Influence of previous pain experience on the episode incidence of low back pain: results from the South Manchester Back Pain Study.
A pathological cause cannot be identified for most new episodes of low back pain (LBP) presenting to the general practitioner. One important potential influence on susceptibility is previous pain experience. To accurately investigate the contribution of this phenomenon to the onset of new episodes of LBP a prospective population study is required. To determine the relationship of prior pain in the back and other musculoskeletal sites to risk of subsequent new episodes of LBP. The population studied included all 2715 adults from the South Manchester Back Pain Study who were free of LBP during the month prior to the baseline survey. At baseline a detailed musculoskeletal pain history was obtained. New episodes of LBP over the subsequent 12 months were ascertained by: (i) prospectively monitoring all primary care consultations in the study cohort (consulting episodes) and (ii) a follow-up survey after 1 year to determine new episodes during that 12-month period not leading to consultation (non-consulting episodes). The 12-month cumulative incidence of new consulting episodes was 3% in males and 5% in females, and for new non-consulting episodes 31% in males and 32% in females. Those with a history of previous LBP had twice the rate of new episodes, both consulting and non-consulting, compared to those with no LBP in the past. Neck pain or pain in other musculoskeletal sites at baseline also doubled the risk of a subsequent new episode of LBP. Adjusting for psychological distress and the other pain variables had little influence on the findings. In those currently free of LBP a previous history of the symptom substantially increases the risk of a further episode, with pain in other sites an equally strong independent predictor of subsequent LBP.


Does neuroimaging research examining the pathophysiology of posttraumatic stress disorder require medication-free patients?
In an attempt to avoid unknown influence, most neuroimaging studies examining the pathophysiology of posttraumatic stress disorder (PTSD) exclude patients taking medications. Here we review the empirical evidence for relevant medications having a confounding effect on task performance or cerebral blood flow (CBF) in this population. The evidence for potentially confounding effects of psychotherapy in PTSD are also discussed. The literature that we reviewed was obtained through a PubMed search from 1980 to 2009 using the search terms posttraumatic stress disorder, PTSD, psychotropic medications, neuroimaging, functional magnetic resonance imaging, positron emission tomography, cerebral blood flow, CBF, serotonin-specific reuptake blocker, benzodiazepine, ketamine, methamphetamine, lamotrigine and atypical antipsychotic agents. The empirical evidence for relevant medications having a confounding effect on task performance or CBF in relevant areas remains sparse for most psychotropic medications among patients with PTSD. However, considerable evidence is accumulating for 2 of the most commonly prescribed medication classes (serotonin-specific reuptake inhibitors and benzodiazepines) in healthy controls. Compelling data for the potentially confounding effects on brain areas relevant to PTSD for psychotherapeutic interventions are also accumulating. Neuroimaging studies examining the pathophysiology of PTSD should ideally recruit both medicated (assuming that the medication treatment has not resulted in the remission of symptoms) and unmedicated participants, to allow the findings to be generalized with greater confidence to the entire population of patients with PTSD. More research is needed into the independent effects of medications on task performance and CBF in regions of interest in PTSD. Neuroimaging studies should also take into account whether patients are currently engaged in psychotherapeutic treatment.


Design and characterization of a mutation outside the active site of human thymidylate synthase that affects ligand binding.
Owing to its central role in DNA synthesis, human thymidylate synthase (hTS) is a well-established target for chemotherapeutic agents, such as fluoropyrimidines. The use of hTS inhibitors in cancer therapy is limited by their toxicity and the development of cellular drug resistance. Here, with the aim of shedding light on the structural role of the A-helix in fluoropyrimidine resistance, we have created a fluoropyrimidine-resistant mutant by making a single point mutation, Glu30Trp. We postulated that residue 30, which is located in the A-helix, close to but outside the enzyme active site, could have a long-range effect on inhibitor binding. The mutant shows 100 times lower specific activity with respect to the wild-type hTS and is resistant to the classical inhibitor, FdUMP, as shown by a 6-fold higher inhibition constant. Circular dichroism experiments show that the mutant is folded. The results of molecular modeling and simulation suggest that the Glu30Trp mutation gives rise to resistance by altering the hydrogen-bond network between residue 30 and the active site.


Playing linear numerical board games promotes low-income children's numerical development.
The numerical knowledge of children from low-income backgrounds trails behind that of peers from middle-income backgrounds even before the children enter school. This gap may reflect differing prior experience with informal numerical activities, such as numerical board games. Experiment 1 indicated that the numerical magnitude knowledge of preschoolers from low-income families lagged behind that of peers from more affluent backgrounds. Experiment 2 indicated that playing a simple numerical board game for four 15-minute sessions eliminated the differences in numerical estimation proficiency. Playing games that substituted colors for numbers did not have this effect. Thus, playing numerical board games offers an inexpensive means for reducing the gap in numerical knowledge that separates less and more affluent children when they begin school.


Lateral wedge osteotomy for pediatric post-traumatic cubitus varus: Kirschner-wires or locking angular plate?
This study aimed to evaluate and compare two types of internal fixation, locking angular plate (group 1) and Kirschner-wires (group 2), for post-traumatic cubitus varus. The parameters used were Laupattarakasem's criteria (for range of motion in extension/flexion, correction of carrying angle, and the 'lazy S' deformity) and the Barrett's questionnaire (for patient satisfaction). In group I (plate+screws), we had three excellent results and five good. In group II (Kirschner-wires), we had two good results, three fair, and two poor. Statistical analysis showed a better outcome for group I (plate+screws) considering the correction of the humeral-elbow-wrist angle (P<0.003), the postoperative lateral prominence index (P<0.048), and the patient satisfaction (P<0.011). We recommend the locking angular plate, because it can rigidly stabilize the osteotomy, ensuring an excellent functional and cosmetic outcome.


Mycoplasma hominis and Ureaplasma urealyticum in patients with sexually transmitted diseases.
Mycoplasma hominis and Ureaplasma urealyticum can be isolated with considerable frequency from the human urogenital tract and are thought to cause various syndromes such as nongonococcal urethritis, pelvic inflammatory disease, pyelonephritis or infertility. The aim of this study was the evaluation of the presence of different genital pathogens in patients with sexually transmitted diseases (STD) and, in particular, the detection of mycoplasmas in individuals infected with genital microbes and an assessment of the presence of genital microorganisms in patients harbouring Mycoplasma hominis or Ureaplasma urealyticum. Furthermore, the occurrence of mycoplasmas in women with bacterial vaginosis was established. Specimens were collected from a total of 41,980 persons attending the Outpatients' Centre for Infectious Venero-Dermatological Diseases in Vienna from 1994 to 1996. Of all genital pathogens, Ureaplasma urealyticum was cultured most frequently in men and women. Mycoplasma hominis and Ureaplasma urealyticum were detected more often in the vaginal fluid than in the male urethra. By contrast, infection rates with Neisseria gonorrhoeae and Chlamydia trachomatis were higher in men than in women. In both men and women, trichomoniasis increased colonisation with Mycoplasma hominis, while mycoplasmas occurred less frequently together with genital candidiasis. Mycoplasma hominis was cultivated significantly more often in women with bacterial vaginosis than in those without. In contrast to urethral infections in men, cervical infections with Neisseria gonorrhoeae or Chlamydia trachomatis raised the incidence of Mycoplasma hominis in the vaginal fluid.


The intracellular localization of Pseudomonas aeruginosa lectins.
The localization of the Pseudomonas aeruginosa lectins (PA-I and PA-II) was studied using methods of osmotic shock, freezing and thawing and spheroplast formation. Very slight release of the two lectins occurred when P. aeruginosa was exposed to magnesium-osmotic shock or was frozen and thawed. Under these conditions, release of the periplasmic 5'-nucleotidase occurred, whereas no release of cytoplasmic glucose-6-phosphate dehydrogenase activity was detected. Formation of spheroplasts from P. aeruginosa by gradual removal of the bacterial envelopes revealed low lectin activity in the treatment fluids. Osmotic shock treatment of the lysozyme treated mureinoplasts resulted in low release of glucose-6-phosphate dehydrogenase and the two lectins (10-13%) and a considerable activity (38.4%) of 5'-nucleotidase. The presence of the lectins on the outer and the cytoplasmic membranes enabled intact cells and spheroplasts of P. aeruginosa to agglutinate papain-treated human erythrocytes. These results indicate that the two lectins are located mainly in the cytoplasm with small fractions on the cytoplasmic and outer membranes and in the periplasmic space.


Oxidative balance in follicular fluid of ART patients of advanced maternal age and blastocyst formation.
To evaluate the follicular fluid oxidative balance of infertile patients of advanced-maternal-age and the correlation between oxidative imbalance in the follicular fluid and the embryological outcomes. Follicular fluid (FF) from infertile patients of advanced-maternal-age undergoing ART treatments were collected and frozen in cryovials at -86°C until further use, and analyzed at the Biochemistry and Nutrition Institute of San Marcos University. As controls, we used FF from oocyte donors. The FF was then assayed for oxidative balance by ABTS, FRAP and TBARS assays. In order to establish the correlation between oxidative balance and embryo quality, we correlated the number of usable blastocysts (freshly transferred or frozen blastocysts) with the results from ABTS, FRAP and TBARS. Follicular fluid from patients of Advanced-maternal-age (AMA group) significantly differed from the values found in the control group; the ABTS value was higher and the FRAP value was lower, in comparison to the FF from oocyte donors (control group). The lipid peroxidation was not different between those two groups. Furthermore, there was no significant correlation among the results of the assays, or when correlated with the proportion of usable blastocysts. Ovarian oxidative balance seems to be critical for oocyte quality in advanced-maternal-age patients; however, we still need more studies on oxidative stress indicators, on a larger set of patients.


