Angiotensin II type 2 receptors have a major somatodendritic distribution in vasopressin-containing neurons in the mouse hypothalamic paraventricular nucleus.
The hypothalamic paraventricular nucleus (PVN) and angiotensin II (AngII) play critical roles in cardiovascular and neurohumoral regulation ascribed in part to vasopressin (VP) release. The AngII actions in the PVN are mediated largely through angiotensin II type 1 (AT1) receptors. However, there is indirect evidence that the functionally elusive central angiotensin II type 2 (AT2) receptors are also mediators of AngII signaling in the PVN. We used electron microscopic dual immunolabeling of antisera recognizing the AT2 receptor and VP to test the hypothesis that mouse PVN neurons expressing VP are among the cellular sites where this receptor has a subcellular distribution conducive to local activation. Immunoreactivity for the AT2 receptor was detected in somatodendritic profiles, of which approximately 60% of the somata and approximately 28% of the dendrites also contained VP. In comparison with somata and dendrites, axons, axon terminals, and glia less frequently contained the AT2 receptor. Somatic labeling for the AT2 receptor was often seen in the cytoplasm near the Golgi lamellae and other endomembrane structures implicated in receptor trafficking. AT2 receptor immunoreactivity in dendrites was commonly localized to cytoplasmic endomembranes, but was occasionally observed on extra- or peri-synaptic portions of the plasma membrane apposed by astrocytic processes or by unlabeled axon terminals. The labeled dendritic plasmalemmal segments containing AT2 receptors received asymmetric excitatory-type or more rarely symmetric inhibitory-type contacts from unlabeled axon terminals containing dense core vesicles, many of which are known to store neuropeptides. These results provide the first ultrastructural evidence that AT2 receptors in PVN neurons expressing VP and other neuromodulators are strategically positioned for surface activation by AngII and/or intracellular trafficking.


[Therapeutic importance of trimetazidine in ischemic pathology of the myocardium].
Trimetazidine heralds a new therapeutic class and a new concept in coronary disease: that of cellular anti-ischemic, i.e. agents optimizing myocardial uptake of residual oxygen and substrate supplies and ensuring long-term protection of the myocardium against the harmful effects of ischaemia. The anti-ischemic efficacy of trimetazidine evidenced in all experimental models studied, its original mode of action, high degree of selectivity and convenience in use explain that clinical studies consistently underscore the therapeutic benefit of trimetazidine, with the following characteristics: whatever the clinical situation, trimetazidine always results in a rapid and major improvement in clinical and ECG signs; the therapeutic benefit with trimetazidine appears rapidly; trimetazidine is the only effective first-line antianginal agent that can freely be combined or co-prescribed with other agents; trimetazidine improves the efficacy of co-prescribed antianginal agents, and allows their dosages to be reduced, thereby decreasing the incidence of side effects; trimetazidine has no known contraindications, a strong advantage for coronary patients in whom other therapies are potentially dangerous. Further research is in progress to determine the therapeutic value of trimetazidine in other situations, e.g. acute stage of myocardial infarction or other conditions calling for effective myocardial protection.


Interpenetrating network formation in agarose--kappa-carrageenan gel composites.
Thermal, mechanical, turbidity, and microscope evidence is provided which strongly suggests molecular interpenetrating network (IPN) formation by mixtures of the seaweed polysaccharides agarose and kappa-carrageenan. Over a range of ionic strength, and potassium content, there is no evidence for synergistic coupling of the networks, and simple phase separation (demixing) can definitely be ruled out. At low ionic strength, where the agarose gels first, differential scanning calorimetry evidence shows some influence of the carrageenan on the agarose ordering enthalpy, particularly at higher polymer concentrations. As the potassium level is increased, however, and the order of gelling is reversed, this effect disappears. Cure behavior for the systems at high ionic strength can be described as a simple summation of the pure component contributions. At low ionic strength, on the other hand, the modulus behavior is more complex, suggesting either a modification, in the mixture, of the kappa-carrageenan gelling parameters or a more complex modulus additivity rule.


Regulator of G-Protein Signaling 5 Reduces HeyA8 Ovarian Cancer Cell Proliferation and Extends Survival in a Murine Tumor Model.
The regulator of G-protein signaling 5 (RGS5) belongs to a family of GTPase activators that terminate signaling cascades initiated by extracellular mediators and G-protein-coupled receptors. RGS5 has an interesting dual biological role. One functional RGS5 role is as a pericyte biomarker influencing the switch to angiogenesis during malignant progression. Its other functional role is to promote apoptosis in hypoxic environments. We set out to clarify the extent to which RGS5 expression regulates tumor progression-whether it plays a pathogenic or protective role in ovarian tumor biology. We thus constructed an inducible gene expression system to achieve RGS5 expression in HeyA8-MDR ovarian cancer cells. Through this we observed that inducible RGS5 expression significantly reduces in vitro BrdU-positive HeyA8-MDR cells, although this did not correlate with a reduction in tumor volume observed using an in vivo mouse model of ovarian cancer. Interestingly, mice bearing RGS5-expressing tumors demonstrated an increase in survival compared with controls, which might be attributed to the vast regions of necrosis observed by pathological examination. Additionally, mice bearing RGS5-expressing tumors were less likely to have ulcerated tumors. Taken together, this data supports the idea that temporal expression and stabilization of RGS5 could be a valuable tactic within the context of a multicomponent approach for modulating tumor progression.


Heterogeneity of beta-galactosidase from rabbit spleen. Separation and characterization of different forms.
Two forms, I and II, of an acid beta-galactosidase from rabbit spleen were separated by DEAE-cellulose chromatography and then characterized. Both forms of the enzyme showed different heat-stability (form I being heat-labile and form II heat-stable), and different pI (6.7 for form I and 5.3 and 6.7 for form II). Their gel filtration patterns were also different: form I was resolved in a single peak of mol. wt. 75,000, whereas form II was resolved in one or two peaks of mol. wt. 120,000 and greater than 200,000, depending on the pH of elution. However, both forms had similar pH stability and behavior toward alpha-methyl-beta-D-galactopyranoside, alpha-methyl-beta-D-glucopyranoside, urea and KCl. Differences in pH optima, optimal temperature and Km values were not marked.


Ocular disconjugacy cannot be measured without establishing a solid spatial reference.
This correspondence points out a need for clarification concerning the methodology utilized in the study "Eye tracking detects disconjugate eye movements associated with structural traumatic brain injury and concussion", recently published in Journal of Neurotrauma. The authors of the paper state that binocular eye movements were recorded using a single-camera video-oculography technique and that binocular disconjugate characteristics were analyzed without calibration of eye orientation. It is claimed that a variance-based disconjugacy metric was found to be sensitive to the severity of a concussive brain injury and to the status of recovery after the original injury. However, the reproducibility of the paper's findings may be challenged simply by the paucity of details in the methodological description. More importantly, from the information supplied or cited in the paper, it is difficult to evaluate the validity of the potentially interesting conclusions of the paper.


Impact of Connecticut's graduated driver licensing system on teenage motor vehicle crash rates.
In response to high rates of teen motor vehicle crashes (MVCs) many states have enacted graduated driver licensing (GDL) systems. GDL delays full licensure and allows beginners to obtain experience under lower risk conditions. The purpose of this study is to evaluate the impact over the past 10 years to determine its effect on teen MVCs. Connecticut MVC data from 1999 to 2008 were analyzed. Percent change (1999 vs. 2008) in MVC rates per 10,000 registered drivers was calculated by age, gender, during the night restriction (11:00 pm and 5:00 am), and MVCs with passengers. Linear regression analysis estimated the decrease of MVC rates each year. The MVC rate decreased by 40% for 16-year-old and 30% for 17-year-old drivers. In comparison, rates among 18-year-old, 19-year-old, 25- to 29-year-old, and 30- to 59-year-old drivers were reduced by 16%, 7%, 8%, and 11%, respectively. The MVC rate for 20- to 24-year-old drivers increased by 1%. During nighttime restricted driving times, MVC rates decreased by 54% among 16-year-old and 49% among 17-year-old drivers. The MVC rate with passengers decreased by 65% for 16-year-old and 53% for 17-year-old drivers. In comparison, rates of nighttime and with passenger MVCs among older drivers were significantly less. Implementation of Connecticut's GDL system has resulted in significant reductions in MVC rates among novice drivers. This analysis provides a method for other states to examine the impact of their GDL system.


[The lower esophageal sphincter in patients with Chagas' disease with peristalsis and aperistalsis].
The opening of the lower esophageal sphincter (LES) were studied by intraluminal manometry in 23 control subjects, 10 chagasic patients with peristalsis in esophagus and 15 chagasic patients with aperistalsis in esophagus. The opening of the LES were 2,1 +/- 0,7 seconds after wet deglutitions in controls, 3,2 +/- 1,2 seconds in chagasic with peristalsis and 3,5 +/- 1,7 seconds in chagasic with aperistalsis. The duration of relaxation were 7,9 +/- 1,5 seconds in controls, 5,2 +/- 1,0 seconds in chagasic wih peristalsis and 5,9 +/- 1,3 seconds in chagasic with aperistalsis. In Chagas' disease the LES may open delay or incomplete in patients with peristalsis or aperistalsis.


Impact of anatomical and functional severity of coronary atherosclerotic plaques on the transmural perfusion gradient: a [15O]H2O PET study.
Myocardial ischaemia occurs principally in the subendocardial layer, whereas conventional myocardial perfusion imaging provides no information on the transmural myocardial blood flow (MBF) distribution. Subendocardial perfusion measurements and quantification of the transmural perfusion gradient (TPG) could be more sensitive and specific for the detection of coronary artery disease (CAD). The current study aimed to determine the impact of lesion severity as assessed by the fractional flow reserve (FFR) on subendocardial perfusion and the TPG using [(15)O]H2O positron emission tomography (PET) imaging in patients evaluated for CAD. Sixty-six patients with anginal chest pain were prospectively enrolled and underwent [(15)O]H2O myocardial perfusion PET imaging. Subsequently, invasive coronary angiography was performed and FFR obtained in all coronary arteries irrespective of the PET imaging results. Thirty (45%) patients were diagnosed with significant CAD (i.e. FFR ≤0.80), whereas on a per vessel analysis (n = 198), 53 (27%) displayed a positive FFR. Transmural hyperaemic MBF decreased significantly from 3.09 ± 1.16 to 1.67 ± 0.57 mL min(-1) g(-1) (P < 0.001) in non-ischaemic and ischaemic myocardium, respectively. The TPG decreased during hyperaemia when compared with baseline (1.20 ± 0.14 vs. 0.94 ± 0.17, P < 0.001), and was lower in arteries with a positive FFR (0.97 ± 0.16 vs. 0.88 ± 0.18, P < 0.01). A TPG threshold of 0.94 yielded an accuracy to detect CAD of 59%, which was inferior to transmural MBF with an optimal cutoff of 2.20 mL min(-1) g(-1) and an accuracy of 85% (P < 0.001). Diagnostic accuracy of subendocardial perfusion measurements was comparable with transmural MBF (83 vs. 85%, respectively, P = NS). Cardiac [(15)O]H2O PET imaging is able to distinguish subendocardial from subepicardial perfusion in the myocardium of normal dimensions. Hyperaemic TPG is significantly lower in ischaemic myocardium. This technique can potentially be employed to study subendocardial perfusion impairment in more detail. However, the diagnostic accuracy of subendocardial hyperaemic perfusion and TPG appears to be limited compared with quantitative transmural MBF, warranting further study.


