WMGHMDA: a novel weighted meta-graph-based model for predicting human microbe-disease association on heterogeneous information network.
An increasing number of biological and clinical evidences have indicated that the microorganisms significantly get involved in the pathological mechanism of extensive varieties of complex human diseases. Inferring potential related microbes for diseases can not only promote disease prevention, diagnosis and treatment, but also provide valuable information for drug development. Considering that experimental methods are expensive and time-consuming, developing computational methods is an alternative choice. However, most of existing methods are biased towards well-characterized diseases and microbes. Furthermore, existing computational methods are limited in predicting potential microbes for new diseases. Here, we developed a novel computational model to predict potential human microbe-disease associations (MDAs) based on Weighted Meta-Graph (WMGHMDA). We first constructed a heterogeneous information network (HIN) by combining the integrated microbe similarity network, the integrated disease similarity network and the known microbe-disease bipartite network. And then, we implemented iteratively pre-designed Weighted Meta-Graph search algorithm on the HIN to uncover possible microbe-disease pairs by cumulating the contribution values of weighted meta-graphs to the pairs as their probability scores. Depending on contribution potential, we described the contribution degree of different types of meta-graphs to a microbe-disease pair with bias rating. Meta-graph with higher bias rating will be assigned greater weight value when calculating probability scores. The experimental results showed that WMGHMDA outperformed some state-of-the-art methods with average AUCs of 0.9288, 0.9068 ±0.0031 in global leave-one-out cross validation (LOOCV) and 5-fold cross validation (5-fold CV), respectively. In the case studies, 9, 19, 37 and 10, 20, 45 out of top-10, 20, 50 candidate microbes were manually verified by previous reports for asthma and inflammatory bowel disease (IBD), respectively. Furthermore, three common human diseases (Crohn's disease, Liver cirrhosis, Type 1 diabetes) were adopted to demonstrate that WMGHMDA could be efficiently applied to make predictions for new diseases. In summary, WMGHMDA has a high potential in predicting microbe-disease associations.


Ovarian tumorB1-mediated heat shock transcription factor 1 deubiquitination is critical for glycolysis and development of endometriosis.
Endometriosis is a common chronic condition characterized by abnormal growth of the endometrium outside the uterus. Heat shock transcription factor 1 (HSF1) is a significant regulator of the proteotoxic stress response and plays an essential role in developing endometriosis. However, the mechanisms regulating HSF1 protein stability in endometriosis remain unclear. Here, we demonstrate that OTUB1 interacts with HSF1 and promotes HSF1 protein stability through deubiquitination. In addition, OTUB1 enhances glycolysis and epithelial-mesenchymal transition of endometriosis cells, leading to promote proliferation, migration, and invasion of endometriosis cells. The progression of endometriosis is inhibited in an OTUB1-knockout mouse model. In summary, OTUB1 promotes the development of endometriosis by up-regulating HSF1. OTUB1/HSF1 axis may become a new therapeutic target for endometriosis.


Synthesis and evaluation of 4-substituted-4-androstene-3,17-dione derivatives as aromatase inhibitors.
The synthesis and biological evaluation of 4-amino-, 4-alkoxy-, 4-aryloxy-, 4-alkyl- and 4-aryl-4-androstenedione derivatives as inhibitors of estrogen synthetase (aromatase) are described. Inhibitory activity of synthesized compounds was assessed using a human placental microsomal preparation as the enzyme source and [1 beta-3H] androstenedione as substrate. Synthesized compounds exhibiting aromatase inhibitory activity were evaluated further under initial velocity conditions to determine apparent Ki values. Several compounds were effective competitive inhibitors and have apparent Ki values ranging from 38 to 1290 nM, with the apparent Km for androstenedione being 47 nM. Alkylation or arylation of 4-N, S, or O-substituted steroids results in compounds that are effective competitive inhibitors that are devoid of time-dependent inactivation and that the free pair of electrons on N, S, or O is not an essential requirement for 4-substituted androstenedione derivatives to be effective aromatase inhibitors. The results obtained from this investigation are consistent with our previous studies which show that aromatase has a hydrophobic pocket in the active site around the C-4 alpha region of androstenedione.


Value Insider Season 1 Episode 3: How Does Budget Impact and Affordability in Healthcare Work? (BI and Affordability) [Podcast].
How does budget impact and affordability in healthcare work? In this episode of the Value Insider podcast, host Mike Chambers speaks with Prof. Sean Sullivan about affordability and budget impact for the "payers" of healthcare interventions. Prof. Sullivan is Dean of the University of Washington School of Pharmacy. He is past president of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and served as chair of the health technology assessment (HTA) committee of US Health Insurer Premera Blue Cross, was part of the US Governmental Medicare coverage evidence committee and led the ISPOR Task Force on Methods for Conducting and Reporting Budget Impact Assessments. Prof. Sullivan explains how budget impact and affordability are intertwined and how this plays a role in decisions in the US, but also the rest of the world.


Mollicutes DNA polymerases: characterization of a single enzyme from Mycoplasma mycoides and Ureaplasma urealyticum and of three enzymes from Acholeplasma laidlawii.
The DNA polymerase activity of different members of Mollicutes was studied. A single DNA polymerase was found in Mycoplasma mycoides and Ureaplasma urealyticum, type species of the genera Mycoplasma and Ureaplasma, and was compared with the previously described Mycoplasma orale enzyme. Most of their properties were comparable; an immunological relationship was demonstrated between M. orale and M. mycoides enzymes by immunoblotting. In contrast to these results, three different DNA polymerases were purified in Acholeplasma laidlawii, type species of the genus Acholeplasma which, in this aspect, resembles the genus Spiroplasma. A 3'-5' exonuclease activity was found in the different purified preparations. In M. mycoides, M. orale and one of the three A. laidlawii preparations, the 3'-5' exonuclease could be separated from the DNA polymerase by non-denaturing PAGE. The presence of a single DNA polymerase seems to be a typical feature of the Mycoplasmataceae, which include the genera Mycoplasma and Ureaplasma, in contrast to the occurrence of three enzymes within the Acholeplasmataceae and Spiroplasmataceae. These results are in agreement with the phylogenetic tree of Mollicutes proposed from their 5 S and 16 S rRNA sequence comparisons, in which the evolution of Acholeplasma and Spiroplasma branches led, by genome reductions, to Mycoplasma and Ureaplasma species.


Occurrence and characterization of acyclovir-resistant herpes simplex virus isolates: report on a two-year sensitivity screening survey.
For the past 2 years, a survey network was established for the screening of acyclovir (ACV)-resistant clinical isolates of herpes simplex virus (HSV). Among 889 strains tested for in vitro ACV sensitivity, 14 HSV-1 and 6 HSV-2 were resistant to ACV concentrations exceeding 3 micrograms/ml. These resistant isolates were most often obtained after prolonged ACV treatment of severely immunocompromised patients. For five patients, the emergence of ACV-resistant virus correlated with treatment failure. In particular, a decrease in the in vitro sensitivity to ACV was observed for eight successive HSV-1 isolates from one immunodeficient patient undergoing therapy. All ACV-resistant isolates were studied for their sensitivity to different antiherpetic compounds and showed various cross-sensitive and -resistant patterns. The examination of viral populations by plaque autoradiography procedures frequently revealed their heterogeneity in terms of thymidine kinase (TK) phenotype and allowed the detection of various proportions of TK-positive (TK+), TK-deficient (TKD), or TK-altered (TKA) viruses. Our data underline the importance of monitoring the emergence of drug-resistant virus during the course of antiviral therapy, and the need for the detection and characterization of TK mutants in clinical specimens. The routine examination of drug sensitivity of HSV isolates provides useful information to clinicians for the management of ACV treatment in the hope of preventing ACV-resistant mutants from becoming predominant in mixed viral populations.


A study in Polish patients with cardiomyopathy emphasizes pathogenicity of phospholamban (PLN) mutations at amino acid position 9 and low penetrance of heterozygous null PLN mutations.
In humans mutations in the PLN gene, encoding phospholamban - a regulator of sarcoplasmic reticulum calcium ATPase (SERCA), cause cardiomyopathy with prevalence depending on the population. Our purpose was to identify PLN mutations in Polish cardiomyopathy patients. We studied 161 unrelated subjects referred for genetic testing for cardiomyopathies: 135 with dilated cardiomyopathy, 22 with hypertrophic cardiomyopathy and 4 with other cardiomyopathies. In 23 subjects multiple genes were sequenced by next generation sequencing and in all subjects PLN exons were analyzed by Sanger sequencing. Control group included 200 healthy subjects matched with patients for ethnicity, sex and age. Large deletions/insertions were screened by real time polymerase chain reaction. We detected three different heterozygous mutations in the PLN gene: a novel null c.9_10insA:(p.Val4Serfs*15) variant and two missense variants: c.25C > T:(p.Arg9Cys) and c.26G > T:(p.Arg9Leu). The (p.Val4Serfs*15) variant occurred in the patient with Wolff-Parkinson-White syndrome in whom the diagnosis of cardiomyopathy was not confirmed and his mother who had concentric left ventricular remodeling but normal left ventricular mass and function. We did not detect large deletions/insertions in PLN in cohort studied. In Poland, similar to most populations, PLN mutations rarely cause cardiomyopathy. The 9(th) PLN residue is apparently a mutation hot spot whereas a single dose of c.9_10insA, and likely other null PLN mutations, cause the disease only with low penetrance or are not pathogenic.


Benefits of PCR and decentralization of diagnosis in regional laboratories in the management of Bluetongue in France.
Since 1998, Bluetongue virus (BTV) serotypes 1, 2, 4, 6, 8, 9, 11 and 16 have spread throughout Europe. In 2006, BTV serotype 8 (BTV‑8) emerged unexpectedly in Northern Europe, in countries such as Belgium, France, Germany, Luxembourg, and the Netherlands, to spread rapidly in the following year throughout the rest of Europe. In 2007, BTV‑1 spread in Southern Europe, in Spain and in South of France. In 2008, 2 more BTV serotypes were detected in Northern Europe: BTV‑6 in the Netherlands and in Germany, and BTV‑11 in Belgium. The European incursion of BTV has caused considerable economic losses, including direct losses from mortality and reduced production, as well as indirect losses generated by ensuing bans on trade of ruminants between infected and non-infected areas. Given the significance of the disease, all affected countries have established control and eradication measures that have evolved together with the availability of detection and prevention tools such as Polymerase Chain Reaction (PCR) tests and vaccines, respectively. This paper describes how the French National Reference Laboratory for BT has managed diagnosis during the fast and massive spread of BTV‑1 and 8 in 2007 and 2008.