Neural correlates of visual versus abstract letter processing in Roman and Arabic scripts.
In alphabetic orthographies, letter identification is a critical process during the recognition of visually presented words. In the present experiment, we examined whether and when visual form influences letter processing in two very distinct alphabets (Roman and Arabic). Disentangling visual versus abstract letter representations was possible because letters in the Roman alphabet may look visually similar/dissimilar in lowercase and uppercase forms (e.g., c-C vs. r-R) and letters in the Arabic alphabet may look visually similar/dissimilar, depending on their position within a word (e.g., [Formula: see text] - [Formula: see text] vs. [Formula: see text] - [Formula: see text]). We employed a masked priming same-different matching task while ERPs were measured from individuals who had learned the two alphabets at an early age. Results revealed a prime-target relatedness effect dependent on visual form in early components (P/N150) and a more abstract relatedness effect in a later component (P300). Importantly, the pattern of data was remarkably similar in the two alphabets. Thus, these data offer empirical support for a universal (i.e., across alphabets) hierarchical account of letter processing in which the time course of letter processing in different scripts follows a similar trajectory from visual features to visual form independent of abstract representations.


Aroma active volatiles in four southern highbush blueberry cultivars determined by gas chromatography-olfactometry (GC-O) and gas chromatography-mass spectrometry (GC-MS).
Aroma active volatiles in four southern highbush blueberry cultivars ('Prima Dona', 'Jewel', 'Snow Chaser', and 'Kestrel') were determined using solid phase microextraction (SPME) in combination with gas chromatography-olfactometry (GC-O) and identified via GC-PFPD and GC-MS using retention indices of reference compounds and mass spectral data. The aromas of total, unseparated SPME extracts evaluated using GC-O were rated 8.2-9.0/10 for the four cultivars in terms of similarity to the original blueberry homogenates. In terms of GC-O aroma similarity, those aroma active volatile groups characterized as green, fruity, and floral were most intense. Of the 43 volatiles found to have aroma activity, 38 were identified and 13 had not been previously reported in blueberries. Although linalool and (E)-2-hexenal were common major aroma impact volatiles, dominant aroma-active volatiles were different for each cultivar. Principal component analysis confirmed that each cultivar possessed a unique aroma active profile as each cultivar was clustered into a separate score plot quadrant.


A generic approach for the purification of signaling complexes that specifically interact with the carboxyl-terminal domain of G protein-coupled receptors.
G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and are major drug targets. Recent progress has shown that GPCRs are part of large protein complexes that regulate their activity. We present here a generic approach for identification of these complexes that is based on the use of receptor subdomains and that overcomes the limitations of currently used genetics and proteomics approaches. Our approach consists of a carefully balanced combination of chemically synthesized His6-tagged baits, immobilized metal affinity chromatography, one- and two-dimensional gel electrophoresis separation and mass spectrometric identification. The carboxyl-terminal tails (C-tails) of the human MT1 and MT2 melatonin receptors, two class A GPCRs, were used as models to purify protein complexes from mouse brain lysates. We identified 32 proteins that interacted with the C-tail of MT1, 14 proteins that interacted with the C-tail of MT2, and eight proteins that interacted with both C-tails. Several randomly selected proteins were validated by Western blotting, and the functional relevance of our data was further confirmed by showing the interaction between the full-length MT1 and the regulator of G protein signaling Z1 in transfected HEK 293 cells and native tissue. Taken together, we have established an integrated and generic purification strategy for the identification of high quality and functionally relevant GPCR-associated protein complexes that significantly widens the repertoire of available techniques.


A Phase 3, Multicenter, Open-Label, 12-Month Extension Safety and Tolerability Trial of Lisdexamfetamine Dimesylate in Adults With Binge Eating Disorder.
A 12-month, open-label extension study assessed the long-term safety and tolerability of lisdexamfetamine dimesylate (LDX) in adults with binge eating disorder (BED). Adults (aged 18-55 y) with BED who completed 1 of 3 antecedent studies were enrolled in a 52-week, open-label extension study (dose optimization, 4 weeks [initial titration dose, 30-mg LDX; target doses, 50- or 70-mg LDX]; dose maintenance, 48 weeks). Safety evaluations included the occurrence of treatment-emergent adverse events (TEAEs), vital sign and weight assessments, and Columbia-Suicide Severity Rating Scale responses. Of the 604 enrolled participants, 599 (521 women and 78 men) comprised the safety analysis set, and 369 completed the study. Mean (SD) LDX exposure was 284.3 (118.84) days; cumulative LDX exposure duration was 12 months or longer in 344 participants (57.4%). A total of 506 participants (84.5%) reported TEAEs (TEAEs leading to treatment discontinuation, 54 [9.0%]; severe TEAEs, 42 [7.0%]; serious TEAEs, 17 [2.8%]). Treatment-emergent adverse events reported in greater than or equal to 10% of participants were dry mouth (27.2%), headache (13.2%), insomnia (12.4%), and upper respiratory tract infection (11.4%). Mean (SD) changes from antecedent study baseline in systolic and diastolic blood pressure, pulse, and weight at week 52/early termination (n = 597) were 2.19 (11.043) and 1.77 (7.848) mm Hg, 6.58 (10.572) beats per minute, and -7.04 (7.534) kg, respectively. On the Columbia-Suicide Severity Rating Scale, there were 2 positive responses for any active suicidal ideations; there were no positive responses for suicidal behavior or completed suicides. In this 12-month, open-label, extension study, the long-term safety and tolerability of LDX in adults with BED were generally consistent with its established profile for attention-deficit/hyperactivity disorder.


Missing data, incomplete taxa, and phylogenetic accuracy.
The problem of missing data is often considered to be the most important obstacle in reconstructing the phylogeny of fossil taxa and in combining data from diverse characters and taxa for phylogenetic analysis. Empirical and theoretical studies show that including highly incomplete taxa can lead to multiple equally parsimonious trees, poorly resolved consensus trees, and decreased phylogenetic accuracy. However, the mechanisms that cause incomplete taxa to be problematic have remained unclear. It has been widely assumed that incomplete taxa are problematic because of the proportion or amount of missing data that they bear. In this study, I use simulations to show that the reduced accuracy associated with including incomplete taxa is caused by these taxa bearing too few complete characters rather than too many missing data cells. This seemingly subtle distinction has a number of important implications. First, the so-called missing data problem for incomplete taxa is, paradoxically, not directly related to their amount or proportion of missing data. Thus, the level of completeness alone should not guide the exclusion of taxa (contrary to common practice), and these results may explain why empirical studies have sometimes found little relationship between the completeness of a taxon and its impact on an analysis. These results also (1) suggest a more effective strategy for dealing with incomplete taxa, (2) call into question a justification of the controversial phylogenetic supertree approach, and (3) show the potential for the accurate phylogenetic placement of highly incomplete taxa, both when combining diverse data sets and when analyzing relationships of fossil taxa.


Electrolyte-gated transistors for enhanced performance bioelectronics.
Electrolyte-gated transistors (EGTs), capable of transducing biological and biochemical inputs into amplified electronic signals and stably operating in aqueous environments, have emerged as fundamental building blocks in bioelectronics. In this Primer, the different EGT architectures are described with the fundamental mechanisms underpinning their functional operation, providing insight into key experiments including necessary data analysis and validation. Several organic and inorganic materials used in the EGT structures and the different fabrication approaches for an optimal experimental design are presented and compared. The functional bio-layers and/or biosystems integrated into or interfaced to EGTs, including self-organization and self-assembly strategies, are reviewed. Relevant and promising applications are discussed, including two-dimensional and three-dimensional cell monitoring, ultra-sensitive biosensors, electrophysiology, synaptic and neuromorphic bio-interfaces, prosthetics and robotics. Advantages, limitations and possible optimizations are also surveyed. Finally, current issues and future directions for further developments and applications are discussed.


Identification of a common secondary mutation in the Neurospora crassa knockout collection conferring a cell fusion-defective phenotype.
Gene-deletion mutants represent a powerful tool to study gene function. The filamentous fungus Neurospora crassa is a well-established model organism, and features a comprehensive gene knockout strain collection. While these mutant strains have been used in numerous studies, resulting in the functional annotation of many Neurospora genes, direct confirmation of gene-phenotype relationships is often lacking, which is particularly relevant given the possibility of background mutations, sample contamination, and/or strain mislabeling. Indeed, spontaneous mutations resulting in phenotypes resembling many cell fusion mutants have long been known to occur at relatively high frequency in N. crassa, and these secondary mutations are common in the Neurospora deletion collection. The identity of these mutations, however, is largely unknown. Here, we report that the Δada-3 strain from the N. crassa knockout collection, which exhibits a cell fusion defect, harbors a secondary mutation responsible for this phenotype. Through whole-genome sequencing and genetic analyses, we found a ~30-Kb deletion in this strain affecting a known cell fusion-related gene, so/ham-1, and show that it is the absence of this gene-and not of ada-3-that underlies its cell fusion defect. We additionally found three other knockout strains harboring the same deletion, suggesting that this mutation may be common in the collection and could have impacted previous studies. Our findings provide a cautionary note and highlight the importance of proper functional validation of strains from mutant collections. We discuss our results in the context of the spread of cell fusion-defective cheater variants in N. crassa cultures. IMPORTANCE This study emphasizes the need for careful and detailed characterization of strains from mutant collections. Specifically, we found a common deletion in various strains from the Neurospora crassa gene knockout collection that results in a cell fusion-defective phenotype. This is noteworthy because this collection is known to contain background mutations-of a largely unclear nature-that produce cell fusion-defective phenotypes. Our results describe an example of such mutations, and highlight how this common genetic defect could have impacted previous studies that have used the affected strains. Furthermore, they provide a cautionary note about the use of Neurospora strains with similar phenotypes. Lastly, these findings offer additional details relevant to our understanding of the origin and spread of cell fusion-defective cheater variants in N. crassa cultures.


Statics and dynamics of electroactuation with single-charge-carrier ionomers.
A simple theory of electromechanical transduction for single-charge-carrier double-layer electroactuators is developed, in which the ion distribution and curvature are mutually coupled. The obtained expressions for the dependence of the curvature and charge accumulation on the applied voltage, as well as the electroactuation dynamics, are compared with literature data. The mechanical or sensor performance of such electroactuators appears to be determined by just three cumulative parameters, with all of their constituents measurable, permitting a scaling approach to their design.


