The metabolic activation of 2-aminofluorine, 4-aminobiphenyl, and benzidine by cytochrome P-450-107S1 of Pseudomonas aeruginosa.
Pseudomonas aeruginosa is an important opportunistic pathogen of the human urinary bladder. Similar to rat liver S9, the cell-free extract from P. aeruginosa caused significant increase of histidine reversion numbers with the Salmonella typhimurium tester strain TA98 in the Ames Salmonella mutagenicity assay in the presence of either 2-aminofluorene, 4-aminobiphenyl, or benzidine procarcinogens. The presence of cytochrome P-450 protein in the cell-free extract was demonstrated by the carbon monoxide difference spectrum. We employed gene knockout technology to inactivate one of the three known putative cytochrome P-450 genes of P. aeruginosa, namely CYP107S1, which we postulated to be the most likely to induce activation. The ampicillin resistant gene from PUC19 DNA confers carbenicillin resistance to P. aeruginosa. We inserted a synthetic ampicillin gene flanked by 40 base-pairs of the 5' and 3' untranslated region of the CYP gene by electroporating the synthetic gene into electrocompetent P. aeruginosa cells. CYP107S1 knockout strains were selected on 1000 microg/ml carbenicillin plates. A single cloned carbenicillin resistant colony was isolated and used to determine its mutagenic capacity using Ames Salmonella mutagenicity assay. The results showed that Salmonella TA98 tester strain returned the number of revertants to its baselines level indicating the lack of metabolic activation of procarcinogens in the P. aeruginosa CYP107S1 knockout cell-free extract. In addition, the characteristic cytochrome P-450 peak determined by the carbon monoxide difference spectrum was completely absent in the cell-free extract from this CYP107S1 knockout strain bacterium. Homologous recombination of the synthetic ampicillin gene on the CYP 107S1 P-450 locus was confirmed by PCR on purified genomic DNA extracted from the knockout bacterium. The metabolic activation of tested procarcinogens is, therefore, carried out by CYP107S1 in P. aeruginosa.


Inhibition of cyclooxygenase-2-mediated matriptase activation contributes to the suppression of prostate cancer cell motility and metastasis.
Chronic inflammation plays an important role in cancer development and progression. Cyclooxygenases-2 (COX-2) is a key enzyme in generating prostaglandins causing inflammation, is often found to be overexpressed in prostate cancer (PCa) and is correlated with PCa cell invasion and metastasis. We aim to investigate the molecular mechanism of how COX-2 promotes PCa cell invasion and metastasis and to evaluate the effect of COX-2 inhibitors in a selected model of PCa progression. Our results showed that the expression of COX-2 and Interleukin 1β (IL-1β) was upregulated in highly invasive PCa cells and was correlated with the activated levels of membrane-anchored serine protease matriptase. The expression levels of COX-2 were increased and were correlated with matriptase levels in PCa specimens. Moreover, results showed that COX-2 overexpression or a COX-2 product Prostaglandin E2 (PGE2) caused an increase in matriptase activation and PCa cell invasion, whereas COX-2 silencing antagonized matriptase activation and cell invasion. In addition, the inhibition of COX-2-mediated matriptase activation by Celebrex and sulindac sulfide suppressed the androgen-independent and COX2-overexpressing PCa PC-3 cell invasion, tumor growth and lung metastasis in an orthotopic xenograft model. Our results indicate that COX-2/matriptase signaling contributes to the invasion, tumor growth and metastasis of COX-2-overexpressing and androgen-independent PCa cells.


Revisiting the Appendiceal Diameter via Ultrasound for the Diagnosis of Acute Appendicitis.
This study aims to investigate the optimal outer appendiceal diameter via ultrasound for the diagnosis of acute appendicitis. A retrospective chart review was conducted on patients (ages, 2-18 years) presenting to an urban pediatric emergency department between January 1, 2009 and December 31, 2010 with suspected acute appendicitis. Children were considered as having "suspected acute appendicitis" if they (1) presented with acute abdominal pain and had either a surgical consult or an abdominal ultrasound, or (2) presented or transferred with the stated suspicion of acute appendicitis. Pathology reports were used to confirm the diagnosis of appendicitis. The appendiceal diameters were determined by board-certified pediatric radiologists. A total of 320 patient charts were reviewed (females, 57%; mean age, 10.9; SD, 3.9). Seventy-two percent (N = 230) of the patients screened positive for acute appendicitis via ultrasound, 69% (N = 222) had confirmed acute appendicitis, 75% (N = 239) of the ultrasound reports included an outer appendiceal diameter. Overall, ultrasound was found to be highly sensitive (91%) and moderately specific (74%). With an outer appendiceal diameter of 6 mm as a cutoff, ultrasound had an excellent sensitivity (100%) but poor specificity (43%). With an outer diameter of 7 mm as a cutoff, sensitivity decreased to 94% but specificity increased to 71%. With increasing cutoff size, the sensitivity decreased and specificity increased. Our data suggest that the optimal outer appendiceal diameter for the diagnosis of acute appendicitis should be 7 mm instead of the currently used 6 mm.


Recursive time-varying filter banks for subband image coding.
Filter banks, subband/wavelets, and multiresolution decompositions that employ recursive filters have been considered previously and are recognized for their efficiency in partitioning the frequency spectrum. This paper presents an analysis of a new infinite impulse response (IIR) filter bank in which these computationally efficient filters may be changed adaptively in response to the input. The new filter bank framework is presented and discussed in the context of subband image coding. In the absence of quantization errors, exact reconstruction can be achieved. By the proper choice of an adaptation scheme, it is shown that recursive linear time-varying (LTV) filter banks can yield improvement over conventional ones.


Changes in Phospholipid/Ceramide Profiles and Eicosanoid Levels in the Plasma of Rats Irradiated with UV Rays and Treated Topically with Cannabidiol.
Chronic UV radiation causes oxidative stress and inflammation of skin and blood cells. Therefore, in this study, we assessed the effects of cannabidiol (CBD), a natural phytocannabinoid with antioxidant and anti-inflammatory properties, on the phospholipid (PL) and ceramide (CER) profiles in the plasma of nude rats irradiated with UVA/UVB and treated topically with CBD. The results obtained showed that UVA/UVB radiation increased the levels of phosphatidylcholines, lysophospholipids, and eicosanoids (PGE2, TxB2), while downregulation of sphingomyelins led to an increase in CER[NS] and CER[NDS]. Topical application of CBD to the skin of control rats significantly upregulated plasma ether-linked phosphatidylethanolamines (PEo) and ceramides. However, CBD administered to rats irradiated with UVA/UVB promoted further upregulation of CER and PEo and led to significant downregulation of lysophospholipids. This was accompanied by the anti-inflammatory effect of CBD, manifested by a reduction in the levels of proinflammatory PGE2 and TxB2 and a dramatic increase in the level of anti-inflammatory LPXA4. It can therefore be suggested that topical application of CBD to the skin of rats exposed to UVA/UVB radiation prevents changes in plasma phospholipid profile resulting in a reduction of inflammation by reducing the level of LPE and LPC species and increasing antioxidant capacity due to upregulation of PEo species.


Carrier mobility of MoS2 nanoribbons with edge chemical modification.
We have investigated the electronic structures and carrier mobilities of MoS2 monolayer sheets and armchair nanoribbons with chemical modification using the density functional theory combined with the Boltzmann transport method with relaxation time approximation. It is shown that the hole mobility (96.62 cm(2) V(-1) s(-1)) in monolayer sheets is about twice that of the electron mobility (43.96 cm(2) V(-1) s(-1)). The charge mobilities in MoS2 armchair nanoribbons can be regulated by edge modification owing to the changing electronic structures. In pristine armchair nanoribbons, the electron and hole mobilities are about 30 cm(2) V(-1) s(-1) and 25 cm(2) V(-1) s(-1), respectively. When the edges are terminated by H or F atoms, the hole mobility will enhance obviously even 10 times that in pristine ribbons, and the electron mobility is comparable with that in MoS2 sheets.


A five-marker panel in a multiplex PCR accurately detects microsatellite instability-high colorectal tumors without control DNA.
Microsatellite instability (MSI) testing is used to screen for Lynch syndrome. The current technique for MSI determination requires DNA from normal and neoplastic tissue and is expensive and laborious. Five quasi-monomorphic markers (NR-21, BAT-25, MONO-27, NR-24, and BAT-26) are included in the Promega MSI analysis kit. With the working hypothesis that this 5-marker panel can accurately determine the MSI status of colorectal tumors without using paired control DNA, we evaluated 478 colorectal tumors and divided them into a test group (N=172, colorectal adenocarcinomas) and a validation group (N=306 including 179 colorectal adenocarcinomas and 127 adenomas). The quasi-monomorphic variation range of each marker was generated from the test group (172 normal samples) and used as a reference value in the subsequent interpretation of MSI status in the test and validation groups. Considering the MSI result using a 5-marker panel with paired control DNA as the gold standard, we identified 136 microsatellite stable (MSS) and 36 microsatellite instability-high (MSI-H) colorectal tumors in the test group and 259 MSS and 47 MSI-H colorectal tumors in the validation group. Using the quasi-monomorphic variation range of each marker rather than paired normal DNA, the 5-marker panel identified all MSI-H colorectal tumors in the test and validation groups, when MSI-H was defined as ≥2 unstable markers. Our study demonstrates that the 5-marker panel within a multiplex polymerase chain reaction of the Promega MSI analysis kit accurately identifies all MSI-H and 95.2% MSS colorectal tumors without using paired normal DNA.


