Effects of topical ethacrynic acid adducts on intraocular pressure in rabbits and monkeys.
We evaluated the effect of topical ethacrynic acid on rabbit and monkey intraocular pressure. In a preliminary experiment, 100-mmol/L ethacrynic acid applied topically to Dutch-Belted rabbit eyes was associated with an 8-mm Hg lowering of intraocular pressure. However, corneal edema was severe, and the corneal epithelium sloughed off. To try to maintain the pressure-lowering effect but reduce the corneal side effects, we attempted to create an adduct of ethacrynic acid by utilizing ethacrynic acid's sulfhydryl reactivity. Ethacrynic acid was mixed with equimolar cysteine to bind the sulfhydryl-reactive sites on ethacrynic acid. The goal was to expose the cornea to adducted ethacrynic acid, which might then dissociate in the anterior chamber via a retro-Michael reaction. Intraocular pressure decreased 8.9 mm Hg (n = 40) with this treatment, and corneal edema was lessened (32 of 40 eyes had mild to no edema). However, we observed that when the eye was treated before ethacrynic acid-cysteine administration with topical acetylcysteine, the corneal side effects were reduced further and the intraocular pressure effect remained. In living cynomolgus monkeys receiving a single pretreatment drop of 75-mmol/L acetylcysteine followed by two drops of 130-mmol/L ethacrynic acid and 130-mmol/L cysteine, an intraocular pressure lowering of 9.9 mm Hg was observed (n = 7). However, in three of seven eyes corneal edema developed. Pretreatment with two drops of acetylcysteine eliminated the pressure-lowering effect but did not confer any added corneal protection. Our results indicate that topical ethacrynic acid-cysteine is effective in lowering the intraocular pressure of rabbits and cynomolgus monkeys and, when combined with acetylcysteine pretreatment, may offer the potential for a new topical therapeutic regimen for use in glaucoma.


Computational models of signalling networks for non-linear control.
Artificial signalling networks (ASNs) are a computational approach inspired by the signalling processes inside cells that decode outside environmental information. Using evolutionary algorithms to induce complex behaviours, we show how chaotic dynamics in a conservative dynamical system can be controlled. Such dynamics are of particular interest as they mimic the inherent complexity of non-linear physical systems in the real world. Considering the main biological interpretations of cellular signalling, in which complex behaviours and robust cellular responses emerge from the interaction of multiple pathways, we introduce two ASN representations: a stand-alone ASN and a coupled ASN. In particular we note how sophisticated cellular communication mechanisms can lead to effective controllers, where complicated problems can be divided into smaller and independent tasks.


Systematic Underestimation of Pesticide Burden for Invertebrates under Field Conditions: Comparing the Influence of Dietary Uptake and Aquatic Exposure Dynamics.
Pesticides used in agriculture can end up in nearby streams and can have a negative impact on nontarget organisms such as aquatic invertebrates. During registration, bioaccumulation potential is often investigated using laboratory tests only. Recent studies showed that the magnitude of bioaccumulation in the field substantially differs from laboratory conditions. To investigate this discrepancy, we conducted a field bioaccumulation study in a stream known to receive pollutant loadings from agriculture. Our work incorporates measurements of stream pesticide concentrations at high temporal resolution (every 20 min), as well as sediment, leaves, and caged gammarid analyses (every 2-24 h) over several weeks. Of 49 investigated pesticides, 14 were detected in gammarids with highly variable concentrations of up to 140 ± 28 ng/gww. Toxicokinetic modeling using laboratory-derived uptake and depuration rate constants for azoxystrobin, cyprodinil, and fluopyram showed that despite the highly resolved water concentrations measured, the pesticide burden on gammarids remains underestimated by a factor of 1.9 ± 0.1 to 31 ± 3.0, with the highest underestimations occurring after rain events. Including dietary uptake from polluted detritus leaves and sediment in the model explained this underestimation only to a minor proportion. However, suspended solids analyzed during rain events had high pesticide concentrations, and uptake from them could partially explain the underestimation after rain events. Additional comparison between the measured and modeled data showed that the pesticide depuration in gammarids is slower in the field. This observation suggests that several unknown mechanisms may play a role, including lowered enzyme expression and mixture effects. Thus, it is important to conduct such retrospective risk assessments based on field investigations and adapt the registration accordingly.


Influence of supraglottic airway device placement on cerebral hemodynamics.
Supraglottic airway devices (SGDs) are of current use in anesthesia practice and in emergency conditions. It has been suggested that cerebral blood flow (CBF) can decrease after SGD insertion or cuff inflation; however, it is uncertain if this reduction is caused by the SGD or the anesthetic drugs utilized for the anesthetic procedure. During minor surgery we separated CBF measurements by an adequate time interval in order to measure the distinctive changes in cerebral hemodynamics associated with anesthesia induction, SGD insertion and cuff inflation. Patients scheduled for minor surgery requiring general anesthesia and SGD placement were included. Middle cerebral artery mean flow velocity (FVm-mca) and the Pulsatility Index (PI) were measured through use of trans-cranial Doppler (TCD) at baseline, after anesthesia induction, SGD insertion and cuff inflation, once a steady cardio-circulatory state was reached and end tidal CO2 (etCO2) was within normal range. A total of 21 patients were included. Following anesthesia induction, in concomitance to a reduction in mean arterial pressure (MAP), there was a mean decrease in FVm-mca by 16.60 cm/s, P<0.005 and a mean increase in PI by 0.24, P<0.0015. MAP, FVm-mca and PI did not change significantly, neither after SGD placement (P>0.05), nor after SGD cuffing (P>0.05). SGD insertion and cuff inflation did not influence cerebral hemodynamics in anesthetized patients undergoing minor surgery. At normal etCO2 range, the CBF reduction with transient increase in PI was associated with anesthesia induction and not SGD insertion itself.


T-lymphocyte navigation and migration: beyond the PI3K paradigm.
The co-ordinated and directional trafficking of T-lymphocytes in lymphoid and peripheral tissues is an important process in lymphoid development, immunosurveillance and immune responses. Members of the chemokine superfamily play a key role in providing navigational cues for T-cells and chemokine receptors couple with a wide range of biochemical signals including phosphoinositide lipid metabolism, elevation of intracellular calcium levels, activation of a wide array of protein kinases as well as small GTPases. One of the most robust biochemical signals elicited by chemokines in T-lymphocytes is the activation of several members of the PI3K (phosphoinositide 3-kinase) family. In many cell systems, PI3Ks are known to contribute to several aspects of the migratory machinery, although their role in T-cell migration has been unclear and will be considered in the present paper.


In hypertension, the kidney is not always the heart of the matter.
Blood pressure abnormalities are thought to originate from intrinsic changes in the kidney, a concept that has been largely unchallenged for more than 4 decades. However, recent molecular, cellular, and transgenic mouse studies support an alternative hypothesis: primary abnormalities in vascular cell function can also directly cause abnormalities of blood pressure. In this issue of the JCI, Crowley and coworkers describe the application of an elegant cross-renal transplant model to type 1A angiotensin (AT(1A)) receptor-deficient mice and their wild-type littermates to explore the relative contributions of renal and extrarenal tissues to the low blood pressure seen in the AT(1A) receptor-deficient animals. Their studies further support the emerging paradigm that primary abnormalities of the vasculature can make unique, nonredundant contributions to blood pressure regulation; the findings have potentially important implications for the ways we diagnose and treat blood pressure diseases in humans.


The cardiovascular risk factors of the Roma (gypsies) people in Central-Eastern Europe: a review of the published literature.
Estimated number of the Roma people in central-eastern Europe cannot be precisely appreciated, but official data suggest that in the 2004 they were approximately 4.2 million. At this time, there are few available data about the health status of the Roma people, mostly assessing genetic and infectious diseases, which reflect poverty, overcrowding, and lack of education. There is even less data regarding non-communicable and chronic diseases, especially cardiovascular diseases. We searched the published literature on the cardiovascular risk factors in Roma people using PubMed from January 2000 to July 2011. The searching criteria were: (1) randomized, prospective observational, retrospective and meta-analysis; (2) adult patients with cardiac diseases or cardiovascular risk factors (3) data available for cardiovascular patients. Search terms included dyslipidemia, obesity, tobacco, hypertension, and diabetes mellitus. Twenty-five studies were identified. Approximately 75% of them were related to just four countries: Slovakia, Croatia, Czech Republic, and Serbia. This paper is a review based on existing literature concerning classical risk factors in Roma people with emphasis on their ethnical features. Despite limited data, the results showed that this ethnicity has the incriminated risk factors more frequently than the majority and consequently a higher cardiovascular morbidity rate. Quantification of the cardiovascular risk factor and their implication in the shortening of life expectancy in Roma population was a provocation due to a paucity of reliable data. At this time, we should pay more attention on the Roma health issues and the cultural concerns that might affect them in the context of borderless Europe.