Performance indicators and gastrointestinal response of rabbits to dietary soybean meal replacement with silkworm pupae and mealworm larvae meals.
The objective of this study was to determine the effects of silkworm pupae meal (SPM) and mealworm larvae meal (MLM) on the production results and function of the digestive system in rabbits. Thirty male New Zealand White growing rabbits were divided into three feeding groups: control (C) (10% soybean meal [SBM] in the diet), group SPM (5% SBM and 4% SPM) and group MLM (5% SBM and 4% MLM). Compared with group C, rabbits of groups SPM and MLM, were characterised by higher final body weight and daily body weight gains. They were also found to have better apparent total tract digestibility (ATTD) of ether extract, and acid detergent fibre (ADF) and acid detergent lignin (ADL). Increased digesta viscosity was observed in these rabbits, as well as reduced extracellular activity of bacterial α-glucosidase, β-glucosidase, α-arabinofuranosidase and β-xylosidase in the caecal digesta. Similar differences between groups were also noted for the intracellular activity of β-glucuronidase, total activity of β-xylosidase and α-glucosidase. The SPM and MLM treatments contributed to an increase in the extracellular and total activity of N-acetyl-β-D-glucosaminidase (NAGase) in the caecal digesta. The SPM and MLM treatments were characterised by increased extracellular/total activity of colonic bacterial NAGase as well as increased release rates of NAGase and β-cellobiosidase, compared with group C. The rabbits fed the MLM diet had the lowest caecal concentrations of acetic acid, propionic acid, and total short chain fatty acids (SCFA). The proportion of butyric acid in the caecal SCFA profile was significantly lower in group MLM than in group C. The SPM treatment reduced the colonic concentration of iso-valeric acid. Group C had the highest colonic SCFA pool. It can be concluded that an inclusion of 4% SPM and 4% MLM in rabbit diets improved their production results, as well as beneficially increased the ATTD of fat, ADF and ADL without compromising the ATTD of other nutrients and energy. Although both dietary insect-derived products caused a mobilisation of microbiota to utilise of chitin (see NAGase activity), they stifled the metabolism of large intestinal microbiota, as manifested by decreased enzyme activity and lower SCFA concentrations.


Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease.
In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic-pituitary-gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease.


Etoposide induces G2/M arrest and apoptosis in neural progenitor cells via DNA damage and an ATM/p53-related pathway.
Etoposide (VP-16), an anti-tumor agent, is a topoisomerase II inhibitor that causes DNA damage. In our previous studies, it was shown that VP-16 induces S-phase accumulation and G2/M arrest, eventually resulting in apoptosis, through p53-related pathway in the mouse fetal brain. We injected 4 mg/kg of VP-16 into pregnant mice on day 12 of gestation, and the fetuses were investigated for the cell cycle checkpoint and mechanism of apoptosis. The transition of the neural progenitor cells in the fetuses was delayed as compared to that in the control, and most of the apoptotic cells were BrdU positive. VP-16-induced S-phase accumulation was brought about by the acceleration of G1/S transition rather than by the inhibition of S-phase progression. Phosphorylation of ataxia telangiectasia-mutated kinase (ATM) at Ser1981 and gammaH2AX after VP-16 treatment showed DNA damage. p53 was phosphorylated at Ser15 and 20 and increased after activation of the ATM kinase pathway. Cdc25A degradation might induce the inhibition of S-phase progression. It is supposed that an increase in cyclin A might accelerate G1/S progression. It is also indicated that VP-16-induced G2/M arrest is caused by p21, which inactivates cyclin B-Cdc2 complex and eventually prevents mitotic entry. In p53-deficient fetal brains, G2/M and apoptosis were almost abrogated, although S-phase accumulation still occurred. It is suggested that VP-16 induced p53-independent S-phase accumulation, and p53-dependent G2/M arrest and apoptosis of the neural progenitor cells in fetal mouse brain.


[Surgical treatment of obesity in 2006].
Roux-en-Y gastric bypass (RYGB), mostly since it is performed laparoscopically, is presently the technique of choice for the treatment of morbid obesity. In the United States, more than 80% of all bariatric procedures are RYGB, and our country follows the same way with more than 60% of RYGB in 2004. In Switzerland, this procedure can be considered for morbidly obese patients only (Body Mass Index > or = 40 kg/m2). RYGB is both strongly restrictive and lightly malabsorptive, and induces a 60% mean excess weight loss with a dramatic resolution of comorbidities. The mortality and morbidity of this operation are very low, particularly when compared to the death and disease risks associated with obesity. These patients should be treated by a specialized multidisciplinary team.


In vitro expression of chloroplast genes in lysates of higher plant chloroplasts.
A DNA-dependent in vitro-coupled transcription-translation system has been prepared from lysates of isolated chloroplasts. These lysates are comparable to those of Escherichia coli in transcriptional and translational fidelity and efficiency in response to a given template DNA. When Nicotiana tabacum chloroplast DNA is used as template with chloroplast lysates (N. tabacum or spinach) or E. coli lysates, NaDodSO4 gel analysis reveals similar polypeptide patterns that are distinct from the patterns obtained with E. coli DNA. Genes in recombinant plasmids containing chloroplast DNA are also expressed in these in vitro systems. DNA . RNA hybridization experiments show that transcripts are synthesized from most of the chloroplast genome. Newly synthesized large subunit of ribulosebisphosphate carboxylase/oxygenate and a transcript of the large subunit gene (rbcL) are observed in chloroplast lysates using as template chloroplast DNA or cloned fragments of tobacco chloroplast DNA that contain the large subunit gene. Results suggest that differential expression of chloroplast genes occurs in vitro. By using cloned chloroplast DNA templates in this homologous system, it is possible to identify and map structural genes for chloroplast proteins.


Physiologic aspects of continence after colectomy, mucosal proctectomy, and endorectal ileo-anal anastomosis.
We examined the physiology of continence in 12 patients at least four months after colectomy, mucosal proctectomy, and endorectal ileo-anal anastomosis for ulcerative colitis and familial polyposis. The mean fecal output (+/-SEM) was 598 +/- 60 gm, passed as 12 +/- 4 movements/24 hr, of which 4 +/- 1 were passed at night. The patients were generally continent during the day and could distinguish gas from stool, but 11 of 12 leaked stools at night. Anal sphincter resting pressures (71 +/- 8 cm H2O) and squeeze pressures (171 +/- 15 cm H2O) of patients were similar to those of ten healthy controls (P greater than 0.05), although the rectal inhibitory reflex was absent in the patients. After operation, the distal bowel had a pressure-volume curve of greater slope (0.15 +/- 0.05 ml/cm H2O) than it had in controls (0.07 +/- 0.01 ml/cm H2O, P less than 0.05) and a lesser maximum capacity (patients, 248 +/- 31 ml; controls, 406 +/- 26 ml; P less than 0.05). The greater the capacity of the neorectum, the fewer was the number of bowel movements/day (r = 0.91, P less than 0.001). We concluded that the operation preserved the anal sphincter, although it decreased the capacity and compliance of the distal bowel and impaired continence.


Protective effect of triphlorethol-A from Ecklonia cava against ionizing radiation in vitro.
We studied the cytoprotective effect of triphlorethol-A against gamma-ray radiation-induced oxidative stress. In this study, hydrogen peroxide, which is a reactive oxygen species (ROS), was detected using 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) assay. Triphlorethol-A reduced intracellular hydrogen peroxide generated by gamma-ray radiation. This compound provided protection against radiation-induced membrane lipid peroxidation and cellular DNA damage which are the main targets of radiation-induced damage. Triphlorethol-A protected the cell viability damaged by the radiation through inhibition of apoptosis. Triphlorethol-A reduced the expression of bax and activated caspase 3 induced by radiation, but recovered the expression of bcl-2 decreased by radiation. Taken together, the results suggest that triphlorethol-A protects cells against oxidative damage induced by radiation through reducing ROS.


Interactions of cold exposure and starvation on glucose tolerance and insulin response.
The metabolic interactions of cold exposure, cold acclimation, and starvation on glucose tolerance and plasma insulin levels were studied in precannulated, unrestrained, and unanesthetized rats. Cold exposure (48 h at 5 degrees C) significantly reduced the insulin response to intravenous glucose injection (P less than 0.01) while improving glucose tolerance (P less than 0.01). Starvation (48 h at 25 degrees C) also reduced the insulin response (P less than 0.01) but did not significantly alter glucose tolerance. "Accelerated starvation" induced by starving rats for 48 h at 5 degrees C dramatically reduced both basal and glucose-stimulated insulin levels while even improving glucose tolerance, resulting in a 15-fold reduction in the insulinogenic index. Cold acclimation (3 wk at 5 degrees C) induced essentially the same alterations as cold exposure. Approximately reversed changes were observed when cold-acclimated rats were returned to a warm environment for 15-18 h. Results from these studies indicate that 1) cold exposure and starvation, but not cold acclimation, act synergistically in decreasing the sensitivity and/or the capacity of pancreatic islets for secreting insulin in response to glucose stimulation; 2) glucose tolerance and possibly insulin sensitivity of peripheral tissues are enhanced by cold exposure and starvation, although glucose tolerance is improved by cold exposure only, not by starvation; 3) an improved glucose tolerance with barely detectable plasma insulin levels was obtained in cold-starved rats under normal physiological conditions.


Origins of introns based on the definition of exon modules and their conserved interfaces.
Central to the unraveling of the early evolution of the genome is the origin and role of introns. The evolution of the genome can be characterized by a continuous expansion of functional modules that occurs without the interruption of existing processes. The design-by-contract methodology of software development offers a modular approach to design that seeks to increase flexibility by focusing on the design of constant interfaces between functional modules. Here, it is shown that design-by-contract can offer a framework for genome evolution. The definition of an ancient exon module with identical splice sites leads to a relatively simple sequence of events that explains the role of introns, intron phase differences and the evolution of multi-exon proteins in an RNA world. An interaction of the experimentally defined six-nucleotide splicing consensus sequence together with a limited number of primitive ribozymes can account for a rapid creation of protein diversity.


