may regulate the Zenk-dependent transcription of different subsets of genes in different auditory nuclei. The numbers of neurons expressing Zenk staining increased from seven- to 43-fold over control levels when the birds listened to a repeating unfamiliar call. Familiarization of the subjects with the call stimulus, through repeated playbacks, greatly reduced the induction of Zenk expression to the call when it was presented again after an intervening 24-h interval. To determine if neurons exhibiting contact call-driven Zenk expression project to the vocal control system, call stimulation was coupled with dextran amines pathway tracing. The results indicated that tracer injections in the vocal nucleus HVo (oval nucleus of the hyperstriatum ventrale), in fields lateral to HVo and in NLs labeled many Zenk-positive neurons in HVvm, NFl, and NLs. These results support the idea that, in these neurons, egr-1 couples auditory stimulation to the synthesis of proteins involved in either the storing of new perceptual engrams for vocal learning or the processing of novel and/or meaningful acoustic stimuli related to vocal learning or the context in which it occurs.


Leachate treatment in landfills is a significant N2O source.
The importance of methane (CH4) emissions from landfills has been extensively documented, while the nitrous oxide (N2O) emissions from landfills are considered negligible. In this study, three landfills were selected to measure CH4 and N2O emissions using the static chamber method. Dongbu (DB) and Dongfu (DF) landfills, both located in Xiamen city, Fujian Province, were classified as sanitary. The former started to receive solid waste from Xiamen city in 2009, and the latter was closed in 2009. Nanjing (NJ) landfill, located in Nanjing county, Fujian Province, was classified as managed. Results showed that for the landfill reservoirs, CH4 emissions were significant, while N2O emissions occurred mainly in operating areas (on average, 16.3 and 19.0mgN2Om-2h-1 for DB and NJ landfills, respectively) and made a negligible contribution to the total greenhouse gas emissions in term of CO2 equivalent. However, significant N2O emissions were observed in the leachate treatment systems of sanitary landfills and contributed 72.8% and 45.6% of total emissions in term of CO2 equivalent in DB and DF landfills, respectively. The N2O emission factor (EF) of the leachate treatment systems was in the range of 8.9-11.9% of the removed nitrogen. The total N2O emissions from the leachate treatment systems of landfills in Xiamen city were estimated to be as high as 8.55gN2O-Ncapita-1yr-1. These results indicated that N2O emissions from leachate treatment systems of sanitary landfills were not negligible and should be included in national and/or local inventories of greenhouse gas emissions.


[Reconstruction of pulmonary blood flow in the Norwood procedure; Blalock-Taussig shunt; from bench to surgery].
Although the right-ventricle to pulmonary artery( RV-PA) shunt as a source of pulmonary blood supply of Norwood procedure has improved early outcomes, disadvantages including right ventricular dysfunction or arrhythmias have been reported. So it has been still remained controversial whether BT shunt or RV-PA conduit should be selected. We examined the influence of Blalock-Taussig( BT) shunt size on regulation of the pulmonary blood flow in experimental model of a univentricular heart to determine the specific guidelines regarding suitable shunt size in the Norwood procedure. The canine univentricular heart model with the ratio of shunt size to body weight (SS/BW) of 0.8 to 1.1 showed significant negative correlation between the pulmonary/systemic blood flow ratio( Qp/Qs)and arterial PCo2, but those with SS/BW of 1.1 to 1.4 did not. Similar phenomena were shown with the grouped data on relationship between the Qp/Qs and inspired oxygen fraction. These findings imply that when SS/BW is 0.8 to 1.1, the Qp/Qs is controllable by physiologic respiratory manipulations. In the context of our clinical experiences, SS/BW of 0.9 to 1.0 is considered a useful index for suitable BT shunt in the Norwood procedure.


CircRILPL1 promotes muscle proliferation and differentiation via binding miR-145 to activate IGF1R/PI3K/AKT pathway.
Many novel non-coding RNAs, such as microRNAs (miRNAs) and circular RNAs (circRNAs), are involved in various physiological and pathological processes. The PI3K/AKT signaling pathway is important for its role in regulating skeletal muscle development. In this study, molecular and biochemical assays were used to confirm the role of miRNA-145 (miR-145) in myoblast proliferation and apoptosis. Based on sequencing data and bioinformatics analysis, we identified a new circRILPL1, which acts as a sponge for miR-145. The interactions between circRILPL1 and miR-145 were examined by bioinformatics, a luciferase assay, and RNA immunoprecipitation. Mechanistically, knockdown or exogenous expression of circRILPL1 in the primary myoblasts was performed to prove the functional significance of circRILPL1. We investigated the inhibitory effect of miR-145 on myoblast proliferation by targeting IGF1R to regulate the PI3K/AKT signaling pathway. A novel circRILPL1 was identified that could sponge miR-145 and is related to AKT activation. In addition, circRILPL1 was positively correlated with muscle proliferation and differentiation in vitro and could inhibit cell apoptosis. The newly identified circRILPL1 functions as a miR-145 sponge to regulate the IGF1R gene and rescue the inhibitory effect of miR-145 on the PI3K/AKT signaling pathway, thereby promoting myoblast growth.


Sequential pancreaticoduodenectomy after living donor liver transplantation for cholangiocarcinoma.
Liver transplantation (LT) for patients with primary sclerosing cholangitis (PSC) is often contraindicated due to concomitant occurrence of cholangiocarcinoma (CC). Cases of simultaneous pancreaticoduodenectomy (PD) with LT have been sporadically reported; however, the applicability of such an invasive procedure to patients with CC has not been validated. We report here a case of sequential PD performed 44 days after a successful living donor liver transplantation (LDLT) using a left lobe graft. Although a clear pancreatic juice leakage through the drain persisted for days after surgery, the patient recovered from the complication and was discharged 32 days after the procedure. Currently, 1 year after LDLT, the patient is doing well with no evidence of recurrence. In conclusion, a sequential PD following LDLT is a safe and feasible option to treat CC complicating PSC. Long-term follow-up and accumulation of cases are necessary to evaluate the effectiveness of this procedure for this complicated disease.


[An Axicon lens for the focusing of ultrasound fields].
In this paper the properties of an ultrasonic axicon lens of 10 cm diameter are investigated. This device generates a narrow ultrasonic beam in a range of 20 cm. The beam width varies from 1.7 to 0.5 mm in the frequency range from 1.7 to 5.5 megahertz. For practical applications a water path is necessary.


OpenABC enables flexible, simplified, and efficient GPU accelerated simulations of biomolecular condensates.
Biomolecular condensates are important structures in various cellular processes but are challenging to study using traditional experimental techniques. In silico simulations with residue-level coarse-grained models strike a balance between computational efficiency and chemical accuracy. They could offer valuable insights by connecting the emergent properties of these complex systems with molecular sequences. However, existing coarse-grained models often lack easy-to-follow tutorials and are implemented in software that is not optimal for condensate simulations. To address these issues, we introduce OpenABC, a software package that greatly simplifies the setup and execution of coarse-grained condensate simulations with multiple force fields using Python scripting. OpenABC seamlessly integrates with the OpenMM molecular dynamics engine, enabling efficient simulations with performance on a single GPU that rivals the speed achieved by hundreds of CPUs. We also provide tools that convert coarse-grained configurations to all-atom structures for atomistic simulations. We anticipate that OpenABC will significantly facilitate the adoption of in silico simulations by a broader community to investigate the structural and dynamical properties of condensates.


Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes.
Group III metabotropic glutamate (mGlu) receptors mediate important neuroprotective and anti-inflammatory effects. Stimulation of mGlu4 receptor reduces neuroinflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE) whereas mGlu4 knockout mice display exacerbated EAE clinical scores. We now show that mGlu4 receptors are expressed in oligodendrocytes, astrocytes and microglia in culture. Oligodendrocytes express mGlu4 receptors only at early stages of maturation (O4 positive), but not when more differentiated (myelin basic protein, MBP positive). Treatment of immature oligodendrocytes with the mGlu4 receptor agonist L-2-Amino-4-phosphonobutyrate (L-AP4; 50 μM for 48 h) accelerates differentiation with enhanced branching and earlier appearance of MBP staining. Oligodendrocyte death induced by exposure to 1 mM kainic acid for 24 h is significantly reduced by a 30-min pretreatment with L-AP4 (50 μM), an effect observed only in the presence of astrocytes, mimicked by the specific mGlu4 receptor positive allosteric modulator N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) (30 μM) and prevented by pretreatment with the mGlu4 receptor antagonist, cyclopropyl-4-phosphonophenylglycine (CPPG) (100 μM). In astrocytes, mGlu4 receptor is the most expressed among group III mGlu receptors, as by Quantitative real time PCR (QRT-PCR), and its silencing prevents protective effects. Protection is also observed when conditioned medium (CM) from L-AP4-pretreated astrocytes is transferred to oligodendrocytes challenged with kainic acid. Transforming growth factor β (TGF-β) mediates the increased oligodendrocyte survival as the effect of L-AP4 is mimicked by addition of 10 ng/ml TGF-β and prevented by incubation with a neutralizing anti-TGF-β antibody. In contrast, despite the expression of mGlu4 receptor in resting and activated microglia, CM from L-AP4-stimulated microglia does not modify kainate-induced oligodendrocyte toxicity. Our results suggest that mGlu4 receptors expressed in astrocytes mediate enhanced survival of oligodendrocytes under conditions of excitotoxicity.


Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope.
This prospective multicentre observational study assessed the efficacy of specific therapy based on implantable loop recorder (ILR) diagnostic observations in patients with recurrent suspected neurally mediated syncope (NMS). Patients with three or more clinically severe syncopal episodes in the last 2 years without significant electrocardiographic and cardiac abnormalities were included. Orthostatic hypotension and carotid sinus syncope were excluded. After ILR implantation, patients were followed until the first documented syncope (Phase I). The ILR documentation of this episode determined the subsequent therapy and commenced Phase II follow-up. Among 392 patients, the 1-year recurrence rate of syncope during Phase I was 33%. One hundred and three patients had a documented episode and entered Phase II: 53 patients received specific therapy [47 a pacemaker because of asystole of a median 11.5 s duration and six anti-tachyarrhythmia therapy (catheter ablation: four, implantable defibrillator: one, anti-arrhythmic drug: one)] and the remaining 50 patients did not receive specific therapy. The 1-year recurrence rate in 53 patients assigned to a specific therapy was 10% (burden 0.07 +/- 0.2 episodes per patient/year) compared with 41% (burden 0.83 +/- 1.57 episodes per patient/year) in the patients without specific therapy (80% relative risk reduction for patients, P = 0.002, and 92% for burden, P = 0.002). The 1-year recurrence rate in patients with pacemakers was 5% (burden 0.05 +/- 0.15 episodes per patient/year). Severe trauma secondary to syncope relapse occurred in 2% and mild trauma in 4% of the patients. A strategy based on early diagnostic ILR application, with therapy delayed until documentation of syncope allows a safe, specific, and effective therapy in patients with NMS.