The effect of dietary cricket meal (Gryllus bimaculatus) on growth performance, antioxidant enzyme activities, and haematological response of African catfish (Clarias gariepinus).
This study was conducted to investigate the growth performance, biomarkers of oxidative stress, catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) as well as the haematological response of African catfish after being fed with fish feed containing different levels of cricket meal. The juvenile fish were assigned to three different treatments with isonitrogenous (35 %) and isoenergetic (19 kJ g(-1)) diets containing 100 % cricket meal (100 % CM), 75 % cricket meal (75 % CM), and 100 % fishmeal (100 % FM) as control groups for 7 weeks. The results indicated that a diet containing 100 % CM and 75 % CM improved growth performance in terms of body weight gain and specific growth rate, when compared to 100 % FM. The feed conversion ratio (FCR) and protein efficiency ratio (PER) did not differ significantly between all diets, but reduced FCR and increased PER were observed with a higher inclusion of cricket meal. A haematological examination of fish demonstrated no significant difference of red blood cells in all diets and white blood cells showed a significantly higher value in fishmeal-fed fish. On the other hand, haemoglobin and haematocrit significantly increased with increasing amounts of cricket meal in the diet. Antioxidant activity of CAT was higher in the 100 % CM group compared to fish fed other diets, whereas GST and SOD showed increasing trends with a higher incorporation of cricket, although insignificant differences were observed between all diets. These results suggest that cricket meal could be an alternative to fishmeal as a protein source in the African catfish diet.


Knowledge, attitude, and practice of white coat use among medical students during clinical practice (LAUNDERKAP): A cross-sectional study.
Recent studies found white coats to be reservoirs for bacteria and medical students did not conform to proper hygiene measures when using these white coats. We investigated the knowledge, attitude, and practice (KAP) of medical students toward white coat use in clinical settings (LAUNDERKAP). A validated, online-based survey was disseminated to 670 students from four Malaysian medical schools via random sampling. Scores were classified into good, moderate, or poor knowledge and practice, and positive, neutral, or negative attitude. Mann-Whitney U and Kruskal-Wallis tests were used to analyze the relationship between demographic variables and knowledge, attitude, and practice scores. A total of 492/670 students responded (response rate: 73.4%). A majority showed negative attitudes (n = 246, 50%), poor knowledge (n = 294, 59.8%), and moderate practice (n = 239, 48.6%). Senior and clinical year students had more negative attitudes. Male students had higher knowledge, while students from private medical schools and preclinical years had better practice. There was a significant relationship between attitude and practice (r = 0.224, P < .01), as well as knowledge and practice (r = 0.111, P < .05). The results demonstrate the need for more education to improve medical students' infection control practices. Our results can also guide decision-making among administrators on the role of white coats as part of medical student attire.


A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1.
Autoimmune polyendocrinopathy type 1 (APS1) is an autosomal recessive disorder characterized by autoimmune hypoparathyroidism, autoimmune adrenocortical failure, and mucocutaneous candidiasis. Recently, an autoimmune regulator gene (AIRE-1), which is located on chromosome 21q22.3, has been identified, and mutations in European kindreds with APS1 have been described. We used SSCP analysis and direct DNA sequencing to screen the entire 1,635-bp coding region of AIRE-1 in 12 British families with APS1. A 13-bp deletion (964del13) was found to account for 17 of the 24 possible mutant AIRE-1 alleles, in our kindreds. This mutation was found to occur de novo in one affected subject. A common haplotype spanning the AIRE-1 locus was found in chromosomes that carried the 964del13 mutation, suggesting a founder effect in our population. One of 576 normal subjects was also a heterozygous carrier of the 964del13 mutation. Six other point mutations were found in AIRE-1, including two 1-bp deletions, three missense mutations (R15L, L28P, and Y90C), and a nonsense mutation (R257*). The high frequency of the 964del13 allele and the clustering of the other AIRE-1 mutations may allow rapid molecular screening for APS1 in British kindreds. Furthermore, the prevalence of the 964del13 AIRE-1 mutation may have implications in the pathogenesis of the more common autoimmune endocrinopathies in our population.


A hybrid cost-sensitive ensemble for heart disease prediction.
Heart disease is the primary cause of morbidity and mortality in the world. It includes numerous problems and symptoms. The diagnosis of heart disease is difficult because there are too many factors to analyze. What's more, the misclassification cost could be very high. A cost-sensitive ensemble method was proposed to improve the efficiency of diagnosis and reduce the misclassification cost. The proposed method contains five heterogeneous classifiers: random forest, logistic regression, support vector machine, extreme learning machine and k-nearest neighbor. T-test was used to investigate if the performance of the ensemble was better than individual classifiers and the contribution of Relief algorithm. The best performance was achieved by the proposed method according to ten-fold cross validation. The statistical tests demonstrated that the performance of the proposed ensemble was significantly superior to individual classifiers, and the efficiency of classification was distinctively improved by Relief algorithm. The proposed ensemble gained significantly better results compared with individual classifiers and previous studies, which implies that it can be used as a promising alternative tool in medical decision making for heart disease diagnosis.


Modulation of amygdala response and connectivity in depression by serotonin transporter polymorphism and diagnosis.
Polymorphisms in the serotonin transporter gene (5-HTTLPR) modulate amygdala activity in healthy individuals. Increased responses to negative stimuli in carriers of low transcription alleles have been proposed to contribute to the pathogenesis of depression. We sought to investigate the effects of genotype as well as diagnosis in patients with depression. Subjects with recurrent depression (n=67) and matched healthy controls (n=49) participated in a fMRI task of implicit processing of sad facial stimuli. Effects of biallelic (short (S) and long (L) alleles) and triallelic (including rs25531 A/G single nucleotide variation) models of 5-HTTLPR polymorphisms on amygdala activity and connectivity were investigated. Significant effects were observed of both genotype and diagnosis on amygdala activity. Increased amygdala activity was associated with 5-HTTLPR genotype in low transcription allele carriers as well as with a diagnosis of depression. The connectivity analysis revealed a main effect of genotype with reduced connectivity to the subgenual region of the anterior cingulate in carriers of the low transcription alleles. There was also a main effect of diagnosis with reduced connectivity to the dorsal region of the anterior cingulate and to the dorsolateral prefrontal cortex in depression. There were no interaction effects between genotype and diagnosis in amygdala activity or connectivity. Significant independent effects of genotype and diagnosis on amygdala responsivity were revealed. The effects of genotype and diagnosis on amygdala connectivity showed a regional segregation, suggesting that 5-HTTLPR polymorphisms bias frontal-limbic connectivity while the development of depression involves more extensive neural disturbances. These findings point to the potential of connectivity maps as a diagnostic biomarker for depression.


The potential clinical relevance of visible particles in parenteral drugs.
Visible particulates (VP) are one subclass of defects seen during the final visual inspection of parenteral products and are currently one of the top ten reasons for recalls 1,2. The risk posed by particles is still unclear with limited experience reported in humans but remains an important consideration during the manufacture and use of parenteral products. From the experimental and clinical knowledge of the distribution of particulate matter in the body, clinical complications would include events occurring around parenteral administration e.g., as a result of mechanical pulmonary artery obstruction and injection site reaction, or sub-acute or chronic events e.g., granuloma. The challenge is to better understand the implication for patients of single vials with VP and align the risk with the probabilistic detection process used by manufacturers for accept/reject decisions of individual units of product.


Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group.
To assess the value of chemotherapy and radiotherapy in children with malignant peripheral nerve sheath tumors (MPNSTs) and to identify risk factors associated with outcome. A total of 167 untreated eligible patients enrolled onto the Italian and German studies between 1975 and 1998 entered this analysis. Seventeen percent of patients had neurofibromatosis type 1 (NF1). Chemotherapy was administered to 74% of patients; radiotherapy was administered to 38% of patients. With a median follow-up of 7 years, 5-year overall survival (OS) and progression-free survival (PFS) were 51% and 37%, respectively. The 5-year OS and PFS by Intergroup Rhabdomyosarcoma Study (IRS) groupings were as follows: group I, 82% and 61%; group II, 62% and 37%; group III, 32% and 27%; group IV, 26% and 21%, respectively. Univariate analysis identified IRS groups, size, invasiveness, primary site, age, and presence of NF1 as prognostic factors; multivariate analysis identified absence of NF1, tumor invasiveness T1, IRS groups I to II and extremity of primary site as independent favorable factors for OS. A trend was observed toward a benefit from radiotherapy after initial gross resection. The overall response rate to primary chemotherapy, including minor responses, in group III patients was 45%. MPNST is an aggressive tumor for which complete surgical resection is the mainstay of successful treatment. Postoperative radiotherapy may have a role in improving local control in patients with minimal residual tumor. The reported responses to primary chemotherapy suggest that it may be effective in patients with tumor considered unresectable at diagnosis.