Crural tunica albuginea autograft for corporoplasty: an experimental animal study of hemodynamic, histopathological, and molecular effects in the long term.
Correction of penile deformity caused by Peyronie's disease by a variety of grafts varies in success. A long-term follow-up shows a significant number of graft scarring and erectile dysfunction. The clinical success of autologous crural tunica albuginea graft (TAG) has not resulted in wide application. To identify in healthy baboons the limitations and merits of autologous crural TAG over 1 year in a way difficult to pursue in humans. Under general anesthesia, eight sexually active adult baboons underwent pharmacological cavernosometry (CM) and cavernosography. TAG from crus was implanted in the distal penile shaft. After 6 months, six animals were reevaluated and two were sacrificed, and the penises were excised. After 1 year, the remaining six animals were evaluated and sacrificed. The TAG and underlying corpus cavernosum (CC) were examined histologically and by Western blot analysis for nitric oxide synthase (NOS), neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) isoforms, and transforming growth factor-beta1 (TGF-beta1). Sexual activity, CM, cavernosography, histopathology, and Western blot analysis. All animals resumed normal sexual activity 1 month postsurgery. Cavernous pressure was comparable before, at 6 months, and 1 year after surgery. A cavernovenous insufficiency developed in four animals at 6 months, and ceased in two at 1 year. Penile angulation (<20 degrees) was seen in three animals at 6 months, and an additional two at 1 year. Histologically, TAG was indistinguishable from the adjacent tunica with no fibrosis. In CC, iNOS and nNOS decreased at 1 year, whereas there was no change in TGF-beta1 levels. In TAG, there was no significant change in TGF-beta1 and eNOS levels, but there was a significant decrease in iNOS at 1 year. Autologous free TAG is associated with normal sexual activity, minimal hemodynamic changes, excellent histological outcome, and no rise in iNOS or TGF-beta1. However, cavernovenous insufficiency, mild penile angulation, and decreased nNOS persisted at 1 year.


Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration.
The adult mammalian heart has limited regenerative capacity, mostly attributable to postnatal cardiomyocyte cell cycle arrest. In the last 2 decades, numerous studies have explored cardiomyocyte cell cycle regulatory mechanisms to enhance myocardial regeneration after myocardial infarction. Pkm2 (Pyruvate kinase muscle isoenzyme 2) is an isoenzyme of the glycolytic enzyme pyruvate kinase. The role of Pkm2 in cardiomyocyte proliferation, heart development, and cardiac regeneration is unknown. We investigated the effect of Pkm2 in cardiomyocytes through models of loss (cardiomyocyte-specific Pkm2 deletion during cardiac development) or gain using cardiomyocyte-specific Pkm2 modified mRNA to evaluate Pkm2 function and regenerative affects after acute or chronic myocardial infarction in mice. Here, we identify Pkm2 as an important regulator of the cardiomyocyte cell cycle. We show that Pkm2 is expressed in cardiomyocytes during development and immediately after birth but not during adulthood. Loss of function studies show that cardiomyocyte-specific Pkm2 deletion during cardiac development resulted in significantly reduced cardiomyocyte cell cycle, cardiomyocyte numbers, and myocardial size. In addition, using cardiomyocyte-specific Pkm2 modified RNA, our novel cardiomyocyte-targeted strategy, after acute or chronic myocardial infarction, resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. We mechanistically show that Pkm2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and β-catenin. We demonstrate that Pkm2 is an important intrinsic regulator of the cardiomyocyte cell cycle and oxidative stress, and highlight its therapeutic potential using cardiomyocyte-specific Pkm2 modified RNA as a gene delivery platform.


In tepid defense of population health: physicians and antibiotic resistance.
Antibiotic resistance menaces the population as a dire public health threat and costly social problem. Recent proposals to combat antibiotic resistance focus to a large degree on supply side approaches. Suggestions include tinkering with patent rights so that pharmaceutical companies have greater incentives to discover novel antibiotics as well as to resist overselling their newer drugs already on market. This Article argues that a primarily supply side emphasis unfortunately detracts attention from physicians' important demand side influences. Physicians have a vital and unavoidably necessary role to play in ensuring socially optimal access to antibiotics. Dismayingly, physicians' management of the antibiotic supply has been poor and their defense of population health tepid at best. Acting as a prudent steward of the antibiotic supply often seems to be at odds with a physician's commonly understood fiduciary duties, ethical obligations, and professional norms, all of which traditionally emphasize the individual health paradigm as opposed to population health responsibilities. Meanwhile, physicians face limited incentives for antibiotic conservation from other sources, such as malpractice liability, regulatory standards, and reimbursement systems. While multifaceted efforts are needed to combat antibiotic resistance effectively, physician gatekeeping behavior should become a priority area of focus. This Article considers how health law and policy tools could favorably change the incentives physicians face for antibiotic conservation. A clear lesson from the managed care reform battles of the recent past is that interventions, to have the best chance of success, need to respect physician interest in clinical autonomy and individualized medicine even if, somewhat paradoxically, vigorously promoting population health perspectives. Also, physicians' legal and ethical obligations need to be reconceptualized in the antibiotic context in order to better support gatekeeping in defense of population health. The principal recommendation is for increased use of financial incentives to reward physicians for compliance with recommended guidelines on antibiotic prescribing. Although not a panacea, greater experimentation with financial incentives can provide a much needed jump-start to physician interest in antibiotic conservation and likely best address physicians' legitimate clinical autonomy concerns.


Paternal age increases the risk for autism in an Iranian population sample.
Autism is a neurodevelopmental disorder which is known to have a strong genetic component and is most likely oligogenic. However, the necessary role of environmental factors has been well documented. Prior research suggests that parental characteristics, such as age and level of education, may be associated with a risk of autism. Parental age has been shown to be associated with many disorders, such as schizophrenia, childhood cancer and fetal death. However, results from studies of parental age and autism are inconsistent. In the present study, we investigated the association of autism with parental age in 179 autism cases and 1611 matched cohort children from Iran. Each case was matched with nine cohort controls on parental education, sex, order of birth, consanguineous marriage, urbanism and province of residence. The Cox regression model was used to carry out conditional logistic regression on the matched data. There was a significant association between higher paternal age, but not maternal age, and an increasing risk of autism. An analysis of the combined effect of parental age and education also revealed that parents with higher education had an increased risk of having autistic children, with a dose-response effect of parental age. This study, which is the first epidemiological study of autism in Iran, provides evidence of the association of paternal age and risk of autism.


Effects of antihypertensive treatment on the cerebral microvasculature of spontaneously hypertensive rats.
Experiments were performed in anesthetized 18-19-week-old spontaneously hypertensive rats (SHR) to evaluate the effects of delayed antihypertensive treatment on cerebrovascular function. Animals were treated for 25 +/- 1 days with an oral antihypertensive regimen consisting of hydralazine, reserpine, and chlorothiazide, resulting in normotension within 2 weeks. Cerebral arterioles were examined via a constantly suffused open cranial window and video microscopy. Resting cerebral blood flow was measured using radioactive microspheres and the reference organ method. While untreated SHR exhibited reductions in arteriolar diameter compared with normotensive Wistar Kyoto rats (WKY), treatment restored arteriolar dimensions to normal. Increments in microvascular wall area, associated with medial hypertrophy in untreated SHR, were completely reversed in treated SHR to a magnitude not different from control. Resting cerebral blood flow was, however, decreased in treated SHR compared with both untreated SHR and WKY; this was due to an increase in total cerebrovascular resistance compared with WKY. Additionally, microvascular pressure in the largest arterioles in treated SHR was reduced compared with both WKY and untreated SHR. There was a significant increase in the relative pressure drop accounted for by the arterial vessels upstream from the cerebral microcirculation in treated SHR. These results suggest that 1) cerebral microvascular abnormalities induced by chronic hypertension are reversed by delayed antihypertensive therapy, and 2) there is a persistent elevation in cerebrovascular resistance upstream from the microcirculation representing large vessel adaptations that may not be readily reversible with treatment.


The Relation between Trait Mindfulness and Early Maladaptive Schemas in Men Seeking Substance Use Treatment.
Recent research has examined the relation between mindfulness and substance use, demonstrating that lower trait mindfulness is associated with increased substance use, and that mindfulness-based interventions help to reduce substance use. Research has also demonstrated that early maladaptive schemas are prevalent among individuals seeking substance use treatment and that targeting early maladaptive schemas in treatment may improve outcomes. However, no known research has examined the relation between mindfulness and early maladaptive schemas despite theoretical and empirical reasons to suspect their association. Therefore, the current study examined the relation between trait mindfulness and early maladaptive schemas among adult men seeking residential substance abuse treatment (N = 82). Findings demonstrated strong negative associations between trait mindfulness and 15 of the 18 early maladaptive schemas. Moreover, men endorsing multiple early maladaptive schemas reported lower trait mindfulness than men with fewer early maladaptive schemas. The implications of these findings for future research and treatment are discussed.


Directed anisotropy in bis(acetato-kappa2O,O')diaquazinc(II) at 110 and 250 K.
The molecule of the title compound, [Zn(C(2)H(3)O(2))(2)(H(2)O)(2)], is located on a twofold axis in the crystal structure. The displacement parameters and the thermal expansion of the crystal show significant anisotropy. This is explained by the two-dimensional hydrogen-bonded structure, with only very weak interactions perpendicular to it. Besides the overall molecular motion, there are internal vibrations, which cause the Zn-O(carboxylate) bonds to fail the Hirshfeld rigid-bond test. It is shown that this can be interpreted in terms of the steric strain in the four-membered chelate ring due to the bidentate carboxylate coordination.


Micrornas in prostate cancer: an overview.
Prostate cancer is the second highest cause of cancer mortality after lung tumours. In USA it affects about 2.8 million men and the incidence increases with age in many countries. Therefore, early diagnosis is a very important step for patient clinical evaluation and for a selective and efficient therapy. The study of miRNAs' functions and molecular mechanisms has brought new knowledge in biological processes of cancer. In prostate cancer there is a deregulation of several miRNAs that may function as tumour suppressors or oncogenes. The aim of this review is to analyze the progress made to our understanding of the role of miRNA dysregulation in prostate cancer tumourigenesis.


Zinc therapy of acrodermatitis enteropathica.
The therapeutic effect of orally administered zinc was evaluated in an adult woman with acrodermatitis enteropathica. When she was off therapy and in clinical relapse the plasma zinc concentration (10 mug per 100 ml), serum alkaline phosphatase (3 1U per liter) and urine zinc excretion rate (39 mug per 24 hours) were extremely low. Di-iodohydroxyquin therapy was accompanied by a modest increase in plasma zinc concentrations. Oral zinc sulfate (220 mg three times a day or 50 mg twice a day) resulted in rapid and complete clinical remission, and in a return of plasma zinc, serum alkaline phosphatase and urinary zinc excretion to normal. These data are compatible with a severe zinc deficiency state and indicate that the inherited defect in this disease is either in or closely related to zinc metabolism. The beneficial effects of zinc therapy in this patient provide further confirmation of the efficacy of oral zinc in the treatment of acrodermatitis enteropathica.