Trends in research on premature ejaculation over the past 25 years.
The authors posit that, among other things, the increasing popularity of pharmacological remedies has reinvigorated research interest in premature ejaculation (PE). However, the authors also posit that the emphasis has shifted from psychological-behavioral studies to biological-pharmacological studies, thereby distracting researchers from potent psychological/relationship factors known to play important roles in the recovery of overall sexual satisfaction. To explore actual patterns of research on PE, the authors determined trends in the overall quantity and focus of PE research over the past 25 years. The two major databases, PsychINFO and MEDLINE, were searched from 1979 to 2006 using several key words to identify all PE-related publications. Referenced articles on PE were cataloged by year and assigned to broad hypothetically and empirically based categories representing different approaches to the study of this dysfunction. MEDLINE, but not PsychINFO, exhibited a large increase in publications on PE over the past decade. Although the number of publications on PE increased only in MEDLINE, the 25-year trend showed a decline in the proportion of psychological behavior articles in both databases and a concomitant rise in biological and pharmacological articles. Although several explanations might account for these research trends, the authors worry that researchers are missing the opportunity to investigate important biobehavioral interactions underlying ejaculatory response and dysfunction, and to augment the current biopharmacological paradigm by integrating cognitive-behavioral and sex therapy programs into pharmacological PE treatment.


Expression of bcl-2 and nr-13 in hen ovarian follicles during development.
Follicle atresia is initiated within the granulosa cell layer of ovarian follicles and is mediated via the process of apoptosis. In the hen, at least two populations of granulosa cells can be distinguished during follicle development on the basis of their inherent susceptibility or resistance to apoptosis, in vitro. Given the previously established correlation between expression of bcl-xLong and hen granulosa cell resistance to apoptosis, the present studies were conducted to characterize expression of bcl-2 and an avian bcl-2 homologue, nr-13, in follicles at various stages of development. Levels of nr-13 mRNA were significantly higher only in granulosa cells from the largest (F1) preovulatory follicle compared to 3- to 5-mm prehierarchal follicles. By comparison, bcl-2 mRNA levels were 5- to 9-fold higher in granulosa cells from the three largest preovulatory follicles compared to those from follicles 9 to 12 mm in diameter and prehierarchal follicles. The increase in neither nr-13 nor bcl-2 was correlated with the stage of follicle development associated with the acquisition of resistance to apoptosis in granulosa cells (e.g., at the 9- to 12-mm stage). Results from the present studies do not support a close correlation between constitutive expression of nr-13 or bcl-2 mRNA and the transition from a state of apoptosis susceptibility to apoptosis resistance in hen granulosa cells. Thus, it is proposed that nr-13 and bcl-2 play more of a supportive role in regulating additional aspects of ovarian cell function such as cell proliferation and/or differentiation.


Hirschsprung's disease and mongolism.
Two mongoloid patients with Hirschsprung's disease are presented. Mongoloid children who have severe constipation should be investigated for Hirschsprung's disease.


[The dispensarization of population and the content of prevention activities of physicians in primary health care system].
Nowadays, positive trends in the development of priority principle of public health organization in Russia are observed. The dispensarization of large groups of population, declared by Minzdrav of Russia, made it possible to detect a large percentage of diseases. The implemented measures produced incontestable positive effect, though necessity is obvious to intensify involvement of citizen and families in health promoting activities. The article presents the study results providing important information concerning awareness of population and families about health and necessity to be concerned about health status. The means to enhance population health are in the areas of motivation of personal responsibility and public support from the state.


An adenovirus prime/plasmid boost strategy for induction of equipotent immune responses to two dengue virus serotypes.
Dengue is a public health problem of global significance for which there is neither an effective antiviral therapy nor a preventive vaccine. It is a mosquito-borne viral disease, caused by dengue (DEN) viruses, which are members of the Flaviviridae family. There are four closely related serotypes, DEN-1, DEN-2, DEN-3 and DEN-4, each of which is capable of causing disease. As immunity to any one serotype can potentially sensitize an individual to severe disease during exposure to a heterologous serotype, the general consensus is that an effective vaccine should be tetravalent, that is, it must be capable of affording protection against all four serotypes. The current strategy of creating tetravalent vaccine formulations by mixing together four monovalent live attenuated vaccine viruses has revealed the phenomenon of viral interference leading to the manifestation of immune responses biased towards a single serotype. This work stems from the emergence of (i) the DEN virus envelope (E) domain III (EDIII) as the most important region of the molecule from a vaccine perspective and (ii) the adenovirus (Ad) as a promising vaccine vector platform. We describe the construction of a recombinant, replication-defective Ad (rAd) vector encoding a chimeric antigen made of in-frame linked EDIIIs of DEN virus serotypes 2 and 4. Using this rAd vector, in conjunction with a plasmid vector encoding the same chimeric bivalent antigen, in a prime-boost strategy, we show that it is possible to elicit equipotent neutralizing and T cell responses specific to both DEN serotypes 2 and 4. Our data support the hypothesis that a DEN vaccine targeting more than one serotype may be based on a single DNA-based vector to circumvent viral interference. This work lays the foundation for developing a single Ad vector encoding EDIIIs of all four DEN serotypes to evoke a balanced immune response against each one of them. Thus, this work has implications for the development of safe and effective tetravalent dengue vaccines.


Corneal Anesthesia With Site 1 Sodium Channel Blockers and Dexmedetomidine.
Amino-amide or amino-ester local anesthetics, which are currently used for topical ocular anesthesia, are short acting and may delay corneal healing with long-term use. In contrast, site 1 sodium channel blockers (S1SCBs) are potent local anesthetics with minimal adverse tissue reaction. In this study, we examined topical local anesthesia with two S1SCBs, tetrodotoxin (TTX) or saxitoxin (STX) individually or in combination with α2-adrenergic receptor agonists (dexmedetomidine or clonidine), and compared them with the amino-ester ocular anesthetic proparacaine. The effect of test solutions on corneal healing was also studied. Solutions of TTX ± dexmedetomidine, TTX ± clonidine, STX ± dexmedetomidine, dexmedetomidine, or proparacaine were applied to the rat cornea. Tactile sensitivity was measured by recording the blink response to probing of the cornea with a Cochet-Bonnet esthesiometer. The duration of corneal anesthesia was calculated. Cytotoxicity from anesthetic solutions was measured in vitro. The effect on corneal healing was measured in vivo after corneal debridement followed by repeated drug administration. Addition of dexmedetomidine to TTX or STX significantly prolonged corneal anesthesia beyond that of either drug alone, whereas clonidine did not. Tetrodotoxin or STX coadministered with dexmedetomidine resulted in two to three times longer corneal anesthesia than did proparacaine. S1SCB-dexmedetomidine formulations were not cytotoxic. Corneal healing was not delayed significantly by any of the test solutions. Coadministration of S1SCBs with dexmedetomidine provided prolonged corneal anesthesia without delaying corneal wound healing. Such formulations may be useful for the management of acute surgical and nonsurgical corneal pain.


Increased entrances to side compartments indicate incubation of craving in morphine-induced rat and tree shrew CPP models.
In humans, cues associated with the rewarding effect of drugs of abuse induce drug craving and activate drug-associated memories after prolonged abstinence. In animal studies with the self-administration (SA) paradigm, responses to drug-associated cues increase within time after extinction, a phenomenon described as incubation of craving. Conditioned place preference (CPP) is widely used to measure the rewarding effect of drugs and the reward memory thereof. However, little is known whether responses to drug associated cues progressively increase after abstinence from the drugs in the CPP paradigm. To test whether the drug-associated cues could increase specific responses over the abstinence period in the CPP paradigm, we employed the high dose morphine-induced CPP paradigms in rats and tree shrews in the present study. We examined the CPP scores and the entrances to side chambers of the CPP apparatus to check whether they would progressively increase in the CPP paradigms. Twenty-one male adult Sprague-Dawley rats and eight adult male tree shrews were used to establish morphine-induced CPP and another ten rats treated with saline were controls for the rat experiments. After morphine conditioning, rats and tree shrews showed significant higher CPP scores at the first or second post tests than at baseline but then the CPP scores in the abstinence period decreased gradually. During the abstinence period, animals with morphine-conditioning experiences entered progressively more times to both side compartments, whereas the number of entrances to side chambers of the saline group in rats had no such significant differences. These findings suggest that progressively increased entrances to the side chambers in the extended abstinence period reflect the incubation of craving in high dose morphine-induced CPP paradigms. Also, our data imply that reward memory and drug craving can be distinguished in the CPP paradigm.


Carbon neutrality: The role of banks in optimal environmental management strategies.
This study explores the ecological ambitions of banks by studying the coincidence of economic realities with environmental management strategies. We address this question by studying the environmental performance of US banks and its impact on their tail risk as US is not committed to carbon neutrality in COP 21. We proxy economic reality with tail risk of banks and employ a novel extreme value theory to measure this. We use Asset4 ESG data for environmental performance score and test our hypothesis with a sample of 256 US banks. The results indicate that the US banks are ecologically ambitious and their environmental strategies are likely to reduce their tail risk. This provides evidence that better environmental strategies do coincide with the economic realities. We test the consistency of our results by using alternate proxies for tail risk and find our results robust. Our results are also not driven by endogeneity concerns. Finally, our additional results show that the nature of relationship differs with corporate governance levels, CSR committee existence, institutional ownership presence and crisis period.