The association between complete and partial non-response to psychosocial questions and suicide: the JPHC Study.
Non-participants to psychosocial studies have been shown to have higher mortality, and mortality differs between partial and complete responders to psychosocial questionnaires. Yet, there is very little information available directly linking survey response status with completing suicide. The study population consisted of the participants of the Japanese Public Health Center-based prospective study. Ninety-nine thousand four hundred thirty-nine subjects who returned the 10-year follow-up questionnaire and 31 754 individuals who did not return the questionnaire were included in our analyses. The risk of dying by suicide according to response status was estimated by Cox regression models. There were 358 suicides during 1 128 831 person-years of follow-up (mean follow-up time: 8.6 years). Of those who returned the questionnaire, 53.9% were full responders, 42.8% were partial non-responders, and 3.3% were complete non-responders. The risk of suicide was increased for both complete non-responders [hazard ratio (HR) = 1.84, 95% confidence interval (CI), 0.51, 6.64] and partial non-responders (HR = 1.36, 95% CI, 0.999, 1.84) to the questionnaire as a whole. The adjusting variables explained around 40% of the risk for complete non-responders whereas they did not explain the increased risk of suicide for partial non-responders. The risk of dying by suicide was significantly increased for partial non-responders to the subscale on coping (HR = 1.36, 95% CI, 1.01, 1.85) and for complete non-responders to questions on sleep (HR = 2.07, 95% CI, 1.03, 4.16). Partial and complete non-responders have increased suicide risk compared with full responders. More than one non-responder category should therefore be considered when interpreting data pertaining to psychosocial questionnaires in longitudinal studies.


Molecular mimicry of substrate oxygen atoms by water molecules in the beta-amylase active site.
Soybean beta-amylase (EC 220.127.116.11) has been crystallized both free and complexed with a variety of ligands. Four water molecules in the free-enzyme catalytic cleft form a multihydrogen-bond network with eight strategic residues involved in enzyme-ligand hydrogen bonds. We show here that the positions of these four water molecules are coincident with the positions of four potential oxygen atoms of the ligands within the complex. Some of these waters are displaced from the active site when the ligands bind to the enzyme. How many are displaced depends on the shape of the ligand. This means that when one of the four positions is not occupied by a ligand oxygen atom, the corresponding water remains. We studied the functional/structural role of these four waters and conclude that their presence means that the conformation of the eight side chains is fixed in all situations (free or complexed enzyme) and preserved from unwanted or forbidden conformational changes that could hamper the catalytic mechanism. The water structure at the active pocket of beta-amylase is therefore essential for providing the ligand recognition process with plasticity. It does not affect the protein active-site geometry and preserves the overall hydrogen-bonding network, irrespective of which ligand is bound to the enzyme. We also investigated whether other enzymes showed a similar role for water. Finally, we discuss the potential use of these results for predicting whether water molecules can mimic ligand atoms in the active center.


Notoginsenoside R1 attenuates high glucose-induced endothelial damage in rat retinal capillary endothelial cells by modulating the intracellular redox state.
The aim of this study was to examine whether Notoginsenoside R1 (NR1) attenuates high glucose-induced cell damage in rat retinal capillary endothelial cells (RCECs) and to explore the mechanisms involved. The exposure of rat RCECs to high concentration of glucose (30 mM) for 72 h led to significant cytotoxicity, including decreased cell viability, reduced mitochondrial DNA copy number, increased lactate dehydrogenase release and elevated apoptosis. NR1, when present in the culture medium, markedly attenuated the high glucose-induced cytotoxicity in rat RCECs. Moreover, high glucose also induced a significant increase in intracellular reactive oxygen species and subsequently increased the activity of NADPH oxidase and poly-ADP (ribose) polymerase, whereas the activity of catalase decreased. The addition of NR1 to the medium significantly reduced the generation of reactive oxygen species, inhibited NADPH oxidase and poly-ADP (ribose) polymerase activities and increased catalase activity in RCECs, accompanied by a reduced cellular nitrotyrosine level. To explore the underlying mechanisms involved, the cellular redox status was monitored. Both the cellular NAD+ and NADPH levels decreased significantly in high glucose medium, which resulted in a marked decrease in the NAD+/NADH and NADPH/NADP+ ratios. High glucose stimulation also enhanced the accumulation of GSSG, maintaining the GSH/GSSG ratio lower than that in the control group with 5.5 mM glucose. When treated with NR1, the cellular NAD+, NADPH and GSH concentrations increased, and the ratios of NAD+/NADH, NADPH/NADP+ and GSH/GSSG increased, similar to the control group. These results demonstrate that NR1 attenuates high glucose-induced cell damage in RCECs. Therefore, NR1 may exert its protective effects via mechanisms that involve changes in the cellular redox state.


Law enforcement officers' opinions about gun locks: anchors on life jackets?
One way law enforcement officers support firearm safety is by promoting the use of gun locks. This investigation examined law enforcement officers' willingness to use gun locks on their own guns, as well as their opinions regarding gun locks in general. Law enforcement officers from an urban agency in the southern region of the United States. Free keyed cable gun locks were distributed to all law enforcement officers in one agency who wanted one, and then an anonymous questionnaire survey was conducted about their subsequent use of, and attitudes toward, these devices. About half of the 207 officers collected gun locks (n=103). Nearly three quarters (73%) completed and returned the questionnaire. Two thirds reported that they were not using the gun lock they collected (65%), and over half disagreed that gun lock use should be required (56%). Very few cited any actual or potential technical problems with the device. An important reason given for non-use of gun locks related to being able to access the weapon quickly in case of an emergency. The findings highlight the need for further investigation into law enforcement officers' attitudes toward gun locks, the degree to which their attitudes affect their firearm safety counseling, and the need to develop a gun safety device that can be disengaged quickly.


Elevated High-Density Lipoprotein Cholesterol Is Associated with Hyponatremia in Hypertensive Patients.
Recently, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive lowering of systolic blood pressure is beneficial, but is associated with more adverse events. Hyponatremia was notably more frequent in the intensive treatment group. Investigating its risk factors is crucial for preventing this complication. Our objective in this study was to identify risk factors for hyponatremia in the adult population. We investigated the baseline demographic, clinical, and laboratory data from the 9361 participants of SPRINT to identify the best predictors of hyponatremia (serum sodium ≤130 mEq/L), and adverse events, which could be attributed to hyponatremia, using machine learning and multivariable Cox proportional hazards models. We confirmed our results in the independent National Health and Nutrition Examination Survey (NHANES) cohort between the years 2005 and 2010 (16,501 participants). Elevated baseline high-density lipoprotein cholesterol (HDL-C) was a strong predictor of future hyponatremia. Multivariable Cox regression showed hyponatremia events to be significantly increased for SPRINT participants with baseline HDL-C levels in the highest quintile (hazard ratio [HR] 2.8; 95% confidence interval [CI], 2.2-3.7; P <.001), and were also associated with treatment-related serious adverse events (HR 1.6; 95% CI, 1.3-2.1; P <.001). We confirmed the association between HDL-C and hyponatremia in the NHANES cohort (HR 2.5; 95% CI, 1.7-3.7; P <.001). Elevated HDL-C (≥62 mg/dL) is a risk factor for hyponatremia. Thus, hypertensive patients with elevated HDL-C should be closely monitored for hyponatremia when treated for hypertension.


Clival Chondrosarcoma Associated With an Intra-Axial Cystic Medullary Lesion Responsive to Steroids.
Introduction: Here we present a 75-year-old patient who was admitted with acute-onset right-sided hemiparesis, dysphagia, dysarthria and nystagmus. Repeated MRI scans showed two lesions with contact to one another: one solid stationary extra-axial lesion at the caudal part of the clivus and a rapidly growing intra-axial cystic lesion at the level of the medulla oblongata. Biopsy of the solid lesion demonstrated a low-grade chondrosarcoma, while no tissue sample of the cystic lesion could be retrieved. After initiation of dexamethasone therapy the cystic lesion markedly regressed. Background: A literature search on published cases with the same combination of a stationary solid extra-axial mass at the caudal part of the clivus and a growing intra-axial cystic mass in the medulla oblongata was negative, indicating that the case described here is both unique and novel. Discussion: Considering the rapid progression of symptoms and growth on MR-imaging in combination with the marked response to steroids, an inflammatory response linked to the chondrosarcoma is most likely. At the same time other possible explanations as a second neoplasm, an abscess or an ischemic lesion seem unlikely. Concluding remarks: This case underlines an unusual complication of a rare brainstem tumor and outlines both the differential diagnosis and potential treatment options. For such cystic lesions in combination with chondrosarcoma, a treatment course with steroids should be considered along with surgical exploration necessary to obtain the diagnosis and for potential reduction of mass-effect on the medulla oblongata.


An analysis of the academic capacity of anaesthesia in the UK by publication trends and academic units.
Over a decade ago, bibliometric analysis predicted the disappearance of UK publishing in anaesthesia by 2020. We repeated this analysis to assess if this had turned out to be the case, searching PubMed for papers associated with UK consultant anaesthetists for 2017-2019 across 15 journals. Although the rate of decline has flattened using the same search filter, including a wider range of publication types shows that outputs still remain at half 1990s levels (381 papers for all 3 years combined), authored by 769 anaesthetists, 274 of whom are associated with an academic centre. There are now 11 identifiable academic units, and a further 15 places where anaesthetists have affiliations with academic centres as individuals. The majority of papers (71%) are in secondary analysis (observational, database and association studies, surveys and meta-analyses), rather than in primary research (clinical trials or laboratory studies). These data reflect the current academic capacity in terms of publications, academic units and staffing. We discuss how this information can be used to inform a new strategy for UK academic anaesthesia.