Highly selective biomechanical separation of cancer cells from leukocytes using microfluidic ratchets and hydrodynamic concentrator.
The separation of cells based on their biomechanical properties, such as size and deformability, is important in applications such as the identification of circulating tumor cells, where morphological differences can be used to distinguish target cancer cells from contaminant leukocytes. Existing filtration-based separation processes are limited in their selectivity and their ability to extract the separated cells because of clogging in the filter microstructures. We present a cell separation device consisting of a hydrodynamic concentrator and a microfluidic ratchet mechanism operating in tandem. The hydrodynamic concentrator removes the majority of the fluid and a fraction of leukocytes based on size, while the microfluidic ratchet mechanism separates cancer cells from leukocytes based on a combination of size and deformability. The irreversible ratcheting process enables highly selective separation and robust extraction of separated cells. Using cancer cells spiked into leukocyte suspensions, the complete system demonstrated a yield of 97%, while enriching the concentration of target cancer cells 3000 fold relative to the concentration of leukocytes.


Preoperative weight loss program targeting women with overweight and hypertrophy of the breast - a pilot study.
Among women with hypertrophic breasts, the clear majority are overweight or obese. Owing to increased risk of complications, women with a body mass index (BMI) above 25 kg m -2 are precluded from reduction mammaplasty. The primary aim was to investigate if intensive weight loss could ready women with overweight for breast reduction surgery. Six women, all overweight [BMI 30.9 {28.5; 35.8} kg m -2 ] with symptomatic hypertrophy of the breast, were included a 12-week weight loss program. All women desired reduction mammaplasty and were motivated for preoperational weight loss. The first 8 weeks consisted of a formula-based diet supplying 800 kcal daily, in the subsequent 4 weeks regular foods were reintroduced increasing the intake to 1200 kcal daily. Five women completed the trial, and achieved a median (range) weight loss of 10.2 (6.5; 19) kg. Initial breast volume was 1100-2500 mL per breast, this was reduced by 300 (200; 500) mL after the intervention; equivalent to approximately 19%. Waist, hip, upper arm and thorax circumference were significantly reduced following weight loss. At end of study, all the women still suffered from symptomatic breast hypertrophy to substantiate reduction mammaplasty. Surgeries were performed 2 months thereafter. A 12-week intensive preoperative weight loss program enabled women with obesity for breast reduction surgery. Breast size was reduced proportionally more than total weight loss among women with hypertrophy.


Biomarkers predicting malignant progression of laryngeal epithelial precursor lesions: a systematic review.
Some laryngeal epithelial precursor lesions progress to invasive carcinoma and others do not. Routine light microscopic classification has limited value in predicting the evolution of these lesions. This article reviews the experience to date with the use of molecular markers for the prognostic evaluation of laryngeal epithelial precursor lesions. We conducted a thorough review of the published literature to identify those studies using biomarkers to predict malignant progression of laryngeal epithelial precursor lesions. Of the 336 studies identified in this systematic search, 15 met the inclusion criteria and form the basis of this review. Limited studies suggest that certain biomarkers are potentially reliable predictors of malignant progression including various regulators of cell adhesion and invasion (e.g. FAK, cortactin, osteopontin, and CD44v6) and proliferation-associated markers such as TGF-βRII and Kv3.4. The predictive value of these markers, however, has yet to be confirmed in large-scale prospective studies. Although the cell cycle-related proteins are the most frequently studied markers, none have been consistently reliable across multiple studies. The absence of standardization in methodologies, test interpretation, and other parameters may contribute to study inconsistencies. Various biomarkers have proved to have potential prognostic value and could be clinically relevant. The utility and prognostic power of these biomarkers should be confirmed in large, well-designed, standardized prospective studies.


Using demand mapping to assess the benefits of urban green and blue space in cities from four continents.
The benefits of urban green and blue infrastructure (UGI) are widely discussed, but rarely take into account local conditions or contexts. Although assessments increasingly consider the demand for the ecosystem services that UGI provides, they tend to only map the spatial pattern of pressures such as heat, or air pollution, and lack a wider understanding of where the beneficiaries are located and who will benefit most. We assess UGI in five cities from four continents with contrasting climate, socio-political context, and size. For three example services (air pollution removal, heat mitigation, accessible greenspace), we run an assessment that takes into account spatial patterns in the socio-economic demand for ecosystem services and develops metrics that reflect local context, drawing on the principles of vulnerability assessment. Despite similar overall levels of UGI (from 35 to 50% of urban footprint), the amount of service provided differs substantially between cities. Aggregate cooling ranged from 0.44 °C (Leicester) to 0.98 °C (Medellin), while pollution removal ranged from 488 kg PM2.5/yr (Zomba) to 48,400 kg PM2.5/yr (Dhaka). Percentage population with access to nearby greenspace ranged from 82% (Dhaka) to 100% (Zomba). The spatial patterns of pressure, of ecosystem service, and of maximum benefit within a city do not necessarily match, and this has implications for planning optimum locations for UGI in cities.


Preprogrammed, parallel on-chip immunoassay using system-level capillarity control.
Fully manual use of conventional multiwell plates makes enzyme-linked immunosorbent assay (ELISA)-based immunoassays highly time-consuming and labor-intensive. Here, we present a capillarity-driven on-chip immunoassay that greatly saves time and labor with an inexpensive setup. Our immunoassay process starts with pipetting multiple solutions into multiwells constructed on a microfluidic device chip. Subsequently, capillarity spontaneously transports multiple sample solutions and common reagent solutions into assigned detection channels on the chip in a purely passive and preprogrammed manner. Our device implements capillarity-driven immunoassays involving four sample and six reagent solutions within 30 min by orchestrating the functions of on-chip passive components. Notably, our immunoassay technique reduces the total number of pipetting processes by ~5 times, as compared to assays on multiwell plates (48 vs 10). This assay technique allows us to quantify the concentrations of C-reactive protein and suppressor of tumorigenicity 2 with a detection limit of 8 and 90 pM, respectively. This device should be useful for sophisticated, parallel biochemical microfluidic processing in point-of-care settings under limited resources.


Ovarian follicle development in the laying hen is accompanied by divergent changes in inhibin A, inhibin B, activin A and follistatin production in granulosa and theca layers.
To study the potential involvement of inhibin A (inhA), inhibin B (inhB), activin A (actA) and follistatin (FS) in the recruitment of follicles into the preovulatory hierarchy, growing follicles (ranging from 1 mm to the largest designated F1) and the three most recent postovulatory follicles (POFs) were recovered from laying hens (n=11). With the exception of <4 mm follicles and POFs, follicle walls were dissected into separate granulosa (G) and theca (T) layers before extraction. Contents of inhA, inhB, actA and FS in tissue extracts were assayed using specific two-site ELISAs and results are expressed per mg DNA. InhB content of both G and T followed a similar developmental pattern, although the content was >4-fold higher in G than in T at all stages. InhB content was very low in follicles <4 mm but increased ~50-fold (P<0.0001) to peak in 7-9 mm follicles, before falling steadily as follicles entered and moved up the follicular hierarchy (40-fold; 8 mm vs F2). In stark contrast, inhA remained very low in prehierarchical follicles (< or =9 mm) but then increased progressively as follicles moved up the preovulatory hierarchy to peak in F1 (approximately 100-fold increase; P<0.0001); In F1 >97% of inhA was confined to the G layer whereas in 5-9 mm follicles inhA was only detected in the T layer. Both inhA and inhB contents of POFs were significantly reduced compared with F1. Follicular actA was mainly confined to the T layer although detectable levels were present in G from 9 mm; actA was low between 1 and 9 mm but increased sharply as follicles entered the preovulatory hierarchy (approximately 6-fold higher in F4; P<0.0001); levels then fell approximately 2-fold as the follicle progressed to F1. Like actA, FS predominated in the T although significant amounts were also present in the G of prehierarchical follicles (4-9 mm), in contrast to actA, which was absent from the G. The FS content of T rose approximately 3-fold from 6 mm to a plateau which was sustained until F1. In contrast, the FS content of G was greatest in prehierarchical follicles and fell approximately 4-fold in F4-F1 follicles. ActA and FS contents of POFs were reduced compared with F1. In vitro studies on follicle wall explants confirmed the striking divergence in the secretion of inhA and inhB during follicle development. These findings of marked stage-dependent differences in the expression of inhA, inhB, actA and FS proteins imply a significant functional role for these peptides in the recruitment and ordered progression of follicles within the avian ovary.


Fluorogenic probes for super-resolution microscopy.
Fluorogenic probes efficiently reduce non-specific background signals, which often results in highly improved signal-to-noise ratios. Although this implies improved resolution, fluorogenic probes in the context of super-resolution microscopy are somewhat overlooked. Several excellent reviews summarize recent developments in SRM techniques, labeling techniques or different aspects of small synthetic fluorophores, however there is no comprehensive review on fluorogenic probes suitable for super-resolution microscopy. Herein we wish to fill this gap by providing the readers with an up-to-date summary of fluorogenic probes applied to super-resolution imaging of cellular structures.


Red yeast rice extracts suppress adipogenesis by down-regulating adipogenic transcription factors and gene expression in 3T3-L1 cells.
The effects of red yeast rice extracts (RE) on adipocyte differentiation of 3T3-L1 cells were studied. RE were extracted from embryonic rice fermented with red yeast (Monascus ruber). These extracts significantly decreased glycerol-3-phosphate dehydrogenase (GPDH) activity and lipid accumulation, a marker of adipogenesis, in a dose-dependent manner. Moreover, mRNA expression levels of both CCAAT/enhancer-binding protein (C/EBP) alpha and peroxisome proliferator-activated receptor (PPAR) gamma, the key adipogenic transcription factors, were markedly decreased by RE. RE also inhibited the expression of PPARgamma at protein levels. RE decreased significantly gene expression of adipocyte fatty acid binding protein (aP2) and leptin, which are adipogenic marker proteins and C/EBPalpha and PPARgamma target genes. These results suggest that the inhibitory effect of RE on adipocyte differentiation might be mediated through the down-regulated expression of adipogenic transcription factors and other specific genes.


