Enhanced reduced representation bisulfite sequencing for assessment of DNA methylation at base pair resolution.
DNA methylation pattern mapping is heavily studied in normal and diseased tissues. A variety of methods have been established to interrogate the cytosine methylation patterns in cells. Reduced representation of whole genome bisulfite sequencing was developed to detect quantitative base pair resolution cytosine methylation patterns at GC-rich genomic loci. This is accomplished by combining the use of a restriction enzyme followed by bisulfite conversion. Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) increases the biologically relevant genomic loci covered and has been used to profile cytosine methylation in DNA from human, mouse and other organisms. ERRBS initiates with restriction enzyme digestion of DNA to generate low molecular weight fragments for use in library preparation. These fragments are subjected to standard library construction for next generation sequencing. Bisulfite conversion of unmethylated cytosines prior to the final amplification step allows for quantitative base resolution of cytosine methylation levels in covered genomic loci. The protocol can be completed within four days. Despite low complexity in the first three bases sequenced, ERRBS libraries yield high quality data when using a designated sequencing control lane. Mapping and bioinformatics analysis is then performed and yields data that can be easily integrated with a variety of genome-wide platforms. ERRBS can utilize small input material quantities making it feasible to process human clinical samples and applicable in a range of research applications. The video produced demonstrates critical steps of the ERRBS protocol.


Multifactorial intervention to reduce falls in older people at high risk of recurrent falls: a randomized controlled trial.
Falls occur frequently in older people and strongly affect quality of life. Guidelines recommend multifactorial, targeted fall prevention. We evaluated the effectiveness of a multifactorial intervention in older persons with a high risk of recurrent falls. A randomized controlled trial was conducted from April 3, 2005, to July 21, 2008, at the geriatric outpatient clinic of a university hospital and regional general practices in the Netherlands. Of 2015 persons identified, 217 persons aged 65 years or older were selected to participate. They had a high risk of recurrent falls and no cognitive impairment and had visited the emergency department or their family physician after a fall. The geriatric assessment and intervention were aimed at reduction of fall risk factors. Primary outcome measures were time to first and second falls after randomization. Secondary outcome measures were fractures, activities of daily living, quality of life, and physical performance. Within 1 year, 55 (51.9%) of the 106 intervention participants and 62 (55.9%) of the 111 usual care (control) participants fell at least once. No significant treatment effect was demonstrated for the time to first fall (hazard ratio, 0.96; 95% confidence interval, 0.67-1.37) or the time to second fall (1.13; 0.71-1.80). Similar results were obtained for secondary outcome measures and for per-protocol analysis. One intervention participant died vs 7 in the control group (hazard ratio, 0.15; 95% confidence interval, 0.02-1.21). This multifactorial fall-prevention program does not reduce falls in high-risk, cognitively intact older persons. Trial Registration isrctn.org Identifier: ISRCTN11546541.


Coverage-based treatment planning to accommodate deformable organ variations in prostate cancer treatment.
To compare two coverage-based planning (CP) techniques with standard fixed margin-based planning (FM), considering the dosimetric impact of interfraction deformable organ motion exclusively for high-risk prostate treatments. Nineteen prostate cancer patients with 8-13 prostate CT images of each patient were used to model patient-specific interfraction deformable organ changes. The model was based on the principal component analysis (PCA) method and was used to predict the patient geometries for virtual treatment course simulation. For each patient, an IMRT plan using zero margin on target structures, prostate (CTVprostate) and seminal vesicles (CTVSV), were created, then evaluated by simulating 1000 30-fraction virtual treatment courses. Each fraction was prostate centroid aligned. Patients whose D98 failed to achieve 95% coverage probability objective D98,95 ≥ 78 Gy (CTVprostate) or D98,95 ≥ 66 Gy (CTVSV) were replanned using planning techniques: (1) FM (PTVprostate = CTVprostate + 5 mm, PTVSV = CTVSV + 8 mm), (2) CPOM which optimized uniform PTV margins for CTVprostate and CTVSV to meet the coverage probability objective, and (3) CPCOP which directly optimized coverage probability objectives for all structures of interest. These plans were intercompared by computing probabilistic metrics, including 5% and 95% percentile DVHs (pDVH) and TCP/NTCP distributions. All patients were replanned using FM and two CP techniques. The selected margins used in FM failed to ensure target coverage for 8/19 patients. Twelve CPOM plans and seven CPCOP plans were favored over the other plans by achieving desirable D98,95 while sparing more normal tissues. Coverage-based treatment planning techniques can produce better plans than FM, while relative advantages of CPOM and CPCOP are patient-specific.


Case report of a long-surviving man with metastatic renal cell carcinoma treated with pazopanib.
Renal cell carcinoma is the most common type of kidney cancer in adults. It accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. At the moment several biological agents are used for the treatment of metastatic renal cell carcinoma. We describe the case of a man who has been treated with pazopanib (Votrient) for metastatic renal cell carcinoma since July 2011. At the time of writing, the patient is still receiving treatment (29 months) and is showing a long-lasting response with a favorable safety profile. This is an excellent example of chronic neoplastic disease in a patient who can be defined as long-surviving.


Molecular-scale features that govern the effects of O-glycosylation on a carbohydrate-binding module.
Protein glycosylation is a ubiquitous post-translational modification in all kingdoms of life. Despite its importance in molecular and cellular biology, the molecular-level ramifications of O-glycosylation on biomolecular structure and function remain elusive. Here, we took a small model glycoprotein and changed the glycan structure and size, amino acid residues near the glycosylation site, and glycosidic linkage while monitoring any corresponding changes to physical stability and cellulose binding affinity. The results of this study reveal the collective importance of all the studied features in controlling the most pronounced effects of O-glycosylation in this system. Going forward, this study suggests the possibility of designing proteins with multiple improved properties by simultaneously varying the structures of O-glycans and amino acids local to the glycosylation site.


Genetic and morphometric differentiation between island and mainland southern elephant seal populations.
We compare genetic (both nuclear and mitochondrial) and morphometric measures between two putative populations of southern elephant seal (Mirounga leonina), and interpret the results in the context of data from mark-recapture and satellite-telemetric studies. One population is on the Argentine mainland, while the other is 2,400 km away on South Georgia island. We found pronounced differentiation at the mitochondrial DNA (mtDNA) control region that was distinct from the pattern of variation seen among island rookeries. Some morphometric characters and seven out of ten nuclear-DNA markers also showed differentiation between the island and mainland sites. Diversity at nuclear markers was high in both populations but mtDNA diversity was low in the mainland population, suggesting a founder event and little subsequent immigration of females. Morphological differences may suggest different selective environments at the two sites.


Surgical Management of Long-standing Eagle's Syndrome.
Eagle's syndrome is a rare condition that refers to chronic recurrent pain in the oropharynx, face, and neck due to elongation of the styloid process or calcification of the stylohyoid ligament. It can be treated medically or surgically through a styloidectomy. In this paper, we review our experience with the two surgical approaches for the management of Eagle's syndrome. We conducted a retrospective chart review, which covered the period between 1997 and 2008. The review included seven patients with a long-standing diagnosis of Eagle's syndrome. Six patients underwent surgical intervention and one patient elected to observe her condition. The retrospective design of the study was approved by Boston Medical Center Institutional Review Board with no need for another consent other than the one obtained before surgical interventions. Out of the seven patients identified, there were three men and four women. The median age and mean age at diagnosis were 44 years and 26.2 years, respectively. Neck pain and odynophagia were the most common symptoms reported. Three patients underwent styloidectomy through transoral approach and the three through transcervical approach. The average time to resolution of symptoms was 26.5 days. The review suggests a favorable role for surgery in the management of Eagle's syndrome with all the patients undergoing styloidectomy experiencing complete resolution of symptoms. Both surgical approaches provide the desired outcome; however, the choice of the surgical approach depends on the patient's wishes and the surgeon's experience.


Building global health through a center-without-walls: the Vanderbilt Institute for Global Health.
The Institute for Global Health at Vanderbilt enables the expansion and coordination of global health research, service, and training, reflecting the university's commitment to improve health services and outcomes in resource-limited settings. Global health encompasses both prevention via public health and treatment via medical care, all nested within a broader community-development context. This has fostered university-wide collaborations to address education, business/economics, engineering, nursing, and language training, among others. The institute is a natural facilitator for team building and has been especially helpful in organizing institutional responses to global health solicitations from the National Institutes of Health (NIH), Centers for Disease Control (CDC), and other funding agencies. This center-without-walls philosophy nurtures noncompetitive partnerships among and within departments and schools. With extramural support from the NIH and from endowment and developmental investments from the school of medicine, the institute funds new pilot projects to nurture global educational and research exchanges related to health and development. Vanderbilt's newest programs are a CDC-supported HIV/AIDS service initiative in Africa and an overseas research training program for health science graduate students and clinical fellows. New opportunities are available for Vanderbilt students, staff, and faculty to work abroad in partnership with international health projects through a number of Tennessee institutions now networked with the institute. A center-without-walls may be a model for institutions contemplating strategic investments to better organize service and teaching opportunities abroad, and to achieve greater successes in leveraging extramural support for overseas and domestic work focused on tropical medicine and global health.


Catheter ablation for ventricular tachycardia in patients with cardiac sarcoidosis: a systematic review.
Cardiac sarcoidosis (CS) is associated with a poor prognosis. Important features of CS include heart failure, conduction abnormalities, and ventricular arrhythmias. Ventricular tachycardia (VT) is often refractory to antiarrhythmic drugs (AAD) and immunosuppression. Catheter ablation has emerged as a treatment option for recurrent VT. However, data on the efficacy and outcomes of VT ablation in this context are sparse. A systematic search was performed on PubMed, EMBASE, and Cochrane database (from inception to September 2016) with included studies providing a minimum of information on CS patients undergoing VT ablation: age, gender, VT cycle length, CS diagnosis criteria, and baseline medications. Five studies reporting on 83 patients were identified. The mean age of patients was 50 ± 8 years, 53/30 (males/females) with a maximum of 56 patients receiving immunosuppressive therapy, mean ejection fraction was 39.1 ± 3.1% and 94% had an implantable cardioverter defibrillator in situ. The median number of VTs was 3 (2.6-4.9)/patient, mean cycle length of 360 ms (326-400 ms). Hundred percent of VTs received endocardial ablation, and 18% required epicardial ablation. The complication rates were 4.7-6.3%. Relapse occurred in 45 (54.2%) patients with an incidence of relapse 0.33 (95% confidence interval 0.108-0.551, P < 0.004). Employing a less stringent endpoint (i.e. freedom from arrhythmia or reduction of ventricular arrhythmia burden), 61 (88.4%) patients improved following ablation. These data support the utilization of catheter ablation in selected CS cases resistant to medical treatment. However, data are derived from observational non-controlled case series, with low-methodological quality. Therefore, future well-designed, randomized controlled trials, or large-scale registries are required.