Multiframe image estimation for coded aperture snapshot spectral imagers.
A coded aperture snapshot spectral imager (CASSI) estimates the three-dimensional spatiospectral data cube from a snapshot two-dimensional coded projection, assuming that the scene is spatially and spectrally sparse. For less spectrally sparse scenes, we show that the use of multiple nondegenerate snapshots can make data cube recovery less ill-posed, yielding improved spatial and spectral reconstruction fidelity. Additionally, data acquisition can be easily scaled to meet the time/resolution requirements of the scene with little modification or extension of the original CASSI hardware. A multiframe reconstruction of a 640 × 480 × 53 voxel datacube with 450-650 nm white-light illumination of a scene reveals substantial improvement in the reconstruction fidelity, with limited increase in acquisition and reconstruction time.


MRCISD studies of the dissociation of vinylhydroperoxide, CH2CHOOH: there is a saddle point.
Multireference ab initio methods are used to investigate the dissociation of vinylhydroperoxide CH(2)CHOOH into vinyl oxide and hydroxide radicals. In contrast to some previous studies, which claim the reaction has no saddle point, our calculations confirm that the dissociation is associated with a kinetic barrier (transition state). We further propose the existence of a hitherto undiscovered radical-radical complex on the reaction path. The computed reaction energetics are used to estimate VHP dissociation rates, and the results are discussed in the context of atmospheric ozonolysis pathways. Qualitative aspects of the dissociation of larger, substituted vinylhydroperoxides are also discussed.


Effects of plant diversity, N fertilization, and elevated carbon dioxide on grassland soil N cycling in a long-term experiment.
The effects of global environmental changes on soil nitrogen (N) pools and fluxes have consequences for ecosystem functions such as plant productivity and N retention. In a 13-year grassland experiment, we evaluated how elevated atmospheric carbon dioxide (CO2 ), N fertilization, and plant species richness alter soil N cycling. We focused on soil inorganic N pools, including ammonium and nitrate, and two N fluxes, net N mineralization and net nitrification. In contrast with existing hypotheses, such as progressive N limitation, and with observations from other, often shorter, studies, elevated CO2 had relatively static and small, or insignificant, effects on soil inorganic N pools and fluxes. Nitrogen fertilization had inconsistent effects on soil N transformations, but increased soil nitrate and ammonium concentrations. Plant species richness had increasingly positive effects on soil N transformations over time, likely because in diverse subplots the concentrations of N in roots increased over time. Species richness also had increasingly positive effects on concentrations of ammonium in soil, perhaps because more carbon accumulated in soils of diverse subplots, providing exchange sites for ammonium. By contrast, subplots planted with 16 species had lower soil nitrate concentrations than less diverse subplots, especially when fertilized, probably due to greater N uptake capacity of subplots with 16 species. Monocultures of different plant functional types had distinct effects on N transformations and nitrate concentrations, such that not all monocultures differed from diverse subplots in the same manner. The first few years of data would not have adequately forecast the effects of N fertilization and diversity on soil N cycling in later years; therefore, the dearth of long-term manipulations of plant species richness and N inputs is a hindrance to forecasting the state of the soil N cycle and ecosystem functions in extant plant communities.


Compliance and the benefit/risk relationship of antihypertensive treatment.
Compliance is defined as a patient's behavior in terms of taking prescribed medication, following diets, or executing medically recommended lifestyle changes. Furthermore, compliance measures the extent to which a person's behavior coincides with medical or health advice. The measurement of compliance over time is still a problem. The recently developed medication monitors, however, enable precise documentation of the taking of pills out of the container over long time periods. Long-term compliance with antihypertensive treatments is, referring to the literature, about 50%. The causes of partial compliance are not yet well known. Partial compliance is often accompanied by reduced benefit, e.g., poor blood pressure control. There are even strong arguments that partial compliance increases the risks of treatment, especially with beta-blockers. Thus, the traditional physicians' nonperception of patients' partial compliance is no longer acceptable, as partial compliance has a negative impact on the benefit/risk ratio.


Eukaryotic translation initiation factor 3 subunit e controls intracellular calcium homeostasis by regulation of cav1.2 surface expression.
Inappropriate surface expression of voltage-gated Ca(2+)channels (CaV) in pancreatic ß-cells may contribute to the development of type 2 diabetes. First, failure to increase intracellular Ca(2+) concentrations at the sites of exocytosis impedes insulin release. Furthermore, excessive Ca(2+) influx may trigger cytotoxic effects. The regulation of surface expression of CaV channels in the pancreatic β-cells remains unknown. Here, we used real-time 3D confocal and TIRFM imaging, immunocytochemistry, cellular fractionation, immunoprecipitation and electrophysiology to study trafficking of L-type CaV1.2 channels upon β-cell stimulation. We found decreased surface expression of CaV1.2 and a corresponding reduction in L-type whole-cell Ca(2+) currents in insulin-secreting INS-1 832/13 cells upon protracted (15-30 min) stimulation. This internalization occurs by clathrin-dependent endocytosis and could be prevented by microtubule or dynamin inhibitors. eIF3e (Eukaryotic translation initiation factor 3 subunit E) is part of the protein translation initiation complex, but its effect on translation are modest and effects in ion channel trafficking have been suggested. The factor interacted with CaV1.2 and regulated CaV1.2 traffic bidirectionally. eIF3e silencing impaired CaV1.2 internalization, which resulted in an increased intracellular Ca(2+) load upon stimulation. These findings provide a mechanism for regulation of L-type CaV channel surface expression with consequences for β-cell calcium homeostasis, which will affect pancreatic β-cell function and insulin production.


Deviant Cyber-Sexual Activities in Young Adults: Exploring Prevalence and Predictions Using In-Person Sexual Activities and Social Learning Theory.
Technology has shifted some human interactions to the virtual world. For many young adults, sexual encounters now occur through virtual means, as social media, picture exchanges, sexually explicit Web sites, and video chatting have become popular alternative outlets for these activities to occur. This study used the self-report responses of 812 undergraduate students (282 men and 530 women), collected from an online survey. In addition to using 10 personal demographic control variables, this study used five sexual activity/relationship characteristics (number of sexual partners, relationship status, age to first use pornography, frequency of sexual activity/intercourse, and frequency of masturbation), and the four constructs of Akers' social learning theory (identified as differential association, differential reinforcement, imitation/modeling, and definitions favorable) to predict a seven-item count of deviant cyber-sexual activities, and two measures of "sexting" behaviors. Gender, self-esteem, sexual orientation, race, and religion were strongly significant predictors in the models, but Akers' four elements of social learning performed the strongest in predicting the two measures of sexting and the overall deviant cyber-sexual activities scale. This finding indicates that peer associations and peer reinforcements have a strong influence on individuals' willingness to engage in deviant cyber-sexual activities. This study explored different avenues for young adults' engagement in sexual deviancy and the results suggest that sexual behaviors performed in-person may not be the strongest predictors of online sexual behavior.


Absorption and incorporation into tissue lipids of 3H-arachidonic- and 14C-linoleic acid: effects of ethanol in jejunal tissue cultures and in vivo.
The effects of ethanol in the rat on the absorption and incorporation of 3H-arachidonic (20: 4, n-6) and 14C-linoleic acid (18:2, n-6) into tissue lipids was examined in jejunal tissue cultures in vivo. The pattern of incorporation earlier seen in the small intestine in vivo, ie. a preferential incorporation of 3H-20: 4 in comparison to 14C-18: 2 into phospholipids (PL), particularly phosphatidylethanolamine (PE) and phosphatidylinositol (PI) was seen in the jejunal tissue cultures. 10 mM ethanol slightly decreased the incorporation of 3H-20: 4 into PE and PI, but did not change the partitioning of labelled fatty acids into phospholipids and triacylglycerols (TG). Ethanol (100 mM) decreased the incorporation of both 3H and 14C into both PL and TG and caused a moderate increase in the TG/PL radioactivity ratio. Rats were also infused intraduodenally with either 10% ethanol or saline and given 3H-20: 4 and 14C-18: 2 in Intralipid. Radioactivity of tissue lipids were analysed after 1, 2 and 3 h. Ethanol did not significantly influence the absorption or the retention in small intestine, liver or heart of 3H or 14C, or the time course for the 3H- and 14C lipid radioactivity in serum. The distribution of 3H and 14C between total nonpolar lipids and individual PLs was also similar in the two groups, 3H-20: 4 thus exhibiting the same preferential incorporation into PLs, compared to 14C-18: 2, in both groups. Significant amounts of 3H and 14C appeared in phosphatidylethanol (PEth) of the small intestine, heart and liver, when the tissues from the ethanol-infused animals were stored frozen before extraction. When the tissues were extracted immediately after the experiment, the proportions of 3H and 14C migrating as PEth did not exceed 0.5%. Although sufficient amounts of ethanol and the phospholipase D activity necessary for PEth formation were thus present in the tissues examined, little PEth formation thus occurred during the ethanol infusion. In the ethanol treated group about 1% of the 3H and 14C radioactivity of the small intestine was in ethyl ester. Intraduodenal infusion of 10% ethanol in vivo thus has little acute effects on the metabolism of absorbed 18: 2 and 20: 4 in the intestinal mucosal cells. Formation of some ethyl ester occurs, however.


