Final 5-year results of the United States Zenith Fenestrated prospective multicenter study for juxtarenal abdominal aortic aneurysms.
To report 5-year results of the prospective, multicenter study designed to evaluate the Zenith Fenestrated AAA Endovascular Graft (William A. Cook Australia, Brisbane, Australia) for juxtarenal abdominal aortic aneurysms (AAAs). Sixty-seven patients (54 male, mean age 74 ± 8 years) were prospectively enrolled at 14 U.S. centers from 2005 to 2012. Fenestrated stent grafts were used in patients with infrarenal aortic neck lengths of 4 to 14 mm to target 178 renal-mesenteric arteries with a mean of 2.7 vessels per patient. At 5 years, 42 of the 67 patients completed the final study follow-up, with clinical examination obtained in 41 and computed tomography imaging in 39. Outcomes adjudicated by a clinical events committee included all-cause and aneurysm-related mortality, major adverse events, renal stent occlusion/stenosis, renal function changes and renal infarcts, aneurysm sac enlargement (>5 mm), device migration (≥10 mm), type I/III endoleak, and secondary interventions. Median follow-up was 59.8 months (range, 0.1-67.5 months). There were seven deaths, including one (1.5%) within 30 days (procedure-related) and six beyond 30 days (not procedure-related in five, indeterminate in one). At 5 years, freedom from all-cause mortality was 88.8 ± 4.2% and freedom from aneurysm-related mortality was 96.8 ± 2.3%. There were no aneurysm ruptures or conversions to open surgery. Of the 129 renal arteries targeted by fenestrations, five (4%) occluded and 14 (11%) developed in-stent stenosis. Treatment included redo stenting/angioplasty in 13 vessels, renal artery bypass in 2 vessels, and failed thrombectomy in 1 vessel. Primary and secondary renal target patency was 82.7 ± 4.1% and 95.7 ± 2.1% at 5 years, respectively. Dialysis was required in one patient who had pre-existing chronic kidney disease. During the 5 years, there was 1 type IA endoleak (1.5%), 1 type IB endoleak (1.5%), 2 device migrations (3%), and 4 aneurysm sac enlargements (6%). Overall, 81% of patients had sac shrinkage at 5 years. Of 20 patients who underwent secondary interventions, 12 were for renal in-stent stenosis or occlusion, 7 were for endoleak, and 1 was for both indications. Freedom from secondary intervention was 63.5 ± 7.2% at 5 years. These 5-year results confirm the safety and effectiveness of the Zenith Fenestrated AAA stent graft with no late graft- or aneurysm-related deaths. In-stent stenosis of bare metal renal stents was the most frequent indication for secondary intervention. The low rate of type IA endoleak, sac enlargement, and device migration support its use in patients with juxtarenal AAAs.


Is tumor diameter a risk factor for occult N1 metastasis in patients with peripheral non-small cell lung cancer which is smaller than 3 cm?
The optimum treatment option is surgery for clinical early stage non-small cell lung cancer. Despite all non-invasive and invasive staging effort, occult lymph-node metastasis can be detected in pathological staging. Here, we investigated whether there was any correlation between tumor diameter and occult lymph-node metastasis in N1 stations. Data of patient with non-small cell lung cancer clinical stage 1A were reviewed retrospectively. Those with tumor diameter smaller than 3 cm and pN0-pN1 in pathological staging were included in the study. Overall survival (OS) was calculated by Kaplan-Meier and survival differences between pN0 and pN1 groups were investigated by Log-Rank methods. Cut-off value of tumor diameter for lymph-node metastasis was investigated by Receiver-Operating Characteristics test. Significance between pN0-pN1 and other categorical groups was investigated with Pearson Chi-square or Fisher's exact tests. A total of 257 patients meet to criteria included in the study. Fifty-five (21.4%) of the patients were females. The mean age was 62.7 ± 8.5 and median tumor diameter was 20 mm (Range: 2-30 mm). We detected occult lymph-node metastasis at the N1 stations (pN1) in 33 patients (12.8%) in histopathological examination of resected specimens and lymph-node dissection materials. The cut-off value of tumor diameter was calculated as 21.5 mm for occult lymph-node metastasis by Receiver-Operating Characteristics analysis (Area Under Curved: 70.1%, p = 0.004). There was a significant correlation between pN1 positivity and high tumor diameter (p = 0.02). However, we did not find a correlation between the lymph-node metastasis and age, gender, tumor histopathology, tumor localization, and visceral pleural invasion. Tumor diameter may be an indicator for occult lymph-node metastasis in patients with clinical stage-1A non-small cell lung cancer. This result should be considered in patient with mass which larger than 21.5 mm and planned stereotactic body radiotherapy instead of surgery.


Histopathological variables and DNA cytometry in parathyroid carcinoma.
To undertake an evaluation of histopathological variables in parathyroid carcinoma, 95 cases with this diagnosis were collected from 37 hospitals. Two tumor categories emerged from a review of tissue sections and follow-up information: 56 cases demonstrating extraglandular invasiveness or tumor recurrence were classified as definitive carcinomas, whereas 39 tumors lacking these criteria were classified as equivocal cases. Several morphological variables other than invasiveness differed between the two groups: Fibrosis, necrosis, nuclear atypia (especially macronucleoli), and mitotic figures were significantly more frequent in the carcinoma group. These variables also showed a positive correlation with an aberrant DNA pattern demonstrated by image cytometry. The triad macronucleoli, more than five mitoses per 50 high-power fields, and necrosis were associated with an aggressive behavior in terms of recurrent disease. A minority of the carcinomas had a bland cytologic appearance and differed from benign lesions only by their invasiveness. Certain patterns of fibrosis and necrosis were common but neither pathognomonic nor constant features of malignancy. Mitotic activity constituted a prognostic risk factor but was of limited diagnostic significance. In half of the carcinomas, the frequency of mitoses did not exceed values recorded in benign parathyroid lesions.


Monitoring changes in gene expression in renal ischemia-reperfusion in the rat.
Although acute renal failure (ARF) is a relatively common disorder with major morbidity and mortality, its molecular basis remains incompletely defined. The present study examined global gene expression in the well-characterized ischemia-reperfusion model of ARF using DNA microarray technology. Male Wistar rats underwent bilateral renal ischemia (30 min) or sham operation, followed by reperfusion for 1, 2, 3 or 4 days. Plasma creatinine increased approximately fivefold over baseline, peaking on day 1. Renal total RNA was used to probe cDNA microarrays. Alterations in expression of 18 genes were identified by microarray analysis. Nine genes were up-regulated (ADAM2, HO-1, UCP-2, and thymosin beta4 in the early phase and clusterin, vanin1, fibronectin, heat-responsive protein 12 and FK506 binding protein in the established phase), whereas another nine were down-regulated (glutamine synthetase, cytochrome p450 IId6, and cyp 2d9 in the early phase and cyp 4a14, Xist gene, PPARgamma, alpha-albumin, uromodulin, and ADH B2 in the established phase). The identities of these 18 genes were sequence-verified. Changes in gene expression of ADAM2, cyp2d6, fibronectin, HO-1 and PPARgamma were confirmed by quantitative real-time polymerase chain reaction (PCR). ADAM2, cyp2d6, and PPARgamma have not previously been known to be involved in ARF. Using DNA microarray technology, we identified changes in expression of 18 genes during renal ischemia-reperfusion injury in the rat. We confirmed changes in five genes (fibronectin, ADAM2, cyp 2d6, HO-1 and PPARgamma) by quantitative real-time PCR. Several genes, not previously been identified as playing a role in ischemic ARF, may have importance in this disease.


Cultural variations on optimistic and pessimistic bias for self versus a sibling: is there evidence for self-enhancement in the west and for self-criticism in the east when the referent group is specified?
A culturally relevant framework was used to examine variations on optimistic and pessimistic bias in Westerners and Easterners. Study 1 showed that 136 European Americans compared with 159 Japanese were more likely to predict typical positive events to occur to self than to a sibling. The opposite pattern emerged in the prediction of typical negative events. Study 2 replicated these findings on the basis of predictions for atypical events in 175 European Americans and 130 Japanese. Across both studies, within-groups analyses indicated that European Americans held an optimistic bias in the prediction of positive and negative events, whereas Japanese held a pessimistic bias for negative events. These findings are taken to offer support for presumed cultural differences in self-enhancement and self-criticism between Westerners and Easterners, respectively.


Water vapor adsorption on goethite.
Goethite (α-FeOOH) is an important mineral contributing to processes of atmospheric and terrestrial importance. Their interactions with water vapor are particularly relevant in these contexts. In this work, molecular details of water vapor (0.0-19.0 Torr; 0-96% relative humidity at 25 °C) adsorption at surfaces of synthetic goethite nanoparticles reacted with and without HCl and NaCl were resolved using vibrational spectroscopy. This technique probed interactions between surface (hydr)oxo groups and liquid water-like films. Molecular dynamics showed that structures and orientations adopted by these waters are comparable to those adopted at the interface with liquid water. Particle surfaces reacted with HCl accumulated less water than acid-free surfaces due to disruptions in hydrogen bond networks by chemisorbed waters and chloride. Particles reacted with NaCl had lower loadings below ∼10 Torr water vapor but greater loadings above this value than salt-free surfaces. Water adsorption reactions were here affected by competitive hydration of coexisting salt-free surface regions, adsorbed chloride and sodium, as well as precipitated NaCl. Collectively, the findings presented in this study add further insight into the initial mechanisms of thin water film formation at goethite surfaces subjected to variations in water vapor pressure that are relevant to natural systems.


Patterns of mtDNA introgression suggest population replacement in Palaearctic whiskered bat species.
Secondary contacts can play a major role in the evolutionary histories of species. Various taxa diverge in allopatry and later on come into secondary contact during range expansions. When they meet, their interactions and the extent of gene flow depend on the level of their ecological differentiation and the strength of their reproductive isolation. In this study, we present the multilocus phylogeography of two cryptic whiskered bat species, Myotis mystacinus and M. davidii, with a particular focus on their putative sympatric zone. Our findings suggest that M. mystacinus and M. davidii evolved in allopatry and came into secondary contact during range expansions. Individuals in the area of secondary contact, in Anatolia and the Balkans, have discordant population assignments based on the mitochondrial and the nuclear datasets. These observed patterns suggest that the local M. mystacinus populations hybridized with expanding M. davidii populations, which resulted in mitochondrial introgression from the former. In the introgression area, M. mystacinus individuals with concordant nuclear and mitochondrial genotypes were identified in relatively few locations, suggesting that the indigenous populations might have been largely replaced by invading M. davidii. Changing environmental conditions coupled with ecological competition is the likely reason for this replacement. Our study presents one possible example of a historical population replacement that was captured in phylogeographic patterns.