Combining the outcomes of endoscopy, laboratory testing, and professional judgement in gastroenterological decision-making.
The need to combine the results of multiple separate tests or make decisions based on the judgement by multiple experts permeates the clinical and professional practice of a gastroenterologist. The present analysis is aimed at delineating four different means to combine results of multiple tests and discuss their applicability and limitations. In serial testing, the overall test outcome is rated as being positive if the outcome is positive in all individual tests applied in series. Serial testing increases the overall specificity at the expense of decreasing sensitivity. In parallel testing, the overall test outcome is rated as being positive if the outcome is positive in any of the multiple tests. Parallel testing increases the overall sensitivity at the expense of decreasing specificity. In majority testing, the overall test outcome follows the rating by the majority of testers. Majority testing avoids the trade-off between sensitivity and specificity associated with serial and parallel testing and leads to relatively high overall values for both test characteristics. For majority testing to function well, however, it requires many independent testers, which can render this method costly and impractical in the clinical setting. Sequential testing applies to situations in which the output of a previous test provides the input for a later test. Sequential testing generally results in an overall test with lower sensitivity and specificity values than any of the individual tests and should be avoided if possible. All methods to improve test performance by combining the results of multiple tests have limitations and need to be regarded with skepticism. In the long run, the best solutions are provided by improvements of the individual test or performance by the individual diagnostician/reviewer through training and acquisition of new skills.


Dissociation of multiply charged ICN by Coulomb explosion.
The fragmentations of iodine cyanide ions created with 2 to 8 positive charges by photoionization from inner shells with binding energies from 59 eV (I 4d) to ca. 900 eV (I 3p) have been examined by multi-electron and multi-ion coincidence spectroscopy with velocity map imaging ion capability. The charge distributions produced by hole formation in each shell are characterised and systematic effects of the number of charges and of initial charge localisation are found.


Role of Exact Exchange and Relativistic Approximations in Calculating 19F Magnetic Shielding in Solids Using a Cluster Ansatz.
Calculations of 19F magnetic shielding in various materials are presented. In calculations on gas-phase molecules, the variation of magnetic shielding with the amount of Hartree-Fock exchange (HFX) in the functional demonstrates that excellent agreement with experiment is obtained with an admixture of 50%, here denoted PBE0 (50%). Calculations at the PBE, PBE0 (25%), and PBE0 (50%) levels on 10 crystalline organofluorines and 15 crystalline inorganic fluorides, in which a cluster ansatz is used to model the lattice environment, were performed. For fluorine-containing aromatics, increasing the admixture of HFX results in the prediction of larger magnetic-shielding spans, whereas increasing the admixture of HFX in calculations for CFCl3 decreases the span. In calculations of 19F magnetic shielding of the inorganic fluorides, the use of sufficiently large clusters of inorganic fluorides results in accuracies similar to those calculated for the organofluorines. Relativistic effects on the magnetic shielding of inorganic fluorides, modeled with ZORA at both the scalar and spin-orbit levels, are dominated by the scalar terms that increase the shielding of most 19F sites over the non-relativistic results. These effects appear to scale with the atomic number of the cation. For most elements of the sixth row (Cs, Ba, La, and Pb), the scalar relativistic contribution to the magnetic shielding is in the range of 20-77 ppm. For elements of group XII (Zn, Cd, and Hg) bonded to fluorine, the scalar relativistic contribution results in deshielding of the 19F site.


Methods Used to Assess Student Performance and Course Outcomes at the National Center of Excellence in Dairy Production Medicine Education for Veterinarians.
Between 2012 and 2014, three cohorts of senior veterinary students participated in an 8-week dairy production medicine course created by the National Center of Excellence in Dairy Production Medicine Education for Veterinarians. One goal of this course is to better prepare veterinary students to serve the increasingly complex needs of the dairy industry. In this article, we describe the assessment methods and student performance outcomes of those first three cohorts. A combination of assessment methods was used, including pre- and post-testing; instructor observations and scores on individual and group projects, including a final integrative project; and peer evaluation. Student feedback, collected via anonymous survey, provided insight into students' perceptions about the course and their learning. Performance and feedback suggest that the course was successful in preparing students for careers using skills in dairy production medicine. Pre- and post-testing was conducted for most topic modules in the course. The mean (median) pre- and post-test scores were 47% (50% ) and 83% (88%), respectively. The mean improvement in score was significant (p < .002) for all modules and cohorts. Students indicated a moderate or high degree of confidence in performing dairy production medicine skills after each module. Of students in cohorts 1, 2, and 3, respectively, 55%, 75%, and 82% felt they could provide dairy production medicine services (e.g., records analysis, problem investigation, protocol and standard operating procedure design) either alone or with some mentoring, immediately after graduation. In addition, assessment results and student feedback enabled timely course modifications during these first three cohorts.


Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs.
Canine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease caused by interactions between genetic and environmental factors. Previously, a genome-wide significant risk locus on canine chromosome 27 for CAD was identified in German shepherd dogs (GSDs) and Plakophilin-2 (PKP2) was defined as the top candidate gene. PKP2 constitutes a crucial component of desmosomes and also is important in signalling, metabolic and transcriptional activities. The main objective was to evaluate the role of PKP2 in CAD by investigating PKP2 expression and desmosome structure in nonlesional skin from CAD-affected (carrying the top GWAS SNP risk allele) and healthy GSDs. We also aimed at defining the cell types in the skin that express PKP2 and its intracellular location. Skin biopsies were collected from nine CAD-affected and five control GSDs. The biopsies were frozen for immunofluorescence and fixed for electron microscopy immunolabelling and morphology. We observed the novel finding of PKP2 expression in dendritic cells and T cells in dog skin. Moreover, we detected that PKP2 was more evenly expressed within keratinocytes compared to its desmosomal binding-partner plakoglobin. PKP2 protein was located in the nucleus and on keratin filaments attached to desmosomes. No difference in PKP2 abundance between CAD cases and controls was observed. Plakophilin-2 protein in dog skin is expressed in both epithelial and immune cells; based on its subcellular location its functional role is implicated in both nuclear and structural processes.


Quantifying Fundus Autofluorescence in Patients With Retinitis Pigmentosa.
Using quantitative fundus autofluorescence (qAF), we analyzed short-wavelength autofluorescent (SW-AF) rings in RP. Short-wavelength autofluorescent images (486 nm excitation) of 40 patients with RP (69 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. Mean qAF was measured in eight preset segments (qAF8) and in region of interest (ROI)-qAF (200-700 μm) within and external to the borders of the rings at superior, temporal, and inferior sites relative to the ring. For both groups, qAF in patients with RP was compared to age-similar and race/ethnicity-matched healthy eyes at equivalent retinal locations. In 71% of eyes of RP patients, qAF8 acquired internal to the inner border of the ring, was within the 95% confidence interval (CI) for healthy eyes, while in the remaining RP eyes qAF8 was either higher or lower than the CI. Measured external to the ring, qAF8 values were within the CI in 47% of RP eyes with the other eyes being higher or lower. In 28% of sites measured by ROI-qAF within the SW-AF ring, values were above the 95% CI of healthy controls. Region of interest-qAF measured just external to the ring was within the CI of healthy eyes in 74% of locations. The average local elevation in qAF within the ring was approximately 15%. In SD-OCT scans, photoreceptor-attributable reflectivity bands were thinned within and external to the ring. Increased fluorophore production may be a factor in the formation of the SW-AF rings in RP.


Comparison of 3 Tfr2-deficient murine models suggests distinct functions for Tfr2-alpha and Tfr2-beta isoforms in different tissues.
Transferrin receptor 2 (TFR2) is a transmembrane protein that is mutated in hemochromatosis type 3. The TFR2 gene is transcribed in 2 main isoforms: the full-length (alpha) and a shorter form (beta). alpha-Tfr2 is the sensor of diferric transferrin, implicated in the modulation of hepcidin, the main regulator of iron homeostasis. The function of the putative beta-Tfr2 protein is unknown. We have developed a new mouse model (KI) lacking beta-Tfr2 compared with Tfr2 knockout mice (KO). Adult Tfr2 KO mice show liver iron overload and inadequate hepcidin levels relative to body iron stores, even though they increase Bmp6 production. KI mice have normal transferrin saturation, liver iron concentration, hepcidin and Bmp6 levels but show a transient anemia at young age and severe spleen iron accumulation in adult animals. Fpn1 is strikingly decreased in the spleen of these animals. These findings and the expression of beta-Tfr2 in wild-type mice spleen suggest a role for beta-Tfr2 in Fpn1 transcriptional control. Selective inactivation of liver alpha-Tfr2 in KI mice (LCKO-KI) returned the phenotype to liver iron overload. Our results strengthen the function of hepatic alpha-Tfr2 in hepcidin activation, suggest a role for extrahepatic Tfr2 and indicate that beta-Tfr2 may specifically control spleen iron efflux.


[The Organ Donation Law: changes in the procurement of organs and tissues for transplantation].
The Organ Donation Act fills an old gap in the legislation, leading to improvement of the legal position of those involved. Much attention is given to the protection of the potential donor. A new consent procedure is introduced, including the registration of the consent or refusal of all persons aged 18 years or older. Because of the persistent shortage of donor organs the noncommittal nature of organ procurement is changed. Hospitals and nursing homes are obliged to have a protocol for organizing tissue donation. Also, conditions have been created for a just division of the available organs and tissues for transplantation.


Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.
In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.