Autoradiographic evidence of 3-methylindole covalent binding to pulmonary epithelial cells in the goat.
3-Methylindole (3MI), the main ruminal fermentation product of L-tryptophan, causes acute pulmonary edema and interstitial emphysema in ruminants. Intravenous infusion of 3MI in goats causes necrosis and sloughing of pneumocytes and bronchial epithelial cells. Previous studies indicate that a reactive metabolite or metabolites of 3MI bind covalently to tissue macromolecules in the lung and this binding is associated with the pneumotoxicity of 3MI. We undertook this autoradiographic study of 3MI covalent binding to test the hypothesis that reactive 3MI metabolite(s) bind to the lung cells susceptible to 3MI-induced injury. We infused goats with [3H]3MI and killed them either 0.5, 2 or 6 h after start of the infusion. Sections of fixed lung were extensively washed, alcohol dehydrated and embedded in plastic. Only covalently bound radioactivity remained. Silver grains were quantitated per area in the developed autoradiographs. There was a 2:1 ratio of binding to the small airway epithelium compared to the interalveolar septa in all the goats. Both ciliated and non-ciliated bronchiolar cells were labeled, as were both types I and II pneumocytes. Normal goat lung slices incubated in vitro with [3H]3MI were labeled in the same pattern. Inclusion of either of the inhibitors of cytochrome P-450, SKF-525-A or piperonyl butoxide significantly reduced this binding to both the pneumocytes and the bronchiolar cells. We consider these results supportive of our hypothesis that 3MI is metabolized to reactive intermediates by the epithelial cells of the lung, where they bind to macromolecules, which may cause cellular damage.


Dissection and engineering of the Escherichia coli formate hydrogenlyase complex.
The Escherichia coli formate hydrogenlyase (FHL) complex is produced under fermentative conditions and couples formate oxidation to hydrogen production. In this work, the architecture of FHL has been probed by analysing affinity-tagged complexes from various genetic backgrounds. In a successful attempt to stabilize the complex, a strain encoding a fusion between FdhF and HycB has been engineered and characterised. Finally, site-directed mutagenesis of the hycG gene was performed, which is predicted to encode a hydrogenase subunit important for regulating sensitivity to oxygen. This work helps to define the core components of FHL and provides solutions to improving the stability of the enzyme.


Institutionalizing integrated treatment for concurrent disorders: creating new organizational discourse.
The high overlap of mental health and substance use problems in the Canadian health care system and the subsequent demand for more effective services for clients with these high-risk issues have stimulated the debate on their integrated treatment. Although the idea of integration has been endorsed by decision makers at both programs and system levels, little attention has been paid to factors that have facilitated this process. In this article, the processes by which organizational texts, language, metaphors, and symbols have facilitated institutionalization of integrated treatment are identified and discussed. Findings from a qualitative case study of 2 treatment programs that were part of a large, urban hospital in Ontario providing services for populations with concurrent disorders are presented. Data were collected using semistructured interviews with professionals and clients, analysis of policy and organizational documents, and nonparticipant observations. Research evidence on comorbidity, government reports, and other organizational texts that were created and disseminated across the province has contributed to the dissemination of the concept of integration. Certain ideas might be successfully implemented when environments are conducive to change; such environmental catalysts include the status of professionals who support new discourse, the characteristics and importance of the problem being addressed, and the timing of implementation. The findings clearly demonstrate that the conditions of the wider institutional environment-the emergence of research evidence on comorbidity and the provincial health care reform, with its focus on rationalizing the existing health care system-supported the idea of integration. The ability to understand how discursive activities of program planners, clinicians, and policy makers contribute to making new ideas deeply embedded in organizational structures can become an important mechanism of effective decision-making activities when health managers attempt to promote new plans and strategies.


The cardiovascular effects of quipazine are mediated by peripheral 5-HT2 and 5-HT3 receptors in anaesthetized rats.
Quipazine (0.5-2 mg/kg i.v.) produced transient hypotension and bradycardia followed by sustained hypertension and variable effects on heart rate in anaesthetized rats. The hypotension, bradycardia and sympatho-inhibitory effects of quipazine were attenuated by bivagotomy. In bivagotomized rats, the hypertension produced by quipazine was not modified by hexamethonium or prazosin but was abolished by ritanserin (1 mg/kg i.v.). In ritanserin-treated rats, section of the carotid sinus nerves and vagus nerves or ICS 205.930 (0.1 mg/kg i.v.) abolished the hypotensive, bradycardic and sympatho-inhibitory effects of quipazine; the action of quipazine was not reproducible in these rats. Quipazine also inhibited the Bezold-Jarish reflex elicited by 5-HT (20 micrograms/kg i.v.). In ICS 205.930-treated rats, the hypertension evoked by quipazine was associated with a reduction in splanchnic nerve activity due to stimulation of baroreceptors. The renin-angiotensin system is not involved in the hypertensive response. The increase in heart rate produced by quipazine in bivagotomized rats was reduced by ritanserin and tertatolol (0.1 mg/kg i.v.) and abolished by a combination of both drugs. We conclude that the bradycardic and sympatho-inhibitory effects of quipazine result from activation of 5-HT3 receptors located in the cardiopulmonary area and of carotid body chemoreceptors. The hypertension and tachycardia are mediated by vascular and myocardial 5-HT2 receptors. No evidence was obtained for a central sympatho-excitatory effect.


Hypothalamic Kisspeptin Neurons and the Control of Homeostasis.
Hypothalamic kisspeptin (Kiss1) neurons provide indispensable excitatory transmission to gonadotropin-releasing hormone (GnRH) neurons for the coordinated release of gonadotropins, estrous cyclicity, and ovulation. But maintaining reproductive functions is metabolically demanding so there must be a coordination with multiple homeostatic functions, and it is apparent that Kiss1 neurons play that role. There are 2 distinct populations of hypothalamic Kiss1 neurons, namely arcuate nucleus (Kiss1ARH) neurons and anteroventral periventricular and periventricular nucleus (Kiss1AVPV/PeN) neurons in rodents, both of which excite GnRH neurons via kisspeptin release but are differentially regulated by ovarian steroids. Estradiol (E2) increases the expression of kisspeptin in Kiss1AVPV/PeN neurons but decreases its expression in Kiss1ARH neurons. Also, Kiss1ARH neurons coexpress glutamate and Kiss1AVPV/PeN neurons coexpress gamma aminobutyric acid (GABA), both of which are upregulated by E2 in females. Also, Kiss1ARH neurons express critical metabolic hormone receptors, and these neurons are excited by insulin and leptin during the fed state. Moreover, Kiss1ARH neurons project to and excite the anorexigenic proopiomelanocortin neurons but inhibit the orexigenic neuropeptide Y/Agouti-related peptide neurons, highlighting their role in regulating feeding behavior. Kiss1ARH and Kiss1AVPV/PeN neurons also project to the preautonomic paraventricular nucleus (satiety) neurons and the dorsomedial nucleus (energy expenditure) neurons to differentially regulate their function via glutamate and GABA release, respectively. Therefore, this review will address not only how Kiss1 neurons govern GnRH release, but how they control other homeostatic functions through their peptidergic, glutamatergic and GABAergic synaptic connections, providing further evidence that Kiss1 neurons are the key neurons coordinating energy states with reproduction.


Challenges in structural approaches to cell modeling.
Computational modeling is essential for structural characterization of biomolecular mechanisms across the broad spectrum of scales. Adequate understanding of biomolecular mechanisms inherently involves our ability to model them. Structural modeling of individual biomolecules and their interactions has been rapidly progressing. However, in terms of the broader picture, the focus is shifting toward larger systems, up to the level of a cell. Such modeling involves a more dynamic and realistic representation of the interactomes in vivo, in a crowded cellular environment, as well as membranes and membrane proteins, and other cellular components. Structural modeling of a cell complements computational approaches to cellular mechanisms based on differential equations, graph models, and other techniques to model biological networks, imaging data, etc. Structural modeling along with other computational and experimental approaches will provide a fundamental understanding of life at the molecular level and lead to important applications to biology and medicine. A cross section of diverse approaches presented in this review illustrates the developing shift from the structural modeling of individual molecules to that of cell biology. Studies in several related areas are covered: biological networks; automated construction of three-dimensional cell models using experimental data; modeling of protein complexes; prediction of non-specific and transient protein interactions; thermodynamic and kinetic effects of crowding; cellular membrane modeling; and modeling of chromosomes. The review presents an expert opinion on the current state-of-the-art in these various aspects of structural modeling in cellular biology, and the prospects of future developments in this emerging field.


Facile fabrication of hierarchically nanostructured gold electrode for bio-electrochemical applications.
Nanoporous gold (NPG) is one of the most extensively investigated nanomaterials owing to its tunable pore size, ease of surface modification, and range of applications from catalysis, actuation, and molecular release to the development of electrochemical sensors. In an effort to improve the usefulness of NPG, a simple and robust method for the fabrication of hierarchical and bimodal nanoporous gold electrodes (hb-NPG) containing both macro-and mesopores is reported using electrochemical alloying and dealloying processes to engineer a bicontinuous solid/void morphology. Scanning electron microscopy (color SEM) images depict the hierarchical pore structure created after the multistep synthesis with an ensemble of tiny pores below 100 nm in size located in ligaments spanning larger pores of several hundred nanometers. Smaller-sized pores are exploited for surface modification, and the network of larger pores aids in molecular transport. Cyclic voltammetry (CV) was used to compare the electrochemically active surface area of the hierarchical bimodal structure with that of the regular unimodal NPG with an emphasis on the critical role of both dealloying and annealing in creating the desired structure. The adsorption of different proteins was followed using UV-vis absorbance measurements of solution depletion revealing the high loading capacity of hb-NPG. The surface coverage of lipoic acid on the hb-NPG was analyzed using thermogravimetric analysis (TGA) and reductive desorption. The roughness factor determinations suggest that the fabricated hb-NPG electrode has tremendous potential for biosensor development by changing the scaling relations between volume and surface area which may lead to improved analytical performance. We have chosen to take advantage of the surface architectures of hb-NPG due to the presence of a large specific surface area for functionalization and rapid transport pathways for faster response. It is shown that the hb-NPG electrode has a higher sensitivity for the amperometric detection of glucose than does an NPG electrode of the same geometric surface area.