Automated 3D bioassembly of micro-tissues for biofabrication of hybrid tissue engineered constructs.
Bottom-up biofabrication approaches combining micro-tissue fabrication techniques with extrusion-based 3D printing of thermoplastic polymer scaffolds are emerging strategies in tissue engineering. These biofabrication strategies support native self-assembly mechanisms observed in developmental stages of tissue or organoid growth as well as promoting cell-cell interactions and cell differentiation capacity. Few technologies have been developed to automate the precise assembly of micro-tissues or tissue modules into structural scaffolds. We describe an automated 3D bioassembly platform capable of fabricating simple hybrid constructs via a two-step bottom-up bioassembly strategy, as well as complex hybrid hierarchical constructs via a multistep bottom-up bioassembly strategy. The bioassembly system consisted of a fluidic-based singularisation and injection module incorporated into a commercial 3D bioprinter. The singularisation module delivers individual micro-tissues to an injection module, for insertion into precise locations within a 3D plotted scaffold. To demonstrate applicability for cartilage tissue engineering, human chondrocytes were isolated and micro-tissues of 1 mm diameter were generated utilising a high throughput 96-well plate format. Micro-tissues were singularised with an efficiency of 96.0 ± 5.1%. There was no significant difference in size, shape or viability of micro-tissues before and after automated singularisation and injection. A layer-by-layer approach or aforementioned bottom-up bioassembly strategy was employed to fabricate a bilayered construct by alternatively 3D plotting a thermoplastic (PEGT/PBT) polymer scaffold and inserting pre-differentiated chondrogenic micro-tissues or cell-laden gelatin-based (GelMA) hydrogel micro-spheres, both formed via high-throughput fabrication techniques. No significant difference in viability between the construct assembled utilising the automated bioassembly system and manually assembled construct was observed. Bioassembly of pre-differentiated micro-tissues as well as chondrocyte-laden hydrogel micro-spheres demonstrated the flexibility of the platform while supporting tissue fusion, long-term cell viability, and deposition of cartilage-specific extracellular matrix proteins. This technology provides an automated and scalable pathway for bioassembly of both simple and complex 3D tissue constructs of clinically relevant shape and size, with demonstrated capability to facilitate direct spatial organisation and hierarchical 3D assembly of micro-tissue modules, ranging from biomaterial free cell pellets to cell-laden hydrogel formulations.


H1-histamine receptors on human astrocytoma cells.
The H1-histamine receptor antagonist [3H]mepyramine bound with high affinity (Kd = 3-5 nM) to membranes derived from 1321N1 human astrocytoma cells. The H1-receptor antagonists triprolidine and diphenhydramine inhibited [3H]mepyramine binding with Kj values of 1-5 nM, whereas the Kj of the H2-histamine receptor antagonist cimetidine was greater than 100 microM. Histamine also inhibited [3H]mepyramine binding to 1321N1 cell membranes, and the histamine inhibition curve was shifted to the right and steepened in the presence of 1 microM guanosine 5'-O-(3-thiotriphosphate). Treatment of 1321N1 cells with pertussis toxin had no effect on the capacity of histamine to inhibit [3H]mepyramine binding either in the absence or presence of guanosine 5'-O-(3-thiotriphosphate). Therefore, agonist-occupied histamine receptors in these cells apparently interact with a guanine nucleotide regulatory protein that is not the inhibitory guanine nucleotide regulatory protein of adenylate cyclase. Although adenylate cyclase activity was not affected by histamine in a cell-free preparation, incubation of 1321N1 cells with histamine resulted in an attenuation of cyclic AMP accumulation. Analysis of cyclic AMP degradation in the presence of histamine indicated that the effects of histamine on cyclic AMP accumulation are mediated through activation of phosphodiesterase. This idea was supported by the fact that the phosphodiesterase inhibitor 1-isobutyl 3-methylxanthine blocked attenuation of cyclic AMP accumulation by histamine in a noncompetitive manner. Histamine also markedly increased phosphoinositide breakdown and 45Ca2+ efflux in 1321N1 cells. These histamine-induced effects apparently are mediated through H1-receptors, since triprolidine, but not cimetidine, potently inhibited histamine action. As for histamine interaction with its receptor, pertussis toxin had no effect on histamine-induced phosphoinositide breakdown, 45Ca2+ efflux, or attenuation of cyclic AMP accumulation. Taken together, these data indicate that 1321N1 human astrocytoma cells are a useful model system for the study of H1-histamine receptors and the biochemical responses mediated through these receptors.


Distinct roles for VeA and LaeA in development and pathogenesis of Aspergillus flavus.
Aspergillus flavus, a mycotoxigenic filamentous fungus, colonizes several important agricultural crops, such as maize and peanuts. Two proteins, VeA and LaeA, known to form a nuclear complex in Aspergillus nidulans have been found to positively regulate developmental processes in several Aspergillus species. Here, an examination of near-isogenic A. flavus mutants differing in copy number of veA and laeA alleles (0, 1, or at least 2 each) revealed critical roles for VeA and LaeA in A. flavus development and seed colonization. In contrast to the wild type, both null mutants were unable to metabolize host cell lipid reserves and were inhibited by oleic acid in growth assays. The copy number of LaeA but not VeA appeared critical for a density-dependent sclerotial-to-conidial shift, since the multicopy laeA (MClaeA) strain produced relatively constant sclerotial numbers with increasing population size rather than showing the decrease in sclerotia seen in both the wild-type and MCveA strains. The MCveA-laeA strain yielded an intermediate phenotype. This study revealed unique roles of VeA and LaeA in seed pathogenesis and fungal biology, distinct from their cooperative regulatory functions in aflatoxin and sclerotial development.


Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitors: a novel approach in small molecule discovery.
The calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2) plays a key role in regulation of intracellular calcium levels and signaling pathways. It is involved in activation of downstream signaling pathways that regulate various cellular processes. Dysregulation of CAMKK2 activity has been linked to various diseases including cancer, suggesting that CAMKK2 inhibitors might be beneficial in oncological, metabolic and inflammatory indications. The most pressing issues in small molecule discovery are synthesis feasibility, novel chemical structure and desired biological characteristics. To circumvent this constraint, we employed 'DrugspaceX' for rapid lead identification, followed by repositioning seven FDA-approved drugs for CAMKK2 inhibition. Further, first-level transformation (Set1 analogues) was performed in 'DrugspaceX', followed by virtual screening. The t-SNE visualization revealed that the transformations surrounding Rucaparib, Treprostinil and Canagliflozin are more promising for developing CAMKK2 inhibitors. Second, using the top-ranked Set1 analogues, Set2 analogues were generated, and virtual screening revealed the top-ranked five analogues. Among the top five Set2 analogues, DE273038_5 had the lowest docking score of -11.034 kcal/mol and SA score of 2.59, retaining the essential interactions with Hotspot residues LYS194 and VAL270 across 250 ns simulation period. When compared to the other four compounds, the ligand effectiveness score was 0.409, and the number of rotatable penalties was only three. Further, DE273038_5 after two rounds of transformations was discovered to be novel and had not been previously described in other databases. These data suggest that the new candidate DE273038_5 is likely to have inhibitory activity at the CAMKK2 active site, implying potential therapeutic use.Communicated by Ramaswamy H. Sarma.


Regional myocardial blood flow during graded treadmill exercise in the dog.
Regional myocardial blood flow was measured in nine dogs at rest and during three levels of treadmill exercise by using left atrial injections of 7-10-mum radioactive microspheres. At rest, heart rate was 76 plus or minus 3 beats/min (mean plus or minus SEM), mean left ventricular myocardial flow was 0.94 plus or minus 0.09 ml/min/g and endocardial flow (endo) exceeded epicardial flow (epi) in all regions (endo/epi equals 1.12-1.33). When treadmill exercise was regulated to increase heart rates from 152 plus or minus 3 to 190 plus or minus 3 to 240 plus or minus 6 beats/min, myocardial blood flow (MBF) to all regions of the left ventricle increased linearly with heart rate (HR) from 1.83 plus or minus 0.11 to 2.75 plus or minus 0.22 to 3.90 plus or minus 0.26 ml/min/g (MBF EQUALs 0.0175 HR - 0.523 PLUS OR MINUS 0.614, R EQUALS 0.87). Exercise abolished the gradient of blood flow favoring the left ventricular endocardium at rest, so that the endo/epi flow ratios were not significantly different from 1.00. Right ventricular flows were consistently less than corresponding left ventricular flows, but showed a similar linear increase with heart rate. Right ventricular endo/epi ratios were not different from 1.00 either at rest or during exercise. Thus, exercise resulted in increased myocardial blood flow to all regions of the left and right ventricles with maintenance of subendocardial flow equal to subepicardial flow.


GLYPHOSATE IMPACT on human health and the environment: Sustainable alternatives to replace it in Mexico.
Glyphosate is a broad-spectrum, non-selective herbicide used to control weeds and protect agricultural crops, and it is classified as potentially carcinogenic by the International Agency for Research on Cancer. In Mexico, the use of pesticides is a common practice, including glyphosate. However, on December 31st, 2020, the Mexican government decreed the prohibition of this herbicide as of January 2024. In this review, we investigate the association between glyphosate and cancer risk and found that most of the studies focused using animals showing negative effects such as genotoxicity, cytotoxicity and neurotoxicity, some studies used cancer cell lines showing proliferative effects due to glyphosate exposure. To our knowledge, in Mexico, there are no scientific reports on the association of glyphosate with any type of cancer. In addition, we reviewed the toxicological effects of the herbicide glyphosate, and the specific case of the current situation of the use and environmental damage of this herbicide in Mexico. We found that few studies have been published on glyphosate, and that the largest number of publications are from the International Agency for Research on Cancer classification to date. Additionally, we provide data on glyphosate stimulation at low doses as a biostimulant in crops and analytical monitoring techniques for the detection of glyphosates in different matrices. Finally, we have tried to summarize the actions of the Mexican government to seek sustainable alternatives and replace the use of glyphosate, to obtain food free of this herbicide and take care of the health of the population and the environment.