Mass-ratio and complementarity effects simultaneously drive aboveground biomass in temperate Quercus forests through stand structure.
Forests play a key role in regulating the global carbon cycle, a substantial portion of which is stored in aboveground biomass (AGB). It is well understood that biodiversity can increase the biomass through complementarity and mass-ratio effects, and the contribution of environmental factors and stand structure attributes to AGB was also observed. However, the relative influence of these factors in determining the AGB of Quercus forests remains poorly understood. Using a large dataset retrieved from 523 permanent forest inventory plots across Northeast China, we examined the effects of integrated multiple tree species diversity components (i.e., species richness, functional, and phylogenetic diversity), functional traits composition, environmental factors (climate and soil), stand age, and structure attributes (stand density, tree size diversity) on AGB based on structural equation models. We found that species richness and phylogenetic diversity both were not correlated with AGB. However, functional diversity positively affected AGB via an indirect effect in line with the complementarity effect. Moreover, the community-weighted mean of specific leaf area and height increased AGB directly and indirectly, respectively; demonstrating the mass-ratio effect. Furthermore, stand age, density, and tree size diversity were more important modulators of AGB than biodiversity. Our study highlights that biodiversity-AGB interaction is dependent on the regulation of stand structure that can be even more important for maintaining high biomass than biodiversity in temperate Quercus forests.


Merging of long-term memories in an insect.
Research on comparative cognition has largely focused on successes and failures of animals to solve certain cognitive tasks, but in humans, memory errors can be more complex than simple failures to retrieve information [1, 2]. The existence of various types of "false memories," in which individuals remember events that they have never actually encountered, are now well established in humans [3, 4]. We hypothesize that such systematic memory errors may be widespread in animals whose natural lifestyle involves the processing and recollection of memories for multiple stimuli [5]. We predict that memory traces for various stimuli may "merge," such that features acquired in distinct bouts of training are combined in an animal's mind, so that stimuli that have never been viewed before, but are a combination of the features presented in training, may be chosen during recall. We tested this using bumblebees, Bombus terrestris. When individuals were first trained to a solid single-colored stimulus followed by a black and white (b/w)-patterned stimulus, a subsequent preference for the last entrained stimulus was found in both short-term- and long-term-memory tests. However, when bees were first trained to b/w-patterned stimuli followed by solid single-colored stimuli and were tested in long-term-memory tests 1 or 3 days later, they only initially preferred the most recently rewarded stimulus, and then switched their preference to stimuli that combined features from the previous color and pattern stimuli. The observed merging of long-term memories is thus similar to the memory conjunction error found in humans [6].


The Cognitive Distortions Questionnaire (CD-Quest): Validation in a Sample of Adults with Social Anxiety Disorder.
Cognitive distortions are thought to be central to the development and maintenance of anxiety disorders and are a widely acknowledged treatment target in cognitive-behavioral interventions. However, little research has focused on the measurement of cognitive distortions. The Cognitive Distortions Questionnaire (CD-Quest; de Oliveira, 2015), a brief, 15-item questionnaire, assesses the frequency and intensity of cognitive distortions. The CD-Quest has been shown to have sound psychometric properties in American, Australian, and Brazilian undergraduate samples and one Turkish-speaking outpatient clinical sample. The current study aimed to provide the first evaluation of the psychometric properties of the English version of the CD-Quest in a clinical sample and the first evaluation of any version of the CD-Quest in a sample of adults diagnosed with social anxiety disorder (SAD). In a sample of treatment-seeking adults with SAD, the CD-Quest demonstrated good convergent validity, discriminant validity, known-groups validity, and treatment sensitivity. It also showed good internal consistency, and both confirmatory and exploratory factor analyses supported the previously reported unitary factor structure. Findings extend prior research indicating the reliability and validity of the CD-Quest.


Autonomic and electrocardiographic changes in cardioinhibitory syncope.
Cardioinhibitory syncope (CS) is a neurally mediated response causing bradycardia or asystole. This study reports on changes in blood pressure, heart rate variability (HRV), and ECG patterns before and after syncope with asystole. Thirty-five patients with CS and a matched control group were submitted to 60 degrees head-up tilt for 20 min with the addition of nitroglycerin. Syncope developed after a tilt-duration of 1.082 (range 50-1.734 s). Asystole lasted for 21.3 s (range 3.4-80.2 s) and was preceded by sinus rhythm in 21, junctional rhythm in 10, and atrioventricular block in four. Asystole was followed by sinus rhythm in four, junctional rhythm in 24, atrioventricular block in four, and atrial fibrillation in three. The two groups did not differ with respect to supine heart rate, HRV or blood pressure. Prior to syncope, patients showed significant increases in total and low-frequency HRV with reductions in high-frequency HRV and a progressive shortening of the PR-interval. Syncope was preceded by marked accentuation of sympathetic tone with a sudden shift in heart rate control to vagal dominance. Asystole was accompanied by vagally induced, benign arrhythmia in the majority of the patients.


Blood flow restriction reduces the increases in cardiorespiratory responses and subjective burden without inhibiting muscular activity during cycling at ventilatory threshold in healthy males.
Low-intensity endurance exercise with blood flow restriction (KAATSU) is under consideration for use in cardiac rehabilitation. However, the physiological responses to such exercise have not yet been fully characterized. In an initial effort in healthy males (n = 11, age: 26.3±4.6 y), we compared the physiological responses to low-intensity endurance exercise with and without a thigh KAATSU. Participants performed maximal graded exercise testing using a cycle ergometer with or without KAATSU. We examined responses to cycling exercise at ventilatory threshold (VT) in heart rate (HR), oxygen consumption (VO2), dyspnea, ratings of perceived exertion (RPE), blood pressure (BP), and rectus femoris activation. Participants reached VT at a lower mechanical load, HR, VO2, dyspnea, and double product (HR×systolic BP) with KAATSU vs. no-KAATSU. At VT, RPE, and rectus femoris activity did not differ between the two conditions. These results suggest that KAATSU reduced exercise intensity to reach VT and the physiological responses to exercise at VT without changes in knee extensor muscle activation. Results from this pilot study in healthy males suggest that KAATSU aerobic exercise at VT intensity has the potential to be an effective and low-burden adjuvant to cycling in cardiac rehabilitation.


Molecular insight into patterns of colony composition and paternity in the common mole-rat Cryptomys hottentotus hottentotus.
We report the discovery of intraspecific variation in both colony composition and patterns of paternity in two populations of the social common mole-rat Cryptomys hottentotus hottentotus. These two populations represent the mesic and arid habitat extremes of the species' broad ecological range in South Africa. Until recently colonies of the common mole-rat were thought to consist of familial groups whereby all colony members were the offspring of a monogamous reproductive pair. The remaining colony members were thought to forego reproduction until both social and ecological conditions favoured dispersal and opportunities for independent outbreeding. Results from genetic assignment tests using microsatellite markers indicate that while colony composition is dominated by familial groups, colonies within both populations included both adult and subadult foreign conspecifics. Analysis of parentage reveals that the social organization of C. h. hottentotus is not that of strict monogamy; paternity of offspring was not assigned consistently to the largest, most dominant male within the colony. Moreover, a number of significantly smaller males were found to sire offspring, suggesting a sneak-mating strategy by subordinate within-colony males. Extra-colony extra-pair paternity (ECP) was also found to characterize C. h. hottentotus colonies, occurring with similar frequencies in both habitats. Both dominant established breeding males and subordinate males were identified as siring young in nonsource colonies. Furthermore, established breeding males were found to sire extra-colony young in the same season as siring young within their source colonies. We discuss the significance of these results within the context of the divergent ecological regimes characterizing the two sites and observe that our results revisit the accuracy of using behavioural and morphological characters, which have structured the basis of our understanding of the behavioural ecology of this species, as indicators of breeding status in mark-recapture studies.


Increased production of sonic hedgehog by ballooned hepatocytes.
Ballooned hepatocytes distinguish non-alcoholic steatohepatitis (NASH) from steatosis. Such cells contain dilated endoplasmic reticulum and ubiquitin aggregates, characteristics of endoplasmic reticulum stress. Hepatocyte ballooning increases the risk for fibrosis in NASH, suggesting that ballooned hepatocytes release pro-fibrogenic factors. Hedgehog ligands function as pro-fibrogenic factors in liver diseases, but mechanisms for hedgehog ligand production remain poorly understood. We evaluated the hypothesis that endoplasmic reticulum stress induces hepatocyte production of hedgehog ligands that provide paracrine pro-fibrogenic signals to neighbouring cells. In livers from NASH patients, keratin 8/18 and ubiquitin staining demonstrated enlarged, keratin 8/18-negative/ubiquitin-positive hepatocytes (ballooned hepatocytes) that were positive for Sonic hedgehog. In order to model endoplasmic reticulum stress in vitro, primary mouse hepatocytes were treated with tunicamycin. Compared to vehicle, tunicamycin significantly increased Sonic hedgehog and Indian hedgehog expression. Furthermore, conditioned medium from tunicamycin-treated hepatocytes increased Gli-luciferase reporter activity 14-fold more than conditioned medium from vehicle-treated hepatocytes. Cyclopamine (hedgehog signalling inhibitor) abrogated the effect of conditioned medium from tunicamycin-treated hepatocytes, verifying that soluble hepatocyte-derived factors activate hedgehog signalling. Ballooned hepatocytes in NASH patients did not express the hedgehog target gene, Gli2, α-smooth muscle actin or vimentin, but were surrounded by Gli2-positive stromal cells expressing these myofibroblast markers. Trichrome staining demonstrated the accumulation of ballooned hepatocytes in areas of matrix deposition, and numbers of Sonic hedgehog-positive hepatocytes correlated with the degree of ballooning and fibrosis stage. Hepatocytes undergoing endoplasmic reticiulum stress generate hedgehog ligands which act as paracrine pro-fibrogenic factors for hedgehog-responsive stromal cells. These results help to explain why fibrosis stage correlates with hepatocyte ballooning in NASH.