IncobotulinumtoxinA for upper- and lower-limb spasticity in Japanese patients.
Introduction: The safety and tolerability of incobotulinumtoxinA 400 U for upper- and lower-limb post-stroke spasticity was assessed in a small cohort of Japanese patients during the open-label lead-in tolerability periods (LITP) of two phase 3 studies (CTI-153029 and CTI-153030; Japan Pharmaceutical Information Centre).Methods: Adult patients received a single incobotulinumtoxinA injection session (total dose of 400 U) in the upper (J-PURE) or lower limb (J-PLUS). Adverse events (AEs) were assessed at 1, 4, 8 and 12 weeks post-injection during the 12 week follow-up.Results: The LITP of J-PURE and J-PLUS included 11 patients each. Mild/moderate AEs were reported by 5/11 (45.5%) and 8/11 (72.7%) patients in J-PURE and J-PLUS, respectively. No serious AEs were reported. Non-serious, transient AEs of special interest reported by two patients in J-PURE comprised muscular weakness and eyelid ptosis. No patient discontinued due to AEs.Conclusion: Preliminary results in this small population suggest that incobotulinumtoxinA 400 U is well tolerated for treating upper- or lower-limb post-stroke spasticity in Japanese patients.


Genetic code evolution reveals the neutral emergence of mutational robustness, and information as an evolutionary constraint.
The standard genetic code (SGC) is central to molecular biology and its origin and evolution is a fundamental problem in evolutionary biology, the elucidation of which promises to reveal much about the origins of life. In addition, we propose that study of its origin can also reveal some fundamental and generalizable insights into mechanisms of molecular evolution, utilizing concepts from complexity theory. The first is that beneficial traits may arise by non-adaptive processes, via a process of "neutral emergence". The structure of the SGC is optimized for the property of error minimization, which reduces the deleterious impact of point mutations. Via simulation, it can be shown that genetic codes with error minimization superior to the SGC can emerge in a neutral fashion simply by a process of genetic code expansion via tRNA and aminoacyl-tRNA synthetase duplication, whereby similar amino acids are added to codons related to that of the parent amino acid. This process of neutral emergence has implications beyond that of the genetic code, as it suggests that not all beneficial traits have arisen by the direct action of natural selection; we term these "pseudaptations", and discuss a range of potential examples. Secondly, consideration of genetic code deviations (codon reassignments) reveals that these are mostly associated with a reduction in proteome size. This code malleability implies the existence of a proteomic constraint on the genetic code, proportional to the size of the proteome (P), and that its reduction in size leads to an "unfreezing" of the codon - amino acid mapping that defines the genetic code, consistent with Crick's Frozen Accident theory. The concept of a proteomic constraint may be extended to propose a general informational constraint on genetic fidelity, which may be used to explain variously, differences in mutation rates in genomes with differing proteome sizes, differences in DNA repair capacity and genome GC content between organisms, a selective pressure in the evolution of sexual reproduction, and differences in translational fidelity. Lastly, the utility of the concept of an informational constraint to other diverse fields of research is explored.


A new method for isolation of interstitial fluid from human solid tumors applied to proteomic analysis of ovarian carcinoma tissue.
Major efforts have been invested in the identification of cancer biomarkers in plasma, but the extraordinary dynamic range in protein composition, and the dilution of disease specific proteins make discovery in plasma challenging. Focus is shifting towards using proximal fluids for biomarker discovery, but methods to verify the isolated sample's origin are missing. We therefore aimed to develop a technique to search for potential candidate proteins in the proximal proteome, i.e. in the tumor interstitial fluid, since the biomarkers are likely to be excreted or derive from the tumor microenvironment. Since tumor interstitial fluid is not readily accessible, we applied a centrifugation method developed in experimental animals and asked whether interstitial fluid from human tissue could be isolated, using ovarian carcinoma as a model. Exposure of extirpated tissue to 106 g enabled tumor fluid isolation. The fluid was verified as interstitial by an isolated fluid:plasma ratio not significantly different from 1.0 for both creatinine and Na(+), two substances predominantly present in interstitial fluid. The isolated fluid had a colloid osmotic pressure 79% of that in plasma, suggesting that there was some sieving of proteins at the capillary wall. Using a proteomic approach we detected 769 proteins in the isolated interstitial fluid, sixfold higher than in patient plasma. We conclude that the isolated fluid represents undiluted interstitial fluid and thus a subproteome with high concentration of locally secreted proteins that may be detected in plasma for diagnostic, therapeutic and prognostic monitoring by targeted methods.


Heuristics for designing user-centric drug products: Lessons learned from Human Factors and Ergonomics.
Even the most effective drug product may be used improperly and thus ultimately prove ineffective if it does not meet the perceptual, motor and cognitive capacities of its target users. Currently, no comprehensive guideline for systematically designing user-centric drug products that would help prevent such limitations exists. We have compiled a list of approximate but nonetheless useful strategies-heuristics-for implementing a user-centric design of drug products and drug product portfolios. First, we present a general heuristic for user-centric design based on the framework of Human Factors and Ergonomics (HF/E). Then we demonstrate how to implement this general heuristic for older drug users (i.e., patients and caregivers aged 65 years and older) and with respect to three specific challenges (use-cases) of medication management: (A) knowing what drug product to take/administer, (B) knowing how and when to take/administer it, and (C) actually taking/administering it. The presented heuristics can be applied prospectively to include existing knowledge about user-centric design at every step during drug discovery, pharmaceutical drug development, and pre-clinical and clinical trials. After a product has been released to the market, the heuristics may guide a retrospective analysis of medication errors and barriers to product usage as a basis for iteratively optimizing both the drug product and its portfolio over their life cycle.


In vitro induction of abnormal anaphases by contaminating atmospheric dust from the City of Mexicali, Baja California, Mexico.
Mexicali dust (MD) is a mixture of particles of potassium aluminum silicates (98%) and sodium dioxide (2%) that induces pulmonary damage under experimental conditions, and is capable of inducing in vitro chromosomal alterations in exposed lymphocytes. It has been proposed as an atmospheric contaminant with pathogenic potential. Among the chromosomal alterations observed, numeric alterations were predominant. The present study was designed to evaluate the capacity of MD to induce anaphasic changes in the Balb c 3T3 cell line. Chrysotile asbestos was used as a positive control. MD was found to induce abnormal anaphases, and the percentage of abnormalities increased as the dose increased (27.41% with 20 mg/mL, 29.60% with 40 mg/mL and 37.10% with 80 mg/mL). Multipolar anaphases constituted the most frequent alteration (69.1-78.8%), followed by lagging chromosomes (18.2-29.5%) and anaphasic bridges (1.51-5.9%). The anaphasic alterations induced by MD showed differences in comparison to those observed with asbestos, especially for anaphasic bridges (10.4% vs. 1.51%, p<0.05). The capacity of MD to induce alterations reported in the process of chromosomal disjunction could explain the numeric aberrations reported previously by the authors of this paper. Therefore, these data support that MD could act as a clastogenic agent.


A simulation framework for mapping risks in clinical processes: the case of in-patient transfers.
To model how individual violations in routine clinical processes cumulatively contribute to the risk of adverse events in hospital using an agent-based simulation framework. An agent-based simulation was designed to model the cascade of common violations that contribute to the risk of adverse events in routine clinical processes. Clinicians and the information systems that support them were represented as a group of interacting agents using data from direct observations. The model was calibrated using data from 101 patient transfers observed in a hospital and results were validated for one of two scenarios (a misidentification scenario and an infection control scenario). Repeated simulations using the calibrated model were undertaken to create a distribution of possible process outcomes. The likelihood of end-of-chain risk is the main outcome measure, reported for each of the two scenarios. The simulations demonstrate end-of-chain risks of 8% and 24% for the misidentification and infection control scenarios, respectively. Over 95% of the simulations in both scenarios are unique, indicating that the in-patient transfer process diverges from prescribed work practices in a variety of ways. The simulation allowed us to model the risk of adverse events in a clinical process, by generating the variety of possible work subject to violations, a novel prospective risk analysis method. The in-patient transfer process has a high proportion of unique trajectories, implying that risk mitigation may benefit from focusing on reducing complexity rather than augmenting the process with further rule-based protocols.


Mouse pancreatic endocrine cell transcriptome defined in the embryonic Ngn3-null mouse.
To document the transcriptome of the pancreatic islet during the early and late development of the mouse pancreas and highlight the qualitative and quantitative features of gene expression that contribute to the specification, growth, and differentiation of the major endocrine cell types. A further objective was to identify endocrine cell biomarkers, targets of diabetic autoimmunity, and regulatory pathways underlying islet responses to physiological and pathological stimuli. mRNA expression profiling was performed by microarray analysis of e12.5-18.5 embryonic pancreas from neurogenin 3 (Ngn3)-null mice, a background that abrogates endocrine pancreatic differentiation. The intersection of this data with mRNA expression in isolated adult pancreatic islets and pancreatic endocrine tumor cell lines was determined to compile lists of genes that are specifically expressed in endocrine cells. The data provided insight into the transcriptional and morphogenetic factors that may play major roles in patterning and differentiation of the endocrine lineage before and during the secondary transition of endocrine development, as well as genes that control the glucose responsiveness of the beta-cells and candidate diabetes autoantigens, such as insulin, IA-2 and Slc30a8 (ZnT8). The results are presented as downloadable gene lists, available at https://www.cbil.upenn.edu/RADQuerier/php/displayStudy.php?study_id=1330, stratified by predictive scores of relative cell-type specificity. The deposited data provide a rich resource that can be used to address diverse questions related to islet developmental and cell biology and the pathogenesis of type 1 and 2 diabetes.


Clinicopathological factors and gastric cancer prognosis in the iranian population: a meta-analysis.
Gastric cancer is the most common cancer in the Iranian population. The aim of this study was to determine the effect of clinicopathological factors on prognosis by meta-analysis. A literature search was conducted using MEDLINE, EMBASE and Cochrane library and extensive literature search using the Persian databases until February 2011. Prospective follow up studies with multivariate analysis of overall survival of the patients with gastric cancer were included in this review. The data were analyzed by CMA.2. Publication bias are checked by funnel plot and data are shown as Forest plots. From a total of 63 articles, 14 retrospective studies which examined 5 prognostic factors and involving 10,500 patients were included. Tumor size (>35mm) was the main significant factor predicting an unfavorable prognosis for the patients with gastric cancer (RR=1.829 , p<0.001) followed by presence of distant metastases (RR=1.607 , p<0.001), poor differentiation (RR=1.408 , p<0.001) and male sex (RR=1.194, p<0.001). Lymph node metastases (RR=1.058, p=0.698) and moderate differentiation (RR=0.836, p=0.043) were not statistically significant as prognostic factors. This meta-analysis suggests that tumor size>35mm, poor differentiation, presence of distant metastasis and male gender are strongly associated with a poor prognosis in Iranian patients with gastric cancer.