Lower hemoglobin levels in human immunodeficiency virus-infected patients with a positive direct antiglobulin test (DAT): relationship with DAT strength and clinical stages.
There are conflicting opinions regarding the effect of positive direct antiglobulin test (DAT) on hemoglobin (Hb) levels in human immunodeficiency virus-infected (HIV+) patients. A total of 166 samples from HIV+ outpatients were studied. The DAT was performed with the tube test and column agglutination technology (CAT). The DAT was positive in 18.67 percent with the tube method and 33.73 percent with the CAT. Patients with DAT-positive results showed lower Hb levels than DAT-negative patients, 12.3 g per dL versus 14.3 g per dL (p = 0.0002). The univariate logistic regression enabled us to study the phenomenon better and fit the probability of having a DAT-positive result on the basis of the Hb levels. The relationship between the CAT and the tube test when washing the red blood cells (RBC) at 4 degrees C was stronger than when washing these at room temperature (phi = 0.8156; p = 0.000). The Hb levels were significantly lower in the positive DATs of Stage C (acquired immune deficiency syndrome [AIDS]) and Stage B (symptomatic non-AIDS patients), which showed decreasing Hb values for increasing agglutination strengths (p = 0.000). Anemia was related with the DAT results (odds ratio [OR], 8.005; p = 0.000) but not to the AIDS condition (OR, 1.741; p = 0.221). Our study indicates that the DAT-positive results may be specifically related to lower Hb levels in HIV+ patients. The immunologic RBC clearance could be part of the anemic multifactorial condition in HIV+ patients.


Single-visit program for cervical cancer prevention in a high-risk population.
To evaluate the feasibility of a single-visit cervical neoplasia screening and intervention program. A sample of asymptomatic, nonpregnant, indigent, adult women who had not had a Papanicolaou smear for at least 2 years (N = 126) was recruited through Spanish-language media in Orange County, California. Women who volunteered underwent a free, single-visit program combining a health questionnaire, education, an immediately read Papanicolaou smear, loop electrosurgical excision of the transformation zone for those with dysplastic cytology, and an exit questionnaire gauging satisfaction and educational impact. Main outcome measures included the frequency of cervical cancer risk factors and barriers to health care, incidence of cervical neoplasia, feasibility, short-term educational impact, and acceptability of interventions. All 126 patients had at least one cervical cancer risk factor; 101 (80.2%) reported at least one barrier to health care. One hundred sixteen (92.1%) had a normal Papanicolaou smear, and three (2.4%) with a mildly atypical smear were referred for colposcopy. Seven (5.6%) patients had a dysplastic smear and underwent same-day loop electrosurgical excision of the transformation zone without complication, with histology revealing koilocytotic atypia (two patients), cervical intraepithelial neoplasia (CIN) I (two), CIN II (two), and CIN III (one). No case of invasive cervical carcinoma was identified. The mean time from performance of Papanicolaou smear to receipt of cytologic results was 2.2 hours, and the mean total visit time was 3.6 hours. Patients found the single-visit program to be both beneficial and satisfying. This single-visit program is feasible and may overcome barriers to the diagnosis and management of cervical neoplasia in patients at high risk.


A stable linear algorithm for fitting the lognormal model to survival data.
The lognormal model can be fitted to survival data using a stable linear algorithm. When tested on 800 sets of mathematically generated data, this method proved more stable and efficient than the iterative method of maximum likelihood, which requires initial estimates of model parameters and failed to fit a substantial fraction of data sets. Though maximum likelihood yielded more consistent estimates of proportion cured, mean, and standard deviation of log(survival time), the linear normal algorithm may nevertheless prove useful for these purposes: (i) computing initial estimates of model parameters for the maximum likelihood method; (ii) fitting data sets that cannot be fit by this method; and (iii) deriving the lognormal model directly from cumulative mortality.


Regional and interspecific differences in the ligand binding properties of beta-adrenergic receptors of individual white adipose tissue depots in the sheep and rat.
The ligand binding of beta-adrenergic receptors was characterized in the omental, subcutaneous and popliteal adipose tissue depots in the sheep, and the lumbar and parametrial depots in the rat. Displacement of [125I]iodocyanopindolol ([125I]ICYP) binding to sheep adipose tissue membranes by the beta-adrenergic antagonists CGP 20712A and ICI 118,551 (beta 1- and beta 2-antagonists, respectively) suggested only a single ligand binding site predominantly beta 2 in character in all three depots, but revealed differences in affinity for these ligands between depots. Lactation increased beta-receptor ligand binding in subcutaneous and omental but not popliteal sheep adipose tissue depots, but had no effect on beta-adrenergic receptor affinities for CGP 20712A and ICI 118,551 in the three sheep adipose tissue depots studied. In rat adipocyte membranes, displacement of [125I]ICYP by CGP 20712A and ICI 118,551 was biphasic, indicating high and low affinity sites; displacement profiles differed markedly between lumbar and parametrial depots, the former having a preponderance of beta 1-like receptors and the latter a preponderance of beta 2-like receptors. The properties of the beta-adrenergic receptor binding site thus show species and depot specific differences.


The fate of internal mammary arterial implants and bypass conduits for myocardial revascularization. Experimental angiographic, histologic, and ultrastructural observations.
Experimental angiographic, histologic, and ultrastructural observations were obtained from dogs to determine the fate of internal mammary artery (IMA) implants and aorta-coronary bypass (ACB) conduits in the 3 month postoperative period. Angiographic implant patency and evidence of implants forming collaterals with the coronary circulation did not accurately reflect anatomic luminal narrowing. Subendothelial fibrocellular proliferation similar to that described in saphenous vein grafts occurred with regularity in all IMA implants and ACB conduits. The intimal changes were much more severe in the IMA implants as compared to the ACB conduits: There was 25 to 95 per cent liminal narrowing in the IMA implants, whereas the ACB conduits rarely showed greater than 25 per cent luminal narrowing. Both reduced flow and surgical trauma appeared to be influential determining factors of the intimal proliferative process, whereas devascularization alone seemed less important.


Investigations at the 'Four-Front' of Mammalian Development.
Understanding how and when cells become different during embryogenesis is a goal that is at the forefront of investigations in mammalian development. Two recent studies from the laboratories of Nicholas Plachta and Magdalena Zernicka-Goetz present evidence that cellular heterogeneities detected in four-cell mouse embryos bias the process of cell fate acquisition thereafter.


RT1-linked Ir and Is genes control the immune response to bovine insulin in the rat.
The immune response to bovine or pork insulin (BI or PI, respectively) was studied in the rat using the in vitro insulin-induced lymphocyte-proliferation assay. Results indicated that 11 inbred rat strains were divided into categories of high and low responders. Two high responders, SDJ (RT1u) and BN(RT1n) inbred rat strains, appeared to recognize different antigenic determinant(s) on the insulin molecule. The results of linkage and segregation analyses in F1, F2, backcross, and partially congenic rats showed that the Ir gene (Ir-BI), which encodes the high responsiveness in the SDJ rats, is inherited associated with RT1u, whereas the immune suppression gene (Is-BI), which encodes the low responsiveness in the WKA(RT1k) rats, is inherited together with RT1k. The Is-BI is the first major histocompatibility complex (MHC)-linked Is gene reported in the rat. The LEJ(RT1-AuBb) inbred rat strain showed a low response to BI, indicating that Ir-BI is closer to RT1-B/RT1-D region than to RT1-A.


Probiotics and their Metabolites Reduce Oxidative Stress in Middle-Aged Mice.
Aging is an irreversible physiological degradation of living organisms. Accumulated oxidative stress and dysbiosis accelerate aging. Probiotics such as Lactobacillus and Bifidobacterium and their fermented metabolites (postbiotics) have been discovered to exhibit antioxidative activities that regulate oxidative stress and protect cells from oxidative damage. We screened selected Lactobacillus and Bifidobacterium strains and their postbiotics for potential antioxidative activity by using DPPH (2,2-Diphenyl-1-picrylhydrazyl) assay. Strains with their metabolites were selected for mixed formula in experiments involving aging mice. The aged groups presented higher oxidative stress in the brain, liver, heart, and kidney than did young mice. However, treatment with probiotic strains and their postbiotics elevated antioxidative levels, especially in the high-dose probiotics plus postbiotics group. Next-generation sequencing data revealed positive microbiota alterations of Lactobacillus and Bifidobacterium and Akkermansia in the gut. Lactobacillus johnsonii and Akkermansia muciniphila exhibited effective enlargement of relative abundance. Besides, high-dose probiotics and high-dose probiotics plus postbiotics showed significant elevation in serum SCFAs, especially in butyrate. In conclusion, the formula containing Bifidobacterium animalis subsp. infantis BLI-02, Bifidobacterium breve Bv889, Bifidobacterium bifidum VDD088, B. animalis subsp. lactis CP-9, and Lactobacillus plantarum PL-02 and their metabolites may benefit aged people's health.


Robert Malenka.
In an interview with Neuron, Robert Malenka shares his favorite discovery moments and discusses his philosophy for running a lab, the influence of his clinical training, and his broad interests, ranging from basic synaptic physiology to circuits mediating reward, aversion, and prosocial behaviors.


A novel monoclonal antibody against human Argonaute proteins reveals unexpected characteristics of miRNAs in human blood cells.
Argonaute (Ago) proteins bind to microRNA (miRNAs) and short interfering RNAs (siRNAs) and form the core components of effector complexes that mediate miRNA and siRNA function. Currently, there is a paucity of reliable antibodies against mammalian Ago proteins, thus precluding studies of endogenous Ago proteins from tissues. Here we report the development of 2A8, a novel anti-Ago monoclonal antibody that recognizes human and mouse Ago proteins and efficiently immunoprecipitates miRNAs. We report the characterization of 2A8 and its use to clone miRNAs from human brain and from preparations of human polymorphonuclear leukocytes (neutrophils), which revealed a prevalent miRNA with unusual features.