[Complications of pituitary surgery. Analysis of 120 operations at HUCFF-UFRJ].
We evaluated 120 pituitary operations performed at Hospital Universitario Clementino Fraga Filho of the Universidade Federal do Rio de Janeiro from 1979 to July 1998 with the aim of analysing the immediate post operative morbidity and mortality. The ages ranged from 15 to 70 years and the clinical diagnoses were: nonsecreting adenomas, 46 (38.34%); acromegaly, 30 (25%); prolactinomas, 29 (24.16%) and Cushing's disease 15 (12.5%). The main endocrine complications were: panhypopituitarism, 16 (13.34%); diabetes insipidus, 15 (12.5%) and adrenocortical insufficiency, 4 (3.34%). Neurological complications: infection, 13 (10.84%); and cerebrospinal fluid leakage, 6 (5%). Two patients died. Our results agree with those of the international literature. We identified a progressive decrease of morbidity and mortality due to surgeon's skill increase and to the uniformity of the clinical team which managed those patients.


[Cerebral metabolic monitoring experience in critical neurological patients].
Cerebral metabolic monitoring in critical neurological patients allows the assessment of neuronal tissue response to injury and to plan the best therapy to correct each critical brain situation. To evaluate the usefulness of cerebral metabolic monitoring in patients with acute cerebral injury. A retrospective analysis of 29 patients with acute brain injury, in whom a catheter was located in the bulb of the jugular vein to perform a cerebral metabolic monitoring. These patients were compared with others that were not subjected to this monitoring. The evolution at six months of follow up was assessed using the Glasgow outcome score, considering a favorable evolution when this score was 4 or greater. Patients with an hyperemic state on admission or after optimization of therapy did not have hospital mortality, and 73% had Glasgow outcome score of 4 or greater at six months of follow up. On the other hand, 50% of those with hypoperfusion or global ischemia died during hospitalization and 72% had a Glasgow outcome score of 3 or less at six months. Patients not subjected to cerebral metabolic monitoring behave as those with hypoperfusion or global ischemia. Cerebral metabolic monitoring is an useful tool to optimize the management of patients with acute cerebral injury, and those patients with an hyperemic cerebral state have the best prognosis.


Adult rat hepatic bipotent progenitor cells remain dormant even after extensive hepatectomy.
S It remains unknown whether the normal adult liver contains bipotent stem/progenitor cells, and if it does, then what are the circumstances under which they proliferate. The aim of this study was to clarify whether the normal adult liver contains hepatic stem/progenitor cells, and if it does, will they be activated by extensive hepatectomy? Adult rat liver cells were isolated and cultured at a low-density, and the colony-forming assay was performed to evaluate the cell proliferative capacity. Immunocytochemistry and reverse transcription-polymerase chain reaction were used to investigate the multilineage differentiation capability. The rate of colony formation by cells from the normal liver and those from the regenerating liver after partial hepatectomy (PH) were compared to determine whether progenitor cell proliferation might be activated by PH. Only a few epithelial colonies (0.043+/-0.009% of nonparenchymal cells) continued to proliferate for more than 1 month. Reverse transcription-polymerase chain reaction and immnocytochemistry showed that these progenitor colonies expressed both hepatocyte and cholangiocyte markers. The proportion of progenitor cells that formed bipotential colonies did not differ significantly between the cells obtained from the normal and PH livers. Adult normal liver contains bipotent hepatic progenitor cells, but they are scarcely activated even after extensive hepatectomy.


Live applications of norbormide-based fluorescent probes in Drosophila melanogaster.
In this study we investigated the performance of two norbormide (NRB)-derived fluorescent probes, NRBMC009 (green) and NRBZLW0047 (red), on dissected, living larvae of Drosophila, to verify their potential application in live cell imaging confocal microscopy. To this end, larval tissues were exposed to NRB probes alone or in combination with other commercial dyes or GFP-tagged protein markers. Both probes were rapidly internalized by most tissues (except the central nervous system) allowing each organ in the microscope field to be readily distinguished at low magnification. At the cellular level, the probes showed a very similar distribution (except for fat bodies), defined by loss of signal in the nucleus and plasma membrane, and a preferential localization to endoplasmic reticulum (ER) and mitochondria. They also recognized ER and mitochondrial phenotypes in the skeletal muscles of fruit fly models that had loss of function mutations in the atlastin and mitofusin genes, suggesting NRBMC009 and NRBZLW0047 as potentially useful screening tools for characterizing ER and mitochondria morphological alterations. Feeding of larvae and adult Drosophilae with the NRB-derived dyes led to staining of the gut and its epithelial cells, revealing a potential role in food intake assays. In addition, when flies were exposed to either dye over their entire life cycle no apparent functional or morphological abnormalities were detected. Rapid internalization, a bright signal, a compatibility with other available fluorescent probes and GFP-tagged protein markers, and a lack of toxicity make NRBZLW0047 and, particularly, NRBMC009 highly performing fluorescent probes for live cell microscopy studies and food intake assays in Drosophila.


Learning foreign sounds in an alien world: videogame training improves non-native speech categorization.
Although speech categories are defined by multiple acoustic dimensions, some are perceptually weighted more than others and there are residual effects of native-language weightings in non-native speech perception. Recent research on nonlinguistic sound category learning suggests that the distribution characteristics of experienced sounds influence perceptual cue weights: Increasing variability across a dimension leads listeners to rely upon it less in subsequent category learning (Holt & Lotto, 2006). The present experiment investigated the implications of this among native Japanese learning English /r/-/l/ categories. Training was accomplished using a videogame paradigm that emphasizes associations among sound categories, visual information, and players' responses to videogame characters rather than overt categorization or explicit feedback. Subjects who played the game for 2.5h across 5 days exhibited improvements in /r/-/l/ perception on par with 2-4 weeks of explicit categorization training in previous research and exhibited a shift toward more native-like perceptual cue weights.


A comprehensive evaluation of module detection methods for gene expression data.
A critical step in the analysis of large genome-wide gene expression datasets is the use of module detection methods to group genes into co-expression modules. Because of limitations of classical clustering methods, numerous alternative module detection methods have been proposed, which improve upon clustering by handling co-expression in only a subset of samples, modelling the regulatory network, and/or allowing overlap between modules. In this study we use known regulatory networks to do a comprehensive and robust evaluation of these different methods. Overall, decomposition methods outperform all other strategies, while we do not find a clear advantage of biclustering and network inference-based approaches on large gene expression datasets. Using our evaluation workflow, we also investigate several practical aspects of module detection, such as parameter estimation and the use of alternative similarity measures, and conclude with recommendations for the further development of these methods.


Potent anti-HIV activities and mechanisms of action of a pine cone extract from Pinus yunnanensis.
The anti-HIV activities of a pine cone extract (YNS-PY-F) from Pinus yunnanensis have been evaluated, and its mechanisms of action were also explored. The pine cone extract, YNS-PY-F, potently inhibited HIV-1(IIIB), HIV-1(RF), HIV-1(A17), HIV-1(AO18) and HIV-2(ROD) and induced cytopathic effect in C8166 cells with EC₅₀ values of 0.96 μg/mL, 1.53 μg/mL, 0.88 μg/mL, 7.20 μg/mL and 6.17 μg/mL, respectively. The quantification of a p24 production assay showed that YNS-PY-F significantly inhibited the acute replication of HIV-1(IIIB), HIV-1RF, HIV-1(A17) and HIV-1(AO18) in C8166 cells. An MTT assay showed that YNS-PY-F also significantly inhibited the HIV-1(IIIB) induced cytolysis in MT-4 cells with an EC₅₀ value of 2.22 μg/mL. The mechanism assays showed that YNS-PY-F had potent inhibitory effects on the fusion between infected cells and uninfected cells, and the activity of HIV-1 reverse transcriptase, with EC₅₀ values of 7.60 μg/mL and 4.60 μg/mL, respectively. Overall, these data suggest that the pine cone extract from Pinus yunnanensis has potent inhibitory activities against HIV-1(IIIB), HIV-1(RF), RT inhibitor-resistant strains HIV-1(A17) and HIV-1(AO18), and HIV-2(ROD), and its anti-HIV mechanisms include inhibition of HIV entry and inhibition of reverse transcriptase activity.


Quantitative microbial risk assessment applied to irrigation of salad crops with waste stabilization pond effluents.
A quantitative microbial risk assessment model for estimating infection risks arising from consuming crops eaten raw that have been irrigated with effluents from stabilization ponds was constructed. A log-normal probability distribution function was fitted to a large database from a comprehensive monitoring of an experimental pond system to account for variability in Escherichia coli concentration in irrigation water. Crop contamination levels were estimated using predictive models derived from field experiments involving the irrigation of several crops with different effluent qualities. Data on daily intake of salad crops were obtained from a national survey in Brazil. Ten thousand-trial Monte Carlo simulations were used to estimate human health risks associated with the use of wastewater for irrigating low- and high-growing crops. The use of effluents containing 10(3)-10(4) E. coli per 100 ml resulted in median rotavirus infection risk of approximately 10(-3) and 10(-4) pppy when irrigating, respectively, low- and high-growing crops; the corresponding 95th percentile risk estimates were around 10(-2) in both scenarios. Sensitivity analyses revealed that variations in effluent quality, in the assumed ratios of pathogens to E. coli, and in the reduction of pathogens between harvest and consumption had great impact upon risk estimates.


Prognostic Impact of Renal Function on 5-Year Outcomes After Fractional Flow Reserve-Guided Deferral of Revascularization.
Background Chronic kidney disease (CKD) might influence fractional flow reserve (FFR) value, potentially attenuating its prognostic utility. However, few large-scale data are available regarding clinical outcomes after FFR-guided deferral of revascularization in patients with CKD. Methods and Results From the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), 1218 patients were divided into 3 groups according to renal function: (1) non-CKD (estimated glomerular filtration rate ≥60 mL/min per 1.73 m2), n=385; (2) CKD (estimated glomerular filtration rate 15-59 mL/min per 1.73 m2, n=763); and (3) end-stage renal disease (ESRD) (eGFR <15 mL/min per 1.73 m2, n=70). The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), defined as a composite of cardiac death, target vessel myocardial infarction, and clinical driven target vessel revascularization. Cumulative 5-year incidence of TVF was significantly higher in the ESRD group than in the CKD and non-CKD group, whereas it did not differ between the CKD and non-CKD groups (26.3% versus 11.9% versus 9.5%, P<0.001). Although the 5-year TVF risk increased as the FFR value decreased regardless of renal function, patients with ESRD had a remarkably higher risk of TVF at every FFR value than those with CKD and non-CKD. Conclusions At 5 years, patients with ESRD showed a higher incidence of TVF than patients with CKD and non-CKD, although with similar outcomes between patients with CKD and non-CKD. Patients with ESRD had an excess risk of 5-year TVF at every FFR value compared with those with CKD and non-CKD. Registration URL: https://www.umin.ac.jp; Unique identifier: UMIN000014473.