IoT in the Wake of COVID-19: A Survey on Contributions, Challenges and Evolution.
The novel coronavirus (COVID-19), declared by the World Health Organization (WHO) as a global pandemic, has brought with it changes to the general way of life. Major sectors of the world industry and economy have been affected and the Internet of Things (IoT) management and framework is no exception in this regard. This article provides an up to date survey on how a global pandemic such as COVID-19 has affected the world of IoT technologies. It looks at the contributions that IoT and associated sensor technologies have made towards virus tracing, tracking and spread mitigation. The associated challenges of deployment of sensor hardware in the face of a rapidly spreading pandemic have been looked into as part of this review article. The effects of a global pandemic on the evolution of IoT architectures and management have also been addressed, leading to the likely outcomes on future IoT implementations. In general, this article provides an insight into the advancement of sensor-based E-health towards the management of global pandemics. It also answers the question of how a global virus pandemic has shaped the future of IoT networks.


Melatonin rescues the reproductive toxicity of low-dose glyphosate-based herbicide during mouse oocyte maturation via the GPER signaling pathway.
Glyphosate-based herbicides (GBHs) are a group of widely used broad-spectrum agricultural pesticides. Due to the recalcitrance of GBH, it has been found in food and environment as a contaminant, posing a threat to public health. The health risks associated with GBH have been indicated by reporting acute toxicity data (an acute exposure of GBH at a 0.5% dose), which primarily discuss toxicity in relation to accidental high-rate exposure. Currently, there is little information regarding the toxicity of GBH at environmentally relevant levels. In this study, we used mature mouse oocytes to study the toxic effects of low-dose GBH exposure in vitro (0.00001%-0.00025%) and in vivo (0.0005%, orally administered through daily drinking water) during meiotic maturation. GBH exposure led to meiotic maturation failure with spindle defects and chromosome misalignment. In addition, GBH treatment severely reduced sperm-binding ability and disrupted early embryo cleavage. Moreover, GBH exposure significantly increased the reactive oxygen species (ROS) levels and apoptotic rates. Evidence indicates that such effects in GBH-exposed oocytes are likely due to overexpression of the G-protein estrogen receptor (GPER/GPR30). Remarkably, we found that melatonin administration elicited significant protection against GBH-induced oocyte deterioration via preserving the expression of GPR30, along with activation of its downstream signaling event (pERK/ERK). Taken together, these results revealed that low-dose glyphosate has a certain adverse effect on oocyte maturation and early embryo cleavage, and highlight the protective roles of melatonin.


[The dynamic functional condition of the thyroid residual segment after surgical treatment of mononodular goiter].
The aim of this study was to assess the functional condition of thyroid remains after surgical treatment of mononodular goiter at different time points after operation. The trial has been conducted at Tbilisi N4 hospital. It was based on retrospective analysis of postoperative patients after mononodular goiter. 346 patients with mononodular euthyroid goiter were studied in order to learn the functional activity of thyroid gland in different time points after operation. From the first day after surgical interventions - hemythyroidectomy or subtotal resection one of the parts of thyroid (left or right), patients were getting replacement therapy with 25-50 mcg euthyrox. Monitoring of these patients have been conducted 1, 3, 6 months and 1, 3 and 5 years after operation. The clinical effect of treatment was assessed according to the following data: ultrasound grapy of the remain cult in thyroid gland and blood test data of thyroid hormones, such as FT4, TSH. Euthyrox in doses 50 mcg is recommended from the first day after operation, next the dose is corrected according to TSH data. It is necessary to control TSH level every six months in order to determine either to change the dose of euthyrox or its abrogation. It is recommended to keep TSH level between 0,5-2,0 M/U/L. Thyroid reminder will stabilize to the end of the year after operation. It is necessary a life control of patients after surgical treatment at least once a year (ultrasound of the remain cult of thyroid gland and TSH data.) to determine the condition of thyroid reminder.


The Importance of Species Name Synonyms in Literature Searches.
The synonyms of biological species names are shown to be an important component in comprehensive searches of electronic scientific literature databases but they are not well leveraged within the major literature databases examined. For accepted or valid species names in the Integrated Taxonomic Information System (ITIS) which have synonyms in the system, and which are found in citations within PLoS, PMC, PubMed or Scopus, both the percentage of species for which citations will not be found if synonyms are not used, and the percentage increase in number of citations found by including synonyms are very often substantial. However, there is no correlation between the number of synonyms per species and the magnitude of the effect. Further, the number of citations found does not generally increase proportionally to the number of synonyms available. Users looking for literature on specific species across all of the resources investigated here are often missing large numbers of citations if they are not manually augmenting their searches with synonyms. Of course, missing citations can have serious consequences by effectively hiding critical information. Literature searches should include synonym relationships and a new web service in ITIS, with examples of how to apply it to this issue, was developed as a result of this study, and is here announced, to aide in this.


Structure-Based Optimization of Coumestan Derivatives as Polyketide Synthase 13-Thioesterase(Pks13-TE) Inhibitors with Improved hERG Profiles for Mycobacterium tuberculosis Treatment.
Pks13 was identified as a key enzyme involved in the final step of mycolic acid biosynthesis. We previously identified antitubercular coumestans that targeted Pks13-TE, and these compounds exhibited high potency both in vitro and in vivo. However, lead compound 8 presented potential safety concerns because it inhibits the hERG potassium channel in electrophysiology patch-clamp assays (IC50 = 0.52 μM). By comparing the Pks13-TE-compound 8 complex and the ligand-binding pocket of the hERG ion channel, fluoro-substituted and oxazine-containing coumestans were designed and synthesized. Fluoro-substituted compound 23 and oxazine-containing coumestan 32 showed excellent antitubercular activity against both drug-susceptible and drug-resistant Mtb strains (MIC = 0.0039-0.0078 μg/mL) and exhibited limited hERG inhibition (IC50 ≥ 25 μM). Moreover, 32 exhibited improved metabolic stability relative to parent compound 8 while showing favorable bioavailability in mouse models via serum inhibition titration assays.


Catalytic Synthesis of 8-Membered Ring Compounds via Cobalt(III)-Carbene Radicals.
The metalloradical activation of o-aryl aldehydes with tosylhydrazide and a cobalt(II) porphyrin catalyst produces cobalt(III)-carbene radical intermediates, providing a new and powerful strategy for the synthesis of medium-sized ring structures. Herein we make use of the intrinsic radical-type reactivity of cobalt(III)-carbene radical intermediates in the [CoII (TPP)]-catalyzed (TPP=tetraphenylporphyrin) synthesis of two types of 8-membered ring compounds; novel dibenzocyclooctenes and unprecedented monobenzocyclooctadienes. The method was successfully applied to afford a variety of 8-membered ring compounds in good yields and with excellent substituent tolerance. Density functional theory (DFT) calculations and experimental results suggest that the reactions proceed via hydrogen atom transfer from the bis-allylic/benzallylic C-H bond to the carbene radical, followed by two divergent processes for ring-closure to the two different types of 8-membered ring products. While the dibenzocyclooctenes are most likely formed by dissociation of o-quinodimethanes (o-QDMs) which undergo a non-catalyzed 8π-cyclization, DFT calculations suggest that ring-closure to the monobenzocyclooctadienes involves a radical-rebound step in the coordination sphere of cobalt. The latter mechanism implies that unprecedented enantioselective ring-closure reactions to chiral monobenzocyclooctadienes should be possible, as was confirmed for reactions mediated by a chiral cobalt-porphyrin catalyst.


[Delagil treatment of tumorous pleurisy].
A review of the literature is given on the efficacy of intrapleural use of different drugs (embichine, thiophosphamide, 5-fluorouracil, etc. and also acrichin (chinacrin) for malignant pleural involvement with the presence of exudate in the pleural cavity. Under study was the efficacy of intrapleural injection of delagil in 28 patients with pulmonary cancer, breast cancer and other malignant tumors with the presence of exudate in the pleural cavities. The effect, manifested in the cessation of the fluid accumulation, its encapsulation, was observed in 60 per cent of patients, an average duration of the remission being 8.3 months. In highly sensitive tumors (cancer of ovaries, breast cancer) the treatment should be initiated with intrapleural injection of thiophosphamide or embichine, and in case of failure delagil is to be employed intrapleurally. As a rule, side-effects, manifested in chest pains and temperature rise up to 38.5 degrees are of a short duration and require no special therapy.


Computational analysis of simulated SNP interactions between 26 growth factor-related genes in a breast cancer association study.
Many association studies analyze the genotype frequencies of case and control data to predict susceptibility to diseases and cancers. Without providing the raw data for genotypes, many association studies cannot be interpreted fully. Often, the interactions of the single nucleotide polymorphisms (SNPs) are not addressed and this limits the potential of such studies. To solve these problems, we propose a novel computational method with source codes to generate a stimulated genotype dataset based on published SNP genotype frequencies. In this study we evaluate the combined effect of 26 SNP combinations related to eight published growth factor-related genes involved in carcinogenesis pathways of breast cancer. The genetic algorithm (GA) was chosen to provide simultaneous analysis of multiple independent SNPs. The GA can perform feature selection from different SNP combinations via their corresponding genotype (called the SNP barcode), and the approach is able to provide a specific SNP barcode with an optimized fitness value effectively. The best SNP barcode with the maximal occurrence difference between groups for the control and breast cancer, together with an odds ratio analysis, is used to evaluate breast cancer susceptibility. When they are compared to their corresponding non-SNP barcodes, the estimated odds ratios for breast cancer are less than 1 (about 0.85 and 0.87; confidence interval: 0.7473∼0.9585, p < 0.01) for specific SNP barcodes with two to five SNPs. Therefore, we were able to identify potential combined growth factor-related genes together with their SNP barcodes that were protective against breast cancer by in silico analysis.