Does membrane feeding compromise the quality of Aedes aegypti mosquitoes?
Modified Aedes aegypti mosquitoes are being mass-reared for release in disease control programs around the world. Releases involving female mosquitoes rely on them being able to seek and feed on human hosts. To facilitate the mass-production of mosquitoes for releases, females are often provided blood through artificial membrane feeders. When reared across generations there is a risk that mosquitoes will adapt to feeding on membranes and lose their ability to feed on human hosts. To test adaptation to membrane feeding, we selected replicate populations of Ae. aegypti for feeding on either human arms or membrane feeders for at least 8 generations. Membrane-selected populations suffered fitness costs, likely due to inbreeding depression arising from bottlenecks. Membrane-selected females had higher feeding rates on membranes than human-selected ones, suggesting adaptation to membrane feeding, but they maintained their attraction to host cues and feeding ability on humans despite a lack of selection for these traits. Host-seeking ability in small laboratory cages did not differ between populations selected on the two blood sources, but membrane-selected females were compromised in a semi-field enclosure where host-seeking was tested over a longer distance. Our findings suggest that Ae. aegypti may adapt to feeding on blood provided artificially, but this will not substantially compromise field performance or affect experimental assessments of mosquito fitness. However, large population sizes (thousands of individuals) during mass rearing with membrane feeders should be maintained to avoid bottlenecks which lead to inbreeding depression.


Determinants of mismatch in acute ischaemic stroke.
Multimodal CT or MR imaging may be helpful in guiding reperfusion therapy for stroke. However, access to multimodal imaging may frequently be limited. We hypothesised that certain clinical and non-enhanced CT (NECT) findings at initial assessment can potentially predict mismatch on CT perfusion (CTP) in patients with acute ischaemic stroke. We undertook an analysis of prospectively collected clinical and imaging data of consecutive patients with anterior circulation ischaemic stroke who underwent CTP during their initial assessment. NECT was read for early ischaemic change as measured by the Alberta Stroke Program Early CT Score (ASPECTS), and for hyperdense middle cerebral artery sign (HMCAS). CTP images were evaluated for mismatch. Independent clinical and imaging predictors of a CTP mismatch were identified using stepwise logistic regression. Of the 202 patients, 92 (46%) demonstrated a mismatch, 23 (11%) a matched deficit, and 87 (43%) no perfusion deficit. HMCAS on NECT (OR 13.65, 95% CI 6.04-30.81, p<0.001), female gender (OR 2.37, 95% CI 1.19-4.72, p = 0.015), atrial fibrillation (OR 2.05, 95% CI 1.02-4.11, p = 0.044), and absence of a history of hypertension (OR 0.46, 95% CI 0.22-0.96, p = 0.037) were independent predictors of a CTP mismatch. HMCAS had 58% sensitivity, 91% specificity, 84% positive predictive value and 72% negative predictive value. A HMCAS on the initial NECT is associated with a high probability of mismatch in acute ischaemic stroke, and may identify patients most likely to benefit from recanalisation treatments when access to multimodal CT or MR facilities is limited.


Two-dimensional echocardiographic mitral valve prolapse: evidence for a relationship of echocardiographic morphology to clinical findings and to mitral annular size.
Fifty adult patients with two-dimensional echocardiograms (2DE) meeting standard diagnostic criteria for mitral valve prolapse (MVP) were studied to evaluate the significance of a positive 2DE by using a new morphologic grading system, a simplified method for annular measurement, and clinical data. Patients with mild (grade I) 2DE MVP differed significantly from those with moderate (grade II) to severe (grade III) 2DE MVP. Mild prolapse patients were predominantly female (p = 0.05) and younger (p less than 0.01). Atypical physical findings were associated with mild MVP while mitral insufficiency murmurs were associated with moderate to severe MVP (p less than 0.0025). When present, atypical chest pain and/or low-grade ventricular ectopy were associated with mild 2DE MVP, while pulmonary congestion, high-grade ectopy, and/or endocarditis were associated with moderate to severe 2DE MVP (p less than 0.001). Symptomatic moderate to severe 2DE MVP patients tended to have large annular dimensions. Additional echocardiographic characteristics of mild 2DE MVP included insensitivity of the parasternal long-axis 2DE view in its detection (p = 0.00002), predominance of anterior leaflet involvement in the apical 2DE view (p = 0.01), and absence of significant difference from age- and sex-matched control subjects in any annular dimension. In contrast, moderate to severe 2DE MVP showed highly significant differences from age- and sex-matched control subjects and from each other in all annular dimensions. Echocardiographically mild MVP defines a subgroup which differs quantitatively and clinically from more advanced morphologic variants. The use of mild 2DE MVP as a diagnostic criterion for MVP should be qualified as being "of questionable diagnostic significance." When present, with or without corroborative auscultatory findings, it may define a subgroup of prolapse at lower risk of significant clinical events or one that represents a normal echocardiographic variant. New grading and annular measurement methodologies provide additional tools for 2DE analysis of MVP with potentially important clinical and prognostic implications.


Trichothecenes and zearalenone production by fusarium species isolated from Argentinean black beans.
Isolates of Fusarium species obtained from freshly harvested bean grains for human consumption collected from different Argentinean regions, were investigated for their ability to biosynthesise trichothecenes and zearalenone either on rice grains or beans. Low incidence of toxigenic fungi was observed. These mycotoxigenic species produced several toxins when grown on rice but none or little amount when cultured on beans. The results of this report suggest that contamination of Argentinean beans with Fusarium mycotoxins will not be common and therefore people would be at low mycotoxicosis risk through consumption of beans.


Long-term outcomes of endoscopic submucosal dissection and comparison to surgery for superficial esophageal squamous cancer: a systematic review and meta-analysis.
The aim of this study was to investigate the long-term outcomes of endoscopic submucosal dissection (ESD) for superficial esophageal squamous cancer. A literature search was conducted using PubMed, ProQuest and Cochrane Library databases. Primary outcomes were overall survival, disease-specific survival and recurrence-free survival at 5 years. Secondary outcomes included adverse events, recurrence and metastasis. Hazard ratios were calculated based on time to events for survival analysis, and odds radios were used to compare discrete variables. A total of 3796 patients in 21 retrospective studies, including 5 comparative studies for ESD and esophagectomy were enrolled. The invasion depth was 52.0% for M1-M2, 43.2% for M3-SM1 and 4.7% for SM2 or deeper. The 5-year survival rate was: overall survival 87.3%, disease-specific survival 97.7%, and recurrence-free survival 85.1%, respectively. Pooled local recurrence of ESD was 1.8% and metastasis was 3.3%. In terms of the comparison between ESD and esophagectomy, there was no difference in the overall survival (86.4% versus 81.8%, hazard ratio = 0.66, 95% CI = 0.39-1.11) as well as disease-specific and recurrence-free survival. In addition, ESD was associated with fewer adverse events (19.8 % versus 44.0%, odds ratio = 0.3, 95% CI = 0.23-0.39). For superficial esophageal squamous cancer, ESD may be considered as the primary treatment of for mucosal lesions, and additional treatment should be available for submucosal invasive cancers.


The tryptic peptide composition of the beta chains of hemoglobins A and B of the Domestic cat (Felis catus)
The tryptic peptides from the betaA and betaB chains of cat hemoglobins A and B have isolated and the amino acid compositions determined. Differences between the two chains were found in two peptides, betaT-1 (Glylead toSer) and betaT-14 (Asnlead toSer and Lyslead toArg). The Glylead toSer and Lysleand toArg substitutions areplaced at beta-1 and beta-144 respectively from earlier work, and the third substitution, AsnleadSer at beta-139 is suggested from this work. in addition, the presence of a blocked amino terminus in betaB has been confirmed. Tentative sequences constructed by homology with known beta-chain structures suggest the occurrence of substitutions at alpha1beta1 contacts in betaA and betaB that may be functionally significant. There are at least 18 differences in amino acid composition between cat betaA and dog beta-chains and 22 differences between cat betaA and normal adult human beta-chains.


Experimental determinations and quantum-chemical calculations of the vibrational spectra of β-ZnB4O7 and β-CaB4O7.
The two oxoborates β-ZnB4O7 and β-CaB4O7 were synthesized and investigated by FTIR- and Raman spectroscopy and ab initio quantum chemical calculations. Maximum and mean deviations between experimentally determined bands and calculated modes ranged between 15-36 cm(-1) and 5-7 cm(-1), respectively, allowing band assignments to vibrational modes in most cases. The complex network structures with tetrahedral BO4 and planar OB3 groups are mirrored by the spectra and numerous vibrational modes, not assignable by standard borates classification schemes. It was confirmed that OB3 units, despite similar force constants and geometry, do not absorb in the same range as BO3 units. Bands in the high wavenumber range are rather caused by B-O-(Zn/Ca), O-B-O, B-O-B, and B-O stretching and bending vibrations. The experimental observation of inactive or Raman-active modes in the absorption spectra indicates defects or structural distortions in both compounds.


Radioimmunodetection of human pancreatic tumor xenografts using DU-PAN II monoclonal antibody.
The potential of DU-PAN II, monoclonal antibody (IgM), which was raised against the human tumor cell line, was evaluated for radioimmunodetection of human pancreatic tumors (PAN-5-JCK and EXP-58) grown in nude mice. 125I-labeled DU-PAN II was accumulated into PAN-5-JCK producing DU-PAN II antigen with a tumor-to-blood ratio of 2.72 +/- 3.00, but it did not localize in EXP-58 because of insufficient DU-PAN II. There was no significant uptake of 125I-nonimmunized IgM in PAN-5-JCK. These facts indicated the specific tumor uptake of DU-PAN II. Excellent images of the tumor PAN-5-JCK were obtained 3 days after the injection of 125I-DU-PAN II. Gel chromatography was also investigated with respect to the plasma taken from mice injected with antibody, or incubated with antibody in vitro. The results indicate that circulating antigen affected the tumor uptake of DU-PAN II: The more the tumor grew, the higher the amount of antigen excreted into the blood, leading to the degradation of DU-PAN II before it reached the tumor sites. Consequently, the immunoscintigram of the small tumor was remarkably clear. The catabolism and the radiolysis of the labeled IgM injected are critical points in applying immunoscintigraphy.


Pharmacokinetic approach to intravenous procainamide therapy.
A pharmacokinetic approach was employed to design a dosing regimen for the i.v. use of procainamide (PA) which consisted of a loading infusion given over one hour followed by a maintenance infusion. Therapeutic serum concentrations of PA were achieved in less than 15 min, and toxic serum concentrations were avoided in 12 patients. A mean maximum serum concentration of PA of 5.78 mg/l was obtained with a loading infusion of 16.6 mg/min PA HCl. An average steady-state serum concentration of PA of 5.05 mg/l was obtained with a mean maintenance infusion of 222 mg/hour PA HCl. The total body clearance of PA in slow and fast acetylators averaged 31 and 43 l/h respectively. Use of PA in cardiac patients by i. v. infusion can be safe and effective therapy.