Reproduction and growth following prenatal methylmercuric chloride exposure in mice.
Reproductive effects of the environmental pollutant methylmercuric chloride administered as a single dose per os during pregnancy were studied both in treated mice (G0 generation) and in their prenatally exposed offspring (G1). Treatment at 9.5 days postfertilization caused no observed effects at doses as high as 12-18 mg Hg+/kg. In contrast, treatment at 12.5 and 15.5 days produced toxicity; results were similar and were combined for analysis. Among G0 mice, the percentage capable of delivering one or more viable pups showed an estimated threshold level response at 8.0 mg/kg. The percentage of G1 pups that were viable at 1 day post partum was significantly dose-related, with an approximate threshold exposure level of 4.3 mg/kg. Among the surviving G1 offspring, body weight in adulthood (8 months) showed a statistically significant reduction that was also dose-related. Fertility testing of G1 offspring revealed no treatment effects on mating behavior judged by time interval between pairing and parturition. However, there was a trend (statistically nonsignificant) toward a dose effect on sizes of females' litters. Sterility (inability to produce offspring) did not occur either among G1 males at 4 months of age (N = 30; dose 8-12 mg/kg) or among females up to the advanced reproductive age of 14 months (N = 29; dose 5.3-12 mg/kg). We conclude that mice exposed prenatally to methylmercuric chloride revealed no greater susceptibility to sterility than to perinatal mortality.


Preferred Reporting Items for Diagnostic Accuracy Studies in Endodontics (PRIDASE) guidelines: a development protocol.
Diagnostic accuracy studies play an important role in informing clinical practice and patient management, by evaluating the ability of diagnostic testing and imaging to identify the presence or absence of a disease or condition. These studies compare the relative diagnostic strength of the test or device with a reference standard, therefore, guiding clinical decisions on the reliability of the test, the need for further tests, and whether to monitor or treat a particular condition. Inadequate and incomplete reporting of diagnostic accuracy studies can disguise methodological deficiencies and ultimately result in study bias and the inability to translate research findings into daily clinical practice. The Preferred Reporting Items for Diagnostic Accuracy Studies in Endodontics (PRIDASE) guidelines are being developed in order to improve the accuracy, transparency, completeness and reproducibility of diagnostic accuracy studies in the speciality of Endodontology. The aim of this paper is to report the process used to develop the PRIDASE guidelines based on a well-established consensus process. The project leaders (PD, VN) formed a steering committee of nine members (PD, VN, PA, AF, DR, SP, CK, MP, HD) to oversee and manage the project. The PRIDASE steering committee will develop the initial draft of the PRIDASE guidelines by adapting and modifying the Standards for Reporting of Diagnostic Accuracy Studies (STARD) 2015 guidelines, adding new items related specifically to the nature of Endodontics and incorporate the Clinical and Laboratory Images in Publication (CLIP) principles. The initial guidelines will consist of a series of domains and individual items and will be validated by the members of a PRIDASE Delphi Group (PDG) consisting of a minimum of 30 individuals who will evaluate independently the individual items based on two parameters: 'clarity' using a dichotomous scoring (yes/no) and 'suitability' for inclusion using a 9-point Likert Scale. The scores awarded by each member and any suggestions for improvement will be shared with the PDG to inform an iterative process that will result in a series of items that are clear and suitable for inclusion in the new PRIDASE guidelines. Once the PDG has completed its work, the steering committee will create a PRIDASE Meeting Group (PMG) of 20 individuals from around the world. Members of the PDG will be eligible to be the part of PMG. The draft guidelines and flowchart approved by the PDG will then be presented for further validation and agreement by the PMG. As a result of these discussions, the PRIDASE guidelines will be finalized and then disseminated to relevant stakeholders through publications and via the Preferred Reporting Items for study Designs in Endodontology (PRIDE) website (http://pride-endodonticguidelines.org). Periodic updates to the PRIDASE guidelines will be made based on feedback from stakeholders and end-users.


Purification and characterization of the catalytic subunit of adenosine 3':5'-cyclic monophosphate-dependent protein kinase from bovine liver.
1. The catalytic subunit of bovine liver cyclic AMP-dependent protein kinase (EC18.104.22.168) was purified essentially by the method of Reimann & Corbin [(1976) Fed. Proc. Fed. Am. Soc. Exp. Biol. 35, 1384]. 2. Sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, sedimentation-velocity centrifugation and sedimentation-equilibrium centrifugation showed that the catalytic subunit was monodisperse. Polyacrylamide-gel isoelectric-focusing electrophoresis revealed the presence of at least three isoenzyme forms of catalytic subunit activity with slightly different pI values (6.72, 7.04 and 7.35). 3. Physical properties of the catalytic subunit were determined by several different methods. It had mol.wt. 39000-42000, Stokes radium 2.73-3.08 nm, so20.w 3.14S, f/fo 1.19-1.23 and, assuming a prolate ellipsoid, axial ration 4-5. 4. Amino acid analysis was performed on the catalytic subunit. It had one cysteine residue/molecule which was essential for activity. Inhibition by thiol-specific reagents was partially prevented by the presence of ATP-Mg2+. 5. The circular-dichroic spectrum showed the catalytic subunit contained 29% alpha-helical form, 18% beta-form and 53% aperiodic form. Near-u.v. circular dichroism showed the presence of aromatic residues whose equivalent molar ellipticity was greatly altered by the addition of ATP-Mg2+. 6. Kinetic experiments showed that the catalytic subunit had an apparent Km for ATP of 7 muM. 5'-Adenylyl imidodiphosphate inhibitied competitively with ATP with a Ki of 60 muM. The kinetic plot for histone (Sigma, type II-A) was biphasic showing 'high'-and 'low'-Km segments. Under assay conditions the specific activity of the catalytic subunit was 3 X 10(6) units/mg of protein. Of various metal ions tested, the catalytic subunit was most active with Mg2+.7. When assayed with histone (Sigma, type II-A) as substrate, the activity of the catalytic subunit was increased by non-ionic detergents or urea. No such activation was observed with casein as substrate.


Dravet syndrome: from electroclinical characteristics to molecular biology.
The onset of Dravet syndrome typically occurs within the first year, with prolonged, generalized, or unilateral clonic seizures triggered by fever. In the early stages, other types of refractory seizures usually present that include myoclonic seizures, atypical absences, and partial seizures. Electroencephalography (EEG) findings are not pathognomonic, and signs of cognitive arrest or deterioration progressively appear. In contrast, in adults, myoclonic seizures, atypical absences, and focal seizures tend to disappear, and short tonic-clonic seizures, often associating a focal component, persist particularly during sleep. The sensitivity to fever persists into adulthood, and although mental deterioration occurs in infancy, usually leaving patients with severe mental impairment, further deterioration does not occur. The identification of genes associated with Dravet syndrome and related syndromes hints at the complexity of the etiology of such epilepsies. Identifying SCN1A mutations has become useful as a means to support an early diagnosis of Dravet syndrome, to benefit counseling, and to avoid use of antiepileptic drugs (AEDs) that may have adverse effects. However, the defining characteristics of seizure type and EEG patterns initially identified by Dravet remain fundamental to diagnosis.


Combining biomarkers for prognostic modelling of Parkinson's disease.
Patients with Parkinson's disease (PD) have variable rates of progression. More accurate prediction of progression could improve selection for clinical trials. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be further improved by blood biomarkers. To determine if blood biomarkers (serum neurofilament light (NfL) and genetic status (glucocerebrosidase, GBA and apolipoprotein E (APOE))) are useful in addition to clinical measures for prognostic modelling in PD. We evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients' genetic (GBA and APOE) status. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model, and explored how blood biomarkers compared with clinical variables in distinguishing prognostic phenotypes . 291 patients were assessed in this study. Baseline serum NfL was associated with baseline cognitive status. Nfl predicted a shorter time to dementia, postural instability and death (dementia-HR 2.64; postural instability-HR 1.32; mortality-HR 1.89) whereas APOEe4 status was associated with progression to dementia (dementia-HR 3.12, 95% CI 1.63 to 6.00). NfL levels and genetic variables predicted unfavourable progression to a similar extent as clinical predictors. The combination of clinical, NfL and genetic data produced a stronger prediction of unfavourable outcomes compared with age and gender (area under the curve: 0.74-age/gender vs 0.84-ALL p=0.0103). Clinical trials of disease-modifying therapies might usefully stratify patients using clinical, genetic and NfL status at the time of recruitment.


The Evaluation of Saliva Flow Rate, pH, Buffer Capacity, Microbiological Content and Indice of Decayed, Missing and Filled Teeth in Behçet's Patients.
Several lines of evidence indicate that oral microbial flora play a critical role in the pathogenesis of Behçet disease. Saliva flow rate, buffer capacity and microorganism content are very important in the maintenance of oral health. We aimed to evaluate saliva flow rate, pH, buffer capacity and Streptococcus mutans and Lactobacilli content along with the decayed, missing, and filled tooth index in Behçet's patients. Case-control study. Forty patients with active Behçet disease [female:male (F/M) 21/19, mean age 31.05±11.08 years] and forty healthy persons (F/M 21/19, mean age 31.03±9.14 years) were included in the study. The oral region was first examined, and the decayed, missing, and filled tooth index was calculated for each person. Stimulated saliva was collected and divided into two separate millimetric tubes to calculate the buffer capacity of the saliva, determine Streptococcus mutans and Lactobacilli levels and measure the pH of the saliva. A Caries Risk Test buffer strip was used to calculate the buffer capacity. Caries Risk Test bacterial kit was used to determine Streptococcus mutans and lactobacilli levels. A pH meter was used to measure the pH of the saliva. The mean saliva pH of the patients was higher than the controls (7.76±0.51, 7.18±0.46, respectively) (p<0.001). The mean level of Streptococcus mutans and Lactobacilli in patients was higher than controls (p<0.05). The mean decayed, missing, and filled tooth index of patients was 9.82±6.59 (range 1-28), while the mean decayed, missing, and filled tooth index of the controls was 6.05±3.35 (range 1-16) (p<0.01). There were no significant differences between the patients and the controls with respect to saliva flow rate and saliva buffer capacity (p>0.05). We think that the maintenance of oral health by effective, regular tooth brushing, regular dental check-ups and dental treatment for Behçet patients is very important for the prevention and therapy of Behçet disease.