Brain and Cognition for Addiction Medicine: From Prevention to Recovery Neural Substrates for Treatment of Psychostimulant-Induced Cognitive Deficits.
Addiction to psychostimulants like cocaine, methamphetamine, and nicotine poses a continuing medical and social challenge both in the United States and all over the world. Despite a desire to quit drug use, return to drug use after a period of abstinence is a common problem among individuals dependent on psychostimulants. Recovery for psychostimulant drug-dependent individuals is particularly challenging because psychostimulant drugs induce significant changes in brain regions associated with cognitive functions leading to cognitive deficits. These cognitive deficits include impairments in learning/memory, poor decision making, and impaired control of behavioral output. Importantly, these drug-induced cognitive deficits often impact adherence to addiction treatment programs and predispose abstinent addicts to drug use relapse. Additionally, these cognitive deficits impact effective social and professional rehabilitation of abstinent addicts. The goal of this paper is to review neural substrates based on animal studies that could be pharmacologically targeted to reverse psychostimulant-induced cognitive deficits such as impulsivity and impairment in learning and memory. Further, the review will discuss neural substrates that could be used to facilitate extinction learning and thus reduce emotional and behavioral responses to drug-associated cues. Moreover, the review will discuss some non-pharmacological approaches that could be used either alone or in combination with pharmacological compounds to treat the above-mentioned cognitive deficits. Psychostimulant addiction treatment, which includes treatment for cognitive deficits, will help promote abstinence and allow for better rehabilitation and integration of abstinent individuals into society.


Efficacy and safety of an intravenous C1-inhibitor concentrate for long-term prophylaxis in hereditary angioedema.
The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis. This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP). The international registry (2010-2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason. The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500-3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH-treated attack of 72.0 hours (range, 0.0-166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH-treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port). In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration.


Astroblastoma: beside being a tumor entity, an occasional phenotype of astrocytic gliomas?
The diagnosis of astroblastoma is based on a typical histological aspect with perivascular distribution of cells sending cytoplasmic extensions to the vessels and vascular hyalinization. These criteria are useful for standardizing the identification of the tumor, but, in spite of this, there are discrepancies in the literature concerning the age distribution and the benign or malignant nature of the tumor. Three cases are discussed in this study: Case 1 was a typical high-grade astroblastoma; Case 2 was an oligodendroglioma at the first intervention and an oligoastrocytoma at the second intervention with typical perivascular arrangements in the astrocytic component; Case 3 was a gemistocytic glioma with malignant features and typical perivascular arrangements. Genetic analysis showed genetic alterations that are typical of gliomas of all malignancy grades. Using the neurosphere assay, neurospheres and adherent cells were found to have developed in Case 1, while adherent cells only developed in Case 2, in line with the stemness potential of the tumors. The cases are discussed in relation to their diagnostic assessment as astroblastoma, and it is hypothesized that the typical perivascular distribution of cells may not indicate a separate and unique tumor entity, but may be a peculiarity that can be acquired by astrocytic gliomas when an unknown cause from the tumor microenvironment influences the relationship between vessels and tumor cells.


[Microbial biocenosis of the nasal mucosa in healthy persons and in Staphylococcus carriers].
The normal microflora of the nasal mucosa in man is differentiated into main, complementary and casual microflora, taking into account its isolation rate and characteristics of microbial contamination. The main microflora of adults, in contrast to children, is represented, in addition to coagulaso-negative (CN) staphylococci, by bacteria of the genus Corynebacterium. In staphylococcal carrier state a decrease in the isolation rate and the amount of bacteria belonging to the main and complementary microflora (CN staphylococci, Micrococcus, Streptococcus, Bacillus) was observed. Moreover, in carriers the weakening of the degree of association between CN staphylococci, Micrococcus, Corynebacterium, Streptococcus in symbiotic pairs was noted. In the absence of S. aureus carrier state the main and complementary microflora was characterized by the combination of the factors of antagonism and persistence, while in carrier state the complex of colonization factors was defective in the main microflora and well pronounced in coagulase-positive staphylococcal strains and enterobacteria.


Record High Single-Ion Magnetic Moments Through 4f(n)5d(1) Electron Configurations in the Divalent Lanthanide Complexes [(C5H4SiMe3)3Ln]⁻.
The recently reported series of divalent lanthanide complex salts, namely [K(2.2.2-cryptand)][Cp'3Ln] (Ln = Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm; Cp' = C5H4SiMe3) and the analogous trivalent complexes, Cp'3Ln, have been characterized via dc and ac magnetic susceptibility measurements. The salts of the complexes [Cp'3Dy](-) and [Cp'3Ho](-) exhibit magnetic moments of 11.3 and 11.4 μB, respectively, which are the highest moments reported to date for any monometallic molecular species. The magnetic moments measured at room temperature support the assignments of a 4f(n+1) configuration for Ln = Sm, Eu, Tm and a 4f(n)5d(1) configuration for Ln = Y, La, Gd, Tb, Dy, Ho, Er. In the cases of Ln = Ce, Pr, Nd, simple models do not accurately predict the experimental room temperature magnetic moments. Although an LS coupling scheme is a useful starting point, it is not sufficient to describe the complex magnetic behavior and electronic structure of these intriguing molecules. While no slow magnetic relaxation was observed for any member of the series under zero applied dc field, the large moments accessible with such mixed configurations present important case studies in the pursuit of magnetic materials with inherently larger magnetic moments. This is essential for the design of new bulk magnetic materials and for diminishing processes such as quantum tunneling of the magnetization in single-molecule magnets.


New methods for ALK status diagnosis in non-small-cell lung cancer: an improved ALK immunohistochemical assay and a new, Brightfield, dual ALK IHC-in situ hybridization assay.
The demonstration of anaplastic lymphoma kinase (ALK) positivity in non-small-cell lung cancer (NSCLC) has been hindered by the technical complexity and interpretative challenges of fluorescence in situ hybridization methods for detection of ALK gene rearrangement and by the inadequate sensitivity of existing immunohistochemistry (IHC) methods for ALK protein detection. In this study, we sought to increase the sensitivity of ALK IHC detection and to develop a brightfield assay for concurrent detection of ALK protein expression and ALK gene rearrangement. We developed a horseradish peroxidase-based IHC detection system using the novel, nonendogenous hapten 3-hydroxy-2-quinoxaline (HQ) and tyramide. We also developed a dual gene protein ALK assay combining a brightfield break-apart in situ hybridization ALK assay with another sensitive IHC method using the novel, nonendogenous hapten 5-nitro-3-pyrazole. We examined the sensitivity and accuracy of these methods using surgically resected NSCLC cases examined with ALK fluorescence in situ hybridization. The new HQ-tyramide IHC detection system offered readily interpretable staining with substantially greater sensitivity than conventional ALK IHC, and produced heterogeneous and homogeneous patterns of ALK protein staining among ALK-positive NSCLC surgical cases. The new 5-nitro-3-pyrazole-based IHC detection system was similar in ALK detection sensitivity to the HQ-tyramide IHC system and was compatible with the brightfield in situ hybridization assay. The new HQ-tyramide IHC reagent system allows more sensitive assessment of ALK protein status in NSCLC cases. The new ALK gene-protein assay allows the concurrent visualization of ALK gene and ALK protein status in single cells, allowing more accurate ALK status determination even in heterogeneous specimens.


Application of Intelligent Computer-Assisted Taylor 3D External Fixation in the Treatment of Tibiofibular Fracture: Retrospective Case Study.
With the development of modern society, severe and complex tibial fractures caused by high-energy injuries such as traffic accidents have gradually increased. At present, the commonly used methods for the treatment of tibial fractures include plate fixation, intramedullary nail fixation, and external fixation. Most of these fractures are open wounds with severe soft tissue injury and wound contamination, and some involve bone defects, which makes internal fixation treatment difficult. This study aims to explore the use of intelligent computer-assisted Taylor 3D external fixation for the treatment of tibiofibular fractures. In total, 70 patients were included and divided into the Taylor 3D external fixation (TSF) group (28 patients with severe tibial fractures treated with TSF) and the internal fixation group (42 patients with complicated tibiofibular fractures treated by internal fixation). After the treatment, the follow-up evaluation of TSF for the treatment of tibiofibular fractures noted the incidence of complications, as well as the efficacy and occurrence of internal fixation for the treatment of tibial fractures in our hospital. The results showed that TSF was superior to orthopedics in the treatment of tibiofibular fractures in terms of efficacy and complications. TSF for the treatment of tibiofibular fractures is more effective than internal fixation and the incidence of complications is low. This is a new technology for the treatment of tibiofibular fractures that is worthy of clinical promotion.


The role of autocrine motility factor in tumor and tumor microenvironment.
Autocrine motility factor (AMF) is a tumor-secreted cytokine and is abundant at tumor sites, where it may affect the process of tumor growth and metastasis. AMF is a multifunctional protein capable of affecting cell migration, invasion, proliferation, and survival, and possesses phosphoglucose isomerase activity and can catalyze the step in glycolysis and gluconeogenesis. Here, we review the role of AMF and tumor environment on malignant processes. The outcome of metastasis depends on multiple interactions between tumor cells and homeostatic mechanisms, therefore elucidation of the tumor/host interactions in the tumor microenvironment is essential in the development of new prevention and treatment strategies. Such knowledge might provide clues to develop new future therapeutic approaches for human cancers.