In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes.
In an effort to broaden the applicability of adoptive cellular immunotherapy toward nonmelanoma cancers, we have designed chimeric antibody/T-cell receptor genes composed of the variable domains from mAbs joined to T-cell receptor-signaling chains. We have demonstrated that T cells retrovirally transduced with these genes can recognize antibody-defined antigens and that this recognition leads to T-cell activation, specific lysis, and cytokine release. In this study, we have examined the in vivo activity of murine T cells transduced with a chimeric receptor gene (MOv-gamma) derived from the mAb MOv18, which binds to a folate-binding protein overexpressed on most human ovarian adenocarcinomas. Nude mice that were given i.p. implants of human ovarian cancer (IGROV) cells were treated 3 days later with i.p. murine tumor-infiltrating lymphocytes (TIL) derived from an unrelated tumor. Mice treated with MOv-gamma-transduced TIL (MOv-TIL) had significantly increased survival compared to mice treated with saline only, nontransduced TIL, or TIL transduced with a control anti-trinitrophenyl chimeric receptor gene (TNP-TIL). In another model, C57BL/6 mice were given i.v. injections of a syngeneic methylcholanthrene-induced sarcoma transduced with the folate-binding protein (FBP) gene. Three days later, mice were treated i.v. with various transduced murine TIL (derived from an unrelated tumor), followed by low-dose systemic interleukin 2. Eleven days after tumor injection, mice were sacrificed, and lung metastases were counted. In multiple experiments, mice receiving MOv-TIL had significantly fewer lung metastases than did mice treated with interleukin 2 alone, nontransduced TIL, or TNP-TIL. These studies indicate that T cells can be gene modified to react in vivo against tumor antigens, defined by mAbs. This approach is potentially applicable to a number of neoplastic and infectious diseases and may allow adoptive immunotherapy against types of cancer not previously amenable to cellular immunotherapy.


Adenosine 3':5'-cyclic monophosphate-dependence of protein kinase isoenzymes from mouse liver.
Conditions influencing the cyclic AMP-dependence of protein kinase (ATP-protein phosphotransferase, EC 22.214.171.124) during the phosphorylation of histone were studied. Protein kinase from mouse liver cytosol and the two isoenzymes [PK (protein kinase) I and PK II] isolated from the cytosol by DEAE-cellulose chromatography were tested. A relation between concentration of enzyme and cyclic AMP-dependence was observed for both isoenzymes. Moderate dilution of isoenzyme PK II decreased the stimulation of the enzyme by cyclic AMP. Isoenzyme PK I could be diluted 200 times more than isoenzyme PK II before the same decrease in cyclic AMP-dependence appeared. Long-term incubation with high concentrations of histone increased the activity in the absence of cyclic AMP relative to the activity in the presence of the nucleotide. This was more pronounced for isoenzyme PK II than for isoenzyme PK I. The cyclic AMP concentration needed to give half-maximal binding of the nucleotide was the same as the cyclic AMP concentration (Ka) at which the protein kinase had 50% of its maximal activity. The close correlation between binding and activation is also found in the presence of KCl, which increased the apparent activation constant (Ka) for cyclic AMP. With increasing [KCl], a progressively higher proportion of the histone phosphorylation observed in cytosol was due to cyclic AMP-independent (casein) kinases, leading to an overestimation of the degree of activation of the cyclic AMP-dependent protein kinases present. The relative contributions of cyclic AMP-dependent and -independent kinases to histone phosphorylation at different ionic strengths was determined by use of heat-stable inhibitor and phospho-cellulose chromatography.


Documented combat-related mental health problems in military noncombatants.
Although combat-related posttraumatic stress disorder (PTSD) has been documented for military combatants, little is known about PTSD in noncombatants. Active-duty U.S. Air Force noncombatants (N = 5,367) completed a Post-Deployment Health Assessment upon return from combat zones in Iraq (n = 4,408) or a noncombat zone in Qatar (n = 959). Those deployed to Iraq were significantly more likely to report exposure to someone who was wounded or killed (20.8% vs. 6.3%), feeling in great danger of being killed at some point during deployment (18.9% vs. 3.5%), symptoms of PTSD (4.1% vs. 0.7%), and symptoms of major depression (9.9% vs. 5.4%). These findings suggest that deployment to a war zone is associated with increased mental health problems, even for noncombatants.


Pancreatic enlargement is evident in rats fed diets containing raw soybeans (Glycine max) or cowpeas (Vigna unguiculata) for 800 days but not in those fed diets based on kidney beans (Phaseolus vulgaris) or lupinseed (Lupinus angustifolius).
Pancreatic weights and composition were studied with rats fed diets containing raw legume seeds for up to 800 d. Rapid pancreatic enlargement was induced by dietary soybeans (Glycine max) (high Kunitz and Bowman-Birk trypsin inhibitor contents, moderate lectin content) during the initial 150 d. Over the next 200 d the rate of pancreatic growth was similar to that in controls. After 350 d a second period of rapid pancreatic growth occurred. Macroscopic pancreatic nodules were evident in a number of rats fed soybeans for 500 d or more. A similar pattern of pancreatic growth was observed in rats fed dietary cowpeas (Vigna unguiculata) (high Bowman-Birk inhibitor content, low lectin content). Extensive pancreatic growth was also found in young rats fed moderate dietary levels of kidney beans (Phaseolus vulgaris) (low Bowman-Birk inhibitor content, high lectin content). However, the trophic effects diminished with time, and from 100 d onwards, little enlargement was evident. Consumption of a lupinseed (Lupinus angustifolius) diet (low trypsin inhibitor, low lectin content) did not cause pancreatic enlargement. The initial pancreatic growth induced by dietary soybeans seemed to be due to the lectins and trypsin inhibitors, whereas the second period of pancreatic growth was possibly due primarily to the trypsin inhibitors.


Submacular predominantly hemorrhagic choroidal neovascularization: resolution of bleedings under anti-VEGF therapy.
To report the visual and morphological outcomes following intravitreal bevacizumab in neovascular age-related macular degeneration (nAMD) with submacular, predominantly hemorrhagic, lesions. Retrospective study of patients with a follow-up after 1 year. All eyes with submacular hemorrhages larger than 50% of the total lesion size and received only anti-VEGF (vascular endothelial growth factor) monotherapy (intravitreous administration of 1.25 mg bevacizumab, PRN). The primary endpoint was the change in hemorrhage size and time to resolution, in association with the mean best-corrected visual acuity (BCVA). The eyes were grouped based on the size of the hemorrhage: group A (≥1 to <4 disc area [DA]), group B (≥4 to <9 DA), and group C (≥9 DA). Forty-six consecutive eyes were included. The mean area of the hemorrhage was 6 DA at baseline. Eyes with smaller bleeding (group A) had better chances of stabilized or improved vision. Complete resolution of the hemorrhage was seen in 96% of the eyes within 1 year. The mean BCVA increased from 0.81 logarithm of the minimum angle of resolution (logMAR) (95% confidence interval [CI]: 0.70-0.92) (Snellen 20/125) at baseline to 0.75 logMAR (95% CI: 0.62-0.88) (20/125) after 1 year (P=0.11). BCVA improved (one or more ETDRS [Early Treatment of Diabetic Retinopathy Study] lines) in 57% of the eyes (13/23) in group A; 53% (8/15) in group B; and 38% (3/8) in group C. Many of the eyes with hemorrhagic lesions showed stabilization or improvement of the mean BCVA after treatment within 1 year. Anti-VEGF treatment can be considered as a useful treatment option in eyes with hemorrhages secondary to nAMD.


Differentiation of the asteroid Ceres as revealed by its shape.
The accretion of bodies in the asteroid belt was halted nearly 4.6 billion years ago by the gravitational influence of the newly formed giant planet Jupiter. The asteroid belt therefore preserves a record of both this earliest epoch of Solar System formation and variation of conditions within the solar nebula. Spectral features in reflected sunlight indicate that some asteroids have experienced sufficient thermal evolution to differentiate into layered structures. The second most massive asteroid--4 Vesta--has differentiated to a crust, mantle and core. 1 Ceres, the largest and most massive asteroid, has in contrast been presumed to be homogeneous, in part because of its low density, low albedo and relatively featureless visible reflectance spectrum, similar to carbonaceous meteorites that have suffered minimal thermal processing. Here we show that Ceres has a shape and smoothness indicative of a gravitationally relaxed object. Its shape is significantly less flattened than that expected for a homogeneous object, but is consistent with a central mass concentration indicative of differentiation. Possible interior configurations include water-ice-rich mantles over a rocky core.