Early neurochemical modifications of monoaminergic systems in the R6/1 mouse model of Huntington's disease.
Huntington's disease (HD) is a rare, autosomal neurodegenerative disease characterized by motor and cognitive impairments appearing in adults. The R6/1 mouse model of the disease recapitulates the adult onset of motor symptoms preceded by cognitive and affective deficits. The monoaminergic systems participate in the establishment of motor and cognitive loops and we postulated that their organization and interaction could be precociously altered. Using tissue measurement of dopamine (DA), serotonin (5-HT), noradrenaline, and some metabolites, we observed that DA and/or its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), but not 5-HT or noradrenaline tissue content was reduced in an age-dependent manner (from two to six months) in the striatum, substantia nigra and globus pallidus of R6/1 mice. The metabolite of 5-HT was also lower in R6/1 mice, mainly in the substantia nigra and hippocampus. We then addressed early disorganization of monoaminergic systems in 18 brain regions encompassing several neurobiological networks in 35 day-old animals. DA tissue content was not altered in the striatum or substantia nigra but was decreased in the nucleus accumbens and increased in the globus pallidus. The correlations of monoaminergic index in-between the 18 selected brain regions revealed distinct organizations of monoamines in R6/1 mice, notably marked by a loss of the number of correlations of the DOPAC/DA ratio. The neurochemical analyses show that each monoaminergic system is distinctly altered in the R6/1 mouse model. The early abnormal organization of these systems likely points out altered maturation of neurobiological networks at early stages of HD.


Precision, repeatability and representative ability of faecal egg counts in Heterakis gallinarum infected chickens.
This study investigated whether a precise and repeatable quantification of Heterakis gallinarum egg excretion, which considerably reflects the actual worm burdens, can be achieved based on collection of the daily total amount of faeces from chickens. Three-week-old birds (N=64) were infected with 200 embryonated eggs of H. gallinarum, and placed into individual cages 3 wk after infection for 5 wk to collect daily faeces (N=2240). The total daily faeces was mixed and a randomly taken sample per bird was analyzed to estimate the numbers of eggs per gram of faeces (EPG) and total number of eggs excreted within 24h (EPD). A total of 235 daily faecal collections were randomly selected and further examined to determine between and within sample variations of EPG counts as a measure of precision. For this, two random faecal samples were taken from the daily produced faeces by a bird, and the EPG was determined for each of the samples (EPG1 and EPG2). The second faecal sample was analyzed once more to determine a parallel EPG2 count (EPG2a) of the suspended sample. Precision of an EPG count was defined as its relative closeness to the average of two EPG counts using a relative asymmetry index (Index(EPG)). At an age of 11 wk, i.e. 8 wk p.i. the birds were slaughtered and their worm burdens were determined. There were no significant differences between EPG1 and EPG2 (P=0.764) nor between EPG2 and EPG2a (P=0.700), suggesting that the differences between or within the samples were not different from zero. Correlations between EPG counts, as between and within sample coherences, were r=0.85 and r=0.86, respectively. Precision of EPG counts, as measured by Index(EPG), was not influenced by consistency (P=0.870) and total amount of faeces (P=0.088). However, concentration of eggs in faeces (mean EPG) had a significant effect on the precision of the EPG counts (P<0.001). Similar results were also observed for the within sample precision (Index(EPG2)). A segmented regression analysis indicated an abrupt change in the precision of EPG counts as the response to changing egg concentration in the examined faecal samples. The precision of analyses remarkably heightened up to a breakpoint with an EPG count of ≤ 617. A similar breakpoint was also determined for within sample precision (EPG2 ≤ 621). Moderate repeatabilities (R=0.49) for EPG and EPD were estimated in the first week of egg excretion, whereas the estimates were higher (R=0.67-0.84) in the following weeks. Correlations between number of female worms with daily measured EPG and EPD increased to an almost constant level (r ≥ 0.70; P<0.05) in a few days after the nematode excreted eggs and predominantly remained so for the rest of the sampling period. It is concluded that mixing daily total faeces provides samples with random homogenous distribution of H. gallinarum eggs. Precision of the EPG counts increases as the egg concentration in faecal sample increases. Egg excretion of H. gallinarum, quantified either as EPG or EPD, is highly repeatable and closely correlated with the actual worm burden of birds starting as early as in 5 th wk of infection.


The team survey: a tool for health care team development.
The aim of this study was to validate a psychometric tool, the team survey, in a health care setting with a range of teams from a Large National Health Service (NHS) Trust. The team survey was developed by Millward and Ramsay (1998) to measure the team dimensions identified in the cognitive-motivational model of team effectiveness (Millward & Purvis 1998). The team dimensions are team potency, team identification, Shared Mental Models and team meta-cognitions. The psychometric properties of the tool as a reliable and valid predictor of team effectiveness was assessed by way of a survey of 10 teams (comprising 124 members in all) located on different premises, within a large NHS Trust. Team size ranged between 5 and 19 members, with average team size being 10 members. Two independent ratings of 'effectiveness' were made for each team. Factor and multiple regression analyses were employed to identify the most powerful predictors of health care team effectiveness from a cognitive and motivational perspective. The results suggest that the team survey is psychometrically robust within a health care setting. It is concluded that the tool has a potentially key role in informing and evaluating team development initiatives in support of the work of practice development nurses and nursing team leaders.


Potential Prognostic Biomarkers of OSBPL Family Genes in Patients with Pancreatic Ductal Adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with poor survival outcomes. In addition, oxysterol-binding protein-like (OSBPL) family members are reported to be involved in lipid binding and transport and play critical roles in tumorigenesis. However, relationships between PDAC and OSBPL family members have not comprehensively been elucidated. In this study, we used the Oncomine and GEPIA 2 databases to analyze OSBPL transcription expressions in PDAC. The Kaplan-Meier plotter and TIMER 2.0 were used to assess the relationships between overall survival (OS) and immune-infiltration with OSBPL family members. Co-expression data from cBioPortal were downloaded to assess the correlated pathways with OSBPL gene family members using DAVID. The expressions of OSBPL3, OSBPL8, OSBPL10, and OSBPL11 were found to be highly upregulated in PDAC. Low expressions of OSBPL3, OSBPL8, and OSBPL10 indicated longer OS. The functions of OSBPL family members were mainly associated with several potential signaling pathways in cancer cells, including ATP binding, integrin binding, receptor binding, and the renin-angiotensin system (RAS) signaling pathway. The transcription levels of OSBPL gene family members were connected with several immune infiltrates. Collectively, OSBPL family members are influential biomarkers for the early diagnosis of PDAC and have prognostic value, with the promise of precise treatment of PDAC in the future.


Modeling of drug release from collagen matrices.
Drug release from collagen matrices is in most cases governed by diffusion from swollen matrices but also enzymatic matrix degradation or hydrophobic drug/collagen interactions may contribute. To reduce water uptake and to prolong the release, insoluble collagen matrices have been chemically or dehydrothermally crosslinked. Assuming Fickian diffusion a one-dimensional model was developed and tested that allows description of water penetration, swelling and drug release and that may be expanded considering a subsequent erosion process or interactions. Swelling is described by a volume balance. For dry collagen matrices crosslinked by thermal treatment the existence of a moving front separating the polymer from a gel phase was considered, and a convective term induced by the volume expansion was incorporated. The resulting moving boundary problem was solved using a method based on biquadratic finite elements in both space and time that is stable, shows high accuracy, and is suitable for solving problems with a singularity at the initial time point. The model was verified for insoluble collagen matrices at different crosslinking degrees for both chemical and thermal treatment. For constant diffusion coefficients a close form of the solution was derived yielding equivalent results to the numerical approach.


Characterization and expression of transcripts induced by oxygen deprivation in maize (Zea mays L.).
Until recently, the only genes described in plants induced by oxygen deprivation (anoxia or hypoxia) encoded enzymes of glucose-phosphate metabolism. In the present study, two flooding-induced maize (Zea mays L.) genes that may serve a different function have been identified. These genes, with unique kinetics of mRNA induction under flooding conditions, were not induced by heat, cold, or salt stress or by seedling death. The predicted protein sequence of one gene, wusl1005, is similar to that of several other plant genes, including a nasturtium (Tropaeolum majus L.) xyloglucan-endo-transglycosylase. The predicted protein sequence of the other gene showed no significant homology to genes of known function, indicating that both of these genes may play novel roles in the maize response to oxygen deprivation.


The tempered polymerization of human neuroserpin.
Neuroserpin, a member of the serpin protein superfamily, is an inhibitor of proteolytic activity that is involved in pathologies such as ischemia, Alzheimer's disease, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). The latter belongs to a class of conformational diseases, known as serpinopathies, which are related to the aberrant polymerization of serpin mutants. Neuroserpin is known to polymerize, even in its wild type form, under thermal stress. Here, we study the mechanism of neuroserpin polymerization over a wide range of temperatures by different techniques. Our experiments show how the onset of polymerization is dependent on the formation of an intermediate monomeric conformer, which then associates with a native monomer to yield a dimeric species. After the formation of small polymers, the aggregation proceeds via monomer addition as well as polymer-polymer association. No further secondary mechanism takes place up to very high temperatures, thus resulting in the formation of neuroserpin linear polymeric chains. Most interesting, the overall aggregation is tuned by the co-occurrence of monomer inactivation (i.e. the formation of latent neuroserpin) and by a mechanism of fragmentation. The polymerization kinetics exhibit a unique modulation of the average mass and size of polymers, which might suggest synchronization among the different processes involved. Thus, fragmentation would control and temper the aggregation process, instead of enhancing it, as typically observed (e.g.) for amyloid fibrillation.