Benefits and costs of secondary polygyny in the dampwood termite Zootermopsis angusticollis.
Newly molted female neotenic reproductives of the dampwood termite Zootermopsis angusticollis Hagen were allowed to mature in the presence of a neotenic male, a fixed number of larval helpers, and varying numbers of sibling neotenic queens to assess the impact of secondary polygyny to the individual and colony. Under monogyne conditions, neotenics developed more ovarioles per ovary and had higher individual fecundities after 60 d compared with females under polygyne conditions. Queens in groups of three females were able to gain more body mass than those in groups of five. Although the division of resources provided by helpers reduced individual female development and fecundity under polygyne conditions, it resulted in an overall increase in colony fecundity. In addition, neotenic females in polygynous colonies did not differ significantly in reproductive competence. There was no evidence that neotenics were attacked or injured by other reproductives or larval helpers, suggesting little if any reproductive competition among sibling queens. The physiological responses of neotenics to the increasing queen/worker ratio may have the benefit of enhancing the colony growth at the cost of the fecundity of individual queens.


Deep generative modeling of the human proteome reveals over a hundred novel genes involved in rare genetic disorders.
Identifying causal mutations accelerates genetic disease diagnosis, and therapeutic development. Missense variants present a bottleneck in genetic diagnoses as their effects are less straightforward than truncations or nonsense mutations. While computational prediction methods are increasingly successful at prediction for variants in known disease genes, they do not generalize well to other genes as the scores are not calibrated across the proteome. To address this, we developed a deep generative model, popEVE, that combines evolutionary information with population sequence data and achieves state-of-the-art performance at ranking variants by severity to distinguish patients with severe developmental disorders from potentially healthy individuals. popEVE identifies 442 genes in a cohort of developmental disorder cases, including evidence of 119 novel genetic disorders without the need for gene-level enrichment and without overestimating the prevalence of pathogenic variants in the population. By placing variants on a unified scale, our model offers a comprehensive perspective on the distribution of fitness effects across the entire proteome and the broader human population. popEVE provides compelling evidence for genetic diagnoses even in exceptionally rare single-patient disorders where conventional techniques relying on repeated observations may not be applicable. Interactive web viewer and downloads available at pop.evemodel.org .


Evaluation of an implemented new insulin chart to improve quality and safety of diabetes care in a large university hospital: a follow-up study.
To evaluate structure, documentation, treatment quality of a new implemented standardised insulin chart in adult medical inpatient wards at a university hospital. A before-after study (3 to 5 months after implementation) was used to compare the quality of old versus new insulin charts. University Hospital Graz, Austria. Healthcare professionals (n=237) were questioned regarding structure quality of blank insulin charts. A new standardised insulin chart was implemented and healthcare professionals were trained regarding features of this chart. Data from insulinised inpatients were evaluated regarding documentation and treatment quality of filled-in insulin charts (n=108 old insulin charts vs n=100 new insulin charts). The primary endpoint was documentation error for insulin administration. Healthcare professionals reported an improved structure quality of the new insulin chart with a Likert type response scale increase in all nine items. Documentation errors for insulin administration (primary endpoint) occurred more often on old than new insulin charts (77% vs 5%, p<0.001). Documentation errors for insulin prescription were more frequent on old insulin charts (100% vs 42%) whereas documentation errors for insulin management rarely occurred in any group (10% vs 8%). Patients of both chart evaluation groups (age: 71±11 vs 71±12 years, 47% vs 42% women, 75% vs 87% type 2 diabetes for old vs new charts, respectively) had a mean of 4±2 good diabetes days. Overall, 26 vs 18 hypoglycaemic episodes (blood glucose (BG) <4.0 mmol/L (72 mg/dL), p=0.28), including 7 vs 2 severe hypoglycaemic episodes (BG <3.0 mmol/L (54 mg/dL), p=0.17) were documented on old versus new insulin charts. The implementation of a structured documentation form together with training measures for healthcare professionals led to less documentation errors and safe management of glycaemic control in hospitalised patients in a short time follow-up. A rollout at further medical wards is recommended, and sustainability in the long-term has to be demonstrated.


Early outcome of second line antiretroviral therapy in treatment-experienced human immunodeficiency virus positive patients.
Multi-drug resistance in treatment-experienced human immune deficiency virus (HIV) patients has been a major cause to first line antiretroviral therapy (ART) failure, necessitating a switch to second line therapy. In India, the second line treatment program is still relatively new with little experience and unclear outcomes. It is therefore, critical to assess the clinical, virological and immunological effectiveness and treatment outcome over the 1(st) year of follow-up in the patients' switched to the second line ART at public sector tertiary care center. A prospective, observational study was carried out on HIV positive patients switched on second line ART from January 2010 to December 2010 at ART Centre, Civil Hospital, Ahmedabad. Demographic details, symptoms, adverse drug reactions (ADRs), second line ART regimens, CD4 count, and plasma viral load (PVL) were recorded in a case record form. Patients were followed-up monthly for 12 months. The data was analyzed by t-test, z-test, and Fisher-exact test. Out of 126 patients, 82 received regimen V [zidovudine (ZDV) + lamivudine (3TC) + tenofovir (TDF) + boosted lopinavir (LPV/r)] and 44 received regimen Va [3TC + TDF + LPV/r]. A significant (P < 0.0001) increase in mean body weight and marked reduction in number of patients (7) categorized as WHO stage III/IV was observed at 12 months of second line ART. Moreover, a significant immune reconstitution with increase in mean CD4 count and viral suppression (PVL < 400 copies/ml) in 103 (82%) patients (P < 0.0001) was also observed. A total of 83 ADRs were observed in 69 (55%) patients, the most common being dyslipidemia (57) followed by anemia (9). Early treatment outcome with second line ART was good with 82% success rate in treatment experienced HIV patients. Dyslipidemia and anemia were the common ADRs observed.


Arsenite exposure in human lymphoblastoid cell lines induces autophagy and coordinated induction of lysosomal genes.
Chronic exposure to inorganic arsenic is associated with diverse, complex diseases, making the identification of the mechanism underlying arsenic-induced toxicity a challenge. An increasing body of literature from epidemiological and in vitro studies has demonstrated that arsenic is an immunotoxicant, but the mechanism driving arsenic-induced immunotoxicity is not well established. We have previously demonstrated that in human lymphoblastoid cell lines (LCLs), arsenic-induced cell death is strongly associated with the induction of autophagy. In this study we utilized genome-wide gene expression analysis and functional assays to characterize arsenic-induced effects in seven LCLs that were exposed to an environmentally relevant, minimally cytotoxic, concentration of arsenite (0.75 μM) over an eight-day time course. Arsenic exposure resulted in inhibition of cellular growth and induction of autophagy (measured by expansion of acidic vesicles) over the eight-day exposure duration. Gene expression analysis revealed that arsenic exposure increased global lysosomal gene expression, which was associated with increased functional activity of the lysosome protease, cathepsin D. The arsenic-induced expansion of the lysosomal compartment in LCL represents a novel target that may offer insight into the immunotoxic effects of arsenic.


Lyticase: endoglucanase and protease activities that act together in yeast cell lysis.
Yeast lytic activity was purified from the culture supernatant of Oerskovia xanthineolytica grown on minimal medium with insoluble yeast glucan as the carbon source. The lytic activity was found to consist of two synergistic enzyme activities which copurified on carboxymethyl cellulose and Sephadex G-150, but were resolved on Bio-Gel P-150. The first component was a beta-1,3-glucanase with a molecular weight of 55,000. The K(m) for yeast glucan was 0.4 mg/ml; that for laminarin was 5.9 mg/ml. Hydrolysis of beta-1,3-glucans was endolytic, yielding a mixture of products ranging from glucose to oligomers of 10 or more. The size distribution of products was pH dependent, smaller oligomers predominating at the lower pH. The glucanase was unable to lyse yeast cells without 2-mercaptoethanol or the second lytic component, an alkaline protease. Neither of these agents had any effect on the glucanase activity on polysaccharide substrates. The protease had a molecular weight of 30,000 and hydrolyzed Azocoll and a variety of denatured proteins. The enzyme was unusual in that it had an affinity for Sephadex. Although the activity was insensitive to most protease inhibitors, it was affected by polysaccharides; yeast mannan was a potent inhibitor. The enzyme did not have any mannanase activity, however. Neither pronase nor trypsin could substitute for this protease in promoting yeast cell lysis. A partially purified fraction of the enzymes, easily obtained with a single purification step, had a high lytic specific activity and was superior to commercial preparations in regard to nuclease, protease, and chitinase contamination. Lyticase has been applied in spheroplast, membrane, and nucleic acid isolation, and has proved useful in yeast transformation procedures.


Reciprocity of support in coatis (Nasua nasua).
Primate sociality has received much attention and its complexity has been viewed as a driving force for the evolution of cognitive abilities. Improved analytic techniques have allowed primate researchers to reveal intricate social networks based on the exchange of cooperative acts and services. Although nonprimates are known to show similar behavior (e.g., cooperative hunting, food sharing, coalitions) there seems a consensus that social life is less complex than in primates. Here the authors present the first group-level analysis of reciprocity of social interactions in a social carnivore, the ring-tailed coati (Nasua nasua). The authors found that support in aggressive conflicts is a common feature in coatis and that this behavior is reciprocally exchanged in a manner seemingly as complex as in primates. Given that reciprocity correlations persisted after controlling for the effect of spatial association and subunit membership, some level of scorekeeping may be involved. Further studies will be needed to confirm our findings and understand the mechanisms underlying such reciprocity, but our results contribute to the body of work that has begun to challenge primate supremacy in social complexity and cognition.


Reliability of water volumetry and the figure of eight method on subjects with ankle joint swelling.
Single-group repeated measures with 2 raters. To determine the interrater and intrarater reliability of water volumetry and the figure of eight method on subjects with ankle joint swelling. Measurements of ankle swelling are commonly performed to determine the nature and stage of injury and to monitor progress made during rehabilitation. Water volumetry and the figure of eight method are 2 techniques used to measure ankle swelling. Twenty-nine subjects with ankle swelling were measured by 2 raters with the hypothesis that both measurement techniques would be reliable. Each rater performed 3 measurements of the swollen ankle using both measurement techniques during a single test session. The order of the rater and of the measurement technique was randomized, and the raters were blinded to each other's measurements. We found high interrater reliability for both the water volumetry (ICC [intraclass correlation coefficient] = 0.99) and figure of eight methods (ICC = 0.98). Additionally, intrarater reliability was high for both raters using both methods (ICCs = 0.98-0.99). Both methods are reliable measures of ankle swelling. The authors recommend the figure of eight method because of its ease of use, time efficiency, and cost effectiveness. However, water volumetry may be more appropriate when measuring diffuse lower-extremity swelling. Reliability of these 2 methods was established using subjects with foot or ankle pathology. Therefore, the results are applicable and generalizable to the clinical setting.