Generation of an ICF syndrome model by efficient genome editing of human induced pluripotent stem cells using the CRISPR system.
Genome manipulation of human induced pluripotent stem (iPS) cells is essential to achieve their full potential as tools for regenerative medicine. To date, however, gene targeting in human pluripotent stem cells (hPSCs) has proven to be extremely difficult. Recently, an efficient genome manipulation technology using the RNA-guided DNase Cas9, the clustered regularly interspaced short palindromic repeats (CRISPR) system, has been developed. Here we report the efficient generation of an iPS cell model for immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF) syndrome using the CRISPR system. We obtained iPS cells with mutations in both alleles of DNA methyltransferase 3B (DNMT3B) in 63% of transfected clones. Our data suggest that the CRISPR system is highly efficient and useful for genome engineering of human iPS cells.


Multiscale Reactive Molecular Dynamics for Absolute pKa Predictions and Amino Acid Deprotonation.
Accurately calculating a weak acid's pKa from simulations remains a challenging task. We report a multiscale theoretical approach to calculate the free energy profile for acid ionization, resulting in accurate absolute pKa values in addition to insights into the underlying mechanism. Importantly, our approach minimizes empiricism by mapping electronic structure data (QM/MM forces) into a reactive molecular dynamics model capable of extensive sampling. Consequently, the bulk property of interest (the absolute pKa) is the natural consequence of the model, not a parameter used to fit it. This approach is applied to create reactive models of aspartic and glutamic acids. We show that these models predict the correct pKa values and provide ample statistics to probe the molecular mechanism of dissociation. This analysis shows changes in the solvation structure and Zundel-dominated transitions between the protonated acid, contact ion pair, and bulk solvated excess proton.


Moving from frugivory to seed dispersal: Incorporating the functional outcomes of interactions in plant-frugivore networks.
There is growing interest in understanding the functional outcomes of species interactions in ecological networks. For many mutualistic networks, including pollination and seed dispersal networks, interactions are generally sampled by recording animal foraging visits to plants. However, these visits may not reflect actual pollination or seed dispersal events, despite these typically being the ecological processes of interest. Frugivorous animals can act as seed dispersers, by swallowing entire fruits and dispersing their seeds, or as pulp peckers or seed predators, by pecking fruits to consume pieces of pulp or seeds. These processes have opposing consequences for plant reproductive success. Therefore, equating visitation with seed dispersal could lead to biased inferences about the ecology, evolution and conservation of seed dispersal mutualisms. Here, we use natural history information on the functional outcomes of pairwise bird-plant interactions to examine changes in the structure of seven European plant-frugivore visitation networks after non-mutualistic interactions (pulp pecking and seed predation) have been removed. Following existing knowledge of the contrasting structures of mutualistic and antagonistic networks, we hypothesized a number of changes following interaction removal, such as increased nestedness and lower specialization. Non-mutualistic interactions with pulp peckers and seed predators occurred in all seven networks, accounting for 21%-48% of all interactions and 6%-24% of total interaction frequency. When non-mutualistic interactions were removed, there were significant increases in network-level metrics such as connectance and nestedness, while robustness decreased. These changes were generally small, homogenous and driven by decreases in network size. Conversely, changes in species-level metrics were more variable and sometimes large, with significant decreases in plant degree, interaction frequency, specialization and resilience to animal extinctions and significant increases in frugivore species strength. Visitation data can overestimate the actual frequency of seed dispersal services in plant-frugivore networks. We show here that incorporating natural history information on the functions of species interactions can bring us closer to understanding the processes and functions operating in ecological communities. Our categorical approach lays the foundation for future work quantifying functional interaction outcomes along a mutualism-antagonism continuum, as documented in other frugivore faunas.


The Open Connectome Project Data Cluster: Scalable Analysis and Vision for High-Throughput Neuroscience.
We describe a scalable database cluster for the spatial analysis and annotation of high-throughput brain imaging data, initially for 3-d electron microscopy image stacks, but for time-series and multi-channel data as well. The system was designed primarily for workloads that build connectomes- neural connectivity maps of the brain-using the parallel execution of computer vision algorithms on high-performance compute clusters. These services and open-science data sets are publicly available at openconnecto.me. The system design inherits much from NoSQL scale-out and data-intensive computing architectures. We distribute data to cluster nodes by partitioning a spatial index. We direct I/O to different systems-reads to parallel disk arrays and writes to solid-state storage-to avoid I/O interference and maximize throughput. All programming interfaces are RESTful Web services, which are simple and stateless, improving scalability and usability. We include a performance evaluation of the production system, highlighting the effec-tiveness of spatial data organization.


Comprehensive prediction of robust synthetic lethality between paralog pairs in cancer cell lines.
Pairs of paralogs may share common functionality and, hence, display synthetic lethal interactions. As the majority of human genes have an identifiable paralog, exploiting synthetic lethality between paralogs may be a broadly applicable approach for targeting gene loss in cancer. However, only a biased subset of human paralog pairs has been tested for synthetic lethality to date. Here, by analyzing genome-wide CRISPR screens and molecular profiles of over 700 cancer cell lines, we identify features predictive of synthetic lethality between paralogs, including shared protein-protein interactions and evolutionary conservation. We develop a machine-learning classifier based on these features to predict which paralog pairs are most likely to be synthetic lethal and to explain why. We show that our classifier accurately predicts the results of combinatorial CRISPR screens in cancer cell lines and furthermore can distinguish pairs that are synthetic lethal in multiple cell lines from those that are cell-line specific. A record of this paper's transparent peer review process is included in the supplemental information.


Techniques for endovascular recanalization of supra-aortic trunks.
The supra-aortic are no stranger to endovascular interventions. Since the 1980s, interventionists have been evaluating and refining the use of transluminal techniques for recanalizing stenotic and occlusive lesions in these large-bore, high-flow vessels. The authors present their methodologies for evaluating, selecting, and treating supra-aortic lesions with balloon angioplasty and stenting. Helpful suggestions are offered for optimizing the outcome of these endovascular approaches to atherosclerotic occlusive disease in the supra-aortic trunks.


A Preclinical Study in Rhesus Macaques for Cystic Fibrosis to Assess Gene Transfer and Transduction by AAV1 and AAV5 with a Dual-Luciferase Reporter System.
Cystic fibrosis (CF) is an autosomal recessive disease that is potentially treatable by gene therapy. Since the identification of the gene encoding CF transmembrane conductance regulator, a number of preclinical and clinical trials have been conducted using the first generation of adeno-associated virus, AAV2. All these studies showed that AAV gene therapy for CF is safe, but clinical benefit was not clearly demonstrated. Thus, a new generation of AAV vectors based on other serotypes is needed to move the field forward. This study tested two AAV serotypes (AAV1 and AAV5) using a dual-luciferase reporter system with firefly and Renilla luciferase genes packaged into AAV1 or AAV5, respectively. Two male and two female Rhesus macaques were each instilled in their lungs with both serotypes using a Penn-Century microsprayer. Both AAV1 and AAV5 vector genomes were detected in all the lung samples when measured at the time of necropsy, 45 days after instillation. However, the vector genome number for AAV1 was at least 10-fold higher than for AAV5. Likewise, luciferase activity was also detected in the same samples at 45 days. AAV1-derived activity was not statistically greater than that derived from AAV5. These data suggest that gene transfer is greater for AAV1 than for AAV5 in macaque lungs. Serum neutralizing antibodies were increased dramatically against both serotypes but were less abundant with AAV1 than with AAV5. No adverse events were noted, again indicating that AAV gene therapy is safe. These results suggest that with more lung-tropic serotypes such as AAV1, new clinical studies of gene therapy using AAV are warranted.


How outing conditions relate to the motivation of movement-restricted cattle to access an outdoor exercise yard.
Assessing animal motivation to access a given resource is one method available to evaluate what to provide in the living environments of captive animals. Providing increased opportunities for movement can be seen as an important source of enrichment, but we need to know the point of view of the animal. The objective of our study was to test a novel combination of behaviours in order to assess the motivation of cows to access an outdoor exercise paddock. Three trials were conducted, each enrolling 15-16 tie-stall-housed cows as a model for movement-restricted animals. Cows were provided with access to an outdoor exercise yard 5 days/week for the duration of the trial, each trial presenting different conditions such as paddock size, duration of access and animal handling. We recorded the trips' durations and cows' behaviours during the trips going to (go-out) and coming back (go-in) from the paddock. LMr comparisons on PCA were used to assess cow motivation profiles. The same two dimensions of speed and stop quality emerged from the PCA in all three trials, showing the method's robustness. Additionally, three motivation profiles were established, representing how the cows' motivation was affected by the conditions prevailing in each trial.


Cellular Processing of the ABCG2 Transporter-Potential Effects on Gout and Drug Metabolism.
The human ABCG2 is an important plasma membrane multidrug transporter, involved in uric acid secretion, modulation of absorption of drugs, and in drug resistance of cancer cells. Variants of the ABCG2 transporter, affecting cellular processing and trafficking, have been shown to cause gout and increased drug toxicity. In this paper, we overview the key cellular pathways involved in the processing and trafficking of large membrane proteins, focusing on ABC transporters. We discuss the information available for disease-causing polymorphic variants and selected mutations of ABCG2, causing increased degradation and impaired travelling of the transporter to the plasma membrane. In addition, we provide a detailed in silico analysis of an as yet unrecognized loop region of the ABCG2 protein, in which a recently discovered mutation may actually promote ABCG2 membrane expression. We suggest that post-translational modifications in this unstructured loop at the cytoplasmic surface of the protein may have special influence on ABCG2 processing and trafficking.