Symmetrical and bilateral basal ganglia calcification. Case series and literature review.
Symmetric, bilateral basal ganglia calcification is rare finding that sometimes occurs asymptomatically. Its prevalence increases with age, and the most affected site is the globus pallidus. A series of seven cases with clinical and imaging diagnosis of basal ganglia calcification, recorded during the 2012 to 2016 period at the Department of Internal Medicine of the Hospital Civil de Guadalajara "Fray Antonio Alcalde, is presented. Most common clinical presentation was with altered alertness, headache and seizures. There was one case with movement disorders; there were no cases identified with dementia or tetany. Ganglia calcification can be associated with age-related neurodegenerative changes, but it can be an initial manifestation of a variety of systemic pathologies, including disorders of the calcium metabolism, intoxication by different agents, and autoimmune and genetic diseases. Correlation of typical imaging findings with clinical manifestations and laboratory results should be established to reach a definitive judgment.


Recurrent pleomorphic adenoma of the parotid gland in pediatric and adult patients: value of multiple lesions as a diagnostic indicator.
Recurrent pleomorphic adenoma of the parotid gland is a significant problem. Rates have been as high as 40% in some series of patients who have undergone surgery for the primary lesion. In the imaging literature, anecdotal case reports show multiple lesions in recurrent pleomorphic adenoma. Our aim was to analyze the imaging of a series of patients to determine the reliability of multiple lesions as a tool in diagnosing recurrent disease. Medical records of the patients with recurrent pleomorphic adenoma of the parotid gland referred to our institution were retrospectively reviewed. Before the second surgery, MR imaging had been performed in 15 patients. We retrospectively reevaluated and scored the MR imaging studies with particular attention paid to the location and number of the lesions and the remaining parotid gland tissue. On the basis of imaging findings, eight patients underwent enucleation, superficial parotidectomy had been performed in four patients, and three patients underwent total parotidectomy. For our group, the lesions were multiple in 73.3% of patients. To our knowledge, we present the first large series of imaging studies in recurrent pleomorphic adenoma of the parotid gland. Our findings show that recurrent pleomorphic adenomas are most likely to be multiple. Such multiplicity of lesions is a reliable diagnostic indicator of recurrent disease.


Pulmonary inflammatory reaction and structural changes induced by cigarette smoke exposure in the Guinea pig.
Cigarette smoke (CS) induces an inflammatory process in the lung that may underlie the development of chronic obstructive pulmonary disease (COPD). The nature and characteristics of this process have not been fully established in animal models. We aimed to evaluate the pulmonary inflammatory reaction and its involvement in structural changes in guinea pigs chronically exposed to CS. 19 Hartley guinea pigs were exposed to 7 cigarettes/day, during 3 or 6 months. 18 control guinea pigs were sham-exposed. Numbers of neutrophils, macrophages and eosinophils and lymphoid follicles were assessed in different lung structures. Airway and vessel morphometry, alveolar space size and collagen deposition were also quantified. After 6 months of exposure, CS-exposed guinea pigs showed increased numbers of neutrophils, macrophages and eosinophils in the airways, intrapulmonary vessels and alveolar septa, as well as lymphoid follicles. Increased numbers of muscularized intrapulmonary vessels were apparent at 3 months. After 6 months of exposure, the airway wall thickened and the alveolar space size increased. Collagen deposition was also apparent in airway walls and alveolar septa after 6 months' exposure. The magnitude of airway wall-thickening correlated with the number of infiltrating inflammatory cells, and the extension of collagen deposition correlated with alveolar space size. We conclude that in the guinea pig, 6 months of CS exposure induces inflammatory cell infiltrate in lung structures, at an intensity that correlates with airway remodelling. These changes resemble those observed in COPD, thus endorsing the pathogenic role of CS and the usefulness of this animal model for its study.


In vitro transcription of RNA in nuclei, nucleoli and chromatin from physarum polycephalum.
Methods for isolating nuclei, nucleoli and chromatin from Physarum polycephalum which retain high levels of endogenous RNA polymerase activity are described. Under carefully controlled conditions with respect to mono- and divalent cation concentrations RNA synthesis in nuclei displayed linear kinetics for at least 30 min and the RNA products had a similar size distribution to nuclear RNA synthesis observed in vivo. Chromatin showed 60% of the nuclear transcriptional activity but no conditions were found where faithful transcription of the template occurred. Isolated nucleoli were 5-fold more active than nuclei and the endogenous RNA polymerase activity was insensitive to alpha-amanitin. Under carefully controlled conditions, the nucleoli appeared to support the accurate transcription, re-initiation and processing of rRNA chains in vitro.


The model muddle: in search of tumor growth laws.
In this article, we will trace the historical development of tumor growth laws, which in a quantitative fashion describe the increase in tumor mass/volume over time. These models are usually formulated in terms of differential equations that relate the growth rate of the tumor to its current state and range from the simple one-parameter exponential growth model to more advanced models that contain a large number of parameters. Understanding the assumptions and consequences of such models is important, as they often underpin more complex models of tumor growth. The conclusion of this brief survey is that although much improvement has occurred over the last century, more effort and new models are required if we are to understand the intricacies of tumor growth.


Dishonesty in the name of equity.
Under what conditions do people act dishonestly to help or hurt others? We addressed this question by examining the influence of a previously overlooked factor-the beneficiary or victim of dishonest acts. In two experiments, we randomly paired participants and manipulated their wealth levels through an initial lottery. We then observed how inequity between partners influenced the likelihood of one dishonestly helping or hurting the other, while varying the financial incentives for dishonest behavior. The results show that financial self-interest cannot fully explain people's tendency to dishonestly help or hurt others. Rather, such dishonesty is influenced by emotional reactions to wealth-based inequity, even when the dishonesty bears a personal financial cost. Envy evoked by negative inequity led to hurting behavior, whereas guilt induced by positive inequity motivated helping behavior. Finally, inequity between the partner and third parties triggered dishonest helping through empathy with the partner.


Six monoclonal antibodies to human pancreatic cancer antigens.
Murine monoclonal antibodies were generated against FG, a human pancreatic carcinoma (HPC) cell line. Of the six monoclonal antibodies, five (S3-15, S3-23, S3-41, S3-60, and S3-110) reacted by indirect immunoperoxidase assays with HPC of the ductal type, and another (S3-53) reacted with both ductal and acinar HPC. Strong reactivity was also found with tumors of the stomach, colon, mouth, lung, and cervix, while a large panel of normal human tissues displayed little reactivity. Indirect immunofluorescence staining revealed that, except for S3-23, the antigens recognized by these antibodies are expressed at the cell surface. Immunoprecipitation of metabolically radiolabeled FG cells indicated that the epitopes recognized by these antibodies are carried by distinct proteins or glycoproteins, differentiated on the basis of the apparent molecular weight and/or subunit composition as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This panel of antibodies will be useful to study antigenic variations associated with malignant cell transformation in HPC as well as other tumors.


A Correlative Study between Platelet Count, Mean Platelet Volume and Red Cell Distribution Width with the Disease Severity Index in Psoriasis Patients.
Platelet activation is presumed to play an important role in the immunoinflammatory reactions. Several recent studies on a variety of inflammatory disorders have used Mean Platelet Volume (MPV) as a marker for platelet activation. To determine the relationship between haematological parameters and disease severity index in psoriasis patients. A Case control study was carried out on 50 psoriatic patients and 50 healthy control subjects. Ten haematologic parameters were compared between patients and control subjects. These parameters were also correlated in patients with PASI (Psoriasis Area and Severity Index) score. The data was statistically analysed using IBM SPSS software (Version 21). Spearman Rank Correlation was used to find the correlation between PASI and haematological parameters. When all the patients were considered together, mean values for MPV, Platelet Count (PLT) and Red Cell Distribution Width (RDW) were significantly different between the two groups (Control and Patients). While MPV and RDW were raised, PLT was reduced in patients of both sexes when compared with controls. In Male patients the MPV and RDW showed statistically significant correlation with Psoriasis Area And Severity Index (PASI) (MPV <0.01; RDW<0.05), whereas PLT though reduced in both sexes when compared with controls, it showed significance in female patients alone (p <0.01). The mean values for MPV and RDW were higher and mean platelet values were lower in patients than controls. The MPV values in male patients and Platelet counts in female patients showed strong positive and negative correlation respectively with the PASI score. It can be concluded that rising MPV and decreasing PLT could be good indicators of disease severity and progression. These indicators could also help in assessing the treatment course of the disease.


Manifestation of dipole-induced disorder in self-assembly of ferroelectric and ferromagnetic nanocubes.
The colloidal processing of nearly monodisperse and highly crystalline single-domain ferroelectric or ferromagnetic nanocubes is a promising route to produce superlattice structures for integration into next-generation devices, whereas controlling the local behaviour of nanocrystals is imperative for fabricating highly-ordered assemblies. The current picture of nanoscale polarization in individual nanocrystals suggests a potential presence of a significant dipolar interaction, but its role in the condensation of nanocubes is unknown. We simulate the self-assembly of colloidal dipolar nanocubes under osmotic compression and perform the microstructural characterization of their densified ensembles. Our results indicate that the long-range positional and orientational correlations of perovskite nanocubes are highly sensitive to the presence of dipoles.


Biogenic Guanine Crystals Are Solid Solutions of Guanine and Other Purine Metabolites.
Highly reflective crystals of the nucleotide base guanine are widely distributed in animal coloration and visual systems. Organisms precisely control the morphology and organization of the crystals to optimize different optical effects, but little is known about how this is achieved. Here we examine a fundamental question that has remained unanswered after over 100 years of research on guanine: what are the crystals made of? Using solution-state and solid-state chemical techniques coupled with structural analysis by powder XRD and solid-state NMR, we compare the purine compositions and the structures of seven biogenic guanine crystals with different crystal morphologies, testing the hypothesis that intracrystalline dopants influence the crystal shape. We find that biogenic "guanine" crystals are not pure crystals but molecular alloys (aka solid solutions and mixed crystals) of guanine, hypoxanthine, and sometimes xanthine. Guanine host crystals occlude homogeneous mixtures of other purines, sometimes in remarkably large amounts (up to 20% of hypoxanthine), without significantly altering the crystal structure of the guanine host. We find no correlation between the biogenic crystal morphology and dopant content and conclude that dopants do not dictate the crystal morphology of the guanine host. The ability of guanine crystals to host other molecules enables animals to build physiologically "cheaper" crystals from mixtures of metabolically available purines, without impeding optical functionality. The exceptional levels of doping in biogenic guanine offer inspiration for the design of mixed molecular crystals that incorporate multiple functionalities in a single material.