Presynaptic mechanism for anti-analgesic and anti-hyperalgesic actions of kappa-opioid receptors.
Glutamate neurotransmission plays an important role in the processing of pain and in chronic opioid-induced neural and behavioral plasticity, such as opioid withdrawal and opioid dependence. Kappa-opioid receptors also have been implicated in acute opioid modulation of pain and chronic opioid-induced plasticity, both of which are primarily mediated by mu-opioid receptors. Using whole-cell patch clamp recordings in brain slices in vitro and system analysis of pain behaviors in rats in vivo, this study investigated the functional role of glutamate synaptic transmission and kappa-opioid receptors in two behavioral pain conditions: m-opioid-induced analgesia (decreased pain) and mu-opioid withdrawal-induced hyperalgesia (increased pain). In the nucleus raphe magnus (NRM), a brainstem structure that controls spinal pain transmission, we found that kappa-receptor agonists presynaptically inhibited glutamate synaptic currents in both of the two cell types that are thought to respectively inhibit or facilitate spinal pain transmission. In rats, both glutamate receptor antagonists and the kappa agonist microinjected into the NRM attenuated mu-opioid-induced analgesia, which is most likely mediated through activation of such pain-inhibiting neurons. However, during opioid abstinence-induced withdrawal, the same doses of glutamate receptor antagonists and the kappa agonist administered in the NRM suppressed the withdrawal-induced hyperalgesia, which is thought to be mediated by activation of those pain-facilitating neurons during opioid withdrawal. These results demonstrate that kappa-opioid receptors antagonize mu-receptor-induced effects in both analgesic and hyperalgesic states, and suggest inhibition of glutamate synaptic transmission as a presynaptic mechanism for the kappa antagonism of these two mu receptor-mediated actions.


Cytostructural localization of a tumor-associated antigen.
Tumor cell membrane glycoproteins may be involved in the induction of tumor immunity or in the escape of tumors from immunologic defense mechanisms. Forty-four benign and malignant breast lesions were examined for the presence of a carbohydrate precursor antigen (T antigen) of the human blood group system MN. T antigen was demonstrated by means of an immunohistochemical technique to detect tissue binding of peanut agglutinin, a plant lectin, with affinity for T antigen. Malignant breast lesions showed a pattern of T antigen expression different from that of benign breast tissues. A possible role for T antigen in the modulation of the immune response to breast carcinoma is suggested.


Peripheral primitive neuroectodermal tumor of seminal vesicles: is there a role for relatively aggressive treatment modalities?
A 50 year old white man received an incidental ultrasound diagnosis of hypoechoic mass interesting the right seminal vesicle. A CT scan showed the presence of a 7.8 cm roundish cyst, originating from the right seminal vesicle. He had been followed by the removal of the right seminal vesicle and both the cystic lesion. The histological findings of the specimen documented the presence of small round cells compatible with Ewing's sarcoma/PPNET. The patient received also adjuvant chemotherapy and radiation treatment. After 10 years, the follow-up is still negative.


Prevalence, significance and predictive value of antiphospholipid antibodies in Crohn's disease.
To assess the prevalence and stability of different antiphospholipid antibodies (APLAs) and their association with disease phenotype and progression in inflammatory bowel diseases (IBD) patients. About 458 consecutive patients [Crohn's disease (CD): 271 and ulcerative colitis (UC): 187] were enrolled into a follow-up cohort study in a tertiary IBD referral center in Hungary. Detailed clinical phenotypes were determined at enrollment by reviewing the patients' medical charts. Disease activity, medical treatment and data about evolvement of complications or surgical interventions were determined prospectively during the follow-up. Disease course (development f complicated disease phenotype and need for surgery), occurrence of thrombotic events, actual state of disease activity according to clinical, laboratory and endoscopic scores and accurate treatment regime were recorded during the follow-up, (median, 57.4 and 61.6 mo for CD and UC). Sera of IBD patients and 103 healthy controls (HC) were tested on individual anti-β2-Glycoprotein-I (anti-β2-GPI IgA/M/G), anti-cardiolipin (ACA IgA/M/G) and anti-phosphatidylserine/prothrombin (anti-PS/PT IgA/M/G) antibodies and also anti-Saccharomyces cerevisiae antibodies (ASCA IgA/G) by enzyme-linked immunosorbent assay (ELISA). In a subgroup of CD (n = 198) and UC patients (n = 103), obtaining consecutive samples over various arbitrary time-points during the disease course, we evaluated the intraindividual stability of the APLA status. Additionally, we provide an overview of studies, performed so far, in which significance of APLAs in IBD were assessed. Patients with CD had significantly higher prevalence of both ACA (23.4%) and anti-PS/PT (20.4%) antibodies than UC (4.8%, P < 0.0001 and 10.2%, P = 0.004) and HC (2.9%, P < 0.0001 and 15.5%, P = NS). No difference was found for the prevalence of anti-β2-GPI between different groups (7.2%-9.7%). In CD, no association was found between APLA and ASCA status of the patients. Occurrence of anti-β2-GPI, ACA and anti-PS/PT was not different between the group of patients with active vs inactive disease state according to appropriate clinical, laboratory and endoscopic scores in CD as well as in UC patients. All subtypes of anti-β2-GPI and ACA IgM status were found to be very stable over time, in contrast ACA IgG and even more ACA IgA status showed significant intraindividual changes. Changes in antibody status were more remarkable in CD than UC (ACA IgA: 49.9% vs 23.3% and ACA IgG: 21.2% vs 5.8%). Interestingly, 59.1% and 30.1% of CD patients who received anti-TNF therapy showed significant negative to positive changes in ACA IgA and IgG antibody status respectively. APLA status was not associated with the clinical phenotype at diagnosis or during follow-up, medical therapy, or thrombotic events and it was not associated with the probability of developing complicated disease phenotype or surgery in a Kaplan-Meier analysis. The present study demonstrated enhanced formation of APLAs in CD patients. However, presence of different APLAs were not associated with the clinical phenotype or disease course.


Gallium in cancer treatment.
The trivalent gallium cation is capable of inhibiting tumor growth, mainly because of its resemblance to ferric iron. It affects cellular acquisition of iron by binding to transferrin, and it interacts with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. The abundance of transferrin receptors and the up-regulation of ribonucleotide reductase render tumor cells susceptible to the cytotoxicity of gallium. Remarkable clinical activity in lymphomas and bladder cancer has been documented in clinical studies employing intravenous gallium nitrate, which is currently being re-evaluated in non-Hodgkin's lymphoma. An improved therapeutic index is expected to result from prolonged exposure to low steady-state plasma gallium levels. Attempts to accomplish this by oral administration of gallium chloride failed because of insufficient intestinal absorption. Complexation of gallium with ligands, which stabilize gallium against hydrolysis and facilitate membrane permeation, has been recognized as a promising strategy for overcoming these limitations. Two such gallium complexes, namely tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) and tris(8-quinolinolato)gallium(III) (KP46), which both exhibit high bioavailability when administered via the oral route, are currently being evaluated in the clinical setting.


[New method of thymus transplantation].
A surgical procedure for correction of T-system immunity deficiency in primary immunodeficient states and malignant neoplasms in children is described. To ensure a high physiological activity of the transplant, to prevent anti-recipient reaction and to maintain laminar blood flow in the transplant, thymus glands were obtained from fetuses and separated from breast bone. Blood channel reconstruction was performed before the gland transplant was washed and connected to the patient's blood flow. Thymus transplantation was carried out in 25 cases and neither acute rejection nor anti-recipient reaction were observed. Immune response indices returned to normal within 6-7 months.


Herbal medicines and chemotherapy induced peripheral neuropathy (CIPN): A critical literature review.
Chemotherapy induced peripheral neuropathy [CIPN] is a common significant and debilitating side-effect resulting from the administration of neurotoxic chemotherapeutic agents. These pharmaco-chemotherapeutics can include taxanes, vinca alkaloids, platinum analogues, and others. Moderate to severe CIPN significantly decreases the quality of life and physical abilities of cancer patients and current pharmacotherapy for CIPN e.g. Amifostine, and antidepressants have had limited efficacy and may themselves induce adverse side-effects. To determine the potential use of herbal medicines as adjuvants in cancer treatments, a critical literature review was conducted by electronic and manual search on nine databases. These include PubMed, the Cochrane Library, Science Direct, Scopus, EMBASE, MEDLINE, Google Scholar, and two Chinese databases CNKI and CINAHL. Thirty-four studies were selected from 5614 studies assessed and comprising animal studies, case reports, retrospective studies, and minimal randomized clinical trials investigating the anti-CIPN effect of herbal medicines as the adjuvant intervention in patients administered chemotherapy. The thirty-four studies were assessed on methodological quality and limitations identified. Studies were mixed in their recommendations for herbal medicines as an adjuvant treatment for CIPN. Currently no agent has shown solid beneficial evidence to be recommended for the treatment or prophylaxis of CIPN. Given that the number of cancer survivors is increasing, the long-term side effects of cancer treatment, is of major importance.


Feedback From Facial Expressions Contribute to Slow Learning Rate in an Iowa Gambling Task.
Facial expressions of emotion can convey information about the world and disambiguate elements of the environment, thus providing direction to other people's behavior. However, the functions of facial expressions from the perspective of learning patterns over time remain elusive. This study investigated how the feedback of facial expressions influences learning tasks in a context of ambiguity using the Iowa Gambling Task. The results revealed that the learning rate for facial expression feedback was slower in the middle of the learning period than it was for symbolic feedback. No difference was observed in deck selection or computational model parameters between the conditions, and no correlation was observed between task indicators and the results of depressive questionnaires.