AVDNet: Joint coronary artery and vein segmentation with topological consistency.
Coronary CT angiography (CCTA) is an effective and non-invasive method for coronary artery disease diagnosis. Extracting an accurate coronary artery tree from CCTA image is essential for centerline extraction, plaque detection, and stenosis quantification. In practice, data quality varies. Sometimes, the arteries and veins have similar intensities and locate closely, which may confuse segmentation algorithms, even deep learning based ones, to obtain accurate arteries. However, it is not always feasible to re-scan the patient for better image quality. In this paper, we propose an artery and vein disentanglement network (AVDNet) for robust and accurate segmentation by incorporating the coronary vein into the segmentation task. This is the first work to segment coronary artery and vein at the same time. The AVDNet consists of an image based vessel recognition network (IVRN) and a topology based vessel refinement network (TVRN). IVRN learns to segment the arteries and veins, while TVRN learns to correct the segmentation errors based on topology consistency. We also design a novel inverse distance weighted dice (IDD) loss function to recover more thin vessel branches and preserve the vascular boundaries. Extensive experiments are conducted on a multi-center dataset of 700 patients. Quantitative and qualitative results demonstrate the effectiveness of the proposed method by comparing it with state-of-the-art methods and different variants. Prediction results of the AVDNet on the Automated Segmentation of Coronary Artery Challenge dataset are avaliabel at https://github.com/WennyJJ/Coronary-Artery-Vein-Segmentation for follow-up research.


DNA Translocations through Nanopores under Nanoscale Preconfinement.
To reduce unwanted variation in the passage speed of DNA through solid-state nanopores, we demonstrate nanoscale preconfinement of translocating molecules using an ultrathin nanoporous silicon nitride membrane separated from a single sensing nanopore by a nanoscale cavity. We present comprehensive experimental and simulation results demonstrating that the presence of an integrated nanofilter within nanoscale distances of the sensing pore eliminates the dependence of molecular passage time distributions on pore size, revealing a global minimum in the coefficient of variation of the passage time. These results provide experimental verification that the inter- and intramolecular passage time variation depends on the conformational entropy of each molecule prior to translocation. Furthermore, we show that the observed consistently narrower passage time distributions enables a more reliable DNA length separation independent of pore size and stability. We also demonstrate that the composite nanofilter/nanopore devices can be configured to suppress the frequency of folded translocations, ensuring single-file passage of captured DNA molecules. By greatly increasing the rate at which usable data can be collected, these unique attributes will offer significant practical advantages to many solid-state nanopore-based sensing schemes, including sequencing, genomic mapping, and barcoded target detection.


Treating psoriasis with adalimumab.
Psoriasis is a common, chronic, inflammatory skin disease that can have a significant impact on the quality of life of those who are afflicted. Recent advances in the understanding of the pathophysiology of psoriasis have led to the development of new, genetically engineered, targeted therapies for this disease. Among the most successful strategies for treatment has been the use of biologic immunotherapies targeting tumor necrosis factor alpha (TNF). Recent research has evaluated the efficacy and safety of a new anti-TNF agent, adalimumab. Adalimumab is a human monoclonal antibody that is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of rheumatoid arthritis and psoriatic arthritis. Recently released data from large, randomized clinical trials suggests that adalimumab has significant efficacy for the treatment of chronic plaque psoriasis and is well tolerated. Thus, adalimumab seems to be a promising therapeutic approach for patients who suffer from moderate to severe plaque psoriasis.


A PCR reactor with an integrated alumina membrane for nucleic acid isolation.
Recently, there has been a growing interest in point-of-care devices capable of detecting nucleic acids (NA) in clinical and environmental samples. Nucleic acid detection requires, however, various sample preparation steps that complicate device operation. An attractive remedy is to integrate many, if not all, sample preparation operations and nucleic acid amplification into a single reaction chamber. A microfluidic chip that integrates, in a single chamber, polymerase chain reaction (PCR) amplification with solid-phase extraction of nucleic acids using a nanoporous, aluminium oxide membrane (AOM) is described. Samples suspected of containing target bacteria and/or viruses are mixed with lysis agents and a chaotropic salt and loaded into a plastic chip housing a nanoporous, aluminium oxide membrane. The nucleic acids in the lysate bind to the membrane. The membrane is then washed, the chamber is filled with the PCR reaction reagents, and the chamber's temperature is cycled to amplify the captured nucleic acids and produce detectable products. Both DNA and RNA (with reverse-transcription) isolation and amplification are demonstrated. Due to the dry membrane's high resistance to liquid flow, a specialized flow control system was devised to facilitate sample introduction and membrane washing.


Pulse pressure variation as a guide for volume expansion in dogs undergoing orthopedic surgery.
To investigate whether pulse pressure variation (PPV) can predict fluid responsiveness in healthy dogs during clinical surgery. Prospective clinical study. Thirty-three isoflurane-anesthetized dogs with arterial hypotension during orthopedic surgery. Fluid challenge with lactated Ringer's solution (15 mL kg-1 in 15 minutes) was administered in mechanically ventilated dogs (tidal volume 10 mL kg-1) with hypotension [mean arterial pressure (MAP) < 65 mmHg]. The volume expansion was considered effective if cardiac output (CO; transesophageal Doppler) increased by ≥ 15%. Cardiopulmonary data were analyzed using two-way ANOVA, receiver operating characteristics (ROC) curves and Spearman coefficient; p < 0.05 was considered significant. Effective volume expansion, mean ± standard deviation 42 ± 4% increase in CO (p < 0.0001) was observed in 76% of the dogs, resulting in a decrease in PPV (p < 0.0001) and increase in MAP (p < 0.0001), central venous pressure (CVP; p = 0.02) and ejection fraction (p < 0.0001) compared with before the fluid challenge. None of these changes occurred when volume expansion resulted in a nonsignificant CO increase of 4 ± 5%. No significant differences were observed in blood gas analysis between responsive and nonresponsive dogs. The increase in CO was correlated with the decrease in PPV (r = -0.65; p < 0.0001) but absolute values of CO and PPV were not correlated. The PPV performance (ROC curve area: 0.89 ± 0.06, p = 0.0011) was better than that of CVP (ROC curve area: 0.54 ± 0.12) and MAP (ROC curve area: 0.59 ± 0.13) to predict fluid responsiveness. The best cut-off for PPV to distinguish responders and nonresponders was 15% (50% sensitivity and 96% specificity). In mechanically ventilated, healthy, isoflurane-anesthetized dogs, PPV predicted fluid responsiveness to volume expansion, and MAP and CVP did not show such applicability.


Advances in Understanding the Role of Aloe Emodin and Targeted Drug Delivery Systems in Cancer.
Cancer is one of the important causes of death worldwide. Despite remarkable improvements in cancer research in the past few decades, several cancer patients still cannot be cured owing to the development of drug resistance. Natural sources might have prominence as potential drug candidates. Among the several chemical classes of natural products, anthraquinones are characterized by their large structural variety, noticeable biological activity, and low toxicity. Aloe emodin, an anthraquinone derivative, is a natural compound found in the roots and rhizomes of many plants. This compound has proven its antineoplastic, anti-inflammatory, antiangiogenic, and antiproliferative potential as well as ability to prevent cancer metastasis and potential in reversing multidrug resistance of cancer cells. The anticancer property of aloe emodin, a broad-spectrum inhibitory agent of cancer cells, has been detailed in many biological pathways. In cancer cells, these molecular mechanisms consist of inhibition of cell growth and proliferation, cell cycle arrest deterioration, initiation of apoptosis, antimetastasis, and antiangiogenic effect. In accordance with the strategy of developing potential drug candidates from natural products, aloe emodin's low bioavailability has been tried to be overcome by structural modifications and nanocarrier systems. Consequently, this review summarizes the antiproliferative and anticarcinogenic properties of aloe emodin, as well as the enhanced activity of its derivatives and the advantages of drug delivery systems on bioavailability.


Venovenous Bypass Is Associated With a Lower Incidence of Acute Kidney Injury After Liver Transplantation in Patients With Compromised Pretransplant Renal Function.
Although the hemodynamic benefits of venovenous bypass (VVB) during liver transplantation (LT) are well appreciated, the impact of VVB on posttransplant renal function is uncertain. The aim of this study was to determine if VVB was associated with a lower incidence of posttransplant acute kidney injury (AKI). Medical records of adult (≥18 years) patients who underwent primary LT between 2004 and 2014 at a tertiary hospital were reviewed. Patients who required pretransplant renal replacement therapy and intraoperative piggyback technique were excluded. Patients were divided into 2 groups, VVB and non-VVB. AKI, determined by the Acute Kidney Injury Network criteria, was compared between the 2 groups. Propensity match was used to control selection bias that occurred before VVB and multivariable logistic regression was used to control confounding factors during and after VVB. Of 1037 adult patients who met the study inclusion criteria, 247 (23.8%) received VVB. A total of 442 patients (221 patients in each group) were matched. Aftermatch patients were further divided according to a predicted probability AKI model using preoperative creatinine (Cr), VVB, and intraoperative variables into 2 subgroups: normal and compromised pretransplant renal functions. In patients with compromised pretransplant renal function (Cr ≥1.2 mg/dL), the incidence of AKI was significantly lower in the VVB group compared with the non-VVB group (37.2% vs 50.8%; P = .033). VVB was an independent risk factor negatively associated with AKI (odds ratio, 0.1; 95% confidence interval, 0.1-0.4; P = .001). Renal replacement in 30 days and 1-year recipient mortality were not significantly different between the 2 groups. The incidence of posttransplant AKI was not significantly different between the 2 groups in patients with normal pretransplant renal function (Cr <1.2 mg/dL). In this large retrospective study, we demonstrated that utilization of intraoperative VVB was associated with a significantly lower incidence of posttransplant AKI in patients with compromised pretransplant renal function. Further studies to assess the role of intraoperative VVB in posttransplant AKI are warranted.