No evidence of associations between genetic liability for schizophrenia and development of cannabis use disorder.
Cannabis use and cannabis use disorder (CUD) is increased in patients with schizophrenia. It is important to establish if this is explained by non-causal factors, such as shared genetic vulnerability. We aimed to investigate whether the polygenic risk scores (PRS) for schizophrenia and other psychiatric disorders would predict CUD in controls, patients with schizophrenia, and patients with other psychiatric disorders. We linked nationwide Danish registers and genetic information obtained from dried neonatal bloodspots in an observational analysis. We included people with schizophrenia, other psychiatric disorders, and controls. The exposures of interest were the PRS for schizophrenia, attention-deficit hyperactivity disorder (ADHD) autism spectrum disorder, and anorexia nervosa. The main outcome of interest was the diagnosis of CUD. The study included 88 637 individuals. PRS for schizophrenia did not predict CUD in controls [hazard ratio (HR) = 1.16, 95% CI 0.95-1.43 per standard-deviation increase in PRS, or HR = 1.47, 95% CI 0.72-3.00 comparing highest v. remaining decile], but PRS for ADHD did (HR = 1.27, 95% CI 1.08-1.50 per standard-deviation increase, or HR = 2.02, 95% CI 1.27-3.22 for the highest decile of PRS). Among cases with schizophrenia, the PRS for schizophrenia was associated with CUD. While CUD was a strong predictor of schizophrenia (HR = 4.91, 95% CI 4.36-5.53), the inclusion of various PRS did not appreciably alter this association. The PRS for schizophrenia was not associated with CUD in controls or patients with other psychiatric disorders than schizophrenia. This speaks against the hypothesis that shared genetic vulnerability would explain the association between cannabis and schizophrenia.


Metabotropic glutamate receptors and cell-type-specific vulnerability in the striatum: implication for ischemia and Huntington's disease.
Differential sensitivity to glutamate has been proposed to contribute to the cell-type-specific vulnerability observed in neurological disorders affecting the striatum such as Huntington's disease (HD) and global ischemia. Under these pathological conditions striatal spiny neurons are selectively lost while large aspiny (LA) cholinergic interneurons are spared. We studied the electrophysiological effects of metabotropic glutamate receptor (mGluR) activation in striatal spiny neurons and LA interneurons in order to define the role of these receptors in the pathophysiology of the striatum. DCG-IV and L-SOP, agonists for group II and III mGluRs respectively, produced a presynaptic inhibitory effect on corticostriatal glutamatergic excitatory synaptic potentials in both spiny neurons and LA interneurons. Activation of group I mGluRs by the selective agonist 3,5-DHPG produced no detectable effects on membrane properties and glutamatergic synaptic transmission in spiny neurons while it caused a slow membrane depolarization in LA interneurons coupled to increased input resistance. In combined electrophysiological and microfluorometric recordings, 3,5-DHPG strongly enhanced membrane depolarizations and intracellular Ca2+ accumulation induced by NMDA applications in spiny neurons but not in LA interneurons. Activation of protein kinase C (PKC) by phorbol 12,13-diacetate mimicked this latter action of 3,5-DHPG while the facilitatory effect of 3,5-DHPG was prevented by calphostin C, an inhibitor of PKC. These data indicate that a positive interaction between NMDA receptors and group I mGluRs, via PKC activation, is differently expressed in these two neuronal subtypes. Our data also suggest that differential effects of the activation of group I mGluRs, but not of group II and III mGluRs, might partially account for the selective vulnerability to excitotoxic damage observed within the striatum.


Plant-derived Compounds as Potential Source of Novel Anti-Biofilm Agents Against Pseudomonas aeruginosa.
Pseudomonas aeruginosa is the most common Gram-negative bacterium associated with nosocomial and life-threatening chronic infections in cystic fibrosis patients. This pathogen is wellknown for its ability to attach to surfaces of indwelling medical devices to form biofilms, which consist of a regular array of extracellular polymers. Tenaciously bound to the surface of devices and inherently resilient to antibiotic treatment, P. aeruginosa poses a serious threat in clinical medicine and contributes to the persistence of chronic infections. Studies on microbial biofilms in the past decade involved mainly the understanding of environment signals, genetic elements and molecular mechanisms in biofilm formation, tolerance and dispersal. The knowledge obtained from the studies of these mechanisms is crucial in the establishment of strategies to eradicate or to prevent biofilm formation. Currently, biofilm infections are usually treated with combinations of antibiotics and surgical removal, in addition to frequent replacement of the infected device. More recently, specific natural sources have been identified as antibiofilm agents against this pathogen. This review will highlight the recent progress made by plant-derived compounds against P. aeruginosa biofilm infections in both in vitro or in vivo models.


Structural models of protein-DNA complexes based on interface prediction and docking.
Protein-DNA interactions are the physical basis of gene expression and DNA modification. Structural models that reveal these interactions are essential for their understanding. As only a limited number of structures for protein-DNA complexes have been determined by experimental methods, computation methods provide a potential way to fill the need. We have developed the DISPLAR method to predict DNA binding sites on proteins. Predicted binding sites have been used to assist the building of structural models by docking, either by guiding the docking or by selecting near-native candidates from the docked poses. Here we applied the DISPLAR method to predict the DNA binding sites for 20 DNA-binding proteins, which have had their DNA binding sites characterized by NMR chemical shift perturbation. For two of these proteins, the structures of their complexes with DNA have also been determined. With the help of the DISPLAR predictions, we built structural models for these two complexes. Evaluations of both the DNA binding sites for 20 proteins and the structural models of the two protein-DNA complexes against experimental results demonstrate the significant promise of our model-building approach.


Chondrogenic Differentiation of Mesenchymal Stem Cells on Glycosaminoglycan-Mimetic Peptide Nanofibers.
Glycosaminoglycans (GAGs) are important extracellular matrix components of cartilage tissue and provide biological signals to stem cells and chondrocytes for development and functional regeneration of cartilage. Among their many functions, particularly sulfated glycosaminoglycans bind to growth factors and enhance their functionality through enabling growth factor-receptor interactions. Growth factor binding ability of the native sulfated glycosaminoglycans can be incorporated into the synthetic scaffold matrix through functionalization with specific chemical moieties. In this study, we used peptide amphiphile nanofibers functionalized with the chemical groups of native glycosaminoglycan molecules such as sulfonate, carboxylate and hydroxyl to induce the chondrogenic differentiation of rat mesenchymal stem cells (MSCs). The MSCs cultured on GAG-mimetic peptide nanofibers formed cartilage-like nodules and deposited cartilage-specific matrix components by day 7, suggesting that the GAG-mimetic peptide nanofibers effectively facilitated their commitment into the chondrogenic lineage. Interestingly, the chondrogenic differentiation degree was manipulated with the sulfonation degree of the nanofiber system. The GAG-mimetic peptide nanofibers network presented here serve as a tailorable bioactive and bioinductive platform for stem-cell-based cartilage regeneration studies.


Sodium bicarbonate and renal function after cardiac surgery: a prospectively planned individual patient meta-analysis.
The effect of urinary alkalinization in cardiac surgery patients at risk of acute kidney injury (AKI) is controversial and trial findings conflicting. Accordingly, the authors performed a prospectively planned individual patient data meta-analysis of the double-blind randomized trials in this field. The authors studied 877 patients from three double-blind, randomized controlled trials enrolled to receive either 24 h of intravenous infusion of sodium bicarbonate or sodium chloride. The primary outcome measure was a postoperative increase in serum creatinine concentration of greater than 25% or 0.5 mg/dl (> 44 μM/L) within the first five postoperative days. Secondary outcomes included the raw change in serum creatinine, greater than 50% and greater than 100% rises in serum creatinine, developing AKI (Acute Kidney Injury Network criteria), initiation of renal replacement therapy, morbidity, and mortality. Patients were similar in demographics, comorbidities, and cardiac procedures. Sodium bicarbonate increased plasma bicarbonate (P < 0.001) and urine pH (P < 0.001). There were no differences in the development of the primary outcome (Bicarbonate 45% [39-51%] vs. Saline 42% [36-48%], P = 0.29). This result remained unchanged when controlling for study and covariates (odds ratio [OR], 99% confidence interval [CI]: Bicarbonate vs. Control, 1.11 [0.77-1.60], P = 0.45). There was, however, a significant study-adjusted benefit in elective coronary artery bypass surgery patients in terms of renal replacement therapy (Bicarbonate vs. Control, OR: 0.38 [99% CI: 0.25-0.58], P < 0.0001) and the development of an Acute Kidney Injury Network grade = 3 (Bicarbonate vs. Control, OR: 0.45 [99% CI: 0.43-0.48], P < 0.0001). Urinary alkalinization using sodium bicarbonate infusion is not associated with an overall lower incidence of AKI; however, it reduces severe AKI and need for renal replacement therapy in elective coronary artery bypass patients.


Frontal infrared thermography in healthy individuals and chronic migraine patients: Reliability of the method.
The use of frontal infrared thermography in the diagnosis of primary headaches provided scattering results due to measurement fluctuations and different types of headaches or research protocols. This study aims to assess the reliability of frontal infrared thermography in healthy individuals and provide a preliminary evaluation in chronic migraine patients using a commercial infrared thermal camera. Thermographic images were acquired in 20 controls and 15 patients at three consecutive time-points in two daily sessions. The Side Difference and Asymmetry Index parameters were defined. The reproducibility of the measurements, the correlation of Asymmetry Index and Side Difference with clinical evaluations and patient perceptions, and the ability of the parameters to discriminate between patients and controls were investigated. We reported a good reproducibility of the measurements (Inter-class Correlation Coefficient > 0.75 and Coefficient of Variation < 13.4%), independent from external factors. The Side Difference was significantly different between patients and controls ( p < 0.001). The Asymmetry Index showed good correlation with the side of unilateral pain ( p = 0.0056). Frontal infrared thermography can be used to quantify the difference between the right and the left side of frontal vascular changes in chronic migraine patients, provided that standardized conditions are satisfied.