Optimal Experience in Adult Learning: Conception and Validation of the Flow in Education Scale (EduFlow-2).
While the formulation of Mihaly Csikszentmihalyi's theory of flow, including the experience dimensions, has remained stable since its introduction in 1975, its dedicated measurement tools, research methodologies, and fields of application, have evolved considerably. Among these, education stands out as one of the most active. In recent years, researchers have examined flow in the context of other theoretical constructs such as motivation. The resulting work in the field of education has led to the development of a new model for understanding flow experience in education, specifically dedicated to adult learning. As a result of both a meticulous analysis of existing models and consideration of more recent developments, a new flow scale has thus been developed. The aim of this study is therefore twofold: to validate the new flow measurement scale dedicated to the educational environment, EduFlow-2, and to test a new theoretical model. Students taking a course (N = 6,596), some on-site and others in a MOOC, participated. Several scales were administered online at the end of the participants' course during the 2017 academic year. The factor structure of EduFlow-2 was tested using Exploratory Structural Equation Modeling. Several models were tested. The model with a second-order factor best fit the data. We tested the invariance of the flow scale measure for gender and for the type of training (MOOC/on-site). We were able to show that the flow scale is invariant of the modalities of these two variables. Results revealed good psychometric qualities for the scale, making it suitable for both on-site and distance learning. The analysis also revealed significant relationships with the classic variables of motivation, self-efficacy, learning climate, and life satisfaction. Furthermore, all four dimensions of the model were found to be adequate and consistent with the underlying theoretical arguments. In the end, this new, short flow scale and the theoretical model were demonstrated to be promising for future studies in the field of education.


[Changes in various indicators of nonspecific immunity in operators exposed to high environmental temperature].
30 degrees C temperature conditions caused no vivid changes in the non-specific immunity indices in operators. Temperature levels at 40 degrees C and 60 degrees C caused non-specific immunity marked decrease. The changes registered immediately after exposing to high temperatures were less vivid as compared to those registered three hours later. Repeated exposing to 60 degrees C 1 week later displayed more expressive shifts in the non-specific immunity indices.


Identifying and managing patients at risk of severe allergic reactions to food: Report from two iFAAM workshops.
Food allergy affects a small but important number of children and adults. Much of the morbidity associated with food allergy is driven by the fear of a severe reaction and fatalities continue to occur. Foods are the commonest cause of anaphylaxis. One of the aims of the European Union-funded Integrated Approaches to Food Allergen and Allergy Risk Management (iFAAM) project was to improve the identification and management of children and adults at risk of experiencing a severe reaction. A number of interconnected studies within the project have focused on quantifying the severity of allergic reactions; the impact of food matrix, immunological factors on severity of reactions; the impact of co-factors such as medications on the severity of reactions; utilizing single-dose challenges to understand threshold and severity of reactions; and community studies to understand the experience of patients suffering real-life allergic reactions to food. Associated studies have examined population thresholds and co-factors such as exercise and stress. This paper summarizes two workshops focused on the severity of allergic reactions to food. It outlines the related studies being undertaken in the project indicating how they are likely to impact on our ability to identify individuals at risk of severe reactions and improve their management.


Morphologic characteristics of endometriosis in the mouse model: application to toxicology.
Surgically induced endometriosis in the mouse has been described as a model to investigate the effect of environmental pollutants on the growth of endometriotic implants. The objectives of this study were to evaluate a modified surgical procedure to induce endometriosis and validate the model by comparing the effects of estrogen, 4-chlorodiphenyl ether (4-CDE) as a possible estrogenic contaminant, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a contaminant with predominantly anti-estrogenic activities, on the growth of endometrial implants. Uterine strips (1.0 x 4.0 mm2) were autotransplanted to multiple sites in the abdomen of sexually mature female B6C3F1 mice (n = 33), which were randomly assigned to the following groups: intact control (n = 4); ovariectomized (OVX, n = 9); OVX and treated with 4-CDE (n = 6); OVX and treated with 17 beta-estradiol (E2, n = 9); and OVX and treated with E2 plus TCDD (n = 5). Endometrial implants survived warm ischemia regardless of implant site and appeared as small clear spherical or ovoid fluid-filled cysts. The diameter of the endometrial cysts in the OVX animals was significantly (p < 0.0001) smaller compared with the intact animals and OVX animals replaced with E2 or 4-CDE. In contrast, TCDD treatment inhibited the growth of endometrial cysts in the presence of estrogen. We conclude that autotransplantation of uterine slices to multiple abdominal sites results in formation of endometriotic cysts that are responsive to estrogen, and that environmental contaminants possess the potential to affect the survival and growth of endometrial cysts. Therefore, we concluded that the mouse endometriosis model described in this paper has applications to investigate the possible role of environmental pollutants in the development of endometriosis.


Microbial growth in Arctic tundra soil at -2°C.
There is some evidence that microbes inhabiting permanently frozen environments are capable of cell maintenance and growth under in situ conditions. In contrast, Arctic tundra surface soils that are only frozen during the winter have exhibited CO2 respiration under frozen conditions. This could result from maintenance metabolism fuelled by recycling cell material, but does necessarily indicate growth, which requires the synthesis of new cell material. We used (13) C-glucose to trace C into membrane lipids and 5-bromo-3-deoxyuridine to monitor DNA synthesis in a laboratory microcosm study on Arctic tundra soils. Organisms were not equally active: fungi incorporated more C than any other group. Although some bacteria were growing, Gram(+) bacteria were almost completely inactive. Shrub tundra microbes were more active in early winter than tussock microbes, incorporating more C and synthesizing more DNA. In late winter, the C incorporation pattern reversed, although DNA production was similar. We demonstrated for the first time that microbes in frozen tundra soils synthesized new cell membranes and DNA, processes fundamentally associated with growth. That microbes can grow during Arctic winters may have important implications for C cycle modelling under a changing climate.


Influence of coronary artery anatomy on survival following resection of left ventricular aneurysms and chronic infarcts.
Left ventricular (LV) aneurysms were resected in 27 patients for treatment of congestive heart failure and in five patients for treatment of ventricular arrhythmia. There were eight early (25 per cent) and five late (15 per cent) deaths. Preoperative hemodynamics including analysis of left ventriculograms in the right anterior oblique position did not consistently predict survival. In contrast, coronary artery anatomy appeared to influence the mortality rate strikingly in patients with congestive heart failure. The hospital mortality rate was 6 per cent and the late mortality rate was 13 per cent for 16 patients with one-or two-vessel coronary artery disease, but with unobstructed LV lateral wall blood supply. All but one of the survivors obtained a good late result. In nine patients with two-and three-vessel coronary artery disease and obstructed LV lateral wall blood supply there were six hospital deaths and two late deaths. It is concluded that the presence or absence of occlusive disease in the arteries supplying the LV lateral wall is an important determinant of the mortality rate associated with resection of anterior apical LV aneurysms in patients with severe congestive heart failure.


Doxorubicin synergizes with 34.5ENVE to enhance antitumor efficacy against metastatic ovarian cancer.
Novel therapeutic regimens are needed to improve dismal outcomes associated with late-stage ovarian cancer. Oncolytic viruses are currently being tested in patients with ovarian cancer. Here, we tested the therapeutic efficacy of combining doxorubicin with 34.5ENVE, an oncolytic herpes simplex virus transcriptionally driven by a modified stem cell-specific nestin promoter, and encoding for antiangiogenic Vasculostatin-120 (VStat120) for use against progressive ovarian cancer. Antitumor efficacy of 34.5ENVE was assessed in ovarian cancer cell lines, mouse ascites-derived tumor cells, and primary patient ascites-derived tumor cells by standard MTT assay. The ability of conditioned medium derived from 34.5ENVE-infected ovarian cancer cells to inhibit endothelial cell migration was measured by a Transwell chamber assay. Scope of cytotoxic interactions between 34.5ENVE and doxorubicin were evaluated using Chou-Talalay synergy analysis. Viral replication, herpes simplex virus receptor expression, and apoptosis were evaluated. Efficacy of oncolytic viral therapy in combination with doxorubicin was evaluated in vivo in the murine xenograft model of human ovarian cancer. Treatment with 34.5ENVE reduced cell viability of ovarian cancer cell lines, and mouse ascites-derived and patient ascites-derived ovarian tumor cells. Conditioned media from tumor cells infected with 34.5ENVE reduced endothelial cell migration. When combined with doxorubicin, 34.5ENVE killed synergistically with a significant increase in caspase-3/7 activation, and an increase in sub-G1 population of cells. The combination of doxorubicin and 34.5ENVE significantly prolonged survival in nude mice bearing intraperitoneal ovarian cancer tumors. This study indicates significant antitumor efficacy of 34.5ENVE alone, and in combination with doxorubicin against disseminated peritoneal ovarian cancer.


Progress in the operative management of sporadic primary hyperparathyroidism over 34 years.
Progress in the diagnosis, localization of abnormal parathyroids, and intraoperative management of primary hyperparathyroidism has been observed over the past 34 years. The goal of this study is to report the outcome of patients undergoing 2 different operative approaches in a single institution, showing the evolution of surgical management of sporadic primary hyperparathyroidism (SPHPT). Parathyroidectomy was performed in 890 (827 initial, 63 reoperative) patients with SPHPT using 2 different approaches: traditional bilateral neck exploration (BNE, n = 396) or limited parathyroidectomy guided by parathormone dynamics (LPX, n = 494). Seven hundred eighteen patients (335 BNE, 383 LPX) followed > or = 6 months or identified as operative failures were studied. Operative failure is defined as hypercalcemia and high intact (1-84) parathyroid hormone molecule (iPTH) within 6 months after operation. Successful parathyroidectomy is normocalcemia for 6 months; hypercalcemia and elevated iPTH after this time is recurrent hyperparathyroidism. There were 20 (6%) of 335 operative failures in the BNE group and 11 (3%) of 383 failures in the LPX group (P = 0.04). The incidence of multiglandular disease (MGD) determined by gland size (10%) versus hormone hypersecretion (3%) was statistically different (P < 0.001). Since most of the recurrences occurred later than 30 months, the incidence of recurrent hyperparathyroidism in patients followed for longer than 2.5 years was 4% (11/287) in the BNE group (average, 11.5 years) and 3% (5/183) in the LPX group (average, 4.2 years). LPX, with its reported advantages of minimal dissection, shorter operative time, and use in ambulatory settings, compares favorably with the traditional BNE. Parathyroidectomy guided by parathormone dynamics has an improved success rate and should be considered as a standard operative approach in SPHPT.