Locating structures in aerial images.
A technique for locating desired structures utilizing user specified information about properties of these structures and their relationships with other more easily extracted objects is described. An edge-based and region-based technique is used for scene segmentation. Experimental results of the processing of aerial pictures are presented.


A Simulation-Based Approach to Statistical Alignment.
Classic alignment algorithms utilize scoring functions which maximize similarity or minimize edit distances. These scoring functions account for both insertion-deletion (indel) and substitution events. In contrast, alignments based on stochastic models aim to explicitly describe the evolutionary dynamics of sequences by inferring relevant probabilistic parameters from input sequences. Despite advances in stochastic modeling during the last two decades, scoring-based methods are still dominant, partially due to slow running times of probabilistic approaches. Alignment inference using stochastic models involves estimating the probability of events, such as the insertion or deletion of a specific number of characters. In this work, we present SimBa-SAl, a simulation-based approach to statistical alignment inference, which relies on an explicit continuous time Markov model for both indels and substitutions. SimBa-SAl has several advantages. First, using simulations, it decouples the estimation of event probabilities from the inference stage, which allows the introduction of accelerations to the alignment inference procedure. Second, it is general and can accommodate various stochastic models of indel formation. Finally, it allows computing the maximum-likelihood alignment, the probability of a given pair of sequences integrated over all possible alignments, and sampling alternative alignments according to their probability. We first show that SimBa-SAl allows accurate estimation of parameters of the long-indel model previously developed by Miklós et al. (2004). We next show that SimBa-SAl is more accurate than previously developed pairwise alignment algorithms, when analyzing simulated as well as empirical data sets. Finally, we study the goodness-of-fit of the long-indel and TKF91 models. We show that although the long-indel model fits the data sets better than TKF91, there is still room for improvement concerning the realistic modeling of evolutionary sequence dynamics.


Heterogeneous nuclear ribonucleoprotein F suppresses angiotensinogen gene expression and attenuates hypertension and kidney injury in diabetic mice.
We investigated the impact of heterogeneous nuclear ribonucleoprotein F (hnRNP F) overexpression on angiotensinogen (Agt) gene expression, hypertension, and renal proximal tubular cell (RPTC) injury in high-glucose milieu both in vivo and in vitro. Diabetic Akita transgenic (Tg) mice specifically overexpressing hnRNP F in their RPTCs were created, and the effects on systemic hypertension, Agt gene expression, renal hypertrophy, and interstitial fibrosis were studied. We also examined immortalized rat RPTCs stably transfected with control plasmid or plasmid containing hnRNP F cDNA in vitro. The results showed that hnRNP F overexpression attenuated systemic hypertension, suppressed Agt and transforming growth factor-β1 (TGF-β1) gene expression, and reduced urinary Agt and angiotensin II levels, renal hypertrophy, and glomerulotubular fibrosis in Akita hnRNP F-Tg mice. In vitro, hnRNP F overexpression prevented the high-glucose stimulation of Agt and TGF-β1 mRNA expression and cellular hypertrophy in RPTCs. These data suggest that hnRNP F plays a modulatory role and can ameliorate hypertension, renal hypertrophy, and interstitial fibrosis in diabetes. The underlying mechanism is mediated, at least in part, via the suppression of intrarenal Agt gene expression in vivo. hnRNP F may be a potential target in the treatment of hypertension and kidney injury in diabetes.


Two new species of polystomes (Monogenea: Polystomatidae) from the anuran host Guibemantis liber.
Madapolystoma ramilijaonae n. sp. and Madapolystoma cryptica n. sp. (Monogenea, Polystomatidae) are described from the urinary bladder of disjunct populations of the Madagascar shrub frog Guibemantis liber. Although only minor morphological characters distinguish the new species from the single nominal species of the genus, i.e. Madapolystoma biritika, their strong and concordant differentiation in a mitochondrial and a nuclear gene supplemented by phylogenetic analyses indicates that M. ramilijaonae n. sp. and M. cryptica n. sp. should be regarded as two distinct species. Because anuran polystomes are known to be host-specific, the description of two cryptic species from a single host species points to a taxonomic complex situation in G. liber, a widespread frog that is characterized by the presence of several deep conspecific lineages and possibly by hybridization and admixture with other species of Guibemantis.


Suppressive effect of ghrelin on nicotine-induced clock gene expression in the mouse pancreas.
Those who smoke nicotine-based cigarettes have elevated plasma levels of ghrelin, a hormone secreted from the stomach. Ghrelin has various physiological functions and has recently been shown to be involved in regulating biological rhythms. Therefore, in this study, in order to clarify the significance of the plasma ghrelin increase in smokers, we sought to clarify how nicotine and ghrelin affect the expression dynamics of clock genes using a mouse model. A single dose of nicotine administered intraperitoneally increased plasma ghrelin concentrations transiently, whereas continuous administration of nicotine with an osmotic minipump did not induce any change in the plasma ghrelin concentration. Single administration of nicotine resulted in a transient increase in ghrelin gene expression in the pancreas but not in the stomach, which is the major producer of ghrelin. In addition, in the pancreas, the expression of clock genes was also increased temporarily. Therefore, in order to clarify the interaction between nicotine-induced ghrelin gene expression and clock gene expression in the pancreas, nicotine was administered to ghrelin gene-deficient mice. Administration of nicotine to ghrelin-gene deficient mice increased clock gene expression in the pancreas. However, upon nicotine administration to mice pretreated with octanoate to upregulate ghrelin activity, expression levels of nicotine-inducible clock genes in the pancreas were virtually the same as those in mice not administered nicotine. Thus, our findings indicate that pancreatic ghrelin may suppress nicotine-induced clock gene expression in the pancreas.


[Deep brain stimulation for psychiatric disorders].
Deep brain stimulation for psychiatric disorders Deep brain stimulation is an established treatment for movement disorders. It has been proven to be a safe method; only minor complications have been reported in larger studies. New indications for deep brain stimulation are under investigation; among them major depressive disorder and obsessive-compulsive disorder. Deep brain stimulation for severe and therapy-resistant major depressive disorder and obsessive compulsive-disorder shows promising results. However, the experience of deep brain stimulation in psychiatric disorders is limited. Several potential target areas for stimulation have been presented; which are the most effective is still an open question. Deep brain stimulation in psychiatric disorders is a highly experimental treatment and should only be performed by a multidisciplinary team with extensive experience with deep brain stimulation in other conditions.


Risk of Cancer Among Sarcoidosis Patients With Biopsy-verified Nonnecrotizing Granulomatous Inflammation: Population-based Cohort Study.
To assess the long-term risk of hematologic cancers, invasive solid tumors, and nonmelanoma skin cancer (NMSC) among sarcoidosis patients with biopsy-verified nonnecrotizing granulomatous inflammation. We used Danish administrative registers with nationwide coverage to construct a cohort of 3892 patients with sarcoidosis and an age- and sex-matched comparison cohort of 38,920 population controls. For all patients, a biopsy demonstrating nonnecrotizing granulomatous inflammation had been obtained from the lower respiratory tract at the time of diagnosis. Study outcome was time to diagnosis of cancer. Follow-up began at time of sarcoidosis diagnosis and continued for up to 10 years. We calculated hazard ratios (HRs) as estimates of the cancer risk among the patients with sarcoidosis relative to that among the population controls and used cumulative incidence functions to calculate absolute 10-year risk estimates. We observed an increased long-term risk of hematologic cancers (HR during the first 2 years of follow-up: 2.71 [95% CI 1.18-6.25]; HR after > 2 years of follow-up: 2.12 [95% CI 1.29-3.47]) and NMSC (HR after > 2 years of follow-up: 1.82 [95% CI 1.43-2.32]) among the patients with sarcoidosis. An increased risk of invasive solid tumors was only observed during the first 2 years (HR 1.55, 95% CI 1.18-2.04). Compared with the population controls, the patients with sarcoidosis had an increased absolute 10-year risk of hematologic cancers (risk difference 0.56%, 95% CI 0.11-1.01%) and NMSC (risk difference 1.58%, 95% CI 0.70-2.47%). Sarcoidosis patients with biopsy-verified nonnecrotizing granulomatous inflammation have an increased long-term risk of hematologic cancers and NMSC compared with the general population.


Structure of C3PO and mechanism of human RISC activation.
Assembly of the RNA-induced silencing complex (RISC) consists of loading duplex (guide-passenger) siRNA onto Argonaute (Ago2) and removing the passenger strand. Ago2 contributes critically to RISC activation by nicking the passenger strand. Here we reconstituted duplex siRNA-initiated RISC activity using recombinant human Ago2 (hAgo2) and C3PO, indicating that C3PO has a critical role in hAgo2-RISC activation. Consistently, genetic depletion of C3PO compromised RNA silencing in mammalian cells. We determined the crystal structure of hC3PO, which reveals an asymmetric octamer barrel consisting of six translin and two TRAX subunits. This asymmetric assembly is critical for the function of C3PO as an endonuclease that cleaves RNA at the interior surface. The current work supports a Dicer-independent mechanism for human RISC activation, in which Ago2 directly binds duplex siRNA and nicks the passenger strand, and then C3PO activates RISC by degrading the Ago2-nicked passenger strand.


Proximal tubule function and response to acidosis.
The human kidneys produce approximately 160-170 L of ultrafiltrate per day. The proximal tubule contributes to fluid, electrolyte, and nutrient homeostasis by reabsorbing approximately 60%-70% of the water and NaCl, a greater proportion of the NaHCO3, and nearly all of the nutrients in the ultrafiltrate. The proximal tubule is also the site of active solute secretion, hormone production, and many of the metabolic functions of the kidney. This review discusses the transport of NaCl, NaHCO3, glucose, amino acids, and two clinically important anions, citrate and phosphate. NaCl and the accompanying water are reabsorbed in an isotonic fashion. The energy that drives this process is generated largely by the basolateral Na(+)/K(+)-ATPase, which creates an inward negative membrane potential and Na(+)-gradient. Various Na(+)-dependent countertransporters and cotransporters use the energy of this gradient to promote the uptake of HCO3 (-) and various solutes, respectively. A Na(+)-dependent cotransporter mediates the movement of HCO3 (-) across the basolateral membrane, whereas various Na(+)-independent passive transporters accomplish the export of various other solutes. To illustrate its homeostatic feat, the proximal tubule alters its metabolism and transport properties in response to metabolic acidosis. The uptake and catabolism of glutamine and citrate are increased during acidosis, whereas the recovery of phosphate from the ultrafiltrate is decreased. The increased catabolism of glutamine results in increased ammoniagenesis and gluconeogenesis. Excretion of the resulting ammonium ions facilitates the excretion of acid, whereas the combined pathways accomplish the net production of HCO3 (-) ions that are added to the plasma to partially restore acid-base balance.