Characterization, and comparison, of human clinical and black-headed gull (Larus ridibundus) extended-spectrum beta-lactamase-producing bacterial isolates from Kalmar, on the southeast coast of Sweden.
Antibiotic resistance is one of the great challenges for modern healthcare. In Gram-negative bacteria, CTX-M-type extended-spectrum beta-lactamases (ESBLs) have been rapidly spreading through Europe since the early 2000s. In Sweden, ESBL-producing Escherichia coli are still rare, but a 3-fold increase has been seen from 2004 to 2007. Enterobacteria and normal flora of wild animals, with or without antibiotic resistance traits, constitute a potential source of human infection and colonization. We studied wild birds with the aim to understand the environmental dissemination of antibiotic resistance and, focusing on clinically relevant resistance types, we made comparisons with human clinical samples. In this study, ESBL-producing human clinical isolates and isolates from juvenile black-headed gulls from Kalmar County hospital and the city of Kalmar, respectively, on the southeast coast of Sweden, were characterized and compared. Despite a low frequency of antibiotic resistance among the isolates from gulls, ESBL-producing E. coli isolates were found, two with bla(CTX-M-14) and one with bla(CTX-M-15). The same CTX-M types were dominant among human ESBL isolates. In addition, gull isolates were dispersed among the human samples in the PhenePlate clustering system, indicating that they neither differ from the human isolates nor form any separate clonal clustering. The finding of CTX-M-type ESBLs in E. coli isolated from black-headed gulls in Sweden, where 'background resistance' is low, is consistent with an ongoing environmental spread of these plasmid-borne resistance genes. The results indicate that a potential for transfer between the human population and environment exists even in countries with a low level of antibiotic resistance.


Pathogenesis, diagnosis, treatment, and outcome aspects of cerebral tuberculosis.
Cerebral tuberculosis or tuberculosis of the brain manifests predominantly as tuberculous meningitis followed by tuberculoma, tuberculous abscess, and other concomitant forms such as cerebral miliary tuberculosis, tuberculous encephalopathy, tuberculous encephalitis, and tuberculous arteritis. Different forms of cerebral tuberculosis are mainly caused by Mycobacterium tuberculosis and also by non-tuberculous mycobacteria such as M. avium-intracellulare in human immunodeficiency virus-infected persons. Cerebral tuberculosis is diagnosed based on clinical features, cerebrospinal fluid studies combined with radiological images. Early diagnosis, prompt institution of anti-tubercular treatment, and the clinical stage at which the patient presents are important and deciding factors for final outcome. The present review highlights the pathogenesis, recent strides made in diagnosis, including sensitive and specific molecular diagnostic (immunologic and polymerase chain reaction) tests, treatment, and outcome aspects of cerebral tuberculosis.


Joint functions of protein residues and NADP(H) in oxygen activation by flavin-containing monooxygenase.
The reactivity of flavoenzymes with dioxygen is at the heart of a number of biochemical reactions with far reaching implications for cell physiology and pathology. Flavin-containing monooxygenases are an attractive model system to study flavin-mediated oxygenation. In these enzymes, the NADP(H) cofactor is essential for stabilizing the flavin intermediate, which activates dioxygen and makes it ready to react with the substrate undergoing oxygenation. Our studies combine site-directed mutagenesis with the usage of NADP(+) analogues to dissect the specific roles of the cofactors and surrounding protein matrix. The highlight of this "double-engineering" approach is that subtle alterations in the hydrogen bonding and stereochemical environment can drastically alter the efficiency and outcome of the reaction with oxygen. This is illustrated by the seemingly marginal replacement of an Asn to Ser in the oxygen-reacting site, which inactivates the enzyme by effectively converting it into an oxidase. These data rationalize the effect of mutations that cause enzyme deficiency in patients affected by the fish odor syndrome. A crucial role of NADP(+) in the oxygenation reaction is to shield the reacting flavin N5 atom by H-bond interactions. A Tyr residue functions as backdoor that stabilizes this crucial binding conformation of the nicotinamide cofactor. A general concept emerging from this analysis is that the two alternative pathways of flavoprotein-oxygen reactivity (oxidation versus monooxygenation) are predicted to have very similar activation barriers. The necessity of fine tuning the hydrogen-bonding, electrostatics, and accessibility of the flavin will represent a challenge for the design and development of oxidases and monoxygenases for biotechnological applications.


Connecting Biology to Electronics: Molecular Communication via Redox Modality.
Biology and electronics are both expert at for accessing, analyzing, and responding to information. Biology uses ions, small molecules, and macromolecules to receive, analyze, store, and transmit information, whereas electronic devices receive input in the form of electromagnetic radiation, process the information using electrons, and then transmit output as electromagnetic waves. Generating the capabilities to connect biology-electronic modalities offers exciting opportunities to shape the future of biosensors, point-of-care medicine, and wearable/implantable devices. Redox reactions offer unique opportunities for bio-device communication that spans the molecular modalities of biology and electrical modality of devices. Here, an approach to search for redox information through an interactive electrochemical probing that is analogous to sonar is adopted. The capabilities of this approach to access global chemical information as well as information of specific redox-active chemical entities are illustrated using recent examples. An example of the use of synthetic biology to recognize external molecular information, process this information through intracellular signal transduction pathways, and generate output responses that can be detected by electrical modalities is also provided. Finally, exciting results in the use of redox reactions to actuate biology are provided to illustrate that synthetic biology offers the potential to guide biological response through electrical cues.


Therapeutic effects of an indoor gardening programme for older people living in nursing homes.
To explore the activities of daily living and psychological well-being of older people living in nursing homes and also to examine the effectiveness of a gardening programme in enhancing socilaisation and life satisfaction, reducing loneliness and promoting activities of daily living for older people living in nursing homes. Life in nursing homes can mean very limited physical and social activity, leading to further decline in function for many older people. This was a quasi-experimental pre and posttest control group design. Older people from nursing homes were invited to join the eight week indoor gardening programme (experimental group), while older people in other nursing homes were treated as the control group; they received regular care without the eight week indoor gardening programme. There were 26 older people (25 female and one male; mean age 85 years) in the experimental group and 27 (20 female and seven male; mean age 82 years) in the control group. Demographic data including age, gender, educational level and financial situation were collected, in addition to information regarding life satisfaction, loneliness, physical activity and social network situation, before and after the eight week indoor gardening programme for both the experimental and control groups. Also, details of experimental group subjects' experience of the indoor gardening programme were elicited using open-ended questions. There were significant improvements in life satisfaction and social network and a significant decrease in perception of loneliness for older people in the experimental group after the eight week indoor gardening programme, while the activities of daily living were unchanged for both groups after the programme. Given the positive effects of gardening activities, it is suggested that they be promoted more widely among nursing home residents.


Interleukin-1β inhibitors for the treatment of cryopyrin-associated periodic syndrome.
Cryopyrin-associated periodic syndrome (CAPS) comprises a group of rare, but severe, inherited autoinflammatory disorders associated with aberrant secretion of interleukin (IL)-1. These distinct conditions of autoinflammatory origin include Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease (NOMID), which is also referred to as chronic infantile neurologic cutaneous and articular syndrome. Recently, this group of diseases has been associated with mutations in the NLRP3 gene that encodes for the protein cryopyrin, a component of the inflammasome complex that regulates the maturation and secretion of inflammatory cytokine IL-1β. Immune cells from patients with NOMID secrete higher levels of active IL-1β compared with monocytes from healthy subjects. Overproduction of IL-1 is believed to promote aberrant inflammatory response in CAPS patients. Evidence supporting the clinical value of IL-1β in CAPS has been provided from the complete response of patients after treatment with IL-1 blocking agents.


Serum sclerostin is negatively associated with insulin sensitivity in obese but not lean women.
The mechanisms underlying the development of peripheral insulin resistance are complex. Several studies have linked sclerostin, an osteocyte-derived inhibitor of the Wnt/β-catenin pathway, to obesity and insulin resistance. The aim of this study was to investigate (1) whether serum sclerostin is associated with insulin sensitivity in lean and/or obese women; and (2) whether hyperinsulinaemia affects serum sclerostin concentrations. A cross-sectional study. Insulin sensitivity was measured in lean (BMI < 25 kg/m2) and obese (BMI > 30 kg/m2) women using a hyperinsulinaemic-euglycaemic clamp. Serum sclerostin was measured at baseline and during the clamp procedure. We studied 21 lean and 22 obese women with a median age of 40 and 43 years and a median BMI of 22.4 and 33.5 kg/m2, respectively. Obese women had higher serum sclerostin than lean women (122 ± 33 vs 93 ± 33 nmol/L, P < 0.01). Higher serum sclerostin was associated with lower insulin sensitivity in obese, but not in lean individuals (difference in M-value between highest and lowest quartile: -7.02 mg/kg/min, P = 0.03 and 1.59 mg/kg/min, P = 0.50, respectively). Hyperinsulinaemia did not affect serum sclerostin in lean nor obese women (P > 0.5). Serum sclerostin is negatively associated with insulin sensitivity as measured with the hyperinsulinaemic-euglycaemic clamp in obese, but not lean women. This indicates a potential role of the Wnt/β-catenin pathway in regulating insulin sensitivity particularly in obese individuals. Our findings remain hypothesis-generating and should be confirmed by additional studies.


Extinction ratio regeneration, signal re-amplification (2R), and broadband wavelength switching using a monolithically integrated photocurrent driven wavelength converter.
Detailed wavelength conversion, extinction ratio regeneration, and signal re-amplification experiments are performed using a monolithically integrated, widely tunable photocurrent driven wavelength converter. A -3.5 dB power penalty is observed in bit error rate measurements at 2.5 Gb/s when the extinction ratio of an incoming signal is regenerated from 4 dB to 11 dB, and the input signal wavelength is switched from 1548 nm to an output wavelength range between 1533 nm and 1553 nm. When the input signal extinction ratio is regenerated from 4 to 11 dB, the wavelength converter provides facet to facet conversion gain of 5 dB, 7.7 dB, and 7.6 dB for conversion from 1548 nm to output wavelengths of 1533, 1545 nm, and 1553 nm.