Reduced interference from memory testing: A postretrieval monitoring account.
Initial learning can interfere with subsequent learning (proactive interference [PI]), but recent work indicates initial testing can reduce PI. Here, we tested 2 alternative hypotheses of this effect: Does testing reduce PI by constraining retrieval to the target list, or by facilitating a postretrieval monitoring process? Participants first studied 4 lists of unrelated words. The study-only group performed a distractor task following each list, whereas the tested group recalled each list. After these initial lists, both groups studied and were tested on a final list. Replicating prior work, the tested group recalled more of the final list items and had fewer prior-list intrusions than the study-only group (i.e., initial testing reduced subsequent PI). To test the 2-alternative hypotheses, Experiment 1 used a modified recall test for the final list, whereby participants were asked to recall the final list of words and also report any items from prior lists that inadvertently came to mind. Contrary to the constrained retrieval hypothesis, initial testing did not reduce the number of prior list items that came to mind, but consistent with the postretrieval monitoring hypothesis, testing increased the likelihood that the intrusions would be correctly attributed to prior lists. Experiments 2 and 3 further tested the postretrieval monitoring hypothesis by testing the final list twice. According to the hypothesis, testing all of the lists should render prior testing nondiagnostic of list membership, thereby impairing retrieval monitoring in the test group and minimizing its ability to reduce PI. This prediction was confirmed. (PsycINFO Database Record


Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART.
Many patients infected with human immunodeficiency virus type 1 (HIV-1) and receiving highly active antiretroviral therapy experience intermittent episodes of detectable viremia ("blips"), which may raise concerns about drug resistance, lead to costly repeat measurements of viral RNA, and sometimes trigger alterations in therapy. To test the hypothesis that blips represent random biological and statistical variation around mean steady-state HIV-1 RNA levels slightly below 50 copies/mL rather than biologically significant elevations in viremia. Between June 19, 2003, and February 9, 2004, patients receiving therapy underwent intensive sampling (every 2-3 days) over 3 to 4 months to define the frequency, magnitude, and duration of blips and their association with drug levels and other clinical variables. Blips were defined as HIV-1 RNA measurements greater than or equal to 50 copies/mL preceded and followed by measurements less than 50 copies/mL without a change in treatment. To determine whether blips result from or lead to drug resistance, an ultrasensitive genotyping assay was used to detect drug resistance mutations before, during, and after blips. Patients were 10 HIV-1-infected asymptomatic adults recruited by clinicians and followed up in the Moore Clinic at the Johns Hopkins Hospital. Patients had suppression of viremia to below 50 copies/mL while receiving a stable antiretroviral regimen for 6 months or longer. At each time point, plasma HIV-1 RNA levels were measured in 2 independent laboratories and drug resistance mutations were analyzed by clonal sequencing. With the intensive sampling, blips were detected in 9 of 10 patients. Statistical analysis was consistent with random assay variation around a mean viral load below 50 copies/mL. Blips were not concordant on independent testing and had a short duration (median, <3 days) and low magnitude (median, 79 copies/mL). Blip frequency was not associated with demographic, clinical, or treatment variables. Blips did not occur in relation to illness, vaccination, or directly measured antiretroviral drug concentrations. Blips were marginally associated (P = .08) with reported episodes of nonadherence. Most importantly, in approximately 1000 independent clones sequenced for both protease and reverse transcriptase, no new resistance mutations were seen before, during, or shortly after blips. Most blips in this population appear to represent random biological and statistical variation around mean HIV-1 levels below 50 copies/mL rather than clinically significant elevations in viremia.


Inter-Limb Muscle Synergies and Kinematic Analysis of Hands-and-Knees Crawling in Typically Developing Infants and Infants With Developmental Delay.
Hands-and-knees-crawling is an important motor developmental milestone and a unique window into the development of central nervous system (CNS). Mobility during crawling is regularly used in clinical assessments to identify delays in motor development. However, possible contribution from CNS impairments to motor development delay is still unknown. The aim of this study was to quantify and compare inter-limb muscle synergy and kinematics during crawling among infants at a similar developmental age, however, clinically determined to be typically developing (TD, N = 20) infants, infants at risk of developmental delay (ARDD, N = 33), or infants with confirmed developmental delay (CDD, N = 13). We hypothesized that even though all of the groups are at a similar developmental age, there would be differences in kinematic measures during crawling, and such differences would be associated with CNS impairment as measured by electromyography (EMG) features. Surface EMG of eight arm and leg muscles and the corresponding joint kinematic data were collected while participants crawled on hands and knees at their self-selected velocity. Temporal-spatial parameters and normalized Jerk-Cost (JC) function (i.e., smoothness of movement) were computed from the measured kinematics. The inter-limb muscle synergy and the number of co-activating muscles per synergy were measured using EMGs. We found that the infants with CDD demonstrated higher normalized JC values (less movement smoothness), fewer muscle synergies, and more co-activating muscles per synergy, compared to infants with TD (p < 0.05) and ARDD (p < 0.05). Furthermore, the normalized JC values were correlated (p < 0.05) with the number of co-activation muscles per synergy. Our results suggest a constrained neuromuscular control strategy due to neurological injury in infants with CDD, and such constrain may contribute to the reduced movement smoothness in infant crawling.


Dutch perfusion incident survey.
Cardiopulmonary bypass procedures remain complex, involving many potential risks. Therefore, a nationwide retrospective study was conducted to gain insight into the number of incidents and accidents in Dutch adult perfusion practice. An anonymous postal survey (85 questions about hardware, disposables, fluids and medication, air emboli, anticoagulation, practice, and safety measures) was sent to all Dutch perfusionists involved in adult cardiovascular perfusion during 2006 and 2007. To guarantee complete anonymity, respondents were asked to return the survey to a notary who discarded personal information. The net response rate was 72% and covered 23,500 perfusions. Individual respondents performed 240 ± 103 perfusions during the 2-year study period and had 13.8 ± 8.7 years of practical experience. The incident rate was 1 per 15.6 perfusions and the adverse event rate was 1 per 1,236 perfusions. The three most reported incidents were: (1) persistent inability to raise the activated coagulation time above 400s during perfusion (184 incidents); (2) an allergic or anaphylactic reaction to drugs, fluids, or blood products (114 incidents); and (3) clotting formation in the extracorporeal circuit (74 incidents). Furthermore, pre-bypass safety measures showed no statistically significant association with the reported incidents. In comparison with data from the recent literature, the reported number of incidents is high. Nevertheless, the adverse outcome rate is well matched to other published surveys. The relatively high response rate conveys the impression that the Dutch perfusionist is vigilant and willing to report incidents. Hence, a web-based Dutch perfusion incident registration system is recommended.


The role for autophagy in cancer.
Autophagy is a survival-promoting pathway that captures, degrades, and recycles intracellular proteins and organelles in lysosomes. Autophagy preserves organelle function, prevents the toxic buildup of cellular waste products, and provides substrates to sustain metabolism in starvation. Although in some contexts autophagy suppresses tumorigenesis, in most contexts autophagy facilitates tumorigenesis. Cancers can upregulate autophagy to survive microenvironmental stress and to increase growth and aggressiveness. Mechanisms by which autophagy promotes cancer include suppressing induction of the p53 tumor suppressor protein and maintaining metabolic function of mitochondria. Efforts to inhibit autophagy to improve cancer therapy have thereby attracted great interest.


re3data - Indexing the Global Research Data Repository Landscape Since 2012.
For more than ten years, re3data, a global registry of research data repositories (RDRs), has been helping scientists, funding agencies, libraries, and data centers with finding, identifying, and referencing RDRs. As the world's largest directory of RDRs, re3data currently describes over 3,000 RDRs on the basis of a comprehensive metadata schema. The service allows searching for RDRs of any type and from all disciplines, and users can filter results based on a wide range of characteristics. The re3data RDR descriptions are available as Open Data accessible through an API and are utilized by numerous Open Science services. re3data is engaged in various initiatives and projects concerning data management and is mentioned in the policies of many scientific institutions, funding organizations, and publishers. This article reflects on the ten-year experience of running re3data and discusses ten key issues related to the management of an Open Science service that caters to RDRs worldwide.


Novel polysialogangliosides of skate brain structural determination of tetra, penta and hexasialogangliosides with a NeuAc-GalNAc linkage.
The gangliosides in the brain of a cartilaginous fish, skate (Bathyraja smirnovi), have been isolated and characterized by means of methylation analysis, antibody binding, enzymatic hydrolysis and MALDI-TOF MS. In addition to gangliosides with known structures (GM2, fucosyl-GM1, GD3, GD2, GT3 and GT2), five polysialogangliosides were isolated and characterized as having the following structures. (1) IV3NeuAc, III6NeuAc, II3NeuAc-Gg4Cer; (2) IV3NeuAc2, III6NeuAc, II3NeuAc-Gg4Cer; (3) IV3NeuAc, III6NeuAc, II3NeuAc2-Gg4Cer; (4) IV3NeuAc, III6NeuAc, II3NeuAc3-Gg4Cer; and (5) IV3NeuAc2, III6NeuAc, II3NeuAc3-Gg4Cer. These structures are 'hybrid-type' which comprise combinations of alpha-series and either a, b or c-series structures. Three gangliosides (2), (4) and (5), were novel. The main features of the ganglioside composition of skate brain were an abundance of gangliotriaosyl species, a lack of gangliotetraosyl species (except fucosyl-GM1), and an abundance of hybrid-types. These characteristics closely resemble those in shark brain which we reported previously [Nakamura, K., Tamai, Y. & Kasama, T. (1997) Neurochem. Int. 30, 593-604]. Two of the hybrid-type gangliosides (1) and (4), were examined for their neuritogenic activity toward cultured neuronal cells (Neuro-2A), and were found to have more potent activity than nonhybrid-type gangliosides such as GM1.