Spermicidal efficacy of H2-receptor antagonists and potentiation with 2', 4'-dichlorobenzamil hydrochloride: role of intrasperm Ca2+.
The present investigation was designed to study the possible role of intrasperm Ca(2+) in spermicidal action of H(2)-receptor antagonists. Influence of commonly used H(2)-receptor antagonists cimetidine, ranitidine and famotidine on sperm viability and intrasperm Ca(2+) was evaluated in ejaculated human semen samples. All these drugs were found to reduce sperm viability in a dose- and time-dependent manner. This action was accompanied with elevation of intrasperm Ca(2+). 2', 4'-dichlorobenzamil hydrochloride (DBZ), a Na(+)-Ca(2+) exchange inhibitor, that is known to elevate intrasperm Ca(2+), potentiated the spermicidal action of H(2)-receptor antagonists. Intrasperm Ca(2+) was found to rise at much faster rate when DBZ was combined with any of the three H(2)-receptor antagonists. Due to this, the maximum Ca(2+) level required to produce death of sperm cells was attained much earlier as compared to the per se effect of any one of these drugs. These results suggest that elevation of intrasperm Ca(2+) by H(2)-receptor antagonists plays a key role in influencing sperm viability.


Study of transmembrane potentials on cellular inner and outer membrane--frequency response model and its filter characteristic simulation.
Based on the multilayer dielectric model for a spherical cell, a frequency response model of transmembrane potentials on cellular inner and outer membranes is established with a simulating method. The simulating results indicate that transmembrane potential on the inner membrane shows first-order bandpass filter characteristic, while transmembrane potential on the outer membrane shows first-order low-pass filter characteristic approximately. It could be found that the transmembrane potential on the inner membrane is greater than that on the outer membrane, and can keep a higher value in the range from a center frequency to an upper cutoff frequency, which is desirable to induce intracellular electromanipulation. Both a discussion about an equivalent RC model of the cell and the experimental result are in agreement with the aforementioned conclusion. Therefore, the frequency response model could help to choose reasonable window parameters for the application of a nanosecond pulsed electric field to tumor treatment.


Step change.
Staffat a south east London NHS trust are discovering how dance can improve their communication with patients with learning disabilities. Weekly dance sessions, run by Magpie Dance, are now also being made available to people with dementia, autism and other conditions. Through dance people can express emotion, build confidence and change their lives.


To look or not to look: an eye movement study of hypervigilance during change detection in high and low spider fearful students.
Previous eye movement studies of attentional bias in spider fear reported inconsistent results with respect to early attentional capture, suggesting that overt attentional capture only reliably occurs under specific circumstances. In addition, none of these studies explored covert attention. The present study examined attentional bias in spider phobia using a change detection paradigm that was expected to provide good conditions for documenting attentional capture. In contrast to our expectations, eye movement data showed that all participants' first fixations were fastest on general negative targets, whereas participants' first fixations on spider targets were slower in the spider fearful than in the nonfearful group. In addition, spider fearful participants made more nontarget fixations before fixating on a spider target than did nonfearful participants. Thus, we found that participants' overt attention was more quickly focused on general negative targets, whereas covert attentional processes enabled initial avoidance of fear-relevant (i.e. spider) stimuli. The present findings have important implications for research on attention and fear as they indicate that fearful individuals are not characterized by static attentional orienting toward threat but, under certain conditions, may avert attention from threat automatically.


Parvovirus B19 in HIV+ adult patients with different CD4+ lymphocyte counts.
Human parvovirus B19 (B19V) can cause anemia in immunocompromised patients. We aimed to investigate the presence of B19V in HIV+ adults with different CD4+ T cell counts, to recognise the frequency of B19V in these different conditions and its possible association with anemia. We studied B19V specific IgM, IgG and DNA in 98 HIV+ patients and in 52 healthy individuals. HIV load, CD4+ counts and haemoglobin level were also determined in the patients. No individual in the control group had detectable IgM, 41/52 (78.8 %) had IgG and 5/52 (9.6 %) had B19V DNA. Among HIV+ patients, we found 5/98 (5.1 %) IgM+, 66/98 (67.3 %) IgG+ and 15/98 (15.3 %) had B19V DNA (no significant differences between the two groups compared). Considering the CD4+ cell range in HIV patients, 37 had <200 CD4+ cells ml-1, 31 had 200-500, and 30 had >500. Anti-B19V IgG prevalence in patients with >500 CD4+ cells ml-1 was significantly higher than in the rest (P=0.004) and compared to the control (P=0.046). B19V DNA concentration was always <103 IU ml-1, including 5 healthy individuals and 15 HIV+ patients. There was no significant association between B19V IgM or DNA and anemia nor between B19V DNA and HIV load. The results indicate that B19V is not a high-risk factor for anemia in adult HIV+ patients under HAART treatment. Further studies will contribute to elucidate the mechanisms and significance of B19V DNA prevalence/persistence in adults, independently of the CD4+ cell status.


[Endogenous phospholipase hydrolysis in the cerebral cortex during the development of epileptic activity].
The development of epileptic activity in the rat brain cortex is attended by activation of endogenous phospholipase hydrolysis. The development of primary-generalized epileptic activity induced by intramuscular injection of bemegride increased the content of free fatty acids in the brain tissue from 14 +/- 3 micrograms per mg protein in the control to 35 +/- 4 micrograms/mg. The appearance of focal cortical epileptic activity after penicillin application also provoked an increase in the content of free fatty acids in the brain tissue withdrawn from the hyperactive focus (from 40 +/- 5 micrograms/mg in the control to 75 +/- 10 micrograms/mg). Analysis of the free fatty acid spectrum in the brain tissue by gas-liquid chromatography has shown that the development of epileptic activity induced primary stearic acid accumulation by the brain cortex, a decrease in the relative content of short-chain fatty acids, a tendency towards arachidonic acid accumulation. It is assumed that endogenous phospholipase hydrolysis may be involved in the mechanisms of the development of epileptic activity.


Hemostatic side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia.
The purpose of this study is to investigate the hemostatic side effects of HDMTX. Between 2001 and 2002, 20 children with acute lymphoblastic leukemia at the Dr. Sami Ulus Children's Hospital, Department of Pediatric Hematology and Oncology, treated according to the St. Jude ALL XIII protocol were eligible to this study. Methotrexate at a dose of 2 g/m(2) was infused over 24 hours. Coagulation screening studies included prothrombin time (PT), APTT, fibrinogen, fibrin degradation product (D-Dimer), factor II, factor V, factor VII, factor VIII, factor IX, factor X, PC, PS, AT-III determinations before HDMTX therapy (PreT), 1 day after (PostT(1D)), and 1 week after (PostT(1W)) the end of the HDMTX infusion. We found that PT and APTT were prolonged, PC, PS, and AT-III levels were decreased with a slight increase in D-Dimer 1 day after the administration of HDMTX and all of them returned to the normal levels by 7 days. In addition we found that FVII, FIX, FX were significantly decreased 1 day after therapy and normalised by 7 days.


Prognosis of chronic myelomonocytic leukemia.
Cytopenia caused by ineffective hematopoiesis and monocyte overproduction coexist in CMML, providing grounds for discussion to supporters of a dysplastic versus a proliferative identity for CMML. Follow-up information from a large series of patients may contribute to clarifying the position of this infrequent disease. We analyzed data from 77 patients followed in five institutions. Thirty-two variables were studied for their influence on survival and on progression to acute leukemia by univariate and multivariate analysis. For some parameters, we performed a quartile analysis to reveal a possible non-monotonic influence on survival. Median survival was 17 months. Evolution to acute leukemia (ANLL) occurred in 11 patients (14%) within a median time of 8 months. Multivariate analysis assigned a poorer prognosis to patients presenting with thrombocytopenia, anemia and leukocytosis. Thrombocytopenia and the presence of circulating blasts were risk factors for transformation to ANLL, while raised serum aspartate transaminase at diagnosis seemed to be associated with a lower probability of blastic evolution. The Bournemouth score for CMML proved to be a valid tool for predicting survival but not acute transformation. CMML is a severe disease. The prognostic independence of cytopenia (anemia, thrombocytopenia) and leukocytosis underlines the coexistence of aspects typical of myelodysplastic and myeloproliferative syndromes.


Control of gene editing by manipulation of DNA repair mechanisms.
DNA double-strand breaks (DSBs) are produced intentionally by RNA-guided nucleases to achieve genome editing through DSB repair. These breaks are repaired by one of two main repair pathways, classic non-homologous end joining (c-NHEJ) and homology-directed repair (HDR), the latter being restricted to the S/G2 phases of the cell cycle and notably less frequent. Precise genome editing applications rely on HDR, with the abundant c-NHEJ formed mutations presenting a barrier to achieving high rates of precise sequence modifications. Here, we give an overview of HDR- and c-NHEJ-mediated DSB repair in gene editing and summarize the current efforts to promote HDR over c-NHEJ.


Synaptic information transfer in computer models of neocortical columns.
Understanding the direction and quantity of information flowing in neuronal networks is a fundamental problem in neuroscience. Brains and neuronal networks must at the same time store information about the world and react to information in the world. We sought to measure how the activity of the network alters information flow from inputs to output patterns. Using neocortical column neuronal network simulations, we demonstrated that networks with greater internal connectivity reduced input/output correlations from excitatory synapses and decreased negative correlations from inhibitory synapses, measured by Kendall's τ correlation. Both of these changes were associated with reduction in information flow, measured by normalized transfer entropy (nTE). Information handling by the network reflected the degree of internal connectivity. With no internal connectivity, the feedforward network transformed inputs through nonlinear summation and thresholding. With greater connectivity strength, the recurrent network translated activity and information due to contribution of activity from intrinsic network dynamics. This dynamic contribution amounts to added information drawn from that stored in the network. At still higher internal synaptic strength, the network corrupted the external information, producing a state where little external information came through. The association of increased information retrieved from the network with increased gamma power supports the notion of gamma oscillations playing a role in information processing.