Enhanced invasion of metastatic cancer cells via extracellular matrix interface.
Cancer cell invasion is a major component of metastasis and is responsible for extensive cell diffusion into and major destruction of tissues. Cells exhibit complex invasion modes, including a variety of collective behaviors. This phenomenon results in the structural heterogeneity of the extracellular matrix (ECM) in tissues. Here, we systematically investigated the environmental heterogeneity facilitating tumor cell invasion via a combination of in vitro cell migration experiments and computer simulations. Specifically, we constructed an ECM microenvironment in a microfabricated biochip and successfully created a three-dimensional (3D) funnel-like matrigel interface inside. Scanning electron microscopy demonstrated that the interface was at the interior defects of the nano-scale molecular anisotropic orientation and the localized structural density variations in the matrigel. Our results, particularly the correlation of the collective migration pattern with the geometric features of the funnel-like interface, indicate that this heterogeneous in vitro ECM structure strongly guides and promotes aggressive cell invasion in the rigid matrigel space. A cellular automaton model was proposed based on our experimental observations, and the associated quantitative analysis indicated that cell invasion was initiated and controlled by several mechanisms, including microenvironment heterogeneity, long-range cell-cell homotype and gradient-driven directional cellular migration. Our work shows the feasibility of constructing a complex and heterogeneous in vitro 3D ECM microenvironment that mimics the in vivo environment. Moreover, our results indicate that ECM heterogeneity is essential in controlling collective cell invasive behaviors and therefore determining metastasis efficiency.


Exogenous ochronosis hydroquinone induced: a report of four cases.
Exogenous ochronosis is an infrequent dermatosis characterized as a dark blue hyperpigmentation localized where the causing agent was applied. It may be caused by the use of systemic medication such as antimalarials and by the use of topic substances such as phenol, resorcinol, benzene, or hydroquinone, which is a fenolic compound with depigmentation action, largely used in the treatment of melasma and other hyperpigmentation. The physiopathology of this process is not well clear up to this moment, and the therapeutic measures are not satisfactory either. Here we present four cases of female patients that developed hyperpigmentation on their faces after the use of hydroquinone containing compounds, characterized clinically and histological as ochronosi. We emphasize the possibility of exogenous ochronosis cases being misdiagnosed as a melasma treatment failure. We also emphasize the risks of the indiscriminated use of hydroquinone containing compounds, used, in many instances, without medical prescription.


Molecular cloning and characterization of 5-enolpyruvylshikimate-3-phosphate synthase gene from Convolvulus arvensis L.
5-Enolpyruvylshikimate-3-phosphate synthase (EPSPS), the target enzyme for glyphosate inhibition, catalyzes an essential step in the shikimate pathway for aromatic amino acid biosynthesis. The full-length cDNA of 1,751 nucleotides (CaEPSPS, Genbank accession number: EU698030) from Convolvulus arvensis was cloned and characterized. The CaEPSPS encodes a polypeptide of 520 amino acids with a calculated molecular weight of 55.5 kDa and an isoelectric point of 7.05. The results of homology analysis revealed that CaEPSPS showed highly homologous with EPSPS proteins from other plant species. Tissue expression pattern analysis indicated that CaEPSPS was constitutively expressed in stems, leaves and roots, with lower expression in roots. CaEPSPS expression level could increase significantly with glyphosate treatment, and reached its maximum at 24 h after glyphosate application. We fused CaEPSPS to the CaMV 35S promoter and introduced the chimeric gene into Arabidopsis. The resultant expression of CaEPSPS in transgenic Arabidopsis plants exhibited enhanced tolerance to glyphosate in comparison with control.


Formiminoglutamase from Trypanosoma cruzi is an arginase-like manganese metalloenzyme.
The crystal structure of formiminoglutamase from Trypanosoma cruzi (TcFIGase) is reported at 1.85 Å resolution. Although the structure of this enzyme was previously determined by the Structural Genomics of Pathogenic Protozoa Consortium (PDB accession code 2A0M), this structure was determined at low pH and lacked bound metal ions; accordingly, the protein was simply annotated as "arginase superfamily protein" with undetermined function. We show that reconstitution of this protein with Mn²⁺ confers maximal catalytic activity in the hydrolysis of formiminoglutamate to yield glutamate and formamide, thereby demonstrating that this protein is a metal-dependent formiminoglutamase. Equilibration of TcFIGase crystals with MnCl₂ at higher pH yields a binuclear manganese cluster similar to that observed in arginase, except that the histidine ligand to the Mn²⁺(A) ion of arginase is an asparagine ligand (N114) to the Mn²⁺(A) ion of TcFIGase. The crystal structure of N114H TcFIGase reveals a binuclear manganese cluster essentially identical to that of arginase, but the mutant exhibits a modest 35% loss of catalytic efficiency (k(cat)/K(M)). Interestingly, when TcFIGase is prepared and crystallized in the absence of reducing agents at low pH, a disulfide linkage forms between C35 and C242 in the active site. When reconstituted with Mn²⁺ at higher pH, this oxidized enzyme exhibits a modest 33% loss of catalytic efficiency. Structure determinations of the metal-free and metal-bound forms of oxidized TcFIGase reveal that although disulfide formation constricts the main entrance to the active site, other structural changes open alternative channels to the active site that may help sustain catalytic activity.


Plasma prostaglandins in the normal menstrual cycle.
Plasma prostaglandins were studied by radioimmunoassay on alternate days during the menstrual cycle in fourteen normal women. No cyclic patterns were found for A-like prostaglandins using an assay which measured 13,14-dihydro-PGA. Mean subject values of PGA-like prostaglandin ranged from 367 to 904 pg/ml and varied significantly among women. Prostaglandin E determinations showed an upward trend beginning 8 days before the LH peak. PGE subject means varied significantly and ranged from 182 to 362 pg/ml. Prostaglandin F did not exhibit a cyclic pattern. The average concentration of PGF for individual women ranged from 58 to 153 pg/ml, showing significant variance. The physiologic implications of the results are discussed as well as recommendations for the design of future studies.


Bone turnover following autologous transplantation in multiple myeloma.
Most patients with multiple myeloma have lytic lesions at multiple sites in the axial skeleton. These lesions commonly give pain and are at risk of pathological fracture, and bony disease is therefore a cause of much morbidity in myeloma. Recent data indicates that the Receptor Activator of NF-kappaB ligand (RANKL) and Osteoprotegerin (OPG) may be central to the local pathogenesis of these lytic lesions. Bisphosphonates may ameliorate some of these abnormalities, and clinically these agents improve the skeletal prognosis in myeloma patients. High dose chemotherapy with autologous stem cell rescue is currently under evaluation in the management of myeloma, though little is known of the effect of this therapeutic modality on the skeleton. Studies using biochemical markers of bone turnover suggest that increased osteoclast activity may be present even in apparent plateau phase of myeloma. High dose chemotherapy with autografting may normalise abnormal bone resorption, though the effect may take several weeks to emerge, and may be paralleled by increased osteoblast activity. The findings provide biochemical evidence that autografting may help normalise the abnormal bone turnover characteristic of myeloma.


A comparison of simultaneous cervical cytology, HPV testing, and colposcopy.
This pilot study explores the screening techniques for premalignant and malignant disease of the cervix. Given current knowledge of the etiology and progression of cancer of the cervix, should family physicians screen patients with Papanicolaou (Pap) smears, Human Papillomavirus (HPV) smears, colposcopy, or some combination of these three? In a retrospective audit of 75 patients comparing simultaneous Pap smears and colposcopy, 5 of 8 patients with biopsy-proven cervical intraepithelial neoplasia (CIN) and one with invasive cancer had normal Pap smears. Because of this high false-negative Pap smear rate, a prospective study comparing a simultaneous Pap smear, HPV smear, and colposcopic examination (with biopsy when indicated) was undertaken. Seventy consecutive patients seen by the author for routine pelvic examinations consented to and were enrolled in the study. Seven patients had biopsy-proven CIN lesions; 2 were found by Pap smear, 3 by colposcopy, and 5 by HPV smear. The Pap smear missed 5 lesions, colposcopy missed 4, and the HPV smear missed 2. Further studies are needed to determine the optimal screening method for CIN.


Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation.
Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA) exhibit kidney-protective actions through poorly understood mechanisms. Here we interrogated whether the receptor for advanced glycation end products (RAGE) plays a role in mediating the actions of GLP-1 on inflammation and diabetic kidney disease. Mice with deletion of the GLP-1 receptor displayed an abnormal kidney phenotype that was accelerated by diabetes and improved with co-deletion of RAGE in vivo. Activation of the GLP-1 receptor pathway with liraglutide, an anti-diabetic treatment, downregulated kidney RAGE, reduced the expansion of bone marrow myeloid progenitors, promoted M2-like macrophage polarization and lessened markers of kidney damage in diabetic mice. Single cell transcriptomics revealed that liraglutide induced distinct transcriptional changes in kidney endothelial, proximal tubular, podocyte and macrophage cells, which were dominated by pathways involved in nutrient transport and utilization, redox sensing and the resolution of inflammation. The kidney-protective action of liraglutide was corroborated in a non-diabetic model of chronic kidney disease, the subtotal nephrectomised rat. Thus, our findings identify a novel glucose-independent kidney-protective action of GLP-1-based therapies in diabetic kidney disease and provide a valuable resource for exploring the cell-specific kidney transcriptional response ensuing from pharmacological GLP-1R agonism.


Global analysis of cdc14 dephosphorylation sites reveals essential regulatory role in mitosis and cytokinesis.
Degradation of the M phase cyclins triggers the exit from M phase. Cdc14 is the major phosphatase required for the exit from the M phase. One of the functions of Cdc14 is to dephosphorylate and activate the Cdh1/APC/C complex, resulting in the degradation of the M phase cyclins. However, other crucial targets of Cdc14 for mitosis and cytokinesis remain to be elucidated. Here we systematically analyzed the positions of dephosphorylation sites for Cdc14 in the budding yeast Saccharomyces cerevisiae. Quantitative mass spectrometry identified a total of 835 dephosphorylation sites on 455 potential Cdc14 substrates in vivo. We validated two events, and through functional studies we discovered that Cdc14-mediated dephosphorylation of Smc4 and Bud3 is essential for proper mitosis and cytokinesis, respectively. These results provide insight into the Cdc14-mediated pathways for exiting the M phase.