Elaborate plumage patterning in a Cretaceous bird.
Integumentary patterns and colors can differentiate species, sexes, and life changes and can inform on habitat and ecology. However, they are rarely preserved in the fossil record. Here, we report on an extremely well-preserved specimen of the Cretaceous bird Confuciusornis with unprecedented complexity, including small spots on the wings, crest, and throat. Morphological and chemical evidence suggest that these patterns are produced by melanin, but unusual preservation prevents assignment of specific colors. Based on comparisons with extant birds, these patterns were likely used for camouflage, although other functions including sexual signaling cannot be ruled out. Our data show that even more elaborate plumage patterns than the spangles in Anchiornis and stripes in Sinosauropteryx were present at a relatively early stage of avian evolution, showing the significance of coloration and patterning to feather evolution.


Maskless fabrication of nano-fluidic channels by two-photon absorption (TPA) polymerization of SU-8 on glass substrate.
We present a simple, fast, and repeatable method for fabricating nano-fluidic channels based on two-photon absorption (TPA) polymerization. Since our method does not require any mask, it is relatively cheaper and faster than other conventional lithography techniques. We illustrate that SU-8 has pronounced photoinitiation threshold behavior, which linearly decreases as the repetition rate increases. If the pulse energy and the repetition rate are controlled, channel width can be easily controlled. We report fluidic channels up to 110 nm in width, between polymerized parallel ribs, utilizing TPA and the photoinitiation threshold properties of SU-8. Finally, we also show that high repetition rate laser presents greater controllability in size of the polymerized region by varying fluence.


A Review of Azathioprine-Associated Hepatotoxicity and Myelosuppression in Myasthenia Gravis.
Myasthenia gravis (MG) is an autoimmune disorder in which antibodies interfere with neuromuscular transmission. Azathioprine (AZA) is an immunosuppressant frequently used for treatment of various autoimmune conditions, including MG. The literature suggests that the rates of AZA-associated hepatotoxicity and myelosuppression in MG are highly variable. Published studies have not formally analyzed their pattern, severity, timing, and/or recovery. We assessed the prevalence, pattern and timing of AZA associated toxicity in a large group of MG patients. We identified 113 patients with MG with AZA-associated toxicity among 571 managed with this immunosuppressant. The timing of when toxicities occurred as well as pattern of laboratory abnormalities was assessed. The overall prevalence of hepatotoxicity and myelosuppression was 15.2% and 9.1%, respectively. The most common pattern of hepatotoxicity seen was gamma-glutamyl transpeptidase (GGT) enzyme elevation in 67.8% of patients. Of note, 21.2% of patients with myelosuppression had normocytic anemia, 17.3% had pancytopenia, and another 17.3% developed macrocytic anemia. AZA-associated hepatotoxicity and myelosuppression in MG are not uncommon and may be underrecognized depending on the timing, frequency, and specific tests ordered for blood work monitoring.


Imprecision of creatinine-based GFR estimates in uninephric kidney donors.
To ensure long-term safety of living kidney donors, it is now recommended that they be followed for at least 2 years after donation and that serum creatinine levels be monitored. Such levels are often subjected by clinical laboratories to estimating equations and are reported as estimated GFR (eGFR). The accuracy of such equations in uninephric living donors has yet to be validated. This is especially important in older living donors, who often have senescence-related depression of GFR. We compared urinary creatinine clearance, four-variable Modification of Diet in Renal Disease estimating equation (eGFR), and the recently reported CKD-EPI GFR estimating equation with true GFR measured by the urinary iothalamate clearance (iGFR) in 64 subjects after kidney donation. Creatinine clearance overestimated iGFR. Both creatinine-based estimating equations were poorly correlated with and underestimated iGFR. More than half of kidney donors had eGFR <60 ml/min per 1.73 m(2) after donation, a level that categorized them as having stage 3 chronic kidney disease by our current laboratory reporting, whereas only 25% had iGFR <60 ml/min per 1.73 m(2). This misclassification disproportionately affected older donors age > or =55 years, of whom 80% had eGFR <60 ml/min per 1.73 m(2). Neither significant albuminuria nor hypertension was observed. The current practice of reporting eGFR after donation commonly leads to a misclassification of chronic kidney disease, particularly in older donors. To ensure long-term well-being of living kidney donors, more precise estimates of GFR are required, particularly among older potential donors.


[Repeat cesarean section: a necessary procedure?].
The purpose of this study was to identify the clinical indications for the repeated cesarean section (RCS). In order to determine if the indication was an absolute or a relative one and to establish if it was justified. This is a cross sectional study of all patients with a previous cesarean delivery who underwent a RCS from January 1996 to December 1997 at the National Institute of Perinatology. Multiple pregnancies were excluded. According to the indication two groups were identified: those with an absolute indications and those with a relative one. In order to assess the differences between both groups data were analyzed through chi square test or Fisher's Exact test. During the study period there were 5,545 cesarean deliveries, 664 were RSC (11.9%). Only 641 of the RCS complied with the inclusion criteria for the study. Average maternal age was 30 years. More than half the patients under study (57.2%) did not have any pathological condition during pregnancy, and the rest (42.7%) had at least one (preeclampsia, diabetes mellitus/gestational, chronic hypertension). Indications for the previous cesarean section were absolute in 25.9% and relative in 74.1% (p = 0.0006). Indications for the RCS were also predominantly relative (70.7%), with only 29.3%) absolute (p = 0.0001). The main RCS indications were: elective (20.1%) cephalopelvic disproportion (17.8%), preeclampsia (15.4%), fetal distress (8%). Trial for vaginal delivery was undertaken in 65.4% of the absolute indications group and in 36.9% of the relative indications group (p = 0.0001). Low Apgar one minute and five minute scores were more frequent among the absolute indications group (p = 0.03 and p = 0.01 respectively). Newborns having had an absolute cesarean delivery indication entered the National Intensive Care Unit more frequently (53.6%) than those with relative indications (46.4%) (p = 0.001). The main indication for RCS in our hospital were relative, and thus it is possible to reduce the cesarean rate through a thorough assessment of all cases with a previous cesarean section, and by giving a delivery trial of all this patients.


Nurses' job satisfaction and attitudes towards people living with HIV/AIDS in Russia.
Previous studies internationally have highlighted that working with people living with HIV/AIDS may lead to nurses' stress and burnout. However, this topic has not been well explored in Russia, a country with an exponential growth in HIV/AIDS. This study focused on nurses' job satisfaction and their attitudes towards people living with HIV/AIDS in centres where nurses regularly treat such patients, and in a general hospital where nurses rarely treat such patients. We distributed three self-report questionnaires: demographics, job satisfaction and attitudes towards people living with HIV/AIDS to nurses working in six HIV/AIDS centres and the largest general hospital in Ekaterinburg, Russia. Sixty-nine nurses from the HIV/AIDS centres and 66 from the general hospital (about 90% of those approached) completed these. Nurses who regularly treated people with HIV/AIDS were significantly younger and a greater number held master degrees than those who rarely treated such patients. No significant differences between the two settings emerged for job satisfaction but what did emerge were differences in nurses' attitudes: nurses in HIV/AIDS centres reported less avoidance than nurses in the general hospital. Regarding empathetic attitudes, no significant differences emerged, but empathetic attitudes contributed to the explained variance of job satisfaction. Although our sample was small, the associations found between avoidant attitudes and job satisfaction highlight the need for stigma-reduction strategies and increased disease knowledge. Healthcare managers should consider attitudes towards people living with HIV/AIDS as an important factor in ensuring adequate care for them and initiate education programmes for nurses, especially programmes dealing with HIV/AIDS in general hospitals. Support and supervision can be used as a strategy, for empowering nurses to meet the challenges of working with HIV/AIDS patients.


Patterns in CH4 and CO2 concentrations across boreal rivers: Major drivers and implications for fluvial greenhouse emissions under climate change scenarios.
It is now widely accepted that boreal rivers and streams are regionally significant sources of carbon dioxide (CO2), yet their role as methane (CH4) emitters, as well as the sensitivity of these greenhouse gas (GHG) emissions to climate change, are still largely undefined. In this study, we explore the large-scale patterns of fluvial CO2 and CH4 partial pressure (pCO2 , pCH4) and gas exchange (k) relative to a set of key, climate-sensitive river variables across 46 streams and rivers in two distinct boreal landscapes of Northern Québec. We use the resulting models to determine the direction and magnitude of C-gas emissions from these boreal fluvial networks under scenarios of climate change. River pCO2 and pCH4 were positively correlated, although the latter was two orders of magnitude more variable. We provide evidence that in-stream metabolism strongly influences the dynamics of surface water pCO2 and pCH4 , but whereas pCO2 is not influenced by temperature in the surveyed streams and rivers, pCH4 appears to be strongly temperature-dependent. The major predictors of ambient gas concentrations and exchange were water temperature, velocity, and DOC, and the resulting models indicate that total GHG emissions (C-CO2 equivalent) from the entire network may increase between by 13 to 68% under plausible scenarios of climate change over the next 50 years. These predicted increases in fluvial GHG emissions are mostly driven by a steep increase in the contribution of CH4 (from 36 to over 50% of total CO2 -equivalents). The current role of boreal fluvial networks as major landscape sources of C is thus likely to expand, mainly driven by large increases in fluvial CH4 emissions.


The auditory perceived aperture position of the transition between rooms.
This exploratory study investigates the phenomenon of the auditory perceived aperture position (APAP): the point at which one feels they are in the boundary between two adjoined spaces, judged only using auditory senses. The APAP is likely the combined perception of multiple simultaneous auditory cue changes, such as energy, reverberation time, envelopment, decay slope shape, and the direction, amplitude, and colouration of direct and reverberant sound arrivals. A framework for a rendering-free listening test is presented and conducted in situ, avoiding possible inaccuracies from acoustic simulations, impulse response measurements, and auralisation to assess how close the APAP is to the physical aperture position under blindfold conditions, for multiple source positions and two room pairs. Results indicate that the APAP is generally within ± 1 m of the physical aperture position, though reverberation amount, listener orientation, and source position affect precision. Comparison to objective metrics suggests that the APAP generally falls within the period of greatest acoustical change. This study illustrates the non-trivial nature of acoustical room transitions and the detail required for their plausible reproduction in dynamic rendering and game audio engines.