Aging and the wandering brain: Age-related differences in the neural correlates of stimulus-independent thoughts.
In recent years, several studies have indicated that healthy older adults exhibit a reduction in task-unrelated thoughts compared to young adults. However, much less is known regarding age-related differences in time spent engaging in stimulus-independent thoughts or in their neural correlates in the absence of an ongoing task. In the current study, we collected functional magnetic resonance imaging (fMRI) data while 29 young (mean age = 22y) and 22 older (mean age = 70y) adults underwent experience sampling in the absence of an ongoing task (i.e., at "rest"). Although both age groups reported spending a similar amount of time engaged in stimulus-independent thoughts, older adults rated their thoughts as more present-oriented (rather than atemporal) and more novel. Moreover, controlling for these age-related differences in content, we found that experiencing stimulus-independent thoughts was associated with increased posterior cingulate and left angular gyrus activation across age groups compared to exhibiting an external focus of attention. When experiencing stimulus-independent thoughts, younger adults engaged medial and left lateral prefrontal cortex as well as left superior temporal gyrus to a greater degree than older adults. Taken together, our results suggest that, in the absence of an ongoing task, although young and older adults spend a similar amount of time engaging in stimulus-independent thoughts, the content and neural correlates of these thoughts differ with age.


BRCA2 mutation carriers, reproductive factors and breast cancer risk.
Germline mutations in the BRCA genes dramatically increase the risk of breast cancer. In the general population, breast cancer risk is affected by age at menarche, by age at first birth, by the number of births and by the duration of breast feeding. Whether this is true for mutation carriers is not clear. In a case-control study, nested in a population-based cohort of the Icelandic Cancer Detection Clinic, two groups of cases were defined, matched on year of birth, on age at diagnosis and on age when giving information on reproductive factors: 100 carriers of the Icelandic founder BRCA2 mutation 999del5, and 361 BRCA2-negative cases. The mean age at diagnosis was 48 years. There were 1000 women in a matched group of unaffected controls. Conditional logistic regression was used for the analysis. An increased number of births was associated with a decreased risk of breast cancer in BRCA2-negative cases but not in BRCA2-positive cases. A negative association between risk and duration of breast feeding was observed only in the mutation carriers. These associations were not statistically significant, but the effects of the two variables differed significantly according to mutation status (P = 0.007 and P = 0.045 for interaction with number of births and with duration of breast feeding, respectively). This was maintained when limiting the analysis to women diagnosed older than the age of 40 years. The association between breast cancer and the number of pregnancies and between breast cancer and the duration of breast feeding was not the same for carriers and noncarriers of a detrimental BRCA2 mutation. In the context of other epidemiological and laboratory studies, this may indicate that the product of the BRCA2 gene has a function relating to the differentiation of epithelial tissue in the breast.


Crumpled graphene-molybdenum oxide composite powders: preparation and application in lithium-ion batteries.
Crumpled graphene-MoO2 composite powders are directly prepared by means of spray pyrolysis and from a stable graphene oxide colloidal solution in the presence of Mo ions. The crumpled graphene-MoO2 composite powders are transformed into MoO3 -based composite powders after post-treatment at 300 °C. The transmission electron microscopy and dot-mapping images of the post-treatment composite powders show uniform distribution of MoO3 nanocrystals in the crumpled graphene powders. The two typical D and G bands of graphene are observed at 1350 and 1590 cm(-1) , respectively, in the Raman spectrum of the graphene-MoO3 composite. In addition, the crumpled graphene-MoO3 powders exhibit superior electrochemical behavior compared to that of pure MoO3 as an anode material for lithium-ion batteries. The initial discharge capacities of the graphene-MoO3 composite and bare MoO3 powders at a current density of 2 A g(-1) are 1490 and 1225 mA h g(-1) , respectively. The capacity retention of the graphene-MoO3 composite is 87 % after the first cycle, whereas that of bare MoO3 is 47 %, as measured after 100 cycles. The reversible discharge capacity of the graphene-MoO3 composite decreases slightly from 1228 to 845 mA h g(-1) as the current density increases from 0.5 to 3 A g(-1) .


Identification of 3',4'-Dimethoxy Flavonol-3-β-d-Glucopyranoside Metabolites in Rats by Liquid Chromatography-Electrospray Ionization Ion Trap Mass Spectrometry.
A method using liquid chromatography-electrospray ionization ion trap mass spectrometry was established for the identification of metabolites in feces, urine and bile in rats after oral administration of 3',4'-dimethoxy flavonol-3-β-d-glucopyranoside (abbreviated DF3G). Seven metabolites in rat feces, urine and bile were firstly identified on the basis of their MS fragmentation behaviors. Three metabolites were identified in the feces, 6 in the urine and 2 in the bile, which suggested that demethylation, deglycosylation and deglycosylation followed by glucuronide conjugation were the major metabolic pathways for DF3G in vivo. Hydrolyzation might be the first step in the absorption and metabolism of DF3G. The possible metabolic pathway was proposed for the first time. The established method was simple, reliable and sensitive, revealing that it could be used to rapidly screen and identify the structures of metabolites of DF3G to better understand its metabolism in vivo.


Heritability of baseline and induced micronucleus frequencies.
The scoring of micronuclei (MN) is widely used in biomonitoring and mutagenicity testing as a surrogate marker of chromosomal damage inflicted by clastogenic agents or by aneugens. Individual differences in the response to a mutagenic challenge are known from studies on cancer patients and carriers of mutations in DNA repair genes. However, it has not been studied to which extent genetic factors contribute to the observed variability of individual MN frequencies. Our aim was to quantify this heritable genetic component of both baseline and radiation-induced MN frequencies. We performed a twin study comprising 39 monozygotic (MZ) and 10 dizygotic (DZ) twin pairs. Due to the small number of DZ pairs, we had to recruit controls from which 38 age- and gender-matched random control pairs (CPs) were generated. For heritability estimates, we used biometrical modelling of additive genetic, common environmental, and unique environmental components (ACE model) of variance and direct comparison of variance between the sample groups. While heritability estimates from MZ to DZ comparisons produced inconclusive results, both estimation methods revealed a high degree of heritability (h(2)) for baseline MN frequency (h(2) = 0.68 and h(2) = 0.72) as well as for the induced frequency (h(2) = 0.68 and h(2) = 0.57) when MZ were compared to CP. The result was supported by the different intraclass correlation coefficients of MZ, DZ and CP for baseline (r = 0.63, r = 0.31 and r = 0.0, respectively) as well as for induced MN frequencies (r = 0.79, r = 0.74 and r = 0.0, respectively). This study clearly demonstrates that MN frequencies are determined by genetic factors to a major part. The strong reflection of the genetic background supports the idea that MN frequencies represent an intermediate phenotype between molecular DNA repair mechanisms and the cancer phenotype and affirms the approaches that are made to utilise them as predictors of, for example, cancer risk.


Diffusion of Impaired Driving Laws Among US States.
We examined internal and external determinants of state's adoption of impaired driving laws. Data included 7 state-level, evidence-based public health laws collected from 1980 to 2010. We used event history analyses to identify predictors of first-time law adoption and subsequent adoption between state pairs. The independent variables were internal state factors, including the political environment, legislative professionalism, government capacity, state resources, legislative history, and policy-specific risk factors. The external factors were neighboring states' history of law adoption and changes in federal law. We found a strong secular trend toward an increased number of laws over time. The proportion of younger drivers and the presence of a neighboring state with similar laws were the strongest predictors of first-time law adoption. The predictors of subsequent law adoption included neighbor state adoption and previous legislative action. Alcohol laws were negatively associated with first-time adoption of impaired driving laws, suggesting substitution effects among policy choices. Organizations seeking to stimulate state policy changes may need to craft strategies that engage external actors, such as neighboring states, in addition to mobilizing within-state constituencies.


Asbestos fibers mediate transformation of monkey cells by exogenous plasmid DNA.
We have tested the ability of chrysotile asbestos fibers to introduce plasmid DNA into monkey COS-7 cells and the ability of this DNA to function in both replication and gene expression. Chrysotile fibers are at least as effective as calcium phosphate in standard transfection assays at optimal ratios of asbestos to DNA. After transfection with chrysotile, a minor percentage of introduced plasmid DNA bearing a simian virus 40 origin of replication replicates after 24 hr. Fragmentation of entering DNA is more prominent with asbestos than with calcium phosphate, and after 72 hr most DNA introduced by asbestos is associated with chromosomal DNA. Cells transfected with plasmid p11-4, bearing the p53 protooncogene, express this gene. Cells transfected with pSV2-neo express a gene conferring resistance of antibiotic G418, allowing isolation of colonies of transformed cells after 18 days. The introduction of exogenous DNA into eukaryotic cells could cause mutations in several ways and thus contribute to asbestos-induced oncogenesis.


Renal cell carcinoma associated with tumor thrombus in the inferior vena cava: surgical strategies.
The purpose of this study was to evaluate strategies used for surgical management of renal cell carcinoma with a tumoral thrombus extension in the inferior vena cava (IVC). From January 2000 to December 2001, urological and vascular surgeons jointly undertook surgical treatment on 10 patients with renal cell carcinoma and tumor thrombus in the IVC. There were five women and five men, with a mean age of 60.2 years. The limit of thrombus extension, classified according to the Neves and Zincke system, was level I (renal) in one patient, level II (infrahepatic) in one, level III (retrohepatic) in three, and level IV (atrial) in five. Exposure was achieved by chevron bilateral subcostal laparotomy associated with sternotomy in three patients, bilateral subcostal laparotomy in six, and median sternolaparotomy in one. Radical nephrectomy associated with caval thrombectomy was performed in all patients. Cardiopulmonary bypass was used in four of the five level IV patients. The fifth patient was contraindicated for cardiopulmonary bypass. Transesophageal echography (TEE)-guided endoluminal occlusion of the unobstructed infradiaphragmatic IVC was performed in patients with level III thrombus. Clamping of the IVC was performed in patients with levels I and II thrombus. All procedures were assisted by continuous TEE surveillance. No intraoperative gas or tumor emboli were detected by TEE. The mean number of red blood cell units transfused during the course of hospitalization was 9.7 (range 2-22, median 9). One patient died of multiple organ failure on the day 28 after the procedure. The mean duration of hospitalization was 16 days. The mean duration of follow-up was 9.7 months. During follow-up, two of the remaining nine patients died due to tumor recurrence. Tumor recurrence was also detected in one of the seven surviving patients. Surgery for renal cell carcinoma with tumor thrombus in the IVC must be carried out in a specialized facility with the assistance of TEE surveillance and, in some cases, cardiopulmonary bypass. Operative treatment improves the prognosis of renal cell carcinoma with tumor thrombus in the IVC. In patients with level III thrombus, TEE-guided endoluminal occlusion of the unobstructed infradiaphragmatic IVC simplifies surgical management by obviating the need for exposure of the retrohepatic and supradiaphragmatic IVC.