Clinical pharmacology of tolmetin: comparisons in rheumatoid arthritis patients and normal volunteers.
The pharmacokinetics of tolmetin sodium were studied in five patients with rheumatoid arthritis (RA) and five normal volunteers to determine whether data derived from normals could be applied to RA patients. In addition, prostaglandin E (PGE) levels in synovial fluid were compared with tolmetin levels in serum and synovial fluid. Both groups received 400 mg tolmetin every 6 hours for seven days. During a 24-hour washout period after the dose of tolmetin (400 mg) on day 8, blood and urine samples were obtained from all study participants, and synovial fluid samples from the RA patients only. The patients continued into a second 24-hour drug-free period, after which they received a single 400-mg dose of tolmetin. Blood and urine samples were again collected. No clinically or statistically significant differences in tolmetin kinetics between normal volunteers and RA patients were found. A comparison of multiple-dose and single-dose results in the patient group showed an 11 per cent increase in the tolmetin serum concentration after multiple dosing. Total PGE levels in synovial fluid remained significantly depressed in the patient group for 24 hours after the 400-mg test dose of tolmetin on day 8. These findings suggest that tolmetin serum kinetics may not be an appropriate indicator of the duration of biologic activity of tolmetin.


Bacteria in gene therapy: bactofection versus alternative gene therapy.
Recent advances in gene therapy can be attributed to improvements of gene delivery vectors. New viral and nonviral transport vehicles that considerably increase the efficiency of transfection have been prepared. However, these vectors still have many disadvantages that are difficult to overcome, thus, a new approach is needed. The approach of bacterial delivery could in the future be important for gene therapy applications. In this article we try to summarize the most important modifications that are used for the preparation of applied strains, difficulties that are related with bacterial gene delivery and the current use of bactofection in animal experiments and clinical trials. Important differences to the alternative gene therapy (AGT) are discussed. AGT resembles bacteria-mediated protein delivery, as the therapeutical proteins are produced not by host cells but by the bacteria in situ and the expression can be regulated exogenously. Although the procedure of bacterial gene delivery is far from being definitely solved, bactofection remains a promising technique for transfection in human gene therapy.


Explosive intraocular foreign bodies.
We examined two patients, each with a foreign body composed of smokeless gunpowder in the vitreous body of one eye and multiple similar foreign bodies in the eyelids, conjunctiva, and cornea. No damage to the eye was caused by the retention of these foreign bodies for over three years in one case and two years in the other. The composition of these foreign bodies appeared to be nontoxic to the eye and thus, extraction of the foreign bodies did not seem to be necessary.


The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response.
DNA repair is essential in maintaining genome integrity and defects in different steps of the process have been linked to cancer and aging. It is a long lasting question how DNA repair is spatially and temporarily organized in the highly compartmentalized nucleus and whether the diverse nuclear compartments regulate differently the efficiency of repair. Increasing evidence suggest the involvement of nuclear pore complexes in repair of double-strand breaks (DSBs) in yeast. Here, we show that the human nucleoporin 153 (NUP153) has a role in repair of DSBs and in the activation of DNA damage checkpoints. We explore the mechanism of action of NUP153 and we propose its potential as a novel therapeutic target in cancers.


COVID-19 vaccinations and mental health among U.S. adults: Individual and spillover effects.
The COVID-19 pandemic led to dramatic increases not only in physical illness, but also in mental health symptoms and disorders among U.S. adults. Although the introduction of COVID-19 vaccines dramatically lowered rates of physical illness and death, little is known about the effects of vaccines on mental health. We assessed both individual and spillover effects of COVID-19 vaccination on mental health disorders, and whether effects of individual vaccination varied based on contextual risks indicated by state infection rates and state vaccination rates. Using data from the Household Pulse Survey, we assessed 448,900 adults surveyed within approximately the first six months of the U.S. vaccine rollout (February 3 - August 2, 2021). Coarsened exact matching balanced vaccinated and non-vaccinated participants on demographic and economic characteristics. Logistic regression analyses found 7% lowered odds of depression among vaccinated individuals, but no significant difference in anxiety. Reflecting potential spillover effects, state vaccination rates predicted lowered odds of anxiety and depression (1% decrease in odds for each additional 1% of the state population vaccinated). Although state COVID-19 infection rates did not moderate effects of individual vaccination on mental health outcomes, significant interactions indicated that effects of individual vaccination on mental health were stronger in contexts of lower state vaccination rates, and links between state vaccination rates and mental health problems were stronger among unvaccinated individuals. Results suggest that COVID-19 vaccinations improved the mental health of adults in the U.S., with lower rates of self-reported mental health disorders both among vaccinated individuals themselves and among other individuals living in the same state, particularly when those individuals were not themselves vaccinated. These direct and spillover effects on mental health expand our understanding of the benefits of COVID-19 vaccination for the wellbeing of adults in the U.S.


Europium as an inhibitor of Amyloid-β(1-42) induced membrane permeation.
Soluble Amyloid-beta (Aβ) oligomers are a source of cytotoxicity in Alzheimer's disease (AD). The toxicity of Aβ oligomers may arise from their ability to interact with and disrupt cellular membranes mediated by GM1 ganglioside receptors within these membranes. Therefore, inhibition of Aβ-membrane interactions could provide a means of preventing the toxicity associated with Aβ. Here, using Surface Plasmon field-enhanced Fluorescence Spectroscopy, we determine that the lanthanide, Europium III chloride (Eu(3+)), strongly binds to GM1 ganglioside-containing membranes and prevents the interaction with Aβ42 leading to a loss of the peptides ability to cause membrane permeation. Here we discuss the molecular mechanism by which Eu(3+) inhibits Aβ42-membrane interactions and this may lead to protection of membrane integrity against Aβ42 induced toxicity.


Positive expression of NANOG, mutant p53, and CD44 is directly associated with clinicopathological features and poor prognosis of oral squamous cell carcinoma.
In order to predict long-term prognosis and define individual treatment modalities for patients with oral squamous cell carcinoma (OSCC), more reliable tumor biomarkers are needed during the pretreatment workup period. The present study aimed to identify more reliable immunohistochemical tumor prognostic markers in the pretreatment biopsy specimens of patients with OSCC. We selected 57 patients who were diagnosed with primary OSCC through histopathological analysis. Pretreatment biopsy specimens were immunohistochemically analyzed for the transcription factor NANOG, cancer stem cell marker CD44, and mutant tumor protein 53 (mutant p53). The immunostaining patterns were assessed for their association with the clinicopathological features of OSCC and overall survival rates. Late tumor stage, positive neck node metastasis, and high-grade differentiation were associated with significantly poorer survival rates. Enhanced expression of NANOG and mutant p53 positivity were significantly associated with clinically late-stage tumors, positive neck node metastasis, histologically high-grade tumors, and poor overall survival rates. OSCCs with strong co-detection of NANOG and mutant p53 were linked to significantly lower survival rates than those with both weak NANOG expression and p53 negativity. Increased expression of CD44 had a limited correlation with unfavorable clinicopathological features. High expression of NANOG and positive expression of mutant p53 in the pretreatment biopsy specimens of patients with OSCC were associated with poor survival rates and unfavorable clinicopathological features. These results demonstrate that NANOG, mutant p53, and CD44 could be used as immunohistochemical markers in the pretreatment specimens of OSCC. In particular, analysis for co-expression of NANOG and mutant p53 should be made highly available as a tool for prognosis and selecting individual treatment modalities.


Gas Chromatography-Tandem Mass Spectrometry Verification of Sulfur Mustard Exposure in Humans through the Conversion of Protein Adducts to Free Sulfur Mustard.
Exposures to sulfur mustard (HD; bis(2-chloroethyll) sulfide) are well-known to result in the formation of adducts with free aspartate and glutamate residues of plasma proteins (Lawrence, R. J., Smith, J. R., and Capacio, B. R. 2008 32, (1), 31-36). A modified version of the analytical method reported previously for the verification of HD exposure has been developed (Lawrence, R. J., Smith, J. R., and Capacio, B. R. 2008 32, (1), 31-36). The method reported herein involves the reaction of hydrochloric acid with HD-adducted plasma proteins, resulting in the simultaneous cleavage and conversion of the adduct to free HD. A water scavenger, 2,2-dimethoxypropane, was added to the mixture to increase the reaction yield. Deuterated (d8) thiodiglycol was added as an internal standard and underwent conversion to deuterated sulfur mustard. The analytes were isolated by hexane liquid-liquid extraction and subsequently analyzed by gas chromatography tandem mass spectrometry (GC-MS-MS). An interday and intraday study was performed to evaluate the accuracy and precision of the method. Individual calibration curves with quality control (QC) standards were prepared on 5 days, and a calibration curve with five sets of QCs was prepared on a single day. All results were within the acceptable limits of the validation criteria. Linearity, limit of detection, and limit of quantitation were also verified for each calibration curve. This highly sensitive (pg/mL limit of detection) method can be used for rapid analysis of a definitive marker of sulfur mustard exposure.


Cognitive attributes and aesthetic preferences in assessment and differentiation of landscapes.
The increasing pace and scale of landscape changes involve objective measurements in order to estimate the effects of changes on people's landscape preferences in a meaningful way. In the literature, some attempts have been made to provide a more conceptual base related to landscape preferences. These concepts and their indicators need to be tested empirically in different contexts and landscape types. In the present study, different items related to theoretical concepts of both aesthetic preference and cognitive rating were examined. They were combined in an in situ questionnaire, which was conducted among undergraduate students in geography during two different field excursions. Stimuli consisted of 11 landscape vistas selected during the excursions. All vistas represent rather rural landscapes but they vary with regard to relief, degree of urbanisation, and degree of agricultural land use. Statistical analysis of all data yielded significant correlations between aesthetic and cognitive ratings. However, these correlations did not appear to be very strong. When considering landscape vistas separately, the relations between all cognitive ratings seemed to vary. Further, not all cognitive aspects had an equal predicting value for aesthetic preference. Moreover, this predicting value appeared to vary between different landscape vistas. The groups of interrelated cognitive aspects could not be associated consistently with theoretical concepts. The results demonstrated the inconsistencies existing between the contents of the theoretical concepts and the indicators found within the landscape. The findings argued for the necessity to distinguish between different ratings and landscape types instead of using unitary preference measures and generalized data when studying landscape preference.


Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5-dependent activation of peroxisome proliferator-activated receptor gamma.
The Wnt pathway is critical for normal development, and mutation of specific components is seen in carcinomas of diverse origins. The role of this pathway in lung tumorigenesis has not been clearly established. Recent studies from our laboratory indicate that combined expression of the combination of Wnt 7a and Frizzled 9 (Fzd 9) in Non-small Cell Lung Cancer (NSCLC) cell lines inhibits transformed growth. We have also shown that increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits transformed growth of NSCLC and promotes epithelial differentiation of these cells. The goal of this study was to determine whether the effects of Wnt 7a/Fzd 9 were mediated through PPARgamma. We found that Wnt 7a and Fzd 9 expression led to increased PPARgamma activity. This effect was not mediated by altered expression of the protein. Wnt 7a and Fzd 9 expression resulted in activation of ERK5, which was required for PPARgamma activation in NSCLC. SR 202, a known PPARgamma inhibitor, blocked the increase in PPARgamma activity and restored anchorage-independent growth in NSCLC expressing Wnt 7a and Fzd 9. SR 202 also reversed the increase in E-cadherin expression mediated by Wnt 7a and Fzd 9. These data suggest that ERK5-dependent activation of PPARgamma represents a major effector pathway mediating the anti-tumorigenic effects of Wnt 7a and Fzd 9 in NSCLC.


A comparative scanning electron microscopy study between the effect of an ultrasonic scaler, reciprocating handpiece, and combined approach on the root surface topography in subgingival debridement.
This study aimed to analyze the effectiveness of root-shape inserts mounted on a reciprocating handpiece during the procedure of root surface debridement (RSD) on extracted teeth. Three different approaches were compared: ultrasonic scaling, employment of root-shape inserts mounted on a reciprocating handpiece, and a combination of both. A total of 51 extracted teeth were divided into three groups. The first group was instrumented with an ultrasonic scaler, the second group with flexible root-shape inserts mounted on a reciprocating handpiece (grain size 40, 15, and 4 μm), whereas the final group underwent a combination of both approaches. The time required for the instrumentation was taken. The specimens were subjected to optical and scanning electron microscopy (SEM), and the photographs were evaluated by three examiners who were blinded to the study. The parameters included were: SEM roughness index (SRI) for the roughness calculation, remaining calculus Index (RCI) to evaluate the residual calculus deposits, and loss of tooth substance index (LTSI) to evaluate the loss of tooth substance caused by instrumentation. The results revealed that the time taken for the instrumentation was on average longer when the root-shape inserts were employed alone, meanwhile the combined approach did not show significant difference in comparison with the ultrasonic scaling. The lower average RCI was obtained with a combined approach. The use of root-shape inserts seems to cause a moderate increase in LTSI, especially in a combined approach, whereas it resulted in a better average SRI. The employment of root-shape inserts seems to be effective in the RSD for its ability to obtain a smooth and calculus-free instrumented surface, especially when used in combination with an ultrasonic scaler, and their use can so represent a valid approach to be tested in further in vivo studies.


Primary Tumor Resection Decelerates Disease Progression in an Orthotopic Mouse Model of Metastatic Prostate Cancer.
Radical prostatectomy in oligometastatic prostate cancer is a matter of intense debate. Besides avoiding local complications, it is hypothesized that primary tumor resection may result in better oncological outcomes. The aim of our study was to analyze the effect of primary tumor resection on disease progression in an orthotopic prostate cancer mouse model. First, the optimal time point for primary tumor resection, when metastases have already occurred, but the primary tumor is still resectable, was determined as 8 weeks after inoculation of 5 × 105 LuCaP136 cells. In a second in vivo experiment, 64 mice with metastatic prostate cancer were randomized into two groups, primary tumor resection or sham operation, and disease progression was followed up for 10 weeks. The technique of orthotopic primary tumor resection was successfully established. Compared with the sham operation group, mice with primary tumor resection showed a significantly longer survival (p < 0.001), a significantly slower PSA increase (p < 0.01), and a lower number of lung metastases (p = 0.073). In conclusion, primary tumor resection resulted in slower disease progression and longer survival in an orthotopic mouse model of metastatic prostate cancer. In future studies, this model will be used to unravel the molecular mechanisms of primary tumor/metastasis interaction in prostate cancer.


Effects of tryptophan deficiency on prepulse inhibition of the acoustic startle in rats.
Serotonin (5-HT) plays a key role in the pathophysiology of psychotic disorders, presumably through a modulation of dopamine (DA) transmission. Reduction of 5-HT signaling has been suggested to enhance dopaminergic responses in animal models of psychosis. An intriguing naturalistic strategy to reduce 5-HT brain content is afforded by the dietary restriction to its precursor, l-tryptophan (TRP). We investigated the impact of a TRP-deficient diet in rats on the prepulse inhibition of the startle (PPI), a measure of sensorimotor gating which is typically impaired by psychotomimetic substances. After either short-term (6 h) or long-term (14 days) TRP deprivation, rats were tested for startle reflex and PPI. Moreover, we assessed the impact of both TRP deprivation regimens on PPI reduction induced by the psychotomimetic substance d-amphetamine (AMPH). Both TRP-deficient regimens failed to significantly affect PPI responses. However, chronic, but not short-term, TRP-deficient diet induced a significant sensitization to the effects of AMPH (1.25-2.5 mg/kg, subcutaneous). The enhanced predisposition to PPI disruption elicited by prolonged TRP deprivation was completely reversed 24 h after reinstatement of TRP in the diet, as well as pretreatment with antipsychotic drugs haloperidol (0.1 mg/kg, intraperitoneal) and clozapine (5 mg/kg, intraperitoneal), which exert their therapeutic action mostly through blockade of DA D(2) receptors. The present results confirm and extend previous findings on the impact of serotonergic signaling in the modulation of DA transmission in schizophrenia and point to chronic TRP deprivation as a potential model of environmental manipulation that may produce a sensitization to psychotic-like symptoms induced by dopaminergic activation.


Comparison of pacing electrodes of different shape and material--recommendations.
Recommendations for comparing different pacing electrodes to one another are presented. In most reported studies, such comparisons fall short of the intended goal because they are made with electrode parameters that are not constant. The suggestions presented include timetables for acute and chronic threshold measurements, conditions for measuring lead impedance, and the relationship between rheobase and chronaxy. In addition, the effects of polarization of the electrodes are discussed.


Lymphocytosis as a response biomarker of natalizumab therapeutic efficacy in multiple sclerosis.
Natalizumab is an effective therapy in relapsing-remitting multiple sclerosis (RRMS), as it reduces lymphocyte transmigration through the blood-brain barrier (BBB) and induces lymphocytosis. To analyse natalizumab-induced lymphocytosis (NIL) as a biomarker of drug efficacy. We enrolled 50 relapsing-remitting (RR) and progressive-relapsing (PR) natalizumab-treated patients who had received at least 16 infusions and had been tested for lymphocyte count 24 hours before each administration. Clinical, MRI and hematological data were collected. Patients were divided into responders and sub-optimal responders according to the experience of at least one clinical and/or instrumental relapse during the treatment. In 15 (30%) patients, an instrumental/clinical (14) or only instrumental (one) relapse occurred. We found a statistically significant difference in the mean percentage of the lymphocytes between the two groups over the first ten administrations (p=0.04). The comparison between the time-to-relapse in the groups with high and low levels of lymphocytes showed that the group with a low NIL had a greater risk of relapse (p=0.03). We suggest that NIL could be a biomarker of therapeutic efficacy in patients with RRMS treated with natalizumab, and that the risk of relapse may be higher in patients with a lower-than-expected NIL.


Development of pan-phlebovirus RT-PCR assay.
This study reports the pan-phlebovirus assay capable of detecting both sandfly/mosquito- and tick-borne phleboviruses. Sensitivity and specificity of the assay was verified using a panel of arboviruses. The RT-PCR assay is simple and sensitive, and thus well suited for screening of field samples.


Rapid liquid chromatographic determination of 5-hydroxyindoles and dihydroxyphenylacetic acid in cerebrospinal fluid of the rat.
A stainless steel guide was implanted in the anterior third ventricle of the anesthetized rat and an internal needle shorter than the guide was used to continuously collect cerebrospinal fluid (CSF) at a constant outflow of 1 microliter/min. Five microliter samples were injected directly into a liquid chromatographic column. The mobile phase was adjusted for selective separation of 5-hydroxytryptophan (5-HTP), serotonin (5-HT), dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindolacetic acid (5-HIAA). Electrochemical detection with a limit of 0.05 pmol was used, 5-HTP and 5-HT concentrations were in the 10(-8) M range in controls while DOPAC and 5-HIAA were in the 10(-7) and 10(-6) M range. Brain aromatic amino acid decarboxylase inhibition with high doses of benserazide corresponded to an increased CSF level of 5-HTP. Monoamine oxidase inhibition with tranylcypromine resulted in a diminution of DOPAC and 5-HIAA. L-Tryptophan loading associated with monoamine oxidase inhibition induced an increase in CSF level of serotonin. These pharmacologically induced changes in serotonin and dopamine metabolite levels exemplify the usefulness of these CSF determinations as indices of brain function.


Switching from enoxaparin to dabigatran etexilate: pharmacokinetics, pharmacodynamics, and safety profile.
Dabigatran etexilate is an oral, reversible, direct thrombin inhibitor licensed for the prevention of venous thromboembolism and stroke prevention in patients with atrial fibrillation. The aim of this study was to investigate whether, and to what extent, a switch from enoxparin to dabigatran etexilate affects the pharmacokinetic (PK) and pharmacodynamic (PD) parameters and safety profile of dabigatran. Enoxaparin 40 mg was administered subcutaneously once daily for 3 days followed by a single dose of dabigatran etexilate 220 mg (test treatment) on day 4 in an open-label, two-way cross-over trial in healthy volunteers. Dabigatran plasma levels were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. Anticoagulant activity was measured using a number of clotting tests, including prothrombinase-induced clotting time (PiCT), activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and diluted thrombin time (dTT). PK, PD, and safety data were available for 23 subjects for each treatment. The adjusted geometric mean test/reference ratio of area under the concentration-time curve for total dabigatran was 84% (90% confidence interval 67.2-105.0%) and 86% (67.0-110.0%) for maximum plasma concentration. The PiCT test/reference ratio, which represents the activity of enoxaparin and dabigatran, was elevated by approximately 15% for peak maximum effect ratio to baseline and total area under the effect curve (AUEC₀₋₄₈) activity, suggesting that some anticoagulant activity of enoxaparin was still present. Enoxaparin pre-treatment increased the AUEC₀₋₄₈ of activated partial thromboplastin time by approximately 14%. All other dabigatran-related PD markers were unaffected. Tolerability was good, with only mild and reversible adverse events during the treatment. Prior administration of enoxaparin did not meaningfully affect the PK or PD properties of dabigatran, and the switch from enoxaparin to dabigatran etexilate was well tolerated among the study subjects. These data support the safety of switching patients from enoxaparin to dabigatran etexilate.