Regulation of glucose-transporter function.
Glucose transport in mammals is mediated by a multigene family whose expression can be highly tissue specific. All cells express at least one transporter isoform in a constitutive fashion, because a certain level of glucose uptake is an absolute necessity, regardless of influences by various regulatory factors. The level of the constitutive transporter, usually the erythroid glucose-transporter isoform, can be regulated by environmental factors, e.g., nutrition and transformation. Certain cells express unique transporter isoforms, the quantitatively most important of which is the muscle-adipocyte glucose-transporter isoform that functions in response to insulin to clear most of the blood glucose after a meal. The available data suggest that the major insulin target tissues are uniquely able to produce this transporter isoform, sequester it in a unique organelle, and bring it to the cell surface in response to insulin. This insulin response is dramatically different from that seen in various fibroblastic cells, quantitatively and qualitatively, and suggests the expression in adipose tissue and muscle of a multigene program that defines the insulin-stimulated glucose transport of relevance to organismal glucose homeostasis.


The spatial accuracy of cellular dose estimates obtained from 3D reconstructed serial tissue autoradiographs.
In order to better predict and understand the effects of radiopharmaceuticals used for therapy, it is necessary to determine more accurately the radiation absorbed dose to cells in tissue. Using thin-section autoradiography, the spatial distribution of sources relative to the cells can be obtained from a single section with micrometre resolution. By collecting and analysing serial sections, the 3D microscopic distribution of radionuclide relative to the cellular histology, and therefore the dose rate distribution, can be established. In this paper, a method of 3D reconstruction of serial sections is proposed, and measurements are reported of (i) the accuracy and reproducibility of quantitative autoradiography and (ii) the spatial precision with which tissue features from one section can be related to adjacent sections. Uncertainties in the activity determination for the specimen result from activity losses during tissue processing (4-11%), and the variation of grain count per unit activity between batches of serial sections (6-25%). Correlation of the section activity to grain count densities showed deviations ranging from 6-34%. The spatial alignment uncertainties were assessed using nylon fibre fiduciary markers incorporated into the tissue block, and compared to those for alignment based on internal tissue landmarks. The standard deviation for the variation in nylon fibre fiduciary alignment was measured to be 41 microns cm-1, compared to 69 microns cm-1 when internal tissue histology landmarks were used. In addition, tissue shrinkage during histological processing of up to 10% was observed. The implications of these measured activity and spatial distribution uncertainties upon the estimate of cellular dose rate distribution depends upon the range of the radiation emissions. For long-range beta particles, uncertainties in both the activity and spatial distribution translate linearly to the uncertainty in dose rate of < 15%. For short-range emitters (< 100 microns), such as alpha particle sources, the magnitude of the uncertainty in serial section alignment is comparable with the particle track length. Under these circumstances, dosimetric errors are introduced in proportion to the serial section alignment inaccuracy.


Predictive value and changes of renin secretion in hypertensive patients with unilateral renovascular disease undergoing successful renal angioplasty.
Peripheral and renal vein renin activity was measured in 46 hypertensive patients with arteriographically diagnosed unilateral renal artery stenosis before and six months after technically successful renal angioplasty. The renin-sodium profile was high in 80 percent before angioplasty, fell in all patients, and became normal or low in 85 percent after angioplasty. Renal vein renin activity, which initially showed lateralization of renin secretion to the ischemic kidney with contralateral suppression, became normal. Renal vein renin activity was more reliable for predicting the therapeutic response when expressed as the increment of renin for each renal vein over the infrarenal vena caval value (sensitivity 74 percent, specificity 100 percent) than as the ratio between the two renal veins (sensitivity 62 percent, specificity 60 percent). The predictive value of renal vein renin activity is poor when plasma renin activity is stimulated by long-term administration of captopril. These data support the usefulness and define the limitations of peripheral and renal vein renin measurements in selecting patients for treatment by renal angioplasty.


Current knowledge and perspectives of Paenibacillus: a review.
Isolated from a wide range of sources, the genus Paenibacillus comprises bacterial species relevant to humans, animals, plants, and the environment. Many Paenibacillus species can promote crop growth directly via biological nitrogen fixation, phosphate solubilization, production of the phytohormone indole-3-acetic acid (IAA), and release of siderophores that enable iron acquisition. They can also offer protection against insect herbivores and phytopathogens, including bacteria, fungi, nematodes, and viruses. This is accomplished by the production of a variety of antimicrobials and insecticides, and by triggering a hypersensitive defensive response of the plant, known as induced systemic resistance (ISR). Paenibacillus-derived antimicrobials also have applications in medicine, including polymyxins and fusaricidins, which are nonribosomal lipopeptides first isolated from strains of Paenibacillus polymyxa. Other useful molecules include exo-polysaccharides (EPS) and enzymes such as amylases, cellulases, hemicellulases, lipases, pectinases, oxygenases, dehydrogenases, lignin-modifying enzymes, and mutanases, which may have applications for detergents, food and feed, textiles, paper, biofuel, and healthcare. On the negative side, Paenibacillus larvae is the causative agent of American Foulbrood, a lethal disease of honeybees, while a variety of species are opportunistic infectors of humans, and others cause spoilage of pasteurized dairy products. This broad review summarizes the major positive and negative impacts of Paenibacillus: its realised and prospective contributions to agriculture, medicine, process manufacturing, and bioremediation, as well as its impacts due to pathogenicity and food spoilage. This review also includes detailed information in Additional files 1, 2, 3 for major known Paenibacillus species with their locations of isolation, genome sequencing projects, patents, and industrially significant compounds and enzymes. Paenibacillus will, over time, play increasingly important roles in sustainable agriculture and industrial biotechnology.


Post-exposure anti-rabies prophylaxis in Lublin province (Eastern Poland) in 2004-2005.
Rabies is considered a disease of the highest mortality rate and all humans are vulnerable to infection. Specific anti-rabies immunoprophylaxis is the only efficient method of protection. The analysis of indications for active alone and active and passive immunization among patients reported to the dispensary of rabies prophylaxis in the Department of Infectious Diseases of Medical University of Lublin (eastern Poland) in 2004-2005 is presented. Prophylactic procedures were applied in 120 persons (14.98 % of overall number consulted). Passive immunization, i.e. rabies immune globulin, was administered in 1 person (0.12 %). In 2004, 64 persons (7.99 %) received active vaccination, and 56 patients (6.99 %) were vaccinated in 2005. Most of vaccinated patients lived in an urban area where the risk of rabies should be lower; however, in cities like Lublin there is a higher risk of being bitten by homeless animals. The most common species with rabies suspicion were dogs and cats. The decrease in the number of patients bitten by animals with confirmed rabies in Lublin province, and of the number of cases of animal rabies may indicate that oral vaccination of red foxes, representing a main reservoir of rabies virus in Poland, has been shown to be effective.


Induction of granulomatous experimental autoimmune thyroiditis in IL-4 gene-disrupted mice.
To study the role of IL-4 in development of granulomatous experimental autoimmune thyroiditis (EAT), IL-4 gene-disrupted mice expressing the EAT-susceptible H-2k haplotype were generated and used for EAT induction. Spleen cells from mouse thyroglobulin (MTg) and LPS-primed IL-4(+/+) and IL-4(-/-) donors could induce severe granulomatous EAT when spleen cells were activated with MTg and anti-IL-2R mAb in the presence of IL-12. Thyroid lesions had extensive follicular cell proliferation, large numbers of histiocytes, polymorphonuclear leukocytes, and multinucleated giant cells, in addition to lymphocytes and other mononuclear cells. Expression of IFN-gamma gene mRNA and production of IFN-gamma by effector spleen cells stimulated with MTg and IL-12 were similar for both IL-4(+/+) and IL-4(-/-) mice. Although IL-4 was undetectable in IL-4(-/-) mice, expression of mRNA for IL-5, IL-10, and IL-13 and production of IL-5 by both MTg-activated spleen cells and anti-CD3-activated CD4+ T cells were comparable for cells from IL-4(+/+) and IL-4(-/-) mice, indicating that the absence of IL-4 did not prevent production of other Th2 cytokines. Production of MTg-specific IgG1 was very low or undetectable in IL-4(-/-) mice. IL-4 gene mRNA and MTg-specific IgG1 could be detected in IL-4(+/+) or IL-4(-/-) recipients only when they received effector cells from IL-4(+/+) donor mice, indicating that IL-4- and IgG1-secreting cells are of donor origin. These results demonstrate that IL-4 is not essential for development of granulomatous EAT.


Proximal renal tubular acidosis: association with familial normaldosteronemic hyperpotassemia and hypertension.
Further investigation of a family with normaldosteronemic hyperpotassemia and low-renin hypertension showed seven members from three generations, who ranged in age from 4 to 56 years, to be affected. Results of earlier studies had established a normally functioning renin-aldosterone system and normal renal handling of potassium. Constant, albeit mild and asymptomatic, metabolic acidosis in all those affected prompted bicarbonate loading in both the propositus and his brother, which revealed a maximal renal tubular excretory capacity for bicarbonate reabsorption at serum levels of 18 mmole/liter and proved proximal renal tubular acidosis (PRTA). Further, a linear increase in urinary fractional potassium excretion accompanied that of bicarbonate in both, as in normal individuals. Dextrose-insulin infusion in the brother failed to reduce hyperpotassemia. These data support the hypothesis that a generalized cell membrane defect that specifically impedes potassium influx (as opposed to an isolated renal tubular defect) underlies this autosomal dominant disorder.