Global Profiling of Lysine Acetylation in Borrelia burgdorferi B31 Reveals Its Role in Central Metabolism.
The post-translational modification of proteins has been shown to be extremely important in prokaryotes. Using a highly sensitive mass spectrometry-based proteomics approach, we have characterized the acetylome of B. burgdorferi. As previously reported for other bacteria, a relatively low number (5%) of the potential genome-encoded proteins of B. burgdorferi were acetylated. Of these, the vast majority were involved in central metabolism and cellular information processing (transcription, translation, etc.). Interestingly, these critical cell functions were targeted during both ML (mid-log) and S (stationary) phases of growth. However, acetylation of target proteins in ML phase was limited to single lysine residues while these same proteins were acetylated at multiple sites during S phase. To determine the acetyl donor in B. burgdorferi, we used mutants that targeted the sole acetate metabolic/anabolic pathway in B. burgdorferi (lipid I synthesis). B. burgdorferi strains B31-A3, B31-A3 ΔackA (acetyl-P- and acetyl-CoA-) and B31-A3 Δpta (acetyl-P+ and acetyl-CoA-) were grown to S phase and the acetylation profiles were analyzed. While only two proteins were acetylated in the ΔackA mutant, 140 proteins were acetylated in the Δpta mutant suggesting that acetyl-P was the primary acetyl donor in B. burgdorferi. Using specific enzymatic assays, we were able to demonstrate that hyperacetylation of proteins in S phase appeared to play a role in decreasing the enzymatic activity of at least two glycolytic proteins. Currently, we hypothesize that acetylation is used to modulate enzyme activities during different stages of growth. This strategy would allow the bacteria to post-translationally stimulate the activity of key glycolytic enzymes by deacetylation rather than expending excessive energy synthesizing new proteins. This would be an appealing, low-energy strategy for a bacterium with limited metabolic capabilities. Future work focuses on identifying potential protein deacetylase(s) to complete our understanding of this important biological process.


Dimerization between the holin and holin inhibitor of phage lambda.
Holins are integral membrane proteins that control the access of phage-encoded muralytic enzymes, or endolysins, to the cell wall by the sudden formation of an uncharacterized homo-oligomeric lesion, or hole, in the membrane, at a precisely defined time. The timing of lambda-infected cell lysis depends solely on the 107 codon S gene, which encodes two proteins, S105 and S107, which are the holin and holin inhibitor, respectively. Here we report the results of biochemical and genetic studies on the interaction between the holin and the holin inhibitor. A unique cysteine at position 51, in the middle of the second transmembrane domain, is shown to cause the formation of disulfide-linked dimers during detergent membrane extraction. Forced oxidation of membranes containing S molecules also results in the formation of covalently linked dimers. This technique is used to demonstrate efficient dimeric interactions between S105 and S107. These results, coupled with the previous finding that the timing of lysis depends on the excess of the amount of S105 over S107, suggest a model in which the inhibitor functions by titrating out the effector in a stoichiometric fashion. This provides a basis for understanding two evolutionary advantages provided by the inhibitor system, in which the production of the inhibitor not only causes a delay in the timing of lysis, allowing the assembly of more virions, but also increases effective hole formation after triggering.


A unique zinc-organic framework constructed through in situ ligand synthesis for conversion of CO2 under mild conditions and as a luminescence sensor for Cr2O72-/CrO42.
A novel zinc-organic framework, {[Zn3(tza)2(μ2-OH)2(H2O)2]·H2O}n (1) (H2tza = 1H-tetrazolate-5-acetic acid), was synthesized through an in situ generated tetrazole ligand under hydrothermal conditions. In compound 1, tza2- ligands and Zn2+ are interlinked to form 2D layers, which are further pillared through μ2-OH groups to generate a 3D framework. Thermogravimetric analysis and powder X-ray diffraction confirm that 1 has high thermal stability, pH stability and solvent stability. Catalytic studies show that 1 exhibits excellent catalytic ability for the cycloaddition of CO2 with epoxides under 50 °C and 0.1 MPa. Importantly, 1 can be reused at least six times. Furthermore, luminescence investigations indicate that 1 can serve as a recyclable luminescence sensor to efficiently detect Cr2O72-/CrO42-, and the detection limit can reach 10-6 mol L-1 and 4 × 10-6 mol L-1, respectively.


Effect of Combination Antiretroviral Therapy on HIV-1-specific Antibody-Dependent Cellular Cytotoxicity Responses in Subtype B- and Subtype C-Infected Cohorts.
There is growing interest in immune therapies to clear the latent HIV-1 after combination antiretroviral therapy (cART). There is limited information on the effect of cART on antibody-dependent cellular cytotoxicity (ADCC), and no studies have directly compared ADCC in HIV-1 subtype B- and subtype C-infected subjects. The effect of improving immunocompetence on ADCC to influenza also remains unexplored. The effect of cART on HIV-1- and influenza-specific ADCC was analyzed in 2 cohorts (39 subtype B- and 47 subtype C-infected subjects) before and after 2 years of cART. ADCC analyses included an enzyme-linked immunosorbent assay-based dimeric recombinant soluble (rs) FcγRIIIa-binding assay, antibody-dependent natural killer cell activation assay, and ADCC-mediated killing assays. HIV-1 subtype B and C Env-specific antibody binding to dimeric rsFcγRIIIa were reduced in subtypes B- and C-infected cohorts after 2 years of cART (both P < 0.05). Reduced ADCC-mediated killing of target cells expressing subtype B Env in the subtype B-infected cohort (P = 0.003) was observed after 96 weeks of cART, but not of subtype C Env in the subtype C-infected cohort. A greater reduction in ADCC was detected in subjects with baseline CD4 counts >300 cells/μL (P < 0.05). The resolving immunodeficiency after 96 weeks of cART resulted in improved HA-specific ADCC to 6 strains of influenza (all P < 0.01). cART results in HIV-1 antigen loss and reductions in HIV-1 Env-specific antibodies with Fc functionality in both subtype B- and C-infected subjects, particularly in immunocompetent subjects. Simultaneously, cART improves ADCC to diverse strains of influenza, suggesting reduction in influenza disease after cART.


Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs.
Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited. One of the reasons is the complex physicochemical properties of the heterobifunctional PROTACs. A promising strategy to improve pharmacokinetics of highly lipophilic compounds, such as PROTACs, is encapsulation in liposome systems. Here we describe liposome systems for intravenous administration to enhance the PK properties of two bivalent PROTAC molecules, by reducing clearance and increasing systemic coverage. We developed and characterized a PROTAC-in-cyclodextrin liposome system where the drug was retained in the liposome core. In PK studies at 1 mg/kg for GNE-01 the PROTAC-in-cyclodextrin liposome, compared to the solution formulation, showed a 80- and a 380-fold enhancement in AUC for mouse and rat studies, respectively. We further investigated the same PROTAC-in-cyclodextrin liposome system with the second PROTAC (GNE-02), where we monitored both lipid and drug concentrations in vivo. Similarly, in a mouse PK study of GEN-02, the PROTAC-in-cyclodextrin liposome system exhibited enhancement in plasma concentration of a 23× increase over the conventional solution formulation. Importantly, the lipid CL correlated with the drug CL. Additionally, we investigated a conventional liposome approach for GNE-02, where the PROTAC resides in the lipid bilayer. Here, a 5× increase in AUC was observed, compared to the conventional solution formulation, and the drug CL was faster than the lipid CL. These results indicate that the different liposome systems can be tailored to translate across multiple PROTAC systems to modulate and improve plasma concentrations. Optimization of the liposomes could further improve tumor concentration and improve the overall therapeutic index (TI). This delivery technology may be well suited to bring novel protein targeted PROTACs into clinics.


Capillary-tube-based oxygen/argon micro-plasma system for the inactivation of bacteria suspended in aqueous solution.
An aqueous solution containing Escherichia coli can be completely inactivated within a short treatment time using a capillary-tube-based oxygen/argon micro-plasma source. A capillary-tube-based oxygen/argon micro-plasma system with a hollow inner electrode was ignited by a 13.56 MHz radio frequency power supply with a matching network and characterised by optical emission spectroscopy. An aqueous solution containing E. coli was then treated at various the working distances, plasma exposure durations, and oxygen ratios in argon micro-plasma. The treated bacteria were then assessed and qualitatively investigated. The morphologies of treated bacteria were examined using a scanning electron microscope (SEM). In the proposed oxygen/argon micro-plasma system, the intensities of the main emission lines of the excited species, nitric oxide (NO), hydrated oxide (OH), argon (Ar), and atomic oxygen (O), fluctuated with the addition of oxygen to argon micro-plasma. Under a steady state of micro-plasma generation, the complete inactivation of E. coli in aqueous solution was achieved within 90 s of argon micro-plasma exposure time with a working distance of 3 mm. SEM micrographs reveal obvious morphological damage to the treated E. coli. The addition of oxygen to argon micro-plasma increased the variety of O-containing excited species. At a given supply power, the relative intensities of the excited species, NO and OH, correlated with the ultraviolet (UV) intensity, decreased. For the proposed capillary-tube-based micro-plasma system with a hollow inner electrode, the oxygen/argon micro-plasma source is efficient in inactivating E. coli in aqueous solution. The treatment time required for the inactivation process decreases with decreasing working distance or the increasing synthesised effect of reactive species and UV intensity.


Disseminated MRSA infection with purulent pericarditis.
The risk of developing pericarditis secondary to Methicillin-Resistant Staphylococcus aureus (MRSA) infection in the absence of preceding surgical procedure is extremely low. We present a case report of a 36-year-old woman who developed disseminated MRSA infection leading to purulent pericarditis.