Herpes simplex virus type-2 antibodies in pregnant women: the impact of the stage of pregnancy.
In this study the impact of pregnancy duration on the measured level of HSV-2 antibodies was assessed. The study population comprised 35,940 pregnant women in Norway, in 1992-4, followed during pregnancy. A random sample of 960 women was selected. A mean of 2.6 serum samples from each woman were analysed for HSV-2 specific IgG antibodies at different times in pregnancy. Crude and adjusted odds ratios were estimated in logistic regression models taking all observations per women into account. Twenty-seven percent of the pregnant women had antibodies against HSV-2 in the first trimester. The adjusted odds ratio of being HSV-2 antibody positive decreased during the pregnancy and was 0.5 (0.2-0.9, 95% confidence interval) in the 40th as compared to the 10th week of pregnancy. About 50% of initially HSV-2 positive women did not have detecable antibodies by the end of the pregnancy. This may be explained by haemodilution during pregnancy. Our findings have diagnostic implications and should encourage further studies.


g-Jitter mixed convective slip flow of nanofluid past a permeable stretching sheet embedded in a Darcian porous media with variable viscosity.
The unsteady two-dimensional laminar g-Jitter mixed convective boundary layer flow of Cu-water and Al2O3-water nanofluids past a permeable stretching sheet in a Darcian porous is studied by using an implicit finite difference numerical method with quasi-linearization technique. It is assumed that the plate is subjected to velocity and thermal slip boundary conditions. We have considered temperature dependent viscosity. The governing boundary layer equations are converted into non-similar equations using suitable transformations, before being solved numerically. The transport equations have been shown to be controlled by a number of parameters including viscosity parameter, Darcy number, nanoparticle volume fraction, Prandtl number, velocity slip, thermal slip, suction/injection and mixed convection parameters. The dimensionless velocity and temperature profiles as well as friction factor and heat transfer rates are presented graphically and discussed. It is found that the velocity reduces with velocity slip parameter for both nanofluids for fluid with both constant and variable properties. It is further found that the skin friction decreases with both Darcy number and momentum slip parameter while it increases with viscosity variation parameter. The surface temperature increases as the dimensionless time increases for both nanofluids. Nusselt numbers increase with mixed convection parameter and Darcy numbers and decreases with the momentum slip. Excellent agreement is found between the numerical results of the present paper with published results.


Anticoagulant rodenticides on our public and community lands: spatial distribution of exposure and poisoning of a rare forest carnivore.
Anticoagulant rodenticide (AR) poisoning has emerged as a significant concern for conservation and management of non-target wildlife. The purpose for these toxicants is to suppress pest populations in agricultural or urban settings. The potential of direct and indirect exposures and illicit use of ARs on public and community forest lands have recently raised concern for fishers (Martes pennanti), a candidate for listing under the federal Endangered Species Act in the Pacific states. In an investigation of threats to fisher population persistence in the two isolated California populations, we investigate the magnitude of this previously undocumented threat to fishers, we tested 58 carcasses for the presence and quantification of ARs, conducted spatial analysis of exposed fishers in an effort to identify potential point sources of AR, and identified fishers that died directly due to AR poisoning. We found 46 of 58 (79%) fishers exposed to an AR with 96% of those individuals having been exposed to one or more second-generation AR compounds. No spatial clustering of AR exposure was detected and the spatial distribution of exposure suggests that AR contamination is widespread within the fisher's range in California, which encompasses mostly public forest and park lands Additionally, we diagnosed four fisher deaths, including a lactating female, that were directly attributed to AR toxicosis and documented the first neonatal or milk transfer of an AR to an altricial fisher kit. These ARs, which some are acutely toxic, pose both a direct mortality or fitness risk to fishers, and a significant indirect risk to these isolated populations. Future research should be directed towards investigating risks to prey populations fishers are dependent on, exposure in other rare forest carnivores, and potential AR point sources such as illegal marijuana cultivation in the range of fishers on California public lands.


'If not TB, what could it be?' Chest X-ray findings from the 2016 Kenya Tuberculosis Prevalence Survey.
The prevalence of diseases other than TB detected during chest X-ray (CXR) screening is unknown in sub-Saharan Africa. This represents a missed opportunity for identification and treatment of potentially significant disease. Our aim was to describe and quantify non-TB abnormalities identified by TB-focused CXR screening during the 2016 Kenya National TB Prevalence Survey. We reviewed a random sample of 1140 adult (≥15 years) CXRs classified as 'abnormal, suggestive of TB' or 'abnormal other' during field interpretation from the TB prevalence survey. Each image was read (blinded to field classification and study radiologist read) by two expert radiologists, with images classified into one of four major anatomical categories and primary radiological findings. A third reader resolved discrepancies. Prevalence and 95% CIs of abnormalities diagnosis were estimated. Cardiomegaly was the most common non-TB abnormality at 259 out of 1123 (23.1%, 95% CI 20.6% to 25.6%), while cardiomegaly with features of cardiac failure occurred in 17 out of 1123 (1.5%, 95% CI 0.9% to 2.4%). We also identified chronic pulmonary pathology including suspected COPD in 3.2% (95% CI 2.3% to 4.4%) and non-specific patterns in 4.6% (95% CI 3.5% to 6.0%). Prevalence of active-TB and severe post-TB lung changes was 3.6% (95% CI 2.6% to 4.8%) and 1.4% (95% CI 0.8% to 2.3%), respectively. Based on radiological findings, we identified a wide variety of non-TB abnormalities during population-based TB screening. TB prevalence surveys and active case finding activities using mass CXR offer an opportunity to integrate disease screening efforts. National Institute for Health Research (IMPALA-grant reference 16/136/35).


"Iatrogenic" Segmental Defect: How I Debride High-Energy Open Tibial Fractures.
High-energy, open tibial shaft fractures may result in significant comminution, bone loss, and soft tissue injuries. Early, thorough debridement of all nonviable tissue is of critical importance in treating these fractures as an inadequate initial debridement increases the risk of infection and nonunion. Large iatrogenic bone and soft tissue defects can result from debridement and will require subsequent reconstruction by both orthopaedic and plastic surgeons. Although a variety of approaches exist to address these reconstructions, successful management of bone defects remains a considerable challenge. In this article, we detail our approach to debridement and reconstruction of segmental tibial defects and provide a review on the literature on this topic.


Iridodialysis in a rhesus macaque: a case report.
During routine physical examination, a five-year-old male rhesus macaque (Macaca mulatta) was observed to have gaps in the right iris. Ophthalmic examination revealed inferior and superior iridodialysis with an anterior cortical cataract. The optic nerve head and fundus were normal. Uninvolved areas of the iris and anterior-chamber angle were normal on the basis of results of gonioscopy. Tonometry revealed normal intraocular pressure. The cause of the iridodialysis in this monkey's eye was not known. The animal had been housed individually since arrival due to requirements of the research protocol. Although the concomitant cataract supports a traumatic cause, there was no history of cranial or other ocular injuries. Trauma from fighting through the cage walls, self-trauma or falling inside the cage while under sedation cannot be ruled out. Multiple hematologic evaluations disclosed no abnormalities. This animal did not manifest behavioral abnormalities or any indication of pain. Therefore, treatment was not initiated. Intraocular pressure continues to be monitored at least semiannually.


Chronic Kidney Disease and Coronary Artery Disease: JACC State-of-the-Art Review.
Chronic kidney disease (CKD) is a major risk factor for coronary artery disease (CAD). As well as their high prevalence of traditional CAD risk factors, such as diabetes and hypertension, persons with CKD are also exposed to other nontraditional, uremia-related cardiovascular disease risk factors, including inflammation, oxidative stress, and abnormal calcium-phosphorus metabolism. CKD and end-stage kidney disease not only increase the risk of CAD, but they also modify its clinical presentation and cardinal symptoms. Management of CAD is complicated in CKD patients, due to their likelihood of comorbid conditions and potential for side effects during interventions. This summary of the Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference on CAD and CKD (including end-stage kidney disease and transplant recipients) seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of CAD in CKD and to identify knowledge gaps, areas of controversy, and priorities for research.


Exemestane for breast cancer prevention: a feasible strategy?
Third-generation aromatase inhibitors and inactivators have been successfully implemented in therapy of metastatic breast cancer, and three large phase III trials have revealed superiority compared with tamoxifen monotherapy in the adjuvant setting. Notably, each of these trials recorded a substantial reduction in contralateral breast cancer among patients exposed to the aromatase inhibitor/inactivator. A major concern in implementing use of these compounds in the preventive setting relates to potential detrimental effects of estrogen suppression on bone and lipid metabolism. Recent data from a placebo-controlled study now reveal 2 years of treatment with exemestane compared with placebo to have moderate effects on bone metabolism and plasma lipid profile, supporting further evaluation of exemestane as a potential preventive agent for breast cancer in postmenopausal women.


Gene analogue finder: a GRID solution for finding functionally analogous gene products.
To date more than 2,1 million gene products from more than 100000 different species have been described specifying their function, the processes they are involved in and their cellular localization using a very well defined and structured vocabulary, the gene ontology (GO). Such vast, well defined knowledge opens the possibility of compare gene products at the level of functionality, finding gene products which have a similar function or are involved in similar biological processes without relying on the conventional sequence similarity approach. Comparisons within such a large space of knowledge are highly data and computing intensive. For this reason this project was based upon the use of the computational GRID, a technology offering large computing and storage resources. We have developed a tool, GENe AnaloGue FINdEr (ENGINE) that parallelizes the search process and distributes the calculation and data over the computational GRID, splitting the process into many sub-processes and joining the calculation and the data on the same machine and therefore completing the whole search in about 3 days instead of occupying one single machine for more than 5 CPU years. The results of the functional comparison contain potential functional analogues for more than 79000 gene products from the most important species. 46% of the analyzed gene products are well enough described for such an analysis to individuate functional analogues, such as well-known members of the same gene family, or gene products with similar functions which would never have been associated by standard methods. ENGINE has produced a list of potential functionally analogous relations between gene products within and between species using, in place of the sequence, the gene description of the GO, thus demonstrating the potential of the GO. However, the current limiting factor is the quality of the associations of many gene products from non-model organisms that often have electronic associations, since experimental information is missing. With future improvements of the GO, this limit will be reduced. ENGINE will manifest its power when it is applied to the whole GODB of more than 2,1 million gene products from more than 100000 organisms. The data produced by this search is planed to be available as a supplement to the GO database as soon as we are able to provide regular updates.