Different cardiovascular protective effects of quercetin administered orally or intraperitoneally in spontaneously hypertensive rats.
We tested whether the administration procedure of quercetin affects its metabolite profile and antihypertensive activity. Spontaneously hypertensive rats (SHR) were randomly assigned to four experimental treatments: (1) 1 mL of 1% methylcellulose by oral gavage and 2% DMSO i.p. (control group); (2) 10 mg kg⁻¹ quercetin by oral gavage once daily and 2% DMSO i.p.; (3) 10 mg kg⁻¹ quercetin by oral gavage divided in two daily doses (5 + 5 at 12 h intervals) and 2% DMSO i.p.; (4) 1 mL of 1% methylcellulose by oral gavage and 10 mg kg⁻¹ quercetin i.p. injection. Rats were treated daily for 5 weeks. Single dose and two daily doses, in a long-term oral treatment were equally efficient, both restoring the impaired aortic endothelium-dependent vasodilatation and reducing mesenteric contractile response to phenylephrine, systolic blood pressure, heart rate, and heart and kidney hypertrophy. Attenuation of vascular NADPH oxidase-driven O₂⁻ production was also found in orally treated rats. Intraperitoneal administration reduced, to lesser extent than oral administration, the increased systolic blood pressure, being without effect to the endothelial dysfunction and vascular oxidative stress. In contrast, greater levels of metabolites were quantified following intraperitoneal compared to oral administration at any time point, except for higher plasma methylated quercetin aglycone in oral as compared to intraperitoneal administration at 2 but not at 8 h. In conclusion, oral quercetin was superior to intraperitoneal administration for the protection from cardiovascular complications in SHR. No differences were found between the oral administration as a single daily dose or divided into two daily doses.


Studies in the prophylaxis of herpes infections in severely immunocompromised patients using acyclovir.
That acyclovir is effective therapeutically in herpes simplex virus (HSV) and herpes zoster (VZV) infections in immunocompromised patients has been established [13]. This paper reviews our subsequent studies in prophylaxis of herpes group infections in a high risk group of patients suffering from acute leukaemia. In study 1 we randomised HSV seropositive (greater than or equal to 1:8) patients to receive intravenous acyclovir or placebo. In this stratified study bone marrow transplant (BMT) recipients were completely protected from HSV infections by acyclovir compared with a 50% failure rate for those on placebo. There was significant protection also in the non-BMT group [8]. In study 2 oral acyclovir prophylaxis failed to provide complete protection in BMT recipients despite the achievement of apparently adequate blood levels. In study 1 the secretion of EBV in saliva before and during the trial gave inconclusive results. In each of the first two studies one patient on "active" acyclovir developed a cytomegalovirus (CMV) infection. Thus, at the dosage of drug used, prophylaxis of CMV was unsuccessful suggesting that claims of therapeutic efficacy are unlikely to be supported in controlled trials. Study 3 is current and concerns the pharmacokinetics of an acyclovir prodrug (BW 134U) taken by mouth. This drug is near 100% absorbed and achieves approximately twice the level of active acyclovir in vivo, following conversion by adenosine deaminase (ADA), in normal volunteers.


Effects of oxytocin and an oxytocin receptor antagonist on retention of a nose-poke habituation response in mice.
The present study describes the use of nose-poke habituation as a memory task in mice and demonstrates that it is sensitive to oxytocin (OT) and an oxytocin receptor antagonist (AOT) administered after the learning trial. Habituation of nose-poke behavior of mice was defined as a reduction in number of nose-pokes compared to baseline, and was measured in a hole-board apparatus to which male Swiss mice were exposed on two consecutive days for 5 min, respectively. Immediate post-training subcutaneous administration of OT (2.00 micrograms/kg) impaired retention performance, whereas AOT (0.20 microgram/kg) enhanced it. Neither the impairing effects of OT (2.00 micrograms/kg) nor the enhancing effects of AOT (0.20 microgram/kg) were seen when the training treatment interval was 180 min, suggesting that both treatments influenced the storage of recently acquired information. The effects of OT (2.00 micrograms/kg) on retention were prevented by AOT (0.02 microgram/kg) administered immediately after training but 10 min prior OT treatment. This dose of antagonist did not affect retention by itself which suggest that impairing effects of OT on retention are probably due to an interaction of the neuropeptide with specific receptors. The actions of OT and AOT on retention were not due to enduring proactive effects of the compounds on performance during the retention test, since when given to untrained mice did not modify their spontaneous activities in the hole-board when recorded 24 h later. We suggest that nose-poke habituation learning can be a suitable method to investigate the mnestic effects of drugs, and that oxytocin negatively modulates memory storage of this form of learning elicited by stimuli repeatedly presented without reinforcement.


Keratoconus: overview and update on treatment.
Keratoconus is a non-inflammatory, progressive thinning process of the cornea. It is a relatively common disorder of unknown etiology that can involve each layer of the cornea and often leads to high myopia and astigmatism. Computer- assisted corneal topography devices are valuable diagnostic tools for the diagnosis of subclinical keratoconus and for tracking the progression of the disease. The traditional conservative management of keratoconus begins with spectacle correction and contact lenses. Several newer, more invasive, treatments are currently available, especially for contact lens-intolerant patients. Intrastromal corneal ring segments can be used to reshape the abnormal cornea to improve the topographic abnormalities and visual acuity. Phakic intraocular lenses such as iris-fixated, angle-supported, posterior chamber implantable collamer and toric lenses are additional valuable options for the correction of refractive error. Corneal cross-linking is a relatively new method of stiffening the cornea to halt the progression of the disease. The future management of keratoconus will most likely incorporate multiple treatment modalities, both simultaneous and sequential, for the prevention and treatment of this disease.


Time required to achieve clinically significant outcomes after arthroscopic superior capsular reconstruction.
To investigate the time-dependent nature of clinically significant outcomes, including the minimal clinically important difference (MCID), substantial clinical benefit, and Patient Acceptable Symptomatic State (PASS) after arthroscopic superior capsular reconstruction, and the factors contributing to the achievement of early clinically significant outcomes. Patients who underwent ASCR between March 2015 and September 2020 with complete preoperative and postoperative 6-month, 1-year, and 2-year patient-reported outcome measures (PROMs) were retrospectively analysed. Threshold values for MCID, substantial clinical benefit, and PASS were obtained from the previous literature for the PROMs. The time required to achieve clinically significant outcomes was calculated using Kaplan-Meier analysis. Multivariate Cox regression was performed to evaluate the variables predictive of an earlier or delayed achievement of MCID. Fifty-nine patients with a mean age of 64.5 ± 8.7 years old were included. The time of mean achievement of MCID, substantial clinical benefit, and PASS for VAS was 11.2 ± 0.9, 16.3 ± 1.1, and 16.6 ± 0.9 months, respectively. The time of mean achievement of MCID, substantial clinical benefit, and PASS for ASES was 13.2 ± 1.0, 16.8 ± 1.0, and 18.3 ± 0.9 months, respectively. The time of mean achievement of MCID, substantial clinical benefit, and PASS for the Constant score was 11.6 ± 0.9, 15.1 ± 1.0, and 14.7 ± 0.9 months, respectively. The time of mean achievement of MCID, substantial clinical benefit, and PASS for SANE was 14.4 ± 1.0, 16.1 ± 1.0, and 15.5 ± 0.8 months, respectively. Patients with a higher preoperative VAS score achieved an earlier MCID for VAS (P = 0.014). However, patients with a higher preoperative ASES and SANE scores achieved delayed MCID for ASES and SANE (P = 0.026, and P < 0.001, respectively). Most patients achieved MCIDs around 1 year after arthroscopic superior capsular reconstruction. A higher preoperative VAS score favours faster MCID achievement, while higher preoperative ASES and SANE scores contribute to delayed MCID achievement. Cohort study LEVEL OF EVIDENCE: Level IV.


Combination of Repurposed Drug Diosmin with Amoxicillin-Clavulanic acid Causes Synergistic Inhibition of Mycobacterial Growth.
Effective therapeutic regimens for the treatment of tuberculosis (TB) are limited. They are comprised of multiple drugs that inhibit the essential cellular pathways in Mycobacterium tuberculosis (Mtb). The present study investigates an approach which enables a combination of Amoxicillin-Clavulanic acid (AMC) and a repurposed drug for its synergistic effect towards TB treatment. We identified Diosmin (DIO), by targeting the active site residues of L,D-transpeptidase (Ldt) enzymes involved in Mtb cell wall biosynthesis by using a structure-based drug design method. DIO is rapidly converted into aglycone form Diosmetin (DMT) after oral administration. Binding of DIO or DMT towards Ldt enzymes was studied using molecular docking and bioassay techniques. Combination of DIO (or DMT) and AMC exhibited higher mycobactericidal activity against Mycobacterium marinum as compared to individual drugs. Scanning electron microscopy study of M. marinum treated with AMC-DIO and AMC-DMT showed marked cellular leakage. M. marinum infected Drosophila melanogaster fly model showed an increased fly survival of ~60% upon treatment with a combination of AMC and DIO (or DMT). Finally, the enhanced in vitro antimicrobial activity of AMC-DIO was validated against Mtb H37Ra and a MDR clinical isolate. Our results demonstrate the potential for AMC and DIO (or DMT) as a synergistic combination for the treatment of TB.


Biofabrication of cell-loaded 3D spider silk constructs.
Biofabrication is an emerging and rapidly expanding field of research in which additive manufacturing techniques in combination with cell printing are exploited to generate hierarchical tissue-like structures. Materials that combine printability with cytocompatibility, so called bioinks, are currently the biggest bottleneck. Since recombinant spider silk proteins are non-immunogenic, cytocompatible, and exhibit physical crosslinking, their potential as a new bioink system was evaluated. Cell-loaded spider silk constructs can be printed by robotic dispensing without the need for crosslinking additives or thickeners for mechanical stabilization. Cells are able to adhere and proliferate with good viability over at least one week in such spider silk scaffolds. Introduction of a cell-binding motif to the spider silk protein further enables fine-tuned control over cell-material interactions. Spider silk hydrogels are thus a highly attractive novel bioink for biofabrication.