Patients' perspectives of a spinal cord injury unit.
The purpose of this study is to provide an ethnographic description of the subculture of a spinal cord injury (SCI) unit. The research method was qualitative, combining ethnographic interviews, participant observation, and document review. A 30 bed SCI facility on the west coast was selected as the setting for this ethnographic description. The developmental research sequence model (Spradley, 1980) and grounded theory (Glaser & Strauss, 1967) were used for data analysis. Findings indicate optimal rehabilitation is a creative and individualized process of reintegration. Reintegration prepares the individual for coping with physical limitations, architectural barriers, and societal prejudices while simultaneously making the person feel intact and valued. Successful reintegration promotes a "fit" between the newly injured spinal cord patient and the home environment. The patient learns to compensate for the physical limitations of the spinal cord injury in a manner that promotes safety, comfort, and personal worth. Successful reintegration assures the newly injured SCI patient returns to a viable occupation, feels physically attractive, participates in a rich, full social life, and maintains family ties. Four phases of reintegration emerged: buffering, transcending, toughening, and launching. Buffering is the nurturing and protective process of lessening, absorbing, or protecting the newly injured SCI patient against the shock of multiple ramifications of the injury and the indignities of being a patient; Transcending is the process of helping SCI patients recognize and rise above culturally imposed limitations and negative beliefs about people with disabilities. The "toughening up" process focuses on compensating for physical limitations, gaining independence, and maintaining social interactions without "using the disability." Launching is the process of (1) exposing rehabilitation patients to the real world, (2) exploring the range of options for living in the community, (3) promoting patient autonomy and decision making, and (4) facilitating the ejection of the patient from the rehabilitation program. The study is significant because it offers a new perspective for viewing a spinal cord injury unit. The proposed theoretical model explains patients' attitudes, beliefs, and behavior on SCI units. This model provides a framework for designing a prototype therapeutic milieu in SCI.


Acupuncture for Hypertension in Animal Models: A Systematic Review and Meta-Analysis.
The aim of this study was to summarize and evaluate the efficacy of acupuncture in hypertension animal study. Studies were searched from six databases, including Medline, Embase, Chinese National Knowledge Infrastructure, Wanfang Data, VIP information database, and Chinese Biomedical Literature Database. Study quality of each included study was evaluated according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines, and the risk of bias was evaluated by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were selected as outcomes. Meta-analyses were performed using Stata 12.0 software. The effect size was calculated by combining SBP/DBP/MAP data with the random effects model, respectively. 67 studies containing 1522 animals were included. According to the ARRIVE guideline, 8 items were assessed as poor and 4 items were assessed as excellent. According to the SYRCLE tool, all studies were judged as having high risk of bias. Compared with the hypertension group, the pooled results showed significant antihypertension effects of acupuncture for SBP, DBP, and MAP. Similarly, compared with the sham-acupuncture group, the pooled results showed significant antihypertension effects of acupuncture for SBP, DBP, and MAP. Although pooled data suggested that the acupuncture group was superior to the hypertension group or sham-acupuncture group for SBP/DBP/MAP, the presentation of poor methodological quality, high risk of bias, and heterogeneity deserves cautious interpretation of the results.


Polymorphisms associated with in vitro aspirin resistance are not associated with clinical outcomes in patients with coronary artery disease who report regular aspirin use.
We hypothesized that single-nucleotide polymorphisms (SNPs) associated with heightened in vitro platelet function during aspirin exposure (which we define as "laboratory aspirin resistance") would be associated with greater risk for death, myocardial infarction (MI) or stroke among patients with coronary artery disease regularly using aspirin. Duke Databank for Cardiovascular Disease patients with (n = 3,449, CATHeterization GENetics cohort) or without (n = 11,754, nongenetic cohort) banked DNA with ≥1 coronary stenosis >75% were followed up at 6 months, then annually for death, MI, or stroke occurring during periods of reported aspirin use. We evaluated associations of candidate SNPs from GNB3, PEAR1, ITGB3, VAV3, ITGA2, GPVI, PTGS1, F2R, THBS1, A2AR, and GP1BA with events during follow-up using Cox proportional hazards modeling adjusted for clinical characteristics associated with outcomes in the nongenetic cohort. Over a median of 3.5 years, 2,762 (24%) nongenetic cohort patients and 648 (19%) CATHeterization GENetics cohort patients had the composite outcome during reported aspirin use. No candidate SNPs were significantly associated with death, MI, or stroke in either univariable or multivariable analyses. A prospective analysis demonstrated 80% to 88% power to detect a hazard ratio of ≥1.3 for minor allele carriers. Patients with angiographically significant coronary artery disease regularly using aspirin and carrying SNPs associated with laboratory aspirin resistance were not at higher risk for death, MI, or stroke. Using these SNPs to guide more aggressive antiplatelet therapy is not justified by these results. Direct extrapolation from in vitro findings to the clinical setting should be avoided.


miR-219-5p plays a tumor suppressive role in colon cancer by targeting oncogene Sall4.
Sall4 is a novel oncogene found upregulated in several malignancies including colon cancer. However, its upstream regulatory miRNA is still undefined. miR-219-5p is regarded as a tumor-related miRNA in cancer research. Nevertheless, its actual role of whether inhibiting or promoting tumorigenesis is unclear in colon cancer. Potential interaction between Sall4 and miR-219-5p is predicted by TargetScan. CCK-8 test was used for evaluation of cell proliferation and cell survival rates. Western blot analysis and real-time PCR were applied for detection of target molecules. Luciferase assay was a direct confirmation of mutual interaction. Wound healing assay and transwell assay were conducted for cell migration and invasion tests. Flow cytometry was used for cell apoptosis analysis. Tissue specimens and cell lines were explored for miR-219-5p inhibition on colon cancer proliferation, migration, invasion, apoptosis and drug resistance by targeting Sall4. The results show that miR-219-5p inhibited carcinogenesis of colon cancer by targeting oncogene Sall4.


Dynamic change in ST-segment and spontaneous occurrence of ventricular fibrillation in Brugada syndrome with a novel nonsense mutation in the SCN5A gene during long-term follow-up.
A 67-year-old male underwent genetic testing under the diagnosis of Brugada syndrome because of recurrent ventricular fibrillation with coincident ST-segment elevation in either right precordial, inferior leads or both since the age of 55 years. Screening of gene mutations using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing identified a novel nonsense mutation (R179X) of SCN5A in a heterozygous manner. The functional assay for the identified mutation, using a whole-cell patch clamp in the heterologous expression system, revealed that the nonsense mutation, located in the second transmembrane segment of the first domain (DI-S2) of the alpha-subunit, failed to synthesize the complete structure of the cardiac sodium channel, thus causing the non-functional channel. Coding effects by the gene mutation was altered during the 12-year follow-up, which might affect the clinical features of the patient through the ion channel density in the ventricle, dynamics of repolarization abnormality and conduction disturbance.


Four and one-half-year follow-up of the effectiveness of diphtheria-tetanus toxoids-acellular pertussis/Haemophilus influenzae type b and diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus/H. influenzae type b combination vaccines in Germany.
Recently an increase in the number of invasive Haemophilus influenzae type b (Hib) cases was observed in the United Kingdom, which coincided with a temporary change from diphtheria-tetanus toxoids-wild-type pertussis to diphtheria-tetanus toxoids-acellular pertussis (DTaP) Hib vaccines. A study in Germany based on approximately 2 years of follow-up, estimated vaccine effectiveness (VE) of DTaP/Hib and DTaP-inactivated poliovirus/Hib combination vaccines against invasive Hib disease to be high. To assess VE of DTaP-containing Hib vaccines against Hib in Germany with the use of extended follow-up of case surveillance and vaccine uptake. Cases with confirmed systemic Hib infections in children born between June 1, 1996 and December 31, 1998 were ascertained by a nationwide active surveillance system from January 1998 through June 2002. A representative subcohort of 667 children born in the same time frame was randomly sampled in a nationwide vaccine coverage survey. VE was determined with a case-cohort approach of Cox regression with time-dependent covariates. Thirty-six cases of Hib disease were reported. Of these, 10 were vaccinated with DTaP-containing Hib vaccines only and 20 were not vaccinated. Of the 10 vaccinated cases, 4 had received an incomplete primary series (1-2 doses), and 6 had received the full primary series (3 doses), 3 of whom also received the booster dose. VE of combination vaccines against invasive Hib infection was 89.6% [95% confidence interval (CI), 67.0-96.7] for an incomplete primary series, 96.7% (95% CI 87.7-99.1) for a full primary series and 98.5% (95% CI 94.5-99.6) for a booster dose (irrespective of priming). Hib combination vaccines containing acellular pertussis antigens continue to be highly effective in Germany.


The interrelation between organophosphate toxicity and the epidemiology of depression and suicide.
The literature on an association between organophosphate (OP) toxicity and depression or suicide is scarce. An interrelation exists among populations exposed to OPs, acute OP toxicity, neurobehavioral effects, depression, suicide, and fatality. Acute OP toxicity is characterized by the cholinergic syndrome with systemic and central nervous system effects. Organophosphate-induced neurobehavioral effects result in depression. A potential risk of depression and suicide exists in farm workers exposed to OPs. The sociodemographics of depression include age, gender, race, geographic region, social factors, economics, psychiatric disorders, medical conditions, and hereditary factors. Suicide is a major consequence of depression, with multiple sociodemographic risk factors. Developing countries have a higher incidence of OP toxicity, with limited information on the prevalence of depression. In these countries, the incidence of suicide is high, affecting more females. Suicide is more prevalent in rural areas, and in farming communities, commonly with ingestion of OPs. In industrialized countries, the incidence of OP toxicity is lower, but the prevalence of depression is higher. Suicide rates are lower in industrialized countries, affecting more males, the urban population, and farming communities. Other lethal methods of suicide, such as hanging, firearms, electrocution, and drug overdose are more common in industrialized countries. A potential risk of depression or suicide certainly exists from OP toxicity, largely depending on the epidemiology or sociodemographics of these disorders. Scientific evidence shows that the association between environmental toxicology and psychiatry has important public health implications.


[Size of a human serum albumin molecule in solution].
The size of a human serum albumin molecule in aqueous solution containing 150 mM NaCl was studied using small-angle neutron scattering. The molecular radius of gyration was estimated to be 27.4 +/- 0.35 A. The compact sphere should have a smaller radius of gyration, whereas the popular human serum albumin model, a "cigar" 136 A long, should correspond to a greater radius of gyration. Possible shapes of the human serum albumin molecule which are in accordance with the results obtained, are the following: an extended ellipsoid less than 110 A of length or a nonsymmetrical oblate ellipsoid with a diameter of 85 A. The oblate ellipsoid might be close to the heart"-shaped structure of the crystalline human serum albumin molecule. The size of the albumin molecule does not change significantly as pH increases to 8.9. The possibility of the dynamic coexistence of various human serum albumin conformers in solution is discussed.