Photolysis of Chlorine Dioxide under UVA Irradiation: Radical Formation, Application in Treating Micropollutants, Formation of Disinfection Byproducts, and Toxicity under Scenarios Relevant to Potable Reuse and Drinking Water.
Conversion of potable reuse water utilities and drinking water utilities from a low-pressure UV/H2O2 (LPUV/H2O2) advanced oxidation process (AOP) to alternative AOPs in which oxidants can effectively absorb photons and rapidly generate radicals has attracted great interest. Herein, we propose a novel UVA/ClO2 AOP for different water treatment scenarios because of reduced photon absorption by the background matrix and high molar absorptivity for ClO2 at UVA wavelengths. While the photolysis of ClO2 produces •Cl + O2 or •ClO + O(3P) via distinct product channels, we determined the parameters needed to accurately model the loss of oxidants and the formation of byproducts and combined a kinetic model with experimental data to determine quantum yields (Φ). Modeling incorporating the optimized Φ simultaneously predicted oxidant loss and the formation of major products -HOCl, Cl-, and ClO3-. We also systematically investigated the removal of three contaminants exhibiting different radical reactivities, the formation of 35 regulated and unregulated halogenated disinfection byproducts (DBPs), DBP-associated toxicity, and N-acetylcysteine thiol reactivity in synthetic or authentic RO permeates/surface waters treated by different AOPs. The kinetic model developed in this study was used to optimize operating conditions to control undesired products and improve contaminant removal efficiency. The results indicate that UVA/ClO2 can outperform LPUV/H2O2 in terms of electrical energy per order of contaminant degradation, disinfection byproduct formation, and toxicity indices.


Suppressor thymus-derived lymphocytes in fungal infection.
Thymus-derived lymphocyte (T-cell) function, as determined in vivo by cutaneous reactivity to several antigens and in vitro by responsiveness to mitogens and antigens, was assessed in 14 patients infected with a variety of fungal organisms. While all patients manifested a normal frequency of peripheral blood T cells, only seven patients reacted to at least one of the antigens used for cutaneous testing and demonstrated normal in vitro T proliferative responses. Three patients exhibited cutaneous anergy but normal in vitro T-cell reactivity while four patients demonstrated persistent anergy and marked in vitro T-cell hyporeactivity which was independent of activity of infection, concurrent medication, or any associated disorders. The marked diminution of in vitro T-cell reactivity noted for these later four patients was not due to a deletion of antigen- or mitogen-reactive cells. Thus, patients' cells which had been initially cultured for 7 days without any mitogenic or antigenic stimulus and which were subsequently washed and recultured with phytohemagglutinin, concanavalin A, or histoplasmin demonstrated a marked increase in their responsiveness. Moreover, this reactivity noted for recultured cells could be suppressed by a nonphagocytic, nonadherent, nonimmunoglobulin-bearing, sheep red blood cell rosette-forming population of cells isolated from the fresh peripheral blood mononuclear cells of the same patient. While these "regulator" T cells were capable of suppressing T-proliferative responses to antigens and mitogens, they did not diminish pokeweed mitogen-induced immunoglobulin synthesis by normal bone marrow-derived lymphocytes. Patients in whom suppressor "T" cells were found were at risk for relapsing, disseminated fungal infection.


Management of patients with non-ST-segment elevation acute coronary syndromes: insights from the PURSUIT trial.
The glycoprotein (GP) IIb-IIIa inhibitor eptifibatide (INTEGRILIN, COR Therapeutics, Inc., South San Francisco, California, and Key Pharmaceuticals, Inc., Kenilworth, New Jersey) is a novel and highly potent antithrombotic agent indicated for the management of patients with non-ST-segment elevation acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention. The approval of eptifibatide for non-ST-segment elevation ACS was based on the positive results of the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. With enrollment of almost 11,000 patients, not only is the PURSUIT trial the largest trial of a GP IIb-IIIa inhibitor to date, but it is also the largest clinical study ever conducted in patients with non-ST-segment elevation ACS. The key feature of the PURSUIT trial is that patient management closely resembled standard clinical practice, because decisions about the use and timing of invasive cardiac procedures were made by the individual physicians rather than being prespecified in the study protocol. Eptifibatide therapy was associated with a significant reduction in the incidence of the primary endpoint--a composite of death or myocardial infarction at 30 days (14.2 vs. 15.7% in the placebo group; p = 0.042). Of importance is the fact that the beneficial effect of eptifibatide was independent of the management strategy pursued during study drug infusion (invasive or conservative), and it was achieved with few major safety concerns. These findings demonstrate that the use of eptifibatide should be considered for all patients presenting with signs and symptoms of intermediate- to high-risk non-ST-segment elevation ACS.


[Cancer cells escape from failsafe programs in a simple Twist].
A major obstacle to the expansion of abnormal cells with significant proliferative potential is the induction of either cellular senescence or programmed cell death. Consequently, oncogene-driven hyperproliferation must be associated with apoptosis inhibition to allow malignant outgrowth. The oncogenic cooperation of N-Myc and Twist 1 in the development of neuroblastoma, the most common and deadly solid tumour of childhood, perfectly illustrates such a process. N-Myc promotes cell proliferation whereas Twist 1 counteracts its pro-apoptotic properties by knocking-down the ARF/p53 pathway. This observation provides a mechanistic explanation for the rarity of p53 mutations in neuroblastomas. It also highlights the involvement of two crucial regulators of embryogenesis in human cancer development. In this review, we discuss the possible role of Twist 1 in tumour progression, based on the numerous recent studies reporting its overexpression in a variety of human cancers.


Cutibacterium acnes Central Nervous System Catheter Infection Induces Long-Term Changes in the Cerebrospinal Fluid Proteome.
Cutibacterium acnes is the third most common cause of cerebrospinal fluid (CSF) shunt infection and is likely underdiagnosed due to the difficulty in culturing this pathogen. Shunt infections lead to grave neurologic morbidity for patients especially when there is a delay in diagnosis. Currently, the gold standard for identifying CSF shunt infections is microbiologic culture. However, C. acnes infection often results in falsely negative cultures; therefore, new diagnostic methods are needed. To investigate potential CSF biomarkers of C. acnes CSF shunt infection we adapted a rat model of CSF catheter infection to C. acnes. We found elevated levels of interleukin-1β (IL-1β), IL-6, chemokine ligand 2, and IL-10 in the CSF and brain tissues of animals implanted with C. acnes-infected catheters compared to sterile controls at day 1 postinfection. This coincided with modest increases in neutrophils in the CSF and, to a greater extent, in the brain tissues of animals with C. acnes infection, which closely mirrors the clinical findings in patients with C. acnes shunt infection. Mass spectrometry revealed that the CSF proteome is altered during C. acnes shunt infection and changes over the course of disease, typified at day 1 postinfection by an acute-phase and pathogen neutralization response evolving to a response consistent with wound resolution at day 28 compared to a sterile catheter placement. Collectively, these results demonstrate that it is possible to distinguish C. acnes infection from sterile postoperative inflammation and that CSF proteins could be useful in a diagnostic strategy for this pathogen that is difficult to diagnose.


Critical transition of thermal rectification on complex networks.
Thermal rectification is a mechanism that controls the direction of heat conduction, allowing it to flow freely in one direction and hindering it in the opposite direction. In this study, we propose a heat conduction model on a complex network where the node masses are non-uniformly distributed according to mi∼kiα. Our findings show that the existence of a critical point, α=1, determines the working mode of thermal rectification. For α>1, the working mode of thermal rectification is positive, whereas for α<1, the working mode is negative. Additionally, we discovered that this critical transition is a general phenomenon and does not vary with changes in network size, average degree, or degree distribution. By conducting theoretical analyses based on phonon spectra, we also identified the physical mechanism of the critical transition. These results provide a new approach to implement and enrich thermal diodes, opening up new possibilities for more efficient thermal management.


Additional information from percutaneous cutting needle biopsy following fine-needle aspiration in the diagnosis of chest lesions.
To determine the contribution of percutaneous cutting needle biopsy (PNB) subsequent to fine-needle aspiration (FNA) in the diagnosis of chest lesions. A retrospective review of 220 patients who underwent CT-guided FNA followed immediately by PNB performed at our center between 1988 and 1995 was undertaken. Thirty-eight patients were excluded because FNA and/or PNB specimens were nondiagnostic, yielding a study group of 182 patients. A diagnosis of malignancy was made in 141 (77.5%) and nonmalignancy in 41 (22.5%) cases. The yield of histospecific diagnosis due to FNA was marginally higher than PNB in malignant lesions (86.5% vs 78%, respectively). In contrast, PNB was superior to FNA for the histospecific diagnosis of benign lesions (87.8% for PNB vs 31.7% for FNA, p<0.00001) and lymphomas (88% for PNB vs 56% for FNA, p<0.05). In 58.8% of the patients with benign lesions and in 37.5% of the patients with lymphoma, PNB performances altered clinical management, either by avoiding further surgery or allowing specific medical treatment. Pneumothorax occurred in 24.7% of the cases but only five patients (2.7%) required hospitalization. PNB is extremely effective for making a specific diagnosis in benign lesions compared with FNA. PNB does not increase the yield of histospecific diagnosis for malignant lesions except for the subset of lymphoma, where it seems to provide important additional information in many instances. We recommend that FNA be performed as the initial procedure, followed by PNB in cases of equivocal diagnosis of carcinoma, for lymphoma and for suspected benign lesions.