Factors Associated with Vancomycin-Resistant Enterococcus Colonization in Patients Transferred to Emergency Departments in Korea.
Vancomycin-resistant enterococci (VRE) infections have become a major healthcare-associated pathogen problem worldwide. Nosocomial VRE infections could be effectively controlled by screening patients at high risk of harboring VRE and thereby lowering the influx of VRE into healthcare centers. In this study, we evaluated factors associated with VRE colonization in patients transferred to emergency departments, to detect patients at risk for VRE carriage. This study was conducted in the emergency department of a medical college-affiliated hospital in Korea. Every patient transferred to the emergency department and admitted to the hospital from January to December 2016 was screened for VRE using rectal cultures. In this cross-sectional study, the dependent variable was VRE colonization and the independent variables were demographic and clinical factors of the patients and factors related to the transferring hospital. Patients were divided into two groups, VRE and non-VRE, and previously collected patient data were analyzed. Then we performed logistic regression analyses of characteristics that differed significantly between groups. Out of 650 patients, 106 (16.3%) had positive VRE culture results. Significant variables in the logistic analysis were transfer from geriatric long-term care hospital (adjusted odds ration [aOR]: 8.017; 95% confidence interval [CI]: 1.378-46.651), hospital days (4-7 days; aOR: 7.246; 95% CI: 3.229-16.261), duration of antimicrobial exposure (1-3 days; aOR: 1.976; 95% CI: 1.137-3.436), and age (aOR: 1.025; 95% CI: 1.007-1.043). VRE colonization in patients transferred to the emergency department is associated primarily with factors related to the transferred hospitals rather than demographic and clinical characteristics.


Hypertension in pregnancy.
Blood pressure; extracellular fluid volume; renal plasma flow; glomerular filtration rate; plasma concentrations of renin, angiotensin, aldosterone, desoxycorticosterone, and prostaglandins; responses to infused angiotensin; and many other factors are altered during normal and hypertensive gestation. The diagnosis of the exact disease process responsible for hypertension in pregnancy in an individual patient is extremely difficult if based solely on clinical criteria. The American College of Obstetricians and Gynecologists has suggested the following clinical classifications: (1) preeclampsia-eclampsia, (2) chronic hypertension of whatever cause, (3) chronic hypertension with superimposed preeclampsia, and (4) late or transient hypertension. The three broad categories of renal disease responsible for these clinical syndromes are: (1) preeclampsia-eclampsia, (2) hypertensive changes, and (3) various primary renal diseases. Controversy abounds regarding the aggressiveness of therapy in this syndrome. We prefer a middle-of-the-road approach, bringing blood pressure down to the range of 95 to 100 mm Hg. Hydralazine and Aldomet are the usual drugs of choice. Any intervening nervous system hyperexcitability suggests impending eclampsia and should be immediately treated with magnesium sulfate. The long-term prognosis for the mother with pure preeclampsia appears to be excellent. Most infants born of hypertensive gestations are small for date, with a prognosis that is also affected by the underlying disease of the mother.


Equivalence of partition properties and determinacy.
It is shown that, within L(R), the smallest inner model of set theory containing the reals, the axiom of determinacy is equivalent to the existence of arbitrarily large cardinals below Theta with the strong partition property kappa --> (kappa)(kappa).


Vasoactive intestinal peptide (VIP) receptor type 2 (VPAC2) is the predominant receptor expressed in human thymocytes.
Vasoactive intestinal peptide (VIP) binding sites have been identified in the human thymus, but the receptor subtype and how these receptors are distributed in the human thymus subsets is unknown. To assess gene expression, distribution, and receptor regulation of the two G-protein-associated VIP receptors, VPAC1 and VPAC2 mRNAs were quantified using a novel fluorometric-based kinetic (real-time) RT-PCR. Bulk and fractionated thymocytes were stimulated via the TCR/CD3 receptor complex and anti-CD28. Our results demonstrate that thymocytes express higher levels of VPAC2 compared to VPAC1 expression in bulk thymocytes, CD4+CD8+ selected double positives (DP), and CD8 depleted thymocytes. Double negative cells express low levels of VPAC2 mRNA. We demonstrate T-cell activation-dependent down-regulation of VPAC1, but not VPAC2, in human thymocytes. This study reports the first direct evidence of a differential distribution and selective regulation of VPAC1 and VPAC2 gene expression in normal human thymocyte subsets.


Correction of forearm deformities in children with multiple osteochondroma, by corrective radial osteotomy and ulnar lengthening by distraction osteogenesis.
We retrospectively evaluated the results after ulnar lengthening and radial deformity correction using an external fixator for forearm deformities caused by osteochondromas. Eight forearms were treated surgically in seven patients with multiple hereditary osteochondroma. The mean follow-up time was 40 months (range, 20 to 60 months). The average radial articular angle improved from 43 degrees to 35.5 degrees (range, 28 to 56 degrees) and the carpal slip improved from 69.5% to 55% (range, 40 to 60%) postoperatively. The average shortening of the ulna was reduced from 2.06 cm to 0.44 cm (range 0 to 1 cm) after the treatment. There were no serious complications associated with the surgery; two minor pin track infections were successfully treated by local wound care and antibiotics. Although technically demanding, ulnar osteotomy and gradual lengthening by an external fixator provided promising results in the treatment of forearm deformities in children with multiple osteochondroma.


Seeing the Elephant: A Systematic Scoping Review and Comparison of Patient-Centeredness Conceptualizations from Three Seminal Perspectives.
"Patient-Centeredness" (PC) is a theoretical construct made up of a diverse constellation of distinct concepts, processes, practices, and outcomes that have been developed, arranged, and prioritized heterogeneously by different communities of professional healthcare practice, research, and policy. It is bound together by a common ethos that puts the holistic individual at the functional and symbolic center of their care, a quality deemed essential for chronic disease management and health promotion. Several important contributions to the PC research space have adeptly integrated seminal PC conceptualizations to improve conceptual clarity, measurement, implementation, and evaluation in research and practice. This systematic scoping review builds on that work, but with a purpose to explicitly identify, compare, and contrast the seminal PC conceptualizations arising from the different healthcare professional groups. The rationale for this work is that a deeper examination of the underlying development and corresponding assumptions from each respective conceptualization will lead to a more informed understanding of and meaningful contributions to PC research and practice, especially for healthcare professional groups newer to the topic area like pharmacy. The literature search identified four seminal conceptualizations from the healthcare professions of Medicine, Nursing, and Health Policy. A compositional comparison across the seminal conceptualizations revealed a shared ethos but also six distinguishing features: (1) organizational structure; (2) predominant level of care; (3) methodological approach; (4) care setting origin; (5) outcomes of interest; and (6) language. The findings illuminate PC's stable theoretical foundations and distinctive nuances needed to appropriately understand, apply, and evaluate the construct's operationalization in contemporary healthcare research and practice. These considerations hold important implications for future research into the fundamental aims of healthcare, how it should look when practiced, and what should reasonably be required of it.


Raman lidar monitoring of extinction and backscattering of African dust layers and dust characterization.
Results on the monitoring of strong African dust outbreaks at Lecce in the southeastern corner of Italy (40 degrees 20' N, 18 degrees 6' E) during May 2001 are presented. This activity has been performed in the framework of the European Aerosol Research Lidar Network (EARLINET). The lidar station of Lecce is located on a flat rural area that is approximately 800 km from the northern Africa coast. So it is closer to Africa than most of all other EARLINET stations and allow monitoring African dust transport early in its life cycle, at all levels in the plume. An elastic-backscatter Raman lidar based on a XeF excimer laser (351 nm) has been used to monitor the time evolution and vertical structure of the dust layers and get independent measurements of the aerosol extinction and backscatter coefficients. The findings are presented in terms of vertical profiles of the extinction and backscatter coefficients and of the lidar ratio. A quite deep dust layer extending between 2 and 6 km and characterized by a backscatter coefficient of approximately 0.0016 (km sr)(-1), a lidar ratio of approximately 50 sr, and an aerosol optical depth of 0.26 was observed on 17 May 2001 between 18:55 and 20:07 UT. The layer persisted for approximately five days. Dust layers of lower optical thickness and shorter persistence time have generally been monitored at the lidar site during African dust outbreaks. Results on the chemical and morphological characterization of the dust collected at the lidar station are also given to further support the origin of the monitored aerosol layers.


The significance of clinical change and clinical change of significance: issues and methods.
The emphasis on systematic methods of demonstrating accountability in health care is affecting the delivery of human services at all levels, from hospitals and community centers to individual private practitioners. New procedures are being proposed to meet the accountability demands encountered by therapists. Several recently developed methods for documenting clinical change in patient status are presented, and the relationship of this documentation to traditional research methods is briefly explored. A clinical illustration of the procedures is provided along with a discussion of advantages and limitations.


Foreign body inhalation: a review of patients at the Korle Bu Teaching Hospital, Accra, Ghana.
Foreign body inhalation, a surgical emergency requiring prompt management to avoid morbidity and mortality , poses a diagnostic and management challenge to otolaryngologists. To assess the pattern of foreign body inhalation at the ENT Unit Korle Bu Teaching Hospital Accra, Ghana. The theatre records of patients managed for foreign body inhalation from Ist January 2003 to 31st December 2006 at the ENT Unit of the Korle Bu Teaching Hospital Accra, Ghana were studied with respect to age, sex, clinical presentation, types of foreign bodies removed, location of foreign bodies, and outcomes of the laryngoscopy or bronchoscopy procedures. There were forty patients with an age range of seven months to 15 years with a mean age of 4.78 years and a peak age incidence at zero to four year age group. The commonest inhaled foreign bodies included groundnuts in five (12.5%) patients, fish bones in six (15%) patients, plastic materials in five (12.5%) patients, metal material in five (12.5%) patients and seeds in five (12.5%) patients. The common clinical presentations included respiratory difficulty, irritating cough, choking, painful swallowing and whistling sound during breathing. Foreign bodies were localized in the right main bronchus in 27 (67.5 %) patients, and in the left main bronchus in ten (25%) patients and in the larynx in three (7.5%) patients. One patient died during bronchoscopy and another patient had bronchotomy for failed bronchoscopy. The peak age of occurrence of forein body inhalation is in the zero to four year age group. The commonest inhaled foreign bodies are groundnuts, fish bones, plastic materials, metal materials and seeds. Majority of inhaled foreign bodies tend to localise in the right main bronchus.