Changes in eye blink frequency as a measure of trigeminal stimulation by exposure to limonene oxidation products, isoprene oxidation products and nitrate radicals.
To measure eye blink frequency as a measure of trigeminal stimulation of the eye. Human subjects were exposed to oxidation mixtures representative of reactive indoor pollutants and clean air, from which relative changes in blink frequencies were measured. Male subjects ( n=8) were exposed for 20 min to limonene oxidation products (LOPs), isoprene oxidation products (IOPs), nitrate radicals (NO(3)), their residual reactants, and clean air at 20% relative humidity. A baseline blink frequency was measured prior to and following each exposure (2 x 8 min). The subjects were exposed locally in the non-dominant eye and single blind in random order. Blinking was video-recorded and evaluated for full sessions of 36 min while the subjects viewed an educational film. The initial terpene concentrations were one to two orders of magnitude higher than mean indoor concentrations. The mean blink frequency increased significantly during subjects' exposure to gas-phase oxidation products at lower part-per-billion (ppb) levels of LOPs, 42% ( P<0.0001) and NO(3), 21% ( P<0.022), compared with that at baseline. Neither the residual reactants nor clean air changed the blink frequency significantly. The findings coincided with qualitative reporting of weak eye irritation symptoms. Changes in blink frequency appear to be a promising measure of trigeminal stimulation from exposure to eye irritants in ppb levels. Gaseous products of limonene and ozone, and reactive radicals may cause eye irritation indoors.


Regioselective hydroxylation and glucosylation of alpha- and beta-pinenes with cultured cells of Eucalyptus perriniana.
Cultured plant cells of Eucalyptus perriniana regioselectively hydroxylated (+)- and (-)-alpha-pinenes to the corresponding (+)- and (-)-verbenols. In addition, (+)- and (-)-verbenols were converted into mono-beta-D-glucosides. On the other hand, (+)- and (-)-beta-pinenes were transformed into (+)- and (-)-pinocarveol 3-O-beta-D-glucosides via (+)- and (-)-pinocarveols.


Portal vein ligation as an efficient method of increasing the future liver remnant volume in the surgical treatment of colorectal metastases.
To compare the volumetric increase of segments 2 and 3, segment 4, and the caudate lobe after portal vein ligation (PVL) and portal vein embolization (PVE). The small size of the remnant liver and chemotherapy-induced liver injury increase the risk of postoperative hepatic insufficiency after major hepatic resection for colorectal liver metastases. Portal vein ligation has been suggested to be less effective than embolization in inducing hypertrophy of the remnant liver. We retrospectively reviewed 48 patients with colorectal liver metastases who underwent PVL (n = 17) or PVE (n = 31) at the Istituto per la Ricerca e la Cura del Cancro or the Institut Paoli-Calmette from March 1, 2000, through August 31, 2006. To compare the volume increase of segments 2 and 3, segment 4, and of the caudate lobe in patients who have undergone PVL or PVE in preparation for a major hepatic resection. There were no deaths related to PVE or PVL. Portal vein ligation was associated with resection of synchronous colorectal cancer in 16 patients. Resection of a liver metastasis in the remnant liver was performed in 11 patients. The median estimated baseline volume of segments 2 and 3 was 17.7% in the PVL group and 17.5% in the PVE group (P = .72). After PVL or PVE, it increased to 26.9% and 24.7%, respectively (P = .95), for volumetric increases of 43.1% and 53.4%, respectively (P = .39). The volumetric increases of segment 4 and the caudate lobe were similar. Portal vein ligation is as effective as PVE in inducing hypertrophy of the remnant liver volume.


Correlations between the Recurrence Patterns and Sizes of Lateral Pelvic Lymph Nodes before and after Chemoradiotherapy in Patients with Lower Rectal Cancer.
Factors that predict rectal cancer metastasis to the lungs remain undefined. We investigated whether the lateral pelvic lymph node (LPN) sizes before and after chemoradiotherapy (CRT) correlate with lung metastasis after surgery for lower rectal cancer. Two hundred and forty patients with lower rectal cancer who received preoperative CRT and curative surgery between 2003 and 2017 were examined. Computed tomography-measured LPN sizes before and after CRT were retrospectively determined by 1 colorectal surgeon who was blinded to the patients' clinical and pathological outcomes. The 5-year cumulative lung metastasis rates were 15.2%. The mean LPN sizes in patients who developed lung metastasis were larger than those in patients who did not (pre-CRT: 8.7 vs. 6.3 mm, p = 0.003; post-CRT: 6.8 vs. 4.5 mm, p = 0.001). The cumulative lung metastasis rate in patients with large LPNs was higher than in those with small LPNs both before and after CRT. On multivariate analysis, lung metastasis was independently correlated with the LPN size only after CRT (hazard ratio [HR]: 5.58), together with the ypT stage (HR: 2.96) and the tumor location (HR: 0.38). LPN size after CRT is strongly predictive of postoperative lung metastasis in patients with lower rectal cancer.


Risks and Benefits of Pharmacological Prophylaxis for Venous Thromboembolism Prevention in Patients Undergoing Robotic Partial Nephrectomy.
We investigate the safety and efficacy of pharmacological venous thromboembolism prophylaxis in patients treated with robotic partial nephrectomy at our center. We retrospectively examined our robotic partial nephrectomy database for cases performed between 2006 and 2014. Clinical venous thromboembolism episodes within 6 months from surgery were documented. Patients were stratified according to the administration of pharmacological venous thromboembolism prophylaxis into pharmacological prophylaxis (222) and no pharmacological prophylaxis (762) groups. The groups were compared in terms of perioperative outcomes, complications and adverse hemorrhagic events defined as the administration of 2 or more units of red blood cells, the need for vascular embolization or any procedures related to blood loss. There were no differences between the pharmacological prophylaxis and no pharmacological prophylaxis groups regarding mean operation time, median warm ischemia time and estimated blood loss. The rates of venous thromboembolism events were comparable between the groups (pharmacological prophylaxis 1.8% vs no pharmacological prophylaxis 2.1%, p=0.75). Overall 90% of venous thromboembolism events occurred within the first postoperative month. In the multivariable regression analysis encompassing pharmacological prophylaxis, perioperative aspirin intake, body mass index, operation time, Charlson comorbidity index, fellowship training and tumor complexity, operation time (OR 1.06, p=0.009) and Charlson comorbidity index (OR 1.28, p <0.0001) were associated with adverse hemorrhagic events. The administration of pharmacological prophylaxis did not increase the rate of adverse hemorrhagic events. Isolated inpatient administration of pharmacological prophylaxis after robotic partial nephrectomy does not appear to protect against venous thromboembolism postoperatively in that the majority of venous thromboembolism events occurred within the first 30 days after surgery. Longer duration of pharmacological prophylaxis for the prevention of venous thromboembolism after robotic partial nephrectomy should be considered.


Numerosity estimates for attended and unattended items in visual search.
The goal of this research was to examine memories created for the number of items during a visual search task. Participants performed a visual search task for a target defined by a single feature (Experiment 1A), by a conjunction of features (Experiment 1B), or by a specific spatial configuration of features (Experiment 1C). On some trials following the search task, subjects were asked to recall the total number of items in the previous display. In all search types, participants underestimated the total number of items, but the severity of the underestimation varied depending on the efficiency of the search. In three follow-up studies (Experiments 2A, 2B, and 2C) using the same visual stimuli, the participants' only task was to estimate the number of items on each screen. Participants still underestimated the numerosity of the items, although the degree of underestimation was smaller than in the search tasks and did not depend on the type of visual stimuli. In Experiment 3, participants were asked to recall the number of items in a display only once. Subjects still displayed a tendency to underestimate, indicating that the underestimation effects seen in Experiments 1A-1C were not attributable to knowledge of the estimation task. The degree of underestimation depends on the efficiency of the search task, with more severe underestimation in efficient search tasks. This suggests that the lower attentional demands of very efficient searches leads to less encoding of numerosity of the distractor set.


Involvement of splenic iron accumulation in the development of nonalcoholic steatohepatitis in Tsumura Suzuki Obese Diabetes mice.
Nonalcoholic steatohepatitis (NASH) is a common hepatic manifestation of metabolic syndrome and can lead to hepatic cirrhosis and cancer. It is considered that NASH is caused by multiple parallel events, including abnormal lipid metabolism, gut-derived-endotoxin-induced inflammation, and adipocytokines derived from adipose tissue, suggesting that other tissues are involved in NASH development. Previous studies demonstrated that spleen enlargement is observed during the course of NASH pathogenesis. However, the involvement of splenic status in the progression of NASH remains unclear. In this study, we examined hepatic and splenic histopathological findings in the early stage of NASH using the Tsumura Suzuki Obese Diabetes (TSOD) mouse model established for assessing NASH. We found that 12-week-old TSOD mice clearly exhibited the histopathological features of NASH in the early stage. At this age, the spleen of TSOD mice showed markedly higher iron level than that of control Tsumura Suzuki Non Obesity (TSNO) mice. The level of accumulated iron was significantly decreased by feeding a diet with glucosyl hesperidin, a bioactive flavonoid, accompanied with alleviation of hepatic lesions. Furthermore, we found that splenic iron level was positively correlated with the severity of NASH manifestations, suggesting that abnormalities in the spleen are involved in the development of NASH.


Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study.
Comorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural mechanisms underlying comorbidity. We investigate if the effects of comorbid internalizing and externalizing disorders on anatomical differences represent a simple aggregate of the effects on each disorder and if these comorbidity-associated cortical surface differences relate to a distinct genetic underpinning. We studied the cortical surface area (SA) and thickness (CT) of 11,878 preadolescents (9-10 years) from the Adolescent Brain and Cognitive Development Study. Linear mixed models were implemented in comparative and association analyses among internalizing (dysthymia, major depressive disorder, disruptive mood dysregulation disorder, agoraphobia, panic disorder, specific phobia, separation anxiety disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder), externalizing (attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder) diagnostic groups, a group with comorbidity of the two and a healthy control group. Genome-wide association analysis (GWAS) and cell type specificity analysis were performed on 4468 unrelated European participants from this cohort. Smaller cortical surface area but higher thickness was noted across patient groups when compared to controls. Children with comorbid internalizing and externalizing disorders had more pronounced areal reduction than those without comorbidity, indicating an additive burden. In contrast, cortical thickness had a non-linear effect with comorbidity: the comorbid group had no significant CT differences, while those patient groups without comorbidity had significantly higher thickness compare to healthy controls. Distinct biological pathways were implicated in regional SA and CT differences. Specifically, CT differences were associated with immune-related processes implicating astrocytes and oligodendrocytes, while SA-related differences related mainly to inhibitory neurons. The emergence of comorbidity across distinct clusters of psychopathology is unlikely to be due to a simple additive neurobiological effect alone. Distinct developmental risk moderated by immune-related adaptation processes, with unique genetic and cell-specific factors, may contribute to underlying SA and CT differences. Children with the highest risk but lowest resilience, both captured in their developmental morphometry, may develop a comorbid illness pattern.


Intraocular lens power calculation in eyes with previous hyperopic laser in situ keratomileusis.
To establish a corneal correction equation for the Shammas post-hyperopic laser in situ keratomileusis (LASIK) (Shammas-PHL) formula and to evaluate its accuracy in cases with and without available pre-LASIK data. Private practices, Lynwood, California, and Mesa, Arizona, USA. Retrospective comparative observational study. The corrected corneal power (Kc) was calculated in each eye by adding the refractive change at the corneal level to the pre-LASIK keratometric (K) readings. By comparing Kc with the measured post-LASIK K readings (Kpost), the following equation was derived: Kc = 1.0457 Kpost-1.9538. This equation was combined with the Shammas original formula to obtain the Shammas-PHL formula. The new formula was evaluated in 18 eyes with previous LASIK data and in 24 eyes with no previous LASIK data. Using the Shammas-PHL formula, the mean arithmetic prediction error was -0.03 diopter (D) ± 0.72 (SD) (range -1.57 to +1.54 D) and the median absolute error was 0.38 D in 18 eyes with available pre-LASIK data and 0.05 ± 0.58 D (range -0.56 to +1.40 D) and 0.43 D, respectively, in the 24 eyes with no pre-LASIK data. The Shammas-PHL formula can be used in post-hyperopic LASIK cases whether or not the pre-LASIK data are available.


The effect of rewarding hypothalamic stimulation on behavioral and neural hippocampal responses during trace eyeblink conditioning in rabbit (Oryctolagus cuniculus).
Rabbits were trace-conditioned with a tone as a conditioned stimulus and an airpuff as an unconditioned stimulus. Electrical stimulation to the medial forebrain bundle in the lateral hypothalamus was delivered either before or after the tone-airpuff pair. The purpose of the present study was to test whether the effect of post-trial hypothalamic stimulation differed from the effect of pre-trial hypothalamic stimulation on trace conditioning in the same subjects. Additionally, hippocampal responses were measured during sessions to see if hypothalamic stimulation activated dopaminergic fibres and affected hippocampal cell functioning and thus learning. The results showed that behavioral nictitating membrane conditioned responses were acquired quickly and hippocampal multiple unit activity increased with post-trial hypothalamic stimulation in comparison to almost non-existent conditioned responses and activity changes in the pre-trial hypothalamic stimulation sessions. The results suggest that hypothalamic stimulation affects trace conditioning differently depending on its time of delivery during conditioning.


What is global surgery? Identifying misconceptions among health professionals.
Global surgery has emerged as a new field within academic surgery. Despite attempts to provide a common definition, it is unclear whether health professionals understand what is meant by the term "global surgery." This study aims to characterize current understanding of global surgery among healthcare workers. One hundred medical students, residents, physicians, nurses, and allied health professionals were interviewed on their perceptions of global surgery using a six-question qualitative survey. Responses were coded and analyzed for common themes. Sixty-one percent of participants did not know the meaning of global surgery. Those under age 40 were more likely to relay an accurate definition. Of participants with knowledge of global surgery, 44% had previous exposure to global health and 85% expressed interest in global health or surgery. Although often used in academic surgical settings, the term "global surgery" is not well-understood among health professionals. There is no clear consensus on what it means to be a global surgeon or what constitutes a successful career in global surgery.


The effects of prenatal intraamniotic surfactant or dexamethasone administration on lung development are comparable to changes induced by tracheal ligation in an animal model of congenital diaphragmatic hernia: studies of lung glycogen content, elastic fiber density, and collagen content.
A new noninvasive therapeutic strategy, which consisted of prenatal intraamniotic administration of porcine surfactant or dexamethasone, was previously used to prevent the functional and structural immaturity of lungs associated with congenital diaphragmatic hernia (CDH), and its effects on lung development were comparable with the changes induced by tracheal ligation (TL). The purpose of this study is to verify if this novel therapeutic modality has any effect in the elevated concentration of lung glycogen and altered contents of lung elastic fiber and collagen promoted by CDH. A pilot study was performed to investigate in the rabbit model if the infused drugs in the amniotic cavity were aspirated by the CDH and non-CDH fetuses, and if there was correspondence between lung immaturity and high glycogen concentration in lung tissue. Experimental groups consisted of 50 pregnant rabbits that underwent surgery on gestational day 24 or 25 to create left-sided diaphragmatic hernias in 56 fetuses, which were divided in groups according to the procedures: CDH (n = 12), CDH plus TL (n = 16), CDH plus intraamniotic administration of Curosurf (40 mg, n = 12), and CDH plus intraamniotic administration of dexamethasone (n = 16). On gestational day 30, the fetuses were delivered by cesarean section, and 28 normal unoperated fetuses served as controls. The lungs were weighed and submitted to biochemical determination of glycogen, morphometric evaluation of elastic fibers, and colorimetric analysis of collagen. In all CDH and non-CDH fetuses of the pilot study, the amniotic content was massively aspirated into the lungs and trachea. There was an increase in lung glycogen content of fetuses at 24 days' gestation in comparison with 20-day gestational age fetuses, followed by a decrease in the near full-term fetuses. In the fetuses of the experimental groups, CDH decreased the lung weight to body weight ratios of lungs ipsilateral to the hernia. These changes were reversed by TL but not by intraamniotic administration of surfactant or dexamethasone. Lung glycogen concentrations in the lungs of CDH fetuses were significantly higher than those in the control group. These changes were reversed by intraamniotic administration of surfactant but not by dexamethasone administration or TL. In the lungs ipsilateral to the hernia, surfactant administration promoted a significant decrease in glycogen content to levels lower than control lungs. CDH promoted a decrease in the linear density of elastic fibers in both lungs, ipsilateral and contralateral to the hernia. This alteration was partially corrected by TL and surfactant administration, although dexamethasone administration had no effect. The concentrations of collagen in both lungs were increased significantly by CDH, and these alterations could not be reversed by TL. In the lungs ipsilateral to the hernia, intraamniotic administration of surfactant or dexamethasone promoted a significant decrease in the lung concentration of collagen but not to control levels. The positive effects of intraamniotic surfactant or dexamethasone administration on lung maturity of fetuses with CDH were observed. This therapy may be a substitute for TL.


Regional spread and control of vancomycin-resistant Enterococcus faecium and Enterococcus faecalis in Kyoto, Japan.
The purpose of this investigation was to control the post-outbreak prevalence of vancomycin-resistant enterococci (VRE) in the affected Kyoto region. The study period was from 2005 to 2010. Faecal samples were subjected to VRE screening, and vancomycin resistance genes were detected by polymerase chain reaction (PCR). The genotype was determined by pulsed-field gel electrophoresis (PFGE) of genomic DNA digested with SmaI and by multilocus sequence typing (MLST). A VRE control programme was established in 2006, consisting of a laboratory-based faecal VRE screening system, annual surveillance of hospital inpatients and the promotion of adequate infection control measures. vanA-Enterococcus faecium, vanB-E. faecium and vanB-E. faecalis were detected at 35, 12 and 5 hospitals, respectively. Genotype analysis revealed that all of the vancomycin-resistant E. faecium isolates obtained since 2005 belonged to ST78, and that clonally related vanB-E. faecalis of ST64 had spread to three hospitals. The rate of faecal VRE carriage among the patients enrolled in the annual surveillance increased until 2007, when it reached 24 (1.2%) of the 2,035 enrolled patients. The rate began to decrease in 2008 and, by 2010, reached a low of 4 (0.17%) of the 2,408 enrolled patients. While VRE did spread within the Kyoto region, the VRE control programme succeeded in controlling the overall VRE spread.


Mapping of 41 chemotaxis, flagellar and motility genes to a single region of the Sinorhizobium meliloti chromosome.
Three previously identified gene clusters that contain chemotaxis (che), flagellar (fla) and motility (mot) genes of Sinorhizobium meliloti (formerly Rhizobium meliloti) were mapped to a contiguous 45-kb region of the S. meliloti RU11/001 genome by pulsed-field gel electrophoresis (PFGE) in combination with Southern hybridization. The entire region was cloned and sequenced. The map combines 32 che, fla (flg, flh, fli) and mot genes and nine new open reading frames that probably encode taxis-related functions as well. It is concluded that between 80 and 90% of the genes responsible for chemotaxis and motility are located in a single region of the S. meliloti chromosome near the his-39 marker.


Treatment of jean-wash wastewater by combined coagulation, hydrolysis/acidification and Fenton oxidation.
Performance of a full-scale combined treatment plant for jean-wash wastewater (JWW) was investigated. The combined process consisted of chemical coagulation, hydrolysis/acidification and Fenton oxidation. Chemical coagulation treatment with polymeric ferric sulfate (PFS)/lime alone proved to be effective in removing the COD (>70%) and part of the color (>50%) from the JWW. Fenton oxidation combined with hydrolysis/acidification as pretreatment offered a noticeable BOD removal efficiency. The average removal efficiencies for COD, BOD, SS, color and aromatic compounds of the combined process were about 95%, 94%, 97%, 95% and 90%, respectively, with the average effluent quality of COD 58 mg/L, BOD 19 mg/L, SS 4 mg/L and color 15(multiple), consistent with the national discharge limits for textile wastewater. The result indicated that the combined procedure could offer an attractive solution for JWW treatment with considerable synergistic advantages.