Intake of starch and sugars and total and cause-specific mortality in a Japanese community: the Takayama Study.
Studies on the intake of different types of carbohydrates and long-term mortality are sparse. We examined the association of starch, total and each type of sugar and free sugars with the risk of total and cause-specific mortality in a cohort of the general population in Japan. Study subjects were 29 079 residents from the Takayama Study, Japan, who responded to a self-administered questionnaire in 1992. Diet was assessed by a validated FFQ at the baseline. Mortality was ascertained during 16 years of follow-up. We noted 2901 deaths (974 cancer related and 775 cardiovascular related) in men and 2438 death (646 cancer related and 903 cardiovascular related) in women. In men, intake of starch was inversely associated with total mortality after controlling for covariates (hazard ratio (HR) for the highest quartile v. lowest quartile: 0·71; 95 % CI 0·60, 0·84; Ptrend < 0·001). Intakes of total sugars, glucose, fructose, sucrose, maltose and free and naturally occurring sugars were significantly positively associated with total mortality in men (HR for the highest v. lowest quartile of total sugar: 1·27; 95 % CI 1·12, 1·45; Ptrend < 0·0001). Similar relations were observed for cardiovascular mortality and non-cancer, non-cardiovascular mortality in men. In women, there was no significant association between any type of carbohydrates and mortality except that intake of free sugars was significantly positively associated with total and non-cancer, non-cardiovascular mortality. Data suggest that the high intake of starch reduces mortality, whereas the high intake of sugars, including glucose, fructose and sucrose, increases mortality in Japanese men.


T2DM patients with depression have higher levels of hyperglycemia and cognitive decline than T2DM patients.
The cognitive impairment, depression, a decrease in the ability to perform activities of daily living (ADLs), and salivary gland dysfunction, as indicated by the reduction of alpha-amylase activity, have been reported in patients with type 2 diabetes (T2DM). However, the effects of depression on cognitive function, salivary alpha-amylase activity, and ADLs in T2DM patients have never been investigated. In this study, 115 participants were divided into three groups, including 30 healthy people, 50 T2DM patients without depression, and 35 T2DM patients with depression. Then, the cognitive function, the level of depression, salivary-alpha amylase activity, ADLs, and metabolic parameters were determined. Results showed that T2DM patients had hyperglycemia and cognitive impairment. A decrease in the salivary alpha-amylase activity was observed in T2DM patients. Interestingly, T2DM patients with depression had higher level of hyperglycemia and cognitive impairment than T2DM patients. Additionally, cognitive function was associated with the salivary-alpha amylase activity in T2DM without depression, while the severity of depression was associated with the salivary-alpha amylase activity in T2DM patients with depression. Therefore, we concluded that T2DM caused the impairment of metabolism, decreased salivary alpha-amylase activity, and cognitive impairment. Furthermore, T2DM patients with depression had higher level of hyperglycemia and cognitive decline than T2DM patients.


In Vitro Antiviral Activity of Tyrosinase from Mushroom Agaricus bisporus against Hepatitis C Virus.
Tyrosinases from a commercial Agaricus bisporus protein extract and directly isolated from white mushrooms were purified in order to obtaining the well-known tyrosinase from A. bisporus (TyrAB) of 45 kDa and a newly discovered 50 kDa tyrosinase isoform (Tyr50 kDa), and tested showing high antiviral activity against the hepatitis C virus for the first time. Cell toxicity and antiviral activity of tyrosinases were determined in cultured Huh 5-2 liver tumor cells transfected with a replicon system (a plasmid that includes all non-structural hepatitis C virus proteins and replicates autonomously). TyrAB was able to inhibit the replication of the hepatitis C virus without inducing toxicity in liver cells. In addition, the post-translational isoform Tyr50 kDa showed higher antiviral capacity than the former (up to 10 times greater), also exhibiting 10 times higher activity than the commercial drug Ribavirin®. This antiviral activity was directly proportional to the enzymatic activity of tyrosinases, as no antiviral capacity was observed in the inactive form of the enzymes. The tyrosinases approach could represent a new antiviral inhibition mechanism, through a plausible catalytic mechanism of selective hydroxylation of the key role of tyrosine residues in viral proteases.


Whole School SEND (WSS) Review: study protocol for a two-arm pragmatic parallel cluster randomised controlled trial in 160 English secondary schools.
The trial will study the effects of the Whole School SEND Review on secondary school pupils in English mainstream education, to understand the impact of the intervention on academic attainment, wellbeing, and school attendance. The Review is designed to facilitate whole-school change through providing enhanced, intensive and sustained support and training in inclusive education for school special educational needs coordinators and leadership teams. The trial will have a specific focus on pupils designated as having special educational needs or disabilities. We recruited 160 English secondary schools (approx. 58,000 pupils across two cohorts) to a two-arm pragmatic parallel cluster randomised controlled trial, with allocation at the school level. Randomisation will be stratified by school region. The primary outcome is attainment in English language (using standardised national test results at 16 years) for pupils designated as having a special educational need (approx. 4000 pupils). Secondary outcomes will be measured for pupils both with and without a special educational need designation and include pupil wellbeing (measured using the Strengths and Difficulties Questionnaire), absences and exclusions, and attainment in Mathematics and English language at 16 years. The intervention will be implemented from July 2021 and analysis of outcomes (for the year 9 cohort) will take place in September 2023, with further analysis (for the year 8 cohort) in September 2024 if the evaluation shows that acceptable implementation fidelity has been achieved. Pupils with special educational needs represent a significant and often vulnerable part of the secondary school population, are disproportionately likely to be excluded from school, eligible for free school meals, or supported by children's social care. Despite these multiple important areas of need, school leaders report substantial challenges in making additional provision for this group. Previous research has highlighted the development of inclusive school cultures (rather focusing primarily on targeted individualised approaches) as being important. This trial will investigate how an intervention designed to drive whole school change may lead to outcomes for pupils with and without a special educational needs designation. As such, this trial is expected to make an important contribution to research evidence and to UK educational policy. ISRCTN registry ISRCTN11339306 . Registered on 12 March 2020 (retrospectively registered).


Manipulating cues in involuntary autobiographical memory: verbal cues are more effective than pictorial cues.
In two experiments, pictorial cues were compared with their verbal labels to assess their effectiveness in eliciting involuntary autobiographical memories. Cues were relatively complex in Experiment 1 (e.g., relaxing on a beach) and simple objects in Experiment 2 (e.g., a ball). In both experiments, participants went through a vigilance task in which they were presented with frequent nontarget and rare target visual stimuli. Pictures or their corresponding verbal labels were also displayed on both target and nontarget stimuli, but participants were told that these were irrelevant to the task. They were asked to interrupt the vigilance task whenever they became aware of task-unrelated mental contents and to report them. In both experiments, more involuntary memories were elicited in the verbal cue condition, rather than in the pictorial cue condition. This result is discussed in relation to previous work that highlighted the greater effectiveness of verbal cues in memory tasks.


The volume of fluid injected into the tissue expander and the tissue expansion.
Replacement of the lost tissue is the major concerns of the plastic surgeons. Expanded area should be coherent with the surrounding tissue. Tissue expansion technique is the reforming methods the skin tissue scarcities. Several methods for tissue expansion are available; including usage of silicon balloon and injecting fluid into the tissue expander. In a clinical trial study, 35 patients, with burn scars, in the face, skull and neck area were studied. We provided a tissue expander device with capacities of 125, 250 and 350cc. Fluid was injected inside the device, 3 consecutive weeks with 1-week interval. After 3 months the device was set out and the tissue expansion was measured using a transparent board and the results were analyzed. Multiple regression was done by SPSS 20 to analyze the data. Regression model showed Skin expansion was positively correlated with the volume of the injected fluid. For each centimeter square of skin expansion, about 6-8 ml of fluid must be injected. Correction of skin defects resulting from burning scar is possible using tissue expanders. The tissue expansion is correlated with the amount of the injected fluid.


Soft Tissue Schwannomas of the Hard Palate and the Mandibular Mentum.
Schwannomas are benign, slow growing, encapsulated tumours that originate from the Schwann cells. Intraoral schwannomas are rare, and most of these tumours involve the tongue. They are rarely located in the hard palate or in the facial soft tissue. Herein, we present the clinical and histological features as well as the prognoses of two male patients with schwannoma, one of which was localized to the hard palate and the other to the facial soft tissue around the mandibular mentum and caused swelling.


How things fall apart: understanding the nature of internalizing through its relationship with impairment.
The literature suggests that internalizing psychopathology relates to impairment incrementally and gradually. However, the form of this relationship has not been characterized. This form is critical to understanding internalizing psychopathology, as it is possible that internalizing may accelerate in effect at some level of severity, defining a natural boundary of abnormality. Here, a novel method-semiparametric structural equation modeling-was used to model the relationship between internalizing and impairment in a sample of 8,580 individuals from the 2000 British Office for National Statistics Survey of Psychiatric Morbidity, a large, population-representative study of psychopathology. This method allows one to model relationships between latent internalizing and impairment without assuming any particular form a priori and to compare models in which the relationship is constant and linear. Results suggest that the relationship between internalizing and impairment is in fact linear and constant across the entire range of internalizing variation and that it is impossible to nonarbitrarily define a specific level of internalizing beyond which consequences suddenly become catastrophic in nature. Results demonstrate the phenomenological continuity of internalizing psychopathology, highlight the importance of impairment as well as symptoms, and have clear implications for defining mental disorder.


CodY Regulates SigD Levels and Activity by Binding to Three Sites in the fla/che Operon.
Exponentially growing cultures of Bacillus subtilis (PY79) are composed primarily of nonmotile, chained cells. The alternative sigma factor, SigD, promotes the phenotypic switch from nonmotile, chained cells to unchained, motile cells. In the present work, we investigated the role of the GTP-sensing protein CodY in the regulation of SigD. Deletion of codY resulted in a significant increase in SigD accumulation and activity and shifted the proportion of unchained cells up from ∼15% to ∼75%, suggesting that CodY is an important regulator of SigD. CodY was previously shown to bind to the PD3 and Pfla/che promoters located upstream of the first gene in the sigD-containing fla/che operon. Using electrophoretic mobility shift assays, we found that CodY also binds to two other previously uncharacterized sites within the fla/che operon. Mutations in any one of the three binding sites resulted in SigD levels similar to those seen with the ΔcodY mutant, suggesting that each site is sufficient to tip cells toward a maximal level of CodY-dependent SigD accumulation. However, mutations in all three sites were required to phenocopy the ΔcodY mutant's reduced level of cell chaining, consistent with the idea that CodY binding in the fla/che operon is also important for posttranslational control of SigD activity. One way that bacteria adapt quickly and efficiently to changes in environmental quality is to employ global transcriptional regulators capable of responding allosterically to key cellular metabolites. In this study, we found that the conserved GTP-sensing protein CodY directly regulates cell motility and chaining in B. subtilis by controlling expression and activity of SigD. Our results suggest that B. subtilis becomes poised for cell dispersal as intracellular GTP levels are depleted.