Gait stability of diabetic patients is altered with the rigid rocker shoes.
Rigid-rocker shoes may induce gait instability in diabetics, however, this is not clearly investigated. The present study investigates if rigid-rocker shoes influence diabetic gait stability. Fourteen non-neuropathic and nine neuropathic diabetics, plus eleven healthy young-adults were recruited. Full-body kinematic data was captured during walking. Experimental conditions included barefoot and three rocker-shoe designs according to the rocker angle, apex angle and apex position (R10: 10°, 80°, 60%; R15: 15°, 95°, 52%; R20: 20°, 95°, 60%). Sagittal and frontal stability margin, plus fear of fall were main outcome measures. Sagittal stability margin was not affected by health, however, was increased with R10 and R15 in non-neuropathic diabetics and healthy individuals (R2 = 0.16). Variability of sagittal stability margin was not altered in neuropathic diabetics, but was increased with R15 and R20 in healthy participants, with R15 in non-neuropathic diabetics (R2 = 0.12). Frontal stability margin (R2 = 0.46) and its variability (R2 = 0.39) were significantly increased in neuropathic and non-neuropathic diabetics compared to healthy individuals. Frontal stability margin was significantly higher with R15 in neuropathic diabetics, and with R20 in both non-neuropathic and healthy participants. Sagittal and frontal stability margin were strongly correlated with fear of fall in neuropathic diabetics. R15 and R20 might challenge gait stability of diabetics cause them restrict centre of mass motion thereby imposing a tighter control over walking. However, neuropathic diabetics generally walk very cautious due to neuropathy and increased fear of fall. Frontal stability margin, highly affected by health and experimental condition, is a more sensitive indicator of gait stability.


A Systematic Review of Mental Health Interventions for ASD: Characterizing Interventions, Intervention Adaptations, and Implementation Outcomes.
Youth with autism spectrum disorder (ASD) have high rates of co-occurring mental health needs that necessitate mental health interventions. Given the unique clinical characteristics of youth with ASD, there have been significant efforts to adapt and test mental health interventions for this population. Yet, characterization of the nature and types of interventions adaptations is limited, especially across the wide range of interventions tested for youth with ASD with a focus on implementation factors. Additionally, understanding how these interventions may be implemented in community services is limited. The aims of this systematic review are to characterize the (1) types of interventions tested for co-occurring mental health conditions for youth with ASD; (2) adaptations to mental health interventions for use with youth with ASD; and (3) implementation strategies, outcomes, and determinants of mental health interventions to inform their translation to community service settings. Eighty-three articles testing interventions targeting mental health symptoms in youth with ASD that included implementation factors in analyses were reviewed. The Stirman et al. (2013; 2019) FRAME adaptation, Powell et al. (2012;2015) implementation strategies, and Proctor et al. (2011) implementation outcomes taxonomies were applied to characterize the nature and types of adaptations for use with youth with ASD and types of implementation strategies, outcomes, and determinants used, when available, respectively. Of the interventions examined, the majority (64.1%) were originally designed to target youth mental health concerns and were then adapted to be used with ASD. The most common adaptations included those to the intervention content, particularly adding elements with tailoring or refining aspects of the intervention while maintaining core functions. Half of the articles described at least one implementation strategy used during intervention testing. Fidelity and acceptability were the most frequently examined implementation outcomes, with some examination of appropriateness and feasibility. Nineteen percent of articles described implementation determinants (i.e. barriers/facilitators) of these implementation outcomes. The common adaptations for ASD provide direction for future intervention development and for training community therapists. Further examination, specification, and reporting of implementation strategies and outcomes within ongoing efforts to adapt and interventions to meet the co-occurring mental health needs of youth ASD are needed to facilitate their translation to community settings. Areas for future research as well as clinical implications are discussed.


BRAF(V600E) efficient transformation and induction of microsatellite instability versus KRAS(G12V) induction of senescence markers in human colon cancer cells.
In colorectal cancer, BRAF and KRAS oncogenes are mutated in about 15% and 35% respectively at approximately the same stage of the adenoma-carcinoma sequence. Since these two mutations rarely coexist, further analysis to dissect their function of transformation in colon cancer is required. Caco-2 human colon adenocarcinoma cells were stably transfected with BRAF(V600E) (Caco-BR cells) or KRAS(G12V) (Caco-K cells) oncogenes. BRAF(V600E) is more efficient in transforming Caco-2 cells and altering their morphology. The dominant nature of BRAF(V600E) is evident by its ability to render Caco-2 cells tumorigenic in vivo all be it through selective extracellular signal-related kinase (ERK) 2 phosphorylation and high levels of cyclin D1. As a consequence, the cell cycle distribution of parental cells is altered and microsatellite instability is introduced. Attenuated ERK activation observed correlated with KSR downregulation by BRAF(V600E) without further implications to signaling. Highly activated ERK in case of KRAS(G12V) (Caco-K cells) leads to mild transformation causing Caco-K cells to express premature senescence-related markers and acquire growth factor-dependent viability. Interestingly, BRAF(WT)gets equally activated by upstream KRAS mutations present in colon adenocarcinoma cells such as DLD-1 and SW620. Taken together, these results suggest that the two oncogenes have different transforming capability in colon cancer, although they both use the mitogen-activated protein (MAP) kinase pathway to carry out their effect. In general, BRAF(V600E) presents greater potential in mediating tumorigenic effect as compared to KRAS(G12V) both in vivo and in vitro. These findings may have implications in personalised diagnosis and targeted therapeutics.


Redescription and neotype designation of the Antarctic springtail Folsomotoma octooculata (Collembola: Isotomidae).
The growing interest in Antarctic collembolan species has led us to re-evaluate both the morphological and molecular aspects of different species adapted to the extreme Antarctic environment. The genus Folsomotoma includes nine species mainly distributed in Antarctic and subantarctic areas and a few additionally from Australia and South America. We herein designate the neotype of Folsomotoma octooculata (Willem 1901) and redescribe its morphological characters with particular emphasis on the sensory and ordinary chaetotaxy. Furthermore, based on analyses of both our new and previously published morphological data for F. octooculata, we propose a systematic key of the species for the genus.


Effects of carbon disulfide and FLA-63 on operant behavior in pigeons.
Carbon disulfide (CS2) and FLA-63 [bis(4-methyl-1-homopiperazinylthiocarbonyl)disulfide] were studied in pigeons working on a differential-reinforcement-of low-rates or a multiple fixed-interval fixed-ratio schedule of food reinforcement. Response rate on both schedules decreased after 8-hour exposures to CS2 (2 mg/1) of administration of FLA-63 (40 and 80 mg/kg). The effects of two successive 8-hour exposures to CS2 were cumulative and ten successive 4-hour exposures produced changes in differential-reinforcement-of-low-rates performance resembling those following acute exposure. Fixed-interval performance was disrupted by exposures to CS2 and doses of FLA-63 that left fixed-ratio performance intact.


Patterns of pain induced by distending the thoracic zygapophyseal joints.
The study was designed to investigate the patterns of referral pain associated with the thoracic zygapophyseal joints (C7-T1 to T2-3, T11-12). In 15 patients who had back pain suspected to be of zygapophyseal origin and for whom pain was relieved by injection of local anesthetic into the joints under fluoroscopic guidance, the zygapophyseal joints from C7-T1 to T2-3, T11-12 were distended by injecting contrast medium. If injection reproduced typical pain in the patient, the patient was asked to describe the distribution of pain, which was recorded on a body diagram. A total of 21 joints were studied. Composite pain distribution maps for the thoracic zygapophyseal joints from C7-T1 to T2-3 and for the T11-12 joint were drawn. The distribution of referred pain was as follows: pain in the suprascapular region was referred from C7-T1 and Th1-2; pain in the superior angle of the scapula from C7-T1 and T1-2; pain in the mid-scapular region from C7-T1, T1-2, and Th2-3; and pain in the paravertebral region around the site of injection and the area over the iliac crest from T11-12. The referred pain distribution for joints C7-T1 to Th2-3 showed significant overlap.


A Dynamical Systems Analysis of Adolescent Substance Abuse.
Models from dynamical systems theory were fit to the intraindividual variability In adolescent self-reported cigarette and alcohol use. A dampened linear oscillator model (potentially like a pendulum with friction) and a nonlinear oscillator model with two attractors were compared. The nonlinear oscillator model and two coupled oscillators for cigarette and alcohol use were rejected. Independent dampened linear oscillators for smoking and drinking provided high internal R(2) but were unable to account for a substantial correlation between the acceleration in cigarette usage and alcohol usage; thus evidence was found for an intrinsic self-regulation mechanism in both smoking and drinking behavior, but the hypothesis was rejected that the intrinsic mechanism leading to increases in use in one substance directly predicted increased use in the other substance. Given the hypothesis of independent linear oscillators, the sign of the dampening parameter was found to be positive, indicating a system with dynamic instability; a self-regulation mechanism in which small changes in substance use lead to amplified changes after a short period of time.