Measurement of acoustic backscatter and attenuation in the liver of dogs with experimentally induced steroid hepatopathy.
To determine the usefulness of a new method of measuring acoustic backscatter and attenuation in the liver of dogs with experimental steroid-induced hepatopathy. 10 clinically normal dogs. Steroid hepatopathy was induced by daily injections of prednisone (2 mg/kg of body weight, IM). Dogs were evaluated histologically and were sonographically imaged on days 0, 3, 7, 10, and 14. Acoustic backscatter and attenuation were measured from in vivo images of dogs, using a video signal method, and compared with results obtained from analysis of the unprocessed radio frequency signal. Histologic evaluation revealed midzonal, predominantly water-filled vacuoles in hepatocytes by day 7, which persisted for the remainder of the study and significantly (P = 0.0001) increased liver weight on day 14. Attenuation and backscatter increased during the experimental period. Mean effective attenuation difference was higher (P = 0.015) in the liver imaged through a left paraxyphoid window in experimental dogs by day 3. Significantly (P < 0.05) greater attenuation persisted in the liver of experimental dogs throughout the experimental period. Mean backscatter ratio was significantly increased (P = 0.02) by day 10. Uncorrected pixel intensity of the liver in 2 experimental dogs was approximately equal to that of the spleen on day 10 and greater than that of the spleen on day 14. Administration of prednisone to dogs results in increased acoustic backscatter and attenuation in the liver. The video signal method is a sensitive technique for detecting subtle acoustic changes in the liver of dogs.


Will temperature effects or phenotypic plasticity determine the thermal response of a heterothermic tropical bat to climate change?
The proportion of organisms exposed to warm conditions is predicted to increase during global warming. To better understand how bats might respond to climate change, we aimed to obtain the first data on how use of torpor, a crucial survival strategy of small bats, is affected by temperature in the tropics. Over two mild winters, tropical free-ranging bats (Nyctophilus bifax, 10 g, n = 13) used torpor on 95% of study days and were torpid for 33.5±18.8% of 113 days measured. Torpor duration was temperature-dependent and an increase in ambient temperature by the predicted 2°C for the 21(st) century would decrease the time in torpor to 21.8%. However, comparisons among Nyctophilus populations show that regional phenotypic plasticity attenuates temperature effects on torpor patterns. Our data suggest that heterothermy is important for energy budgeting of bats even under warm conditions and that flexible torpor use will enhance bats' chance of survival during climate change.


Delivery of therapeutic AGT shRNA by PEG-Bu for hypertension therapy.
Gene silencing by RNA interference (RNAi) is a promising approach for gene therapy. However, up to today, it is still a major challenge to find safe and efficient non-viral vectors. Previously, we reported PEI-Bu, a small molecular weight PEI derivative, as an efficient non-viral carrier. However, like many PEI-based polymers, PEI-Bu was too toxic. In order to reduce cytotoxicity while maintain or even enhance transfecion efficiency, we modified PEI-Bu with poly(ethylene glycol) (PEG) to obtain PEG-Bu, and used it to delivery a theraputic short hairpin RNA (shRNA) targeting angiotensinogen (AGT) to normal rat liver cells (BRL-3A), which was a key target for the treatment of hypertension. The structure of PEG-Bu was confirmed by proton nuclear magnetic resonance ((1)H-NMR). Gel permeation chromatography (GPC) showed that the weight average molecular weight (Mw) of PEG-Bu was 5880 Da, with a polydispersity of 1.58. PEG-Bu could condense gene cargo into spherical and uniform nanoparticles with particle size (65-88 nm) and zeta potential (7.3-9.6 mV). Interestingly and importantly, PEG-Bu displayed lower cytotoxicity and enhanced tranfection efficiency than PEI-Bu after PEGylation in both normal cells BRL-3A and tumor cells HeLa. Moreover, PEG-Bu could efficiently delivery AGT shRNA to knockdown the AGT expression. To sum up, PEG-Bu would be a promising non-viral vector for delivering AGT shRNA to BRL-3A cells for hypertension therapy.


Duplication of the POMC gene in the paddlefish (Polyodon spathula): analysis of gamma-MSH, ACTH, and beta-endorphin regions of ray-finned fish POMC.
The proopiomelanocortin (POMC) gene, which encodes the common precursor for MSH-related and beta-endorphin-related end products, appeared early in chordate evolution and features a variety of lineage-specific modifications. Key among these has been the apparent degeneration and subsequent deletion of the gamma-MSH region during the evolution of POMC in the ray-finned fish. A second area of increasing focus has been the role of gene duplication in the evolution of POMC in particular and the opioid/orphanin gene family in general. The cloning and phylogenetic analysis of two POMC cDNAs from the paddlefish (Polyodon spathula) is reported here and biochemical data on their processed end products are presented. Based on conceptual amino acid translations, the paddlefish cDNAs encode all functional domains and, in most cases, the flanking paired-basic amino acid cleavage sites characteristic of gnathostome POMCs (i.e., signal sequence, gamma-MSH-like region, ACTH (alpha-MSH and CLIP), gamma-LPH, beta-MSH, and beta-endorphin). Phylogenetic analysis of the paddlefish POMC sequences in the context of the duplicated POMCs of sturgeon and salmonids suggests that degeneration of the gamma-MSH core sequence and its amino-terminal proteolytic cleavage site was initiated prior to divergence of the sturgeon and paddlefish lineages over 150 mya. Finally, a comparison of the relative rates of evolutionary divergence between paralogously related POMC genes within chondrostean and salmonid lineages provides potential support for the hypothesis that some taxa (e.g., the Chondrosteii) represent relic species as a result of an exceptionally slow rate of evolutionary change.


Patients' and caregivers' needs, experiences, preferences and research priorities in spiritual care: A focus group study across nine countries.
Spiritual distress is prevalent in advanced disease, but often neglected, resulting in unnecessary suffering. Evidence to inform spiritual care practices in palliative care is limited. To explore spiritual care needs, experiences, preferences and research priorities in an international sample of patients with life-limiting disease and family caregivers. Focus group study. Separate patient and caregiver focus groups were conducted at 11 sites in South Africa, Kenya, South Korea, the United States, Canada, the United Kingdom, Belgium, Finland and Poland. Discussions were transcribed, translated into English and analysed thematically. A total of 74 patients participated: median age 62 years; 53 had cancer; 48 were women. In total, 71 caregivers participated: median age 61 years; 56 were women. Two-thirds of participants were Christian. Five themes are described: patients' and caregivers' spiritual concerns, understanding of spirituality and its role in illness, views and experiences of spiritual care, preferences regarding spiritual care, and research priorities. Participants reported wide-ranging spiritual concerns spanning existential, psychological, religious and social domains. Spirituality supported coping, but could also result in framing illness as punishment. Participants emphasised the need for staff competence in spiritual care. Spiritual care was reportedly lacking, primarily due to staff members' de-prioritisation and lack of time. Patients' research priorities included understanding the qualities of human connectedness and fostering these skills in staff. Caregivers' priorities included staff training, assessment, studying impact, and caregiver's spiritual care needs. To meet patient and caregiver preferences, healthcare providers should be able to address their spiritual concerns. Findings should inform patient- and caregiver-centred spiritual care provision, education and research.


Yeasts and filamentous fungi associated with some dairy products in Egypt.
This work aimed to identify and evaluate the diversity of yeasts and filamentous fungi that contaminate some dairy products (fresh buffalo milk, plain yoghurt, butter and Kareisk cheese) in Assiut city, Egypt. The identification was based on phenotypic characteristics, and genotypically in case of yeasts. The pHs of all dairy products lie within the acidic range, but yoghurt registered the highest value. A total of 41 genera and 89 species+3 varieties were recovered from all dairy products investigated on DRBC (26 genera representing 59 species+1 variety), DG18 (32 genera, 56 species+2 varieties) and MY50G (31 genera, 64 species+2 varieties). From these, filamentous fungi were represented by 21 genera and 59 species+2 varieties, and yeasts by 20 genera and 30 species+1 variety. In all products except yoghurt, the xerophilic media (DG18 and MY50G) supported more diversity of fungal species than the general medium (DRBC). Reversely, DRBC supported more propagules originated from all products than DG18 and DRBC. On the other hand, the highest numbers of propagules were recovered from Kareish cheese and butter on MY50G, while the lowest numbers were recorded from yoghurt and raw milk on MY50G. Moreover, yeasts constituted the greatest part of propagules from the four products on the three isolation media except the raw milk on MY50G. From yeasts, Candida, Cyberlindnera, Debaryomyces, Galactomyces, Kazachstania, Kluyveromyces, Myerozyma, Pichia, Rhodotorula, Trichosporon; and from filamentous fungi, only Aspergillus, Cladosporium, Mucor and Penicillium were found contaminating all dairy products. Possible medical problems related to the presence of these fungi or to their metabolic products are discussed.


Head-Only Stunning of Turkeys Part 2: Subjective and Objective Assessment of the Application of AC and DC Waveforms.
Electrical stunning is likely to remain an important stunning method for turkeys at slaughter. The purpose of this study is to understand the application of various waveforms of alternating current (AC) and pulsed direct currents (DC), head-only, to turkeys and to improve the effectiveness of handheld stunning of turkeys. We evaluated the effectiveness of stunning by documenting physical responses and recording electroencephalograms (EEGs). For the assessment of physical responses, the stunning voltage was varied depending on the proportion of animals effectively stunned at a certain voltage level. If all turkeys in a group of 10 were stunned, the voltage was decreased, and the next group was stunned. This was repeated until not all turkeys showed signs of being effectively stunned. The experiment was then repeated at the voltage level just above the one that showed incomplete effective stunning. The effects of the stunning on the EEG recording was assessed in 16 turkeys to measure the occurrence of epileptiform EEGs, in 14 turkeys to assess epileptiform EEGs after neck-cut (bleeding), and in 14 turkeys to assess the effect of increased voltage and reduced frequency on epileptiform EEGs. Assessing EEGs in a laboratory setting contributes considerably to the understanding of electrical stunning procedures. Voltages between 125 and 250 V, depending on the waveform assessed, were effective in producing an effective stun in turkeys in this study.


Genomic sequences necessary for transcriptional activation by amino acid deprivation of mammalian cells.
The human genes for C/EBP homology protein (chop) and asparagine synthetase (AS) are model systems to investigate transcription induced by nutrient limitation and endoplasmic reticulum (ER) stress. The genomic cis-elements in the promoters of these two genes that mediate these responses have been identified and partially characterized. Multiple cis-elements are functional in each gene, but differences exist in the molecular mechanisms by which these genes respond to amino acid or glucose deprivation. Whereas chop expression is associated with cell stress and apoptosis, activation of the AS gene by ER stress indicates that asparagine may also be critical for cellular processes other than protein synthesis.