[The results of treatment of hypopharyngeal carcinoma: some prognostic factors].
Eighty nine patients with hypopharynx carcinoma treated from 1970 to 1997 at the ENT Clinic of Pomeranian Medical Academy were studied retrospectively. There were only IV stage patients. The treatment consisted of surgery alone (n = 21), radiotherapy and post-radiotherapy surgery (n = 7), a planned combination of surgery and post-operative radiotherapy (n = 61). The 3-year survival was 34.88%, whereas the 5-year disease-free survival was 25.04%. The 5-year survival was related to the preoperative nodal staging (N0--52.8%; N1--17.8%; N2--28.3% and N3--0%), the number of lymph nodes metastases (no metastases 45.1%, 1--28.2%, 2-4--23.9%, > 4--0%), and the size of nodes (0 cm--31.6%, 1-3 cm--21.9%, > 3 cm--30.7%). Radiotherapy applied to operative treatment failed to exert any meaningful positive influence on the overall percentage of survivals. 17 patients had local recurrences and 6 node recurrences. Mainly following factors exerted the influence on appearance of nodal recurrence: component N and the number of metastatic nodes. It was pointed out that the result of treatment of hypopharynx carcinoma are still poor and unchanged despite of developing our skills and using new technology of treatment.


A Tree-based Model Averaging Approach for Personalized Treatment Effect Estimation from Heterogeneous Data Sources.
Accurately estimating personalized treatment effects within a study site (e.g., a hospital) has been challenging due to limited sample size. Furthermore, privacy considerations and lack of resources prevent a site from leveraging subject-level data from other sites. We propose a tree-based model averaging approach to improve the estimation accuracy of conditional average treatment effects (CATE) at a target site by leveraging models derived from other potentially heterogeneous sites, without them sharing subject-level data. To our best knowledge, there is no established model averaging approach for distributed data with a focus on improving the estimation of treatment effects. Specifically, under distributed data networks, our framework provides an interpretable tree-based ensemble of CATE estimators that joins models across study sites, while actively modeling the heterogeneity in data sources through site partitioning. The performance of this approach is demonstrated by a real-world study of the causal effects of oxygen therapy on hospital survival rate and backed up by comprehensive simulation results.


Differences in G-actin containing bound ATP or ADP: the Mg2+-induced conformational change requires ATP.
The role of adenosine 5'-triphosphate (ATP) in the Mg2+-induced conformational change of rabbit skeletal muscle G-actin has been investigated by comparing actin containing bound ADP with actin containing bound ATP. As previously described [Frieden, C. (1982) J. Biol. Chem. 257, 2882-2886], N-acetyl-N'-(5-sulfo-1-naphthyl)ethylenediamine-labeled G-actin containing ATP undergoes a time-dependent Mg2+-induced fluorescence change that reflects a conformational change in the actin. Addition of Mg2+ to labeled G-actin containing ADP gives no fluorescence change, suggesting that the conformational change does not occur. The fluorescence change can be restored on the addition of ATP. Examination of the time courses of these experiments suggests that ATP must replace ADP prior to the Mg2+-induced change. The Mg2+-induced polymerization of actin containing ADP is extraordinarily slow compared to that of actin containing ATP. The lack of the Mg2+-induced conformational change, which is an essential step in the Mg2+-induced polymerization, is probably the cause for the very slow polymerization of actin containing ADP. On the other hand, at 20 degrees C, at pH 8, and in 2 mM Mg2+, the elongation rate from the slow growing end of an actin filament, measured by using the protein brevin to block growth at the fast growing end, is only 4 times slower for actin containing ADP than for actin containing ATP.


Investigation of the structures and chemical ordering of small Pd-Au clusters as a function of composition and potential parameterisation.
The energetics, structures and segregation of Pd-Au nanoalloys (all compositions for 34- and 38-atoms) have been studied using a genetic algorithm global optimization technique with the Gupta empirical potential. Three modifications of the Pd-Au parameters have been studied: parameter set I in which all parameters (A, xi, p, q and r(0)) in the Gupta potential are weighted in a symmetrical fashion; parameter set II (symmetric weighting of only the pair and many-body energy scaling parameters A and xi); and parameter set III (antisymmetric weighting of A and xi). Structural analysis reveals competition between a range of structural families; decahedra, polyicosahedra and truncated octahedra (for 34 atoms) and incomplete-icosahedra-Mackay, decahedra, polyicosahedra (low-symmetry), six-fold-polyicosahedra and a mixed octahedron-icosahedron (Oh-Ih) structure (for 38 atoms). It is shown that, by finely tuning the Gupta potential, it is possible to qualitatively reproduce the results observed at higher levels of theory (e.g. Density Functional Theory). There are four main types of chemical ordering which are observed: core-shell; spherical cap; ball-and-cup; and mixed. It is shown that the chemical ordering and the proportion of Pd-Au heteronuclear bonds in these clusters are strongly dependent on the potential parameters. Comparison of the results from parameter set III and two previously fitted potentials shows that the DFT-fit potential gives rise to similar results for energies, and lowest energy structures and homotops to those for parameter set III with w(a) = 0.8, but the exp-fit potential gives rise to qualitatively different results.


Successful preterm pregnancy in a rare variation of Herlyn-Werner-Wunderlich syndrome: a case report.
Herlyn-Werner-Wunderlich syndrome (HWWS) is an uncommon congenital anomaly of the female urogenital tract, characterised by uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis. We reported the difficult pregnancy course complicated by an extremely rare and unique case of this syndrome associated with ectrodactyly, a clinical combination never described in literature. A 28- year-old nulliparous woman previously diagnosed for HWWS associated with ectrodactyly of the right foot and with a history of abdominal left hemi-hysterectomy, ipsilateral salpingectomy, vaginal reconstruction when she was an adolescent. She suffered from threats of abortion in the first trimester, recurrent urinary tract infections during all pregnancy. At 33 weeks + 5 days of gestational age, she was hospitalized for premature rupture of the membranes and uterine contractions and a caesarean section was performed because of breech presentation. Postpartum period was complicated by a pelvic abscess resolved with parental antibiotic therapies. Our literature review shows an unusual aspect in our case: HWWS is not classically associated with skeletal anomalies. Moreover, the most frequent urogenital side affected is the right, not left side as in this woman. Preterm spontaneous rupture of membranes and fetal abnormal presentation represent frequent complications and probably post-caesarean infections are related to pregnancies in the context of this syndrome.


Communication and cultural issues in providing reproductive health care to immigrant women: health care providers' experiences in meeting the needs of [corrected] Somali women living in Finland.
Communication problems due to language and cultural differences between health care professionals and patients are widely recognized. Finns are described as more silent whereas one concurrent large immigrant group, the Somalis, are described as more open in their communication. The aim of the study was to explore physicians-nurses/midwives' communication when providing reproductive and maternity health care to Somali women in Finland. Four individual and three focus group interviews were carried out with 10 gynecologists/obstetricians and 15 nurses/midwives from five selected clinics. The health care providers considered communication (including linguistic difficulties), cultural traditions, and religious beliefs to be problems when working with Somali women. Male and female physicians were generally more similar in communication style, interpersonal contacts, and cultural awareness than the nurses/midwives who were engaged in more partnership-building with the Somali women in the clinics. Despite the communication and cultural problems, there was a tentative mutual understanding between the Finnish reproductive health care professionals and the Somali women in the clinics.


Vascular endothelial growth factor expression in oligodendrogliomas: a correlative study with Sainte-Anne malignancy grade, growth fraction and patient survival.
Microangiogenesis is a delayed but crucial event in the malignant progression of oligodendrogliomas. Accord-ingly, in the new Sainte-Anne grading system of oligodendrogliomas, endothelial hyperplasia and contrast enhancement, both being indicators of microangiogenesis, are key criteria for the distinction of grade A from grade B tumours. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor: a strong correlation between VEGF expression, Sainte-Anne malignancy grade and patient outcome might thus be expected. In order to assess this hypothesis, VEGF immunostaining was performed in a series of 34 oligodendrogliomas that included 11 grade B and 23 grade A, of which nine became grade B during the study period (mean clinical and imaging follow-up: 41 months). VEGF expression correlated strongly with Sainte-Anne tumour grade (P < 0.001), and inversely with patient survival (P < 0.001) and recurrence-free survival (P = 0.002). One hundred per cent of grade B but only 17% of grade A were VEGF-positive. By contrast, the MIB-1 labelling index did not correlate with VEGF expression, total survival or recurrence-free survival. In accordance with the grading system, this study showed that, in oligodendrogliomas, VEGF expression and microangiogenesis are progression-related phenomena that confer on these tumours a growth advantage by presumably reducing hypoxia-induced apoptotic cell death. These findings might have important implications in the future for the indication and timing of anti-angiogenic therapies.