Spectroscopic characterization, DFT studies, molecular docking and cytotoxic evaluation of 4-nitro-indole-3-carboxaldehyde: A potent lung cancer agent.
The 4-nitro-1H-indole-carboxaldehyde (NICA) molecule was characterized experimentally using FT-IR, FT-Raman and UV-Vis spectra, and it was studied theoretically using DFT calculations. The optimized structure of the NICA molecule was determined by DFT calculations using B3LYP functional with cc-pVTZ basis set. The electron localization function (ELF) and local orbital localizer (LOL) studies were performed to visualize the electron delocalization in the molecule. The experimental and theoretical wavenumbers of the title molecule were assigned using VEDA 4.0 program. The charge delocalization and stability of the title molecule were investigated using natural bond orbital (NBO) analysis. Frontier molecular orbitals (FMOs) and related molecular properties were calculated. UV-Vis spectrum was calculated theoretically and validated experimentally. The reactive sites of the molecule were studied from the MEP surface and Fukui function analysis. The molecular docking analysis reveals that the NICA ligand shows better inhibitory activity against RAS, which causes lung cancer. The in vitro cytotoxic activity of the molecule against human lung cancer cell lines (A549) was determined by MTT assay. Thus, the NICA molecule can be used as a potential candidate for the development of the drug against lung cancer.


The cellular program for the formation and dissolution of the synaptonemal complex in Coprinus.
Inhibition of protein synthesis by cycloheximide on processes in meiosis was used to probe the cellular program for the formation and dissolution of the synaptonemal complex (SC) in the synchronous meiotic system of Coprinus cinereus. The pathway for the synthesis and assembly of the synaptonemal complex is proposed to be as follows: (1) synthesis and assembly of lateral components on the chromosomes; (2) synthesis and assembly of the central components in the nucleolus; (3) the lateral components of the homologous chromosomes are brought together to pair when the homologous pairing occurs at zygotene; (4) the transport of the central components from the nucleolus to join the paired lateral components and thus complete the synaptonemal complex. Continued protein synthesis is required for all steps. Step (1) is nearly complete 2 h after the onset of karyogamy, because continued assembly is possible in the presence of cycloheximide. The transition point for step (2) is 4 h after the onset of karyogamy, as inhibition at this point results in accumulation of central components in the nucleolar dense body. The paired lateral components of step (3) are deprived of the central component. The transition point for step (4) is 5 h after the onset of karyogamy, for inhibition at this point no longer prevents transport. Two steps are proposed for dissociation and dissolution of the SC at the end of pachytene. Protein synthesis is required for the dissolution of SC. Inhibition at this point causes accumulation of polycomplexes. Mutations in various organisms from the literature relating to the SC support the validity of the proposed pathway.


[Pharmacoepidemiological study of the use of non-steroid antiinflamatory drugs in high-risk cardiovascular patients].
In order to determine the frequency of extended use of non-steroidal anti-inflammatory drugs (NSAID) in Colombian patients with high cardiovascular risk (HCVR), a retrospective study was developed which identified HCVR patients who used NSAID for over five continuous months from January 2011 and March 2013. Patients chronically receiving nitrates, digitalis and clopidogrel and acetylsalicylic acid (ASA), known as HCVR, were identified. An analysis of the frequencies of use based on the co-medication received was performed. Concomitant use of NSAID was found in 0,35% of consumers of nitrates (average time: 9,5 ± 4,4 months), in 0,36% of consumers of clopidogrel and ASA (average time: 9,3 ± 3,4 months), and in 0,4% of consumers of digitalis (10,2 ± 4,6 months). It is concluded that there is a low proportion of chronic use of NSAID in high-risk cardiovascular patients.


The effect of gender on the prevalence of hypertension in obstructive sleep apnea.
Obstructive sleep apnea (OSA) causes systemic hypertension. However, there is conflicting data on the effect of gender on susceptibility to hypertension in OSA. Some show no gender differences in the prevalence of hypertension while others report either female or male propensity to have hypertension in the context of OSA. The inconsistencies in the results appear to be due to lack of full range of sleep apnea severity and insufficient number of women in the studies. We examined the effect of gender on prevalent hypertension in a cohort with a large representation of females with OSA. A cross-sectional study of a large cohort of subjects referred for sleep disorder evaluation. The cohort comprised of 736 with OSA and 315 without OSA. OSA was defined as apnea-hypopnea index (AHI) of 5/h. There were 529 men and 207 women in the OSA group with mean+/-SD age of 50+/-13 and 51+/-14 years, respectively. The control group consisted of 154 men and 161 women with mean+/-SD age of 44+/-15 and 43+/-14 years, respectively. The AHI in the OSA group varied from 5 to 197 with a median of 24 and a mean of 36 (interquartile range: 11-53). Multiple logistic regression analyses, modeling the association between AHI and hypertension and considering other covariates, showed that odds of hypertension increased with increasing age, BMI, and AHI. There was evidence that men were at higher risk for hypertension than women OR 1.82 (95%CI 1.01, 3.20) at the highest quartile of BMI. We have shown that the prevalence of hypertension increases with increasing age and severity of OSA, and markedly obese men may have a nearly 2-fold greater risk for hypertension than women in this clinic-based population.


Personality traits in juvenile delinquents: relation to criminal behavior and recidivism.
To examine the relation between personality traits and criminal behavior and to determine whether such factors are predictive of future recidivism. A sample of 481 incarcerated males (mean age = 16 years) completed questionnaires assessing distress and restraint relating to personality characteristics. In addition, official criminological data were gathered from subjects' records. A subsample of 148 juveniles was followed up to 4.5 years after release and examined for rearrests and time out of prison since last incarceration. Results indicate a significant association between self-reported levels of distress and restraint and prior criminal behavior as well as behavior during incarceration. Furthermore, of the sample surveyed, 67% were rearrested. Personality traits measured during incarceration were predictive of recidivism rates, above and beyond the effects of such criminological factors as age and number of prior offenses. The results support the view that juvenile delinquents are a heterogeneous population in terms of personality features. These traits have discriminant and predictive validity. Adding personality measures to the assessment of delinquents may further our understanding of how personality influences criminal activity and future recidivism. We may be able to use this understanding to target specific domains of functioning to develop more effective intervention strategies.


Independent associations of serum concentrations of 25-hydroxyvitamin D and parathyroid hormone with blood pressure among US adults.
Vitamin D deficiency or high levels of parathyroid hormone (PTH) appear to be emerging risk factors for hypertension. This study examined whether serum concentrations of 25-hydroxyvitamin D [25(OH)D] and PTH were independently associated with blood pressure and the presence of hypertension or prehypertension among the United States adults. Cross-sectional data from 7228 participants (aged > or =20 years) in the 2003-2006 National Health and Nutrition Examination Survey were analyzed. The least square means and the regression coefficients of systolic blood pressure, diastolic blood pressure, and pulse pressure across quintiles of serum 25(OH)D and PTH were estimated by conducting multiple linear regression analyses. The adjusted prevalence ratios with 95% confidence intervals for hypertension and prehypertension were estimated using the log-binomial method. Among participants not taking blood pressure medications (n = 5414), the mean age- and sex-adjusted systolic and diastolic blood pressure decreased linearly across quintiles of serum 25(OH)D but increased linearly across quintiles of serum PTH (P < 0.001 for all); these relationships remained significant even after extensively adjusting for covariates. Similarly, across quintiles of serum 25(OH)D, the age-adjusted prevalence of hypertension and the adjusted prevalence ratios for both hypertension and prehypertension decreased linearly (P < 0.001 for all). In contrast, the prevalence of hypertension and prehypertension increased nonlinearly (P < 0.05 for both) and the adjusted prevalence ratios for hypertension increased linearly across quintiles of serum PTH (P < 0.001). Serum concentrations of 25(OH)D and PTH were independently associated with blood pressure and with the presence of hypertension or prehypertension among the United States adults, though casual relationships remain to be elucidated.


Effect of a new alpha 2 delta ligand PD-217014 on visceral hypersensitivity induced by 2,4,6-trinitrobenzene sulfonic acid in rats.
PD-217014, a new GABA analog (1 alpha,3 alpha,5 alpha-3-aminomethyl-bicyclo[3.2.0]heptane-3-acetic acid), inhibited [(3)H]-gabapentin binding to alpha(2)delta subunit of voltage-gated calcium channels in a concentration-dependent manner (K(i) = 18 nmol/l). Oral treatment with PD-217014 significantly inhibited the visceral hypersensitivity induced by an intra-colonic injection of trinitrobenzene sulfonic acid in rats. The anti-hyperalgesic effect of PD-217014 increased in a dose-dependent manner, and reached a plateau level at 60 mg/kg p.o. The visceral analgesia produced by PD-217014 at 30 and 60 mg/kg p.o. correlated with blood concentrations within 4 h after dosing, and maximal efficacy was obtained 2 h after dosing when the maximal blood concentration was achieved at either dose. These results indicate that PD-217014 is a potent alpha(2)delta ligand and possesses visceral analgesic activity.


Intermediate filament aggregates cause mitochondrial dysmotility and increase energy demands in giant axonal neuropathy.
Intermediate filaments (IFs) are cytoskeletal polymers that extend from the nucleus to the cell membrane, giving cells their shape and form. Abnormal accumulation of IFs is involved in the pathogenesis of number neurodegenerative diseases, but none as clearly as giant axonal neuropathy (GAN), a ravaging disease caused by mutations in GAN, encoding gigaxonin. Patients display early and severe degeneration of the peripheral nervous system along with IF accumulation, but it has been difficult to link GAN mutations to any particular dysfunction, in part because GAN null mice have a very mild phenotype. We therefore established a robust dorsal root ganglion neuronal model that mirrors key cellular events underlying GAN. We demonstrate that gigaxonin is crucial for ubiquitin-proteasomal degradation of neuronal IF. Moreover, IF accumulation impairs mitochondrial motility and is associated with metabolic and oxidative stress. These results have implications for other neurological disorders whose pathology includes IF accumulation.


[The use of tramal in the orthopedics-traumatology clinic].
There were performed clinical and biochemical investigations of nonnarcotic analgetic tramal application (FRG, Grunenthal) with 196 patients of orthopedic-traumatologic type. The conclusion was drawn that the most effective is tramal application in patients with chronic pains in case of purulent complications and the optimum combination is the coupling of tramal with baralgin and relanium.


Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer's Disease-Studies on Relation to Effective Target Occupancy.
Numerous studies suggest that the majority of amyloid-β (Aβ) peptides deposited in Alzheimer's disease (AD) are truncated and post-translationally modified at the N terminus. Among these modified species, pyroglutamyl-Aβ (pE-Aβ, including N3pE-Aβ40/42 and N11pE-Aβ40/42) has been identified as particularly neurotoxic. The N-terminal modification renders the peptide hydrophobic, accelerates formation of oligomers, and reduces degradation by peptidases, leading ultimately to the accumulation of the peptide and progression of AD. It has been shown that the formation of pyroglutamyl residues is catalyzed by glutaminyl cyclase (QC). Here, we present data about the pharmacological in vitro and in vivo efficacy of the QC inhibitor (S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-one (PQ912), the first-in-class compound that is in clinical development. PQ912 inhibits human, rat, and mouse QC activity, with Ki values ranging between 20 and 65 nM. Chronic oral treatment of hAPPSLxhQC double-transgenic mice with approximately 200 mg/kg/day via chow shows a significant reduction of pE-Aβ levels and concomitant improvement of spatial learning in a Morris water maze test paradigm. This dose results in a brain and cerebrospinal fluid concentration of PQ912 which relates to a QC target occupancy of about 60%. Thus, we conclude that >50% inhibition of QC activity in the brain leads to robust treatment effects. Secondary pharmacology experiments in mice indicate a fairly large potency difference for Aβ cyclization compared with cyclization of physiologic substrates, suggesting a robust therapeutic window in humans. This information constitutes an important translational guidance for predicting the therapeutic dose range in clinical studies with PQ912.


State medical licensure for telemedicine and teleradiology.
Physician medical licensure is state based for historical and constitutional reasons. It may also provide the best method for guaranteeing patient protection from unqualified, incompetent, impaired, or unprofessional practitioners of medicine. However, a significant cost for physicians practicing telemedicine is having to obtain multiple state medical licenses. There is reasonable likelihood that model legislation for the practice of telemedicine across state boundaries will be passed in the next few years, providing physicians with a simpler process for license reciprocity in multiple states via interstate licensing compacts. Physicians would have to be licensed in the state in which the patient resides. Patient complaints would still be adjudicated by the medical licensing board in the state where the patient resides according applicable state legislation.


The effect of menopause and hysterectomy on systemic vascular endothelial growth factor in women undergoing surgery for breast cancer.
Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine produced physiologically by the uterus. Pathological secretion by tumours promotes growth and metastasis. High circulating VEGF levels potentially have a deleterious effect on breast cancer by promoting disease progression. The aims of this study were to investigate circulating VEGF levels in breast cancer patients and assess the effect of menopause or hysterectomy on systemic VEGF. Patients undergoing primary surgery for breast cancer and controls matched for age, menopausal and hysterectomy status were prospectively recruited. Serum VEGF, FSH, LH, estrogen, progesterone and platelet levels were measured. Serum VEGF was corrected for platelet load (sVEGFp) to provide a biologically relevant measurement of circulating VEGF. SVEGFp levels were analyzed with respect to tumor characteristics, menopausal status and hysterectomy status. Two hundred women were included in the study; 89 breast cancer patients and 111 controls. SVEGFp levels were significantly higher in breast cancer patients compared to controls (p = 0.0001), but were not associated with clinico-pathological tumor characteristics. Systemic VEGF levels reduced significantly in the breast cancer patients following tumor excision (p = 0.018). The highest systemic VEGF levels were observed in postmenopausal breast cancer patients. Postmenopausal women who had had a previous hysterectomy had significantly higher VEGF levels than those with an intact postmenopausal uterus (p = 0.001). This study identifies an intact postmenopausal uterus as a potential means of reducing circulating levels of VEGF which could confer a protective effect against breast cancer metastatic potential.


Quality and Safety of Obstetric Practices Using New Modalities- Ultrasound, MR, and CT.
Quality assurance (QA) and safety are important components of obstetric imaging. Quality involves accreditation of the imaging unit as well as equipment inspection for function and image quality. The personnel working in the unit must demonstrate qualifications to perform, evaluate, and interpret the studies. Standardizing the required elements of the examination helps assure that a quality examination has been performed. QA and safety as well as physician requirements and equipment QA programs in ultrasound, computed tomography, and magnetic resonance will be discussed with an in depth look at ultrasound due to its more frequent use in pregnancy.


Variation in hemoglobin F production among normal and sickle cell adults is not related to nucleotide substitutions in the gamma promoter regions.
Single nucleotide substitutions in the promoter regions of the A gamma- and G gamma-globin genes have been associated with increased fetal hemoglobin (HbF) production. We wished to determine whether these or other unrecognized substitutions in the gamma promoter regions are responsible for the 20-fold variation in HbF production in sickle cell patients or normal adults. From a random sampling of 250 sickle cell (SS) patients and 125 normal adults, 17 individuals representing the highest and lowest HbF producers were selected for study. All three common restriction fragment length polymorphism beta-globin region haplotypes (Benin, Central African Republic, and Senegal) were found in both the highest and lowest HbF producers with SS disease. Using the polymerase chain reaction amplification and direct sequencing of the amplified DNA product, we examined the promoter regions of both the A gamma and G gamma genes from -350 bp to +50 bp of the CAP site. No mutations were found in either gamma gene promoter region. We conclude that nucleotide substitutions in the promoter regions (-350 to +50 bp) of both gamma genes are not responsible for the marked variation in HbF production among SS or normal individuals.


Acceleration of hypotension and development of stroke in the spontaneously hypertensive rat by unilateral ureteral obstruction.
Unilateral uareteral obstruction (UUO) in 6-week old male spontaneously hypertensive rats (6-w-SHR) accelerated the elevation of blood pressure and developed stroke with high frequency from 3 weeks after operation, whereas UUO had no effect in either 20-week old SHR or 6-week old normotensive Wistar Kyoto rats. Urinary protein excretion and plasma urea and renin concentrations in 6-w-SHR began to increase 2 weeks after UUO. Removal of the obstructed kidney in 6-w-SHR one week after UUO prevented the acceleration of hypertension, while the same treatment 2 weeks after operation did not. In the ureter-obstructed kidneys of 6-w-SHR, hydronephrotic atrophy was markedly observed already one week after operation, while in the opposite kidneys, hypertensive vascular lesions were manifested from the second week. These results indicate that with regard to reversibility of the hypertensive process, the obstructed kidney is more important in the early postoperative stages and the contralateral kidney more important later.


The effect of hydrocortisone acetate on adult human articular cartilage.
Living adult human articular cartilage has been maintained in tissue culture for eight days. Cartilage explants were cultured in one of three concentrations of hydrocortisone acetate or as control explants without this drug. The concentrations of hydrocortisone used were 0.01 microng/ml, 0.1 microng/ml and 1.0 mg/ml. The amount of proteoglycan shed into the medium was measured and no significant difference was found between the explants exposed to hydrocortisone and those that were not. These results suggest that hydrocortisone does not have a catabolic effect on the proteoglycan of articular cartilage. The widely held view that intra-articular corticosteroid injection causes cartilage damage, must remain in doubt.


Bottle-nosed dolphin: double-slit pupil yields equivalent aerial and underwater diurnal acuity.
In bright daylight, and at best viewing distances, the bottlenosed dolphin resolves visual gratings approximately equally well in air and in water. Aerial resolution improves with increased viewing distance, while underwater resolution improves with decreased viewing distance. The double-slit pipil overcomes the gross myopia in air measured by ophthalmoscope and produces the indicated effects of viewing distance.


Ginsenoside Rg3 enhances the anti-proliferative activity of erlotinib in pancreatic cancer cell lines by downregulation of EGFR/PI3K/Akt signaling pathway.
Erlotinib has shown activity in the management of pancreatic cancer. However, the benefit of EGFR blockade is limited due to EGFR independent PI3K/Akt signaling pathway. Studies have reported that Ginsenoside Rg3 strongly inhibited PI3K-Akt signaling pathway of many carcinomas. We aimed to investigate the activity of Ginsenoside Rg3 to sensitize erlotinib in treating pancreatic cancer in vitro and in vivo. Human pancreatic cancer cell lines BxPC-3 and AsPC-1 were used. Cell proliferation and colony formation assay, Annexin V/PI apoptosis analysis, Western blot analysis, immunohistochemistry and in vivo study were carried out. Ginsenoside Rg3 enhanced the anti-proliferative effects of erlotinib in BxPC-3 and AsPC-1 pancreatic cancer cells and xenograft. Ginsenoside Rg3 enhanced erlotinib-induced apoptosis and increased caspase-3,9 and PARP cleavage expression levels. Erlotinib/Ginsenoside Rg3 treatment decreased the levels of p-EGFR, p-PI3K, and p-Akt expression significantly. Ginsenoside Rg3 could enhance the efficacy of erlotinib to inhibit the proliferation of pancreatic cancer cells via induction of apoptosis and downregulation of the EGFR/PI3K/AKT pathway.


Relationship between the Degree of Illness in Elderly Patients with Rheumatoid Arthritis and Parameters of Musculoskeletal Ultrasound and Oswestry Dysfunction Index and Clinical Value Analysis.
The aim of the study is to explore the relationship between the degree of illness in elderly patients with rheumatoid arthritis (RA) and parameters of musculoskeletal ultrasound (MSUS) and Oswestry Dysfunction Index (ODI) and its clinical value. The clinical data of 100 elderly patients with RA admitted to our hospital from May 2016 to May 2022 were retrospectively analyzed. The patients were divided into four groups, including the remission group (DAS28 ≤ 2.6, n = 25), low activity group (2.6 ≤ DAS28 ≤ 3.2, n = 25), middle activity group (3.2 ≤ DAS28 ≤ 5.1, n = 25), and high activity group (DAS > 5.1, n = 25) according to the disease activity score-28 (DAS28). All patients underwent ultrasonic detection to compare the relationship between the degree of illness in elderly patients with RA and parameters of MSUS and ODI. The total semiquantitative score of MSUS and ODI score in the remission group were obviously lower than those in the other three groups (P < 0.001). The degree of illness in elderly patients with RA was positively correlated with parameters of MSUS (r = 0.886, P < 0.001). The degree of illness in elderly patients with RA was positively correlated with ODI (r = 0.907, P < 0.001). The degree of illness in elderly patients with RA is closely related to parameters of MSUS and ODI, and the parameters of MSUS have a higher evaluation value for the degree of illness in elderly patients with RA, which are correlated with ODI.