The AMPA modulator S 18986 improves declarative and working memory performances in aged mice.
The aim of this study was to further characterize the memory-enhancing profile of S 18986 a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. S 18986 was studied in two mouse models of age-related memory deficits, using radial maze paradigms involving long-term/declarative memory and short-term/working memory. Aged mice exhibited severe deficits when compared with their younger counterparts in the two behavioural tests. S 18986 at the dose of 0.1 mg/kg selectively improved aged mouse performance in the test of long-term/declarative memory flexibility and exerted a beneficial effect on short-term retention of successive arm-visits in the short-term/working memory test. This study confirms the memory-enhancing properties of S 18986 and, in line with emerging data on multiple AMPA modulators, highlights the relevance of targeting AMPA receptors in the development of new memory enhancers.


Cerebral ischemia related to globus pallidus internus stimulation for cervical dystonia.
Deep brain stimulation (DBS) is generally a safe and effective method to treat intractable movement disorders. However, complications of surgery have been reported, such as hemorrhage, infection and hardware failure. We describe an unusual complication associated with DBS of the globus pallidus internus (GPi). The patient was a 34-year-old man with a 5-year history of progressive cervical dystonia that was unresponsive to medical treatment. He underwent bilateral DBS of the posteroventral GPi. After test stimulation, the patient developed left facial weakness, as well as dysarthria and hemiparesis of the left side. Magnetic resonance imaging showed a small infarct in the right posterior internal capsule. There was no misplacement of the microelectrode. The authors present this unique case of cerebral infarction as a complication of DBS. The mechanism of ischemia is unclear. However, in this case, we had performed microstimulation with high amplitude in order to determine the adverse effects. This magnitude of electrical stimulation may have led to small-vessel vasospasm, which may have induced ischemia. Although ischemia after DBS surgery is seldom reported, cerebral ischemia may be a surgical complication after DBS implantation.


Protective and restitutive effects of antihypoxic drugs on posthypoxic dopamine release inhibition.
Exposure of rats to hypoxia results in a substantial decrease of dopamine release from striatum slices for several days. Nootropic drugs (piracetam, meclofenoxate hydrochloride, methylglucamine orotate, nicergoline) accelerate the restitution of posthypoxic release inhibition. In contrast, amphetamine is ineffective in this respect. The antihypoxic action of sedatives (diazepam, phenobarbital) prevents the decrease of dopamine release. Comparable results with free radical scavengers (cysteamine hydrochloride, sodium formiate, ouabain), ascorbic acid, natrii calcii edetas, selenium methionine and acetylsalicylic acid which protect dopamine release from hypoxically produced changes agree with and support the hypothesis of hypoxia induced free radical generation followed by phospholipid peroxidation altering particularly neuronal membrane function. On that account, dopamine release from rat striatum slices reflects not only the vulnerability of neuronal membrane function by hypoxia but also the preventive, protective and restitutive effects of antihypoxic drugs of different type and is able to contribute to discriminating drug investigation.


Antimicrobial effects of continuous versus intermittent administration of carbapenem antibiotics in an in vitro dynamic model.
In an in vitro dynamic model we compared the antimicrobial effects of two carbapenems, imipenem (MIC, 1 microg/ml) and meropenem (MIC, 0.25 microg/ml) on Pseudomonas aeruginosa. The antibiotics were administered either as short-time infusions once or three times a day or as continuous infusions with steady-state levels ranging from 0.5 to 20 microg/ml. From the resulting kill curves the period of time until the onset of bacterial death (dt), the rate constant of bacterial death (ka), the maximal reduction of CFU (mr), and the period of time until bacterial regrowth occurred (tr) were determined. Additionally, the occurrence of bacterial resistance during the simulations (rq) and the postantibiotic effect (PAE) were recorded. For both investigated carbapenems no significant difference in dt, ka, mr, and PAE values between the short-time infusions and continuous infusions with steady-state levels above 2 microg/ml could be detected. The tr was longest with continuous infusions of over approximately 24 h, corresponding to steady-state levels of 3 microg/ml for imipenem and 2.5 microg/ml for meropenem. An increase in MIC was observed only during continuous infusions with steady-state levels below 2 microg/ml. Independent of the chosen method of application and despite the lower MIC of meropenem, imipenem was slightly more effective than meropenem.


Evaluation of Serum Resistin, Visfatin, and Chemerin Levels in Patients with Lung Cancer and Chronic Obstructive Pulmonary Disease.
Cachexia is an important problem in lung cancer and chronic obstructive pulmonary disease (COPD). Some studies report an association between adipokines and cachexia. Our study aimed to investigate the association of three novel adipokines, resistin, visfatin, and chemerin, with lung cancer and COPD. 30 patients with non-smallcell lung cancer, 30 patients with COPD, and 30 healthy volunteers were included in the study. Statistically significant weight loss was found in COPD and lung cancer groups compared with that in the control group (p<0.001). Among the biomarkers, only resistin levels were significantly higher in patients with cachexia than in patients without weight loss in all groups (p=0.006). Resistin level was significantly higher in patients with COPD (p=0.002). Visfatin level was significantly higher in the control group (p=0.001). We found that a higher biomass exposure resulted in a significant increase and decrease in resistin (p=0.007) and visfatin levels (p=0.001), respectively, in the patient groups. For all groups, no statistically significant relationship was found between chemerin levels and weight loss or other variables. No significant relationship was found between the biomarkers and lung cancer type, tumor stage, lymph node stage, and metastasis stage. There was no relationship between the biomarkers by tumor, node, and metastasis and COPD stages (p>0.05). We observed no findings strong enough to support the use of these molecules as markers of disease stage or cachexia. Resistin, visfatin, and chemerin cannot be used as potential biomarkers for lung cancer or COPD or for disease stage or cachexia.


Translation of a tobacco survey into Spanish and Asian languages: the Tobacco Use Supplement to the Current Population Survey.
Because of the vital need to attain cross-cultural comparability of estimates of tobacco use across subgroups of the U.S. population that differ in primary language use, the National Cancer Institute (NCI) Tobacco Use Special Cessation Supplement to the Current Population Survey (TUSCS-CPS) was translated into Spanish, Chinese (Mandarin and Cantonese), Korean, Vietnamese, and Khmer (Cambodian). The questionnaire translations were extensively tested using an eight-step process that focused on both translation procedures and empirical pretesting. The resulting translations are available on the Internet at http://riskfactor.cancer.gov/studies/tus-cps/translation/questionnaires.html for tobacco researchers to use in their own surveys, either in full, or as material to be selected as appropriate. This manuscript provides information to guide researchers in accessing and using the translations, and describes the empirical procedures used to develop and pretest them (cognitive interviewing and behavior coding). We also provide recommendations concerning the further development of questionnaire translations.


Genetic variants in CYP7A1 and risk of myocardial infarction and symptomatic gallstone disease.
Myocardial infarction (MI) and gallstone disease (GSD) are intrinsically linked via cholesterol metabolism. We tested the hypothesis that genetic variants in the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver, are associated with risk of MI and GSD in the general population. We performed tests of association between lipid levels and eight rare non-synonymous mutations and two common variants, rs2081687 and rs3808607, in CYP7A1 in 100 149 individuals from the general population. We further tested whether weighted allele scores for rs2081687 and rs3808607, which were associated with increased plasma levels of low-density lipoprotein (LDL) cholesterol, were associated with an increased risk of both MI and symptomatic GSD. During a mean follow-up of 7 years (0-23 years), MI developed in 2326 individuals and GSD in 2007. For rare mutations, CYP7A1 allele count was associated with an increase in LDL cholesterol of 12% (0.4 mmol/L) for individuals with the highest vs. the lowest allele count (P for trend = 3 × 10-4). For common variants, CYP7A1 weighted allele scores in individuals with a score >0.04 vs. ≤0 were associated with stepwise increases in LDL cholesterol of up to 2.4% (0.08 mmol/L), and with corresponding multifactorially adjusted hazard ratios of 1.25 [95% confidence interval (CI) 1.10-1.41] for MI and 1.39 (95% CI 1.22-1.59) for GSD (P for trend = 5 × 10-4 and 2 × 10-7, respectively). Results were similar in meta-analyses including publicly available data from large consortia. Genetic variants in CYP7A1 which are associated with increased levels of LDL cholesterol, are associated with an increased risk of both MI and GSD.


[The ideal endodontic posts. A review of the literature].
Extensive research has been done regarding endodontic posts. In the majority of cases, only a few aspects are investigated. A literature review was performed regarding the various aspects that have to be considered when selecting a particular endodontic post for clinical application. The dentist has to realize that the ideal endodontic post (still) does not exist for all clinical situations. Most important is to achieve both a durable and a predictable result, sparing as much as possible of the root itself. Based on the literature, data presenting the requirements for an 'ideal' endodontic post are formulated.


[Effect of potassium bichromate on mucous membranes of the nasal cavity and paranasal sinuses in animal experiments].
Common white rats were used in the study of potassium bichromate (PB) influence and paranasal sinuses mucosae. Single 2-10 PB endonasal introductions were performed on hemostatic collagenic sponge and on paraffin. PB revealed ability in significant causing chronic atrophic rhinosinusitis , and demonstrated weak carcinogenic properties through the induction of some nasal tumours after a prolonged contact of the nasal mucosa with the substance.