Impact of gender on outcomes after transcatheter aortic valve implantation.
The influence of gender on clinical outcomes following transcatheter aortic valve implantation (TAVI) was considerably discrepant in previous studies. We aimed to investigate the impact of gender in our registry. The study is a retrospective observational analysis of a prospectively designed cohort (546 consecutive patients treated at the University Hospital Zurich who were enrolled in Swiss TAVI Cohort from May 2008 to April 2014). The Study took place in University Heart Centre at University Hospital Zurich, Switzerland. Both genders were equally represented with 51.5 % (n = 281) of the populations being females, who were significantly older and had a more pronounced history of hypertension (P < 0.001). Males on the other hand showed a higher incidence of diabetes (P = 0.004), coronary artery disease (P < 0.001), chronic obstructive pulmonary disease (P < 0.001) and renal failure requiring renal replacement therapy (P = 0.018). Patients were followed up for a median of 391 days with a 100% complete follow-up at one year. The primary outcome (all-cause mortality) occurred in 6.8% (n = 37) and 15% (n = 82) of patients at 30 days and one year, respectively. The 30-day all-cause mortality outcome did not significantly differ between females (7.5%) and males (6.0%) (P = 0.619), but one year all-cause mortality occurred significantly more in males than in females (18.7% vs. 11.7%, P < 0.037). After TAVI implantation for severe aortic stenosis, males have a less favorable long-term (one year) mortality outcome than females.


gamma-AChR/epsilon-AChR switch at agrin-induced postsynaptic-like apparatus in skeletal muscle.
We transfected the extrajunctional region of denervated soleus muscles in adult rats with neural agrin cDNA to induce myofibers to form postsynaptic-like apparatus containing acetylcholine receptor (AChR) aggregates. By 1 week approximately 30% of the AChR aggregates contained a mixture of epsilon-AChRs and gamma-AChRs while approximately 70% had only gamma-AChRs. If the transfected muscles were reinnervated in the original junctional region, the postsynaptic-like apparatus, despite the absence of apposed axon terminals, gradually came to have only epsilon-AChRs. We conclude that at the postsynaptic apparatus of ectopic neuromuscular junctions formed by a foreign nerve implanted into the extra-junctional region of denervated muscles, agrin secreted by the axon terminal plays a direct role in the gamma-AChR/epsilon-AChR switch that occurs as the apparatus reaches maturity. Our findings, together with results from other studies, indicate further that agrin and acetylcholine are the only nerve-derived factors required for this switch.


Colistin resistance in multidrug-resistant Klebsiella pneumoniae strains at a perinatal maternal institute in Lima, Peru, 2015-2018.
The objective of this study was to evaluate the presence of colistin- and carbapenemic-resistant genes in multidrug-resistant Klebsiella pneumoniae strains isolated at the Instituto Materno Perinatal de Lima (2015-2018). Susceptibility levels were analyzed by disk diffusion and microdilution. The presence of colistin- and carbapenemic-resistant genes was determined by polymerase chain reaction (PCR) and was related to clonality. A total of 36 K. pneumoniae strains were analyzed, 5 (13.8%) were resistant to colistin and belonged to different clonal groups. Only 2 strains were found with carbapenemases (bla KPC and bla NDM), and no colistin plasmid genes were detected. High resistance levels to the other tested antimicrobials were observed, except for amikacin (13.9%). The results highlight the presence of colistin-resistant strains (33.3% in 2018), a worrying situation as they are part of the latest treatment alternatives for infections caused by multiresistant pathogens.


Leptomeningeal Metastases of the Spine: A Systematic Review.
Leptomeningeal metastases (LMs) of the spine have complex management. We reviewed the literature on spine LMs. PubMed, EMBASE, Scopus, Web-of-Science, and Cochrane were searched following the PRISMA guidelines to include studies of spine LMs. We included 46 studies comprising 72 patients. The most frequent primary tumors were lung (19.4%) and breast cancers (19.4%). Median time from primary tumors was 12 months (range=0-252 months). Cauda equina syndrome occurred in 34 patients (48.6%). Nodular spine LMs (63.6%) were more frequent. Concurrent intracranial LMs were present in 27 cases (50.9%). Cerebrospinal fluid cytology was positive in 31 cases (63.6%). Cases were managed using palliative steroids (73.6%) with locoregional radiotherapy (55.6%) chemotherapy (47.2%), or decompressive laminectomy (8.3%). Post-treatment symptom improvement (32%) and favorable radiological response (28.3%) were not different based on treatment (p=0.966; p=0.727). Median overall-survival was 3 months (range=0.3-60 months), not significantly different between radiotherapy and chemotherapy (p=0.217). Spine LMs have poor prognoses. Radiotherapy, chemotherapy, and surgery are only palliative, as described for intracranial LMs.


The effect of speech modification on non-native listeners for matrix-style sentences.
Speech can be modified to promote intelligibility in noise, but the potential benefits for non-native listeners are difficult to predict due to the additional presence of distortion introduced by speech alteration. The current study compared native and non-native listeners' keyword scores for simple sentences, unmodified and with six forms of modification. Both groups showed similar patterns of intelligibility change across conditions, with the native cohort benefiting slightly more in stationary noise. This outcome suggests that the change in masked audibility rather than distortion is the dominant factor governing listeners' responses to speech modification.


Cervical internal carotid artery injuries due to blunt trauma.
Blunt or nonpenetrating trauma to the head and neck occasionally results in damage to the cervical segment of the internal carotid artery. This may produce neurologic signs and symptoms that mimic acute craniocerebral injury. The mortality and morbidity associated with these injuries are alarmingly high. These injuries may be missed if one relies only on computed tomography. Angiography is still the definitive procedure to diagnose these lesions. The clinical and radiographic features as well as the pathogenesis and mechanism of injury are discussed for 21 cases of injury to the cervical internal carotid artery due to blunt trauma.


Characterizing the lateral slope of the aging female eyebrow.
Ideal eyebrow aesthetics give a framework for brow rejuvenation and surgical procedures do not always provide satisfying results. Previous studies have shown elevation of the medial brow with aging; however, they failed to characterize overall shape changes. To characterize changes in eyebrow slope with increasing age to better direct brow rejuvenation. From standardized anteroposterior facial photographs of 100 women 20 to 80 years of age, eyebrow height was measured at the medial limbus and arch apex from a mid-pupillary horizontal. The slope of the eyebrow was calculated. Using group analysis, mean height and slope were compared using the Mann-Whitney U test. Regression analysis was used to determine the relationship between slope and age. Mean slope significantly decreased from 20 to 29 years of age to 40 to 49 years of age (0.22 versus 0.12; P=0.03), and then increased between 40 and 49 years of age and ≥60 years of age (0.12 versus 0.21; P=0.05). Medial height did not change significantly, and arch apex significantly decreased between 20 and 29 years of age and 40 and 49 years of age. Regression analysis showed a quadratic relationship between age and slope, with the decrease in slope until the fifth decade of life being directly related to increasing age. After this, age was not a significant contributor to slope changes. With increasing age, the slope of the eyebrow decreases until the fifth decade dependent on age. After the fifth decade, age no longer plays a significant role. Therefore, choice of brow lift technique should be carefully selected.


Induction of endocannabinoid levels in juvenile rat brain following developmental chlorpyrifos exposure.
The endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) play vital roles during nervous system development. The degradation of 2-AG and AEA is mediated by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. These enzymes are inhibited following developmental chlorpyrifos (CPF) exposure. To investigate whether this inhibition is persistent or whether accumulation of endocannabinoids in the brain occurs, 10-day-old rat pups were orally exposed daily for 7 days to either corn oil or increasing dosages of CPF (1, 2.5, or 5mg/kg), and forebrains were collected at 4, 12, 24, and 48h following the last administration. All dosages inhibited cholinesterase (ChE), FAAH, and MAGL, and elevated AEA and 2-AG levels with the greatest effect occurring at 12h with ChE, FAAH, AEA, and 2-AG and at 4h with MAGL. With the high dosage, return to control levels occurred with 2-AG (48h) only. With the medium dosage, return to control levels occurred with MAGL, 2-AG, and AEA (48h) but not with ChE or FAAH. With the low dosage, return to control levels occurred with MAGL (12h), ChE and 2-AG (24h), and AEA (48h) but not with FAAH. With the lowest dosage, peak inhibition of FAAH (52%) is greater than that of ChE (24%) and that level of FAAH inhibition is sufficient to induce a persistent pattern of elevated AEA. It is possible that this pattern of elevation could alter the appropriate development of neuronal brain circuits.


Variation in Preoperative Testing and Antireflux Surgery in Infants.
Despite the availability of objective tests, gastroesophageal reflux disease (GERD) diagnosis and management in infants remains controversial and highly variable. Our purpose was to characterize national variation in diagnostic testing and surgical utilization for infants with GERD. Using the Pediatric Health Information System, we identified infants <1 year old diagnosed with GERD between January 2011 and March 2015. Outcomes included progression to antireflux surgery (ARS) and use of relevant diagnostic testing. By using adjusted generalized linear mixed models, we compared facility-level ARS utilization. Of 5 299 943 infants, 149 190 had GERD (2.9%), and 4518 (3.0%) of those patients underwent ARS. Although annual rates of GERD and ARS decreased, there was a wide range of GERD diagnoses (1.8%-6.2%) and utilization of ARS (0.2%-11.2%). Facilities varied in the use of laparoscopic versus open ARS (mean: 66%, range: 23%-97%). Variation in facility-level ARS rates persisted after adjustment. Overall 3.8% of patients underwent diagnostic testing, whereas 22.8% of ARS patients underwent diagnostic testing. The proportion of surgeries done laparoscopically was independently associated with ARS utilization (odds ratio: 1.57; 95% confidence interval: 1.21-2.02). Facility-level utilization of diagnostics (P > .1) and prevalence of GERD (P > .1) were not associated with utilization of ARS. There is notable variation in the overall utilization of ARS and in the surgical and diagnostic approach in infants with GERD. Fewer than 4% of infants with GERD undergo diagnostic testing. This variation in care merits development of consensus guidelines and further research.


Antibiotic treatment and resistance in chronic wounds of vascular origin.
The problem of antibiotic resistance is worldwide and affects many types of pathogens. This phenomenon has been growing for decades and nowadays we are faced with a wide range of worrisome pathogens that are becoming resistant and many pathogens that may soon be untreatable. The aim of this study was to determine the resistance and antibiotic treatment in chronic wounds of vascular origin. We performed a cross sectional study on a sample of patients with chronic vascular wounds, hospitalized between October 2014 and August 2015, in the Clinic of Vascular Surgery in Trakia Hospital Stara Zagora. The statistical analysis of data was descriptive, considering the p value of ≤0.05, the threshold of statistical significance. In the group of 110 patients, the significantly most frequent chronic wound (p<0.001) was peripheral arteriopathy (47.3%, CI95%: 38.19-56.54). Among 159 strains, 30% of patients having multiple etiology, the species most frequently isolated were Staphylococcus aureus, E.coli, Enterococcus faecalis, Pseudomonas aeruginosa and Proteus mirabilis with a significant predominance (p<0.05) of the Gram negative (55.1%). The spectrum of strains resistance included the Beta-lactams (36.4%, p<0.001), Macrolides (20%), Tetracyclines (9.1%), Aminoglycosides (8.2%) and Fluoroquinolones (4.5%). Gram negative microorganisms were the main isolates in patients with vascular chronic wound. Significantly predominant was the resistance to the beta-lactam antibiotics.