Towards high-performance bioinspired composites.
Biological composites have evolved elaborate hierarchical structures to achieve outstanding mechanical properties using weak but readily available building blocks. Combining the underlying design principles of such biological materials with the rich chemistry accessible in synthetic systems may enable the creation of artificial composites with unprecedented properties and functionalities. This bioinspired approach requires identification, understanding, and quantification of natural design principles and their replication in synthetic materials, taking into account the intrinsic properties of the stronger artificial building blocks and the boundary conditions of engineering applications. In this progress report, the scientific and technological questions that have to be addressed to achieve this goal are highlighted, and examples of recent research efforts to tackle them are presented. These include the local characterization of the heterogeneous architecture of biological materials, the investigation of structure-function relationships to help unveil natural design principles, and the development of synthetic processing routes that can potentially be used to implement some of these principles in synthetic materials. The importance of replicating the design principles of biological materials rather than their structure per se is highlighted, and possible directions for further progress in this fascinating, interdisciplinary field are discussed.


A mecA-negative strain of methicillin-resistant Staphylococcus aureus with high-level β-lactam resistance contains mutations in three genes.
We previously generated a ceftobiprole-resistant Staphylococcus aureus strain after high inoculum serial passage of a mecA-negative variant of strain COL (R. Banerjee, M. Gretes, L. Basuino, N. Strynadka, and H. F. Chambers, Antimicrob. Agents Chemother. 52:2089-2096, 2008). Genome resequencing of this strain, CRB, revealed that it differs from its parent by five single-nucleotide polymorphisms in three genes, specifically, those encoding PBP4, a low-molecular-weight penicillin-binding protein, GdpP, a predicted signaling protein, and AcrB, a cation multidrug efflux transporter. CRB displayed resistance to a variety of β-lactams but was hypersusceptible to cefoxitin.


Dentatorubrothalamic tract in human brain: diffusion tensor tractography study.
The dentatorubrothalamic tract (DRTT) originates from the dentate nucleus in the cerebellum and terminates in the contralateral ventrolateral nucleus (VL) of the thalamus after decussating to the contralateral red nucleus. Identification of the DRTT is difficult due to the fact that it is a long, multisynaptic, neural tract crossing to the opposite hemisphere. In the current study, we attempted to identify the DRTT in the human brain using a probabilistic tractography technique of diffusion tensor imaging. Diffusion tensor imaging was performed at 1.5-T using a synergy-L sensitivity encoding head coil. DRTTs were obtained by selection of fibers passing through three regions of interest (the dentate nucleus, the superior cerebellar peduncle, and the contralateral red nucleus) from 41 healthy volunteers. Probabilistic mapping was obtained from the highest probabilistic location at 2.3 mm above the anterior commissure-posterior commissure level. DRTTs of all subjects, which originated from the dentate nucleus, ascended through the junction of the superior cerebellar peduncle and the contralateral red nucleus and then terminated at the VL nucleus of the thalamus. The highest probabilistic location for the DRTT at the thalamus was compatible with the location of the VL nucleus. We identified the DRTT in the human brain using probabilistic tractography. Our results could be useful in research on movement control.


The impact of longissimus glycolytic potential and short-term feeding of magnesium sulfate heptahydrate prior to slaughter on carcass characteristics and pork quality.
The objective of this study was to compare the effects of longissimus glycolytic potential (GP) and of time of feeding of supplemental magnesium sulfate heptahydrate on carcass and pork quality traits. The study was carried out in a 2 x 2 x 4 factorial arrangement; the treatments were sex (castrate vs gilt), GP (Low [normal] vs High), and time of feeding of magnesium sulfate-fortified diets (0 [control] vs 2 vs 3 vs 5 d prior to slaughter). Glycolytic potential was determined on a biopsy sample of longissimus from the live animal prior to the start of the study. A total of 144 pigs were allotted to the feeding-time treatments on the basis of sex (castrate and gilt), weight, and GP. Pigs were placed in individual pens and had free access to water. Prior to the start of the study, pigs were given ad libitum access to a standard finisher diet. During the study, animals were fed at a fixed level of 2.75 kg of a standard finisher diet/day; the fortified diet contained 3.2 g/d of additional magnesium. At the end of the feeding period, animals were transported to a commercial packing facility and slaughtered within 15 min of arrival. Fresh meat quality was measured on the longissimus. There were no treatment interactions. Carcass traits were similar across time of feeding treatments. Backfat thickness at the last lumbar vertebra and 10th rib were lower (P < 0 .05) for High than for Low GP pigs. High GP pigs had lower ultimate pH (P < 0.001) and higher drip (P < 0.05) and purge loss (P < 0.01) than Low GP pigs. Drip loss was reduced (P < 0.05) for pigs fed the magnesium-fortified diet for 5 and 2 but not for 3 d compared to controls (8.98, 7.29, 7.89, and 7.41 for the 0-, 2-, 3-, and 5-d treatments, respectively, SEM 0.447). Purge loss was similar for all of the time of feeding treatments. Longissimus L* values were lower (P < 0.05) for the 2-d treatment than for the controls. Results from this study suggest an inconsistent effect of short-term feeding of magnesium sulfate on muscle color and drip loss in pigs with both Low (normal) and High GP.


[Certain aspects of diffuse axonal injury to the brain in the case of head trauma].
The analysis of the special literature and original clinical-morphological investigations provided the data on the localization and pathology of diffuse axonal injuries to the brain at different stages of the craniocerebral trauma. The role of diffuse axonal injury in the development of life-threatening changes and correlation of their development with the rotational theory of head damage are considered.


In vitro activity of Schinus terebinthifolius (Brazilian pepper tree) on Candida tropicalis growth and cell wall formation.
The aim of this study was to evaluate the in vitro antifungal activity of Schinus terebinthifolius (Brazilian pepper tree) tincture on planktonic Candida tropicalis (ATCC 40042), which is a microorganism associated to oral cavity infections. Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) were determined through the microdilution technique. Possible action of the tincture on fungal cell wall formation was also studied by adding an osmotic protector (0.8M sorbitol) to the microplates. Nystatin was used as standard control and tests were performed in triplicate. S. terebinthifolius was found to have MIC and MFC values of 625 microg/mL on the strain assayed, whereas nystatin showed MIC and MFC of 6.25 microg/mL. Results suggest that S. terebinthifolius tincture acts on fungal cell walls, since the sorbitol test indicated a MIC of 1.250 microg/mL. It may be concluded that S. terebinthifolius has potential in vitro antifungal activity against C. tropicalis strains, and probably acts by inhibiting fungal cell wall formation.


Weighted least-squares phase-unwrapping algorithm based on the orientation coherence for discontinuous optical phase patterns.
Phase unwrapping is one of the key steps of optical interferogram analysis, among which phase discontinuity is still a challenge. In this paper, we propose a new weighted least-squares phase-unwrapping algorithm for discontinuous optical phase patterns. In the proposed algorithm, the orientation coherence is introduced to define the new weighting coefficient, which can accurately show the wrapped phase quality. According to our proposed algorithm, the new weighting coefficient has a good performance on distinguishing the continuous regions and the discontinuous regions in wrapped phase patterns. This advantage of our algorithm can ensure a more reliable unwrapped result for discontinuous optical phase patterns. We test the proposed algorithm on the computer-simulated speckle phase images and two experimentally obtained phase images, respectively, and compare them with the other five widely used methods. The experimental results demonstrate the performance of our new weighted least-squares phase-unwrapping algorithm.


An atomic charge-charge flux-dipole flux atom-in-molecule decomposition for molecular dipole-moment derivatives and infrared fundamental intensities.
The molecular dipole moment and its derivatives are determined from atomic charges, atomic dipoles, and their fluxes obtained from AIM formalism and calculated at the MP2(FC)/6-311++G(3d,3p) level for 16 molecules: 6 diatomic hydrides, CO, HCN, OCS, CO2, CS2, C2H2, C2N2, H2O, H2CO, and CH4. Root-mean-square (rms) errors of 0.052 D and 0.019 e are found for the dipole moments and their derivatives calculated using AIM parameters when compared with those obtained directly from the MP2(FC)/6-311++G(3d,3p) calculations and 0.097 D and 0.049 e when compared to the experimental values. The major deviations occur for the NaH, HF, and H2O molecules. Parallel polar tensor elements for the diatomic and linear polyatomic molecules, except H2, HF, LiH, and NaH, have values resulting from cancellations of substantial contributions from atomic charge fluxes and atomic dipole fluxes. These fluxes have a large negative correlation coefficient, -0.97. IR fundamental intensity sums for CO, HCN, OCS, CO2, CS2, C2H2, C2N2, H2CO, and CH4 calculated using AIM charges, charge fluxes, and atomic dipole fluxes have rms errors of 14.9 km mol(-1) when compared with sums calculated directly from the molecular wave function and 36.2 km mol(-1) relative to experimental values. The classical model proposed here to calculate dipole-moment derivatives is compared with the charge-charge flux-overlap model long used by spectroscopists for interpreting IR vibrational intensities. The utility of the AIM atomic charges and dipoles was illustrated by calculating the forces exerted on molecules by a charged particle. AIM quantities were able to reproduce forces due to a +0.1 e particle over a 3-8-A separation range for the CO and HF molecules in collinear and perpendicular arrangements. These results show that IR intensities do contain information relevant to the study of intermolecular interactions.


Neural Correlates of Successful and Unsuccessful Strategical Mechanisms Involved in Uncertain Decision-Making.
The ability to develop successful long-term strategies in uncertain situations relies on complex neural mechanisms. Although lesion studies have shown some of the mechanisms involved, it is still unknown why some healthy subjects are able to make the right decision whereas others are not. The aim of our study was to investigate neurophysiological differences underlying this ability to develop a successful strategy in a group of healthy subjects playing a monetary card game called the Iowa Gambling Task (IGT). In this task, subjects have to win and earn money by choosing between four decks of cards, two were advantageous in the long term and two disadvantageous. Twenty healthy right-handed subjects performed the IGT while their cerebral activity was recorded by electroencephalography. Based on their behavioral performances, two groups of subjects could clearly be distinguished: one who selected the good decks and thus succeeded in developing a Favorable strategy (9 subjects) and one who remained Undecided (11 subjects). No neural difference was found between each group before the selection of a deck, but in both groups a greater negativity was found emerging from the right superior frontal gyrus 600 ms before a disadvantageous selection. During the processing of the feedback, an attenuation of the P200 and P300 waveforms was found for the Undecided group, and a P300 originating from the medial frontal gyrus was found in response to a loss only in the Favorable group. Our results suggest that undecided subjects are hyposensitive to the valence of the cards during gambling, which affects the feedback processing.