Mesenchymal stromal cells inhibit proliferation of virus-specific CD8(+) T cells.
Mesenchymal stromal cells (MSCs) possess broad immunomodulatory capacities that are currently investigated for potential clinical application in treating autoimmune disorders. Third-party MSCs suppress alloantigen-induced proliferation of peripheral blood mononuclear cells providing the rationale for clinical use in graft-versus-host disease (GvHD). We confirmed that MSCs strongly inhibited proliferation of CD8(+) T cells in a mixed lymphocyte reaction. However, MSCs also suppressed proliferation of T cells specifically recognizing cytomegalovirus (CMV) and influenza virus. Inhibition was dose dependent, but independent of the culture medium. MSCs inhibited proliferation of specific CD8(+) T cells and the release of IFN-γ by specific CD8(+) T cells for immunodominant HLA-A2- and HLA-B7- restricted antigen epitopes derived from CMV phosphoprotein 65 and influenza matrix protein. This is in contrast to a recently reported scenario where MSCs exert differential effects on alloantigen and virus-specific T cells potentially having an impact on surveillance and prophylaxis of patients treated by MSCs.


Mechanisms involved in retinal pigment epithelial cell chemotaxis.
Retinal pigment epithelial (RPE) cell chemotaxis may play an important role in proliferative vitreoretinopathy (PVR). Fibronectin and platelet-derived growth factor are chemoattractants for RPE cells. In this study, we used these chemoattractants to examine mechanisms involved in RPE cell chemotaxis. Our results demonstrate that inhibition of RNA and protein synthesis, but not DNA synthesis, are associated with reduced chemotaxis. Microtubules and microfilaments are involved since cytochalasin B and colchicine are potent inhibitors of RPE cell migration. Dexamethasone, to which a beneficial effect has been attributed in an animal model of PVR, had no effect on RPE cell migration. Information concerning mechanisms involved in RPE cell migration may help to explore new avenues of treatment in PVR.


Radiofrequency catheter ablation of accessory pathways during entrainment of AV reentrant tachycardia.
Radiofrequency ablation of accessory pathways must sometimes be done during orthodromic atrioventricular reentrant tachycardia when manifest anterograde accessory pathway conduction is absent or retrograde fusion obscures accessory pathway location during ventricular pacing. Unfortunately, abrupt heart rate slowing upon radiofrequency induced termination of atrioventricular reentrant tachycardia often causes catheter dislodgment. We report our experience in circumventing this problem during radiofrequency ablation by using entrainment of atrioventricular reentrant tachycardia. The latter maintains retrograde activation pattern over the accessory pathway while preventing abrupt ventricular rate change. Eight patients (4 men and 4 women, mean age 37.3 +/- 17.9) with eleven left-sided accessory pathways were included. Ablation during entrainment was used as the first approach in three patients with concealed accessory pathways and one patient with a bidirectional accessory pathway. In another four patients, ablation during entrainment was used after technical difficulties in ablating during tachycardia. Only 1-3 radiofrequency applications were required to eliminate the accessory pathway using the entrainment technique. The catheter remained stable when accessory pathway conduction was interrupted by radiofrequency current. In conclusion, entrainment of atrioventricular reentrant tachycardia during radiofrequency application is useful for maintaining catheter position for accessory pathway ablation during atrioventricular reentrant tachycardia.


Association between anti-C1q antibodies and glomerular tuft necrosis in lupus nephritis.
Proliferative glomerulonephritis includes various glomerular lesions in patients with systemic lupus erythematosus (SLE) that might have distinct pathogenic mechanisms. The aim of the study was to determine whether anti-C1q antibodies, which are associated with lupus nephritis, were specifically associated with given glomerular histopathological lesions. The presence and titer of anti-C1q antibodies were determined in a retrospective study including 63 SLE patients with biopsy-proven lupus nephritis. We confirmed the correlation between the presence of anti-C1q antibodies with both clinical and immunological markers of disease activity. We showed that the presence of anti- C1q antibodies was significantly associated with glomerular tuft necrosis and crescents, major criteria of active lesions. Additionally, no necrosis was found in patients without anti- C1q antibodies, giving anti-C1q antibodies a 100% negative predictive value for glomerular tuft necrosis. Conversely, there was no difference in the percentage of glomeruli showing endocapillary proliferation or wire loops according to the anti-C1q status. Our data highlight for the first time an association of anti-C1q antibodies with necrotizing forms of lupus nephritis suggesting new insights into the pathogenesis and the treatment of this entity.


On farm evaluation of the coproantigen ELISA and coproantigen reduction test in Scottish sheep naturally infected with Fasciola hepatica.
The liver fluke, Fasciola hepatica, is a cause of significant economic losses in sheep farming. Lack of convenient and sensitive diagnostic tests in the live animal hampers the ability to monitor infection status and treatment efficacy. Use of a coproantigen ELISA and coproantigen reduction test, based on this ELISA, may address these issues but has, to date, only been evaluated in experimental challenge studies. We evaluated the coproantigen ELISA under working farm conditions in Scotland to assess its usefulness as a diagnostic test for liver fluke infection and as a diagnostic test to help determine the efficacy of flukicide treatment in sheep. First, liver fluke infection status was monitored longitudinally in a group of lambs, using monthly blood samples for biochemical assays and serum antibody ELISA and using monthly faecal samples for faecal egg count (FEC) and coproantigen ELISA. The average serum antibody ELISA titre became positive in September, two months ahead of faecal indicators of fluke infection. In contrast to results from experimental challenge studies, FEC and coproantigen ELISA became positive at the same time point. Secondly, treatment efficacy was measured in 100 ewes, from two farms, after treatment with triclabendazole (TCBZ) or closantel. Group level estimates of treatment efficacy were similar between faecal egg count reduction testing and coproantigen reduction testing at 7, 14 and 21 days post treatment. For individual animals, some inconsistencies between tests were observed. TCBZ treatment failure was noted on both farms, despite accurate weighing of animals and dosing of treatment products. We conclude that (1) coproantigen ELISA is a more convenient test than faecal egg counts and holds promise as a diagnostic tool for natural fluke infections in sheep but further evaluation of interpretation criteria may be needed; (2) the coproantigen ELISA has performed differently in the field compared with experimental challenge studies in sheep and (3) TCBZ-resistant fluke were present on both farms.


Isolation and properties of a thermostable restriction endonuclease (ENDO R-Bst1503).
A restriction endonuclease was isolated from Bacillus stearothermophilus1503-4R (Bst1503) and purified to homogeneity. The enzyme required Mg2+ ion as a cofactor. Bst1503 exhibited maximal activity between pH 7.5 and 8.0, between 60 and 65 degrees C, and with about 0.2 mM Mg2+. Bst1503 was not inactivated after exposure at 55 or 65 degrees C for up to 10 h. After 2 h of incubation at 70 degrees C, Bst1503 was inactivated by 65%. Bst1503 was rapidly inactivated at 75 degrees C. A single protein-staining band having a molecular weight of 46,000 was observed when Bst1503 was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The enzyme was found to exist in two active forms, the predominating form with an S value of 8.3 (180,000) and the second form with an S value of 5.4 (96,000). No conversion between the 8.3S and 5.4S forms was observed after storage. Bst1503 recognized six sites in TP-1C deoxyribonucleic acid (DNA), one site in pSC101 and simian virus 40 DNAs, and three sites in lambdavir DNA. Bst1503 and BamHI were determined to be isoschizomers. The effect of temperatures on the activity and stability of BamHI was determined.


Correlation of skeletal maturation with stature and body weight of southern Chinese girls in Hong Kong.
Correlations of skeletal maturation with stature and body weight were studied in one hundred and seventeen Southern Chinese girls aged eleven years nine months and twelve years three months born and brought up in Hong Kong. The skeletal maturation was assessed from the left hand and wrist radiographs by the Greulich and Pyle Atlas Method. The early maturers in skeletal development were significant taller and heavier than the late maturers with p less than 0.001.


ATLes: the strategic application of Web-based technology to address learning objectives and enhance classroom discussion in a veterinary pathology course.
A case-based program called ATLes (Adaptive Teaching and Learning Environments) was designed for use in a systemic pathology course and implemented over a four-year period. Second-year veterinary students working in small collaborative learning groups used the program prior to their weekly pathology laboratory. The goals of ATLes were to better address specific learning objectives in the course (notably the appreciation of pathophysiology), to solve previously identified problems associated with information overload and information sorting that commonly occur as part of discovery-based processes, and to enhance classroom discussion. The program was also designed to model and allow students to practice the problem-oriented approach to clinical cases, thereby enabling them to study pathology in a relevant clinical context. Features included opportunities for students to obtain additional information on the case by requesting specific laboratory tests and/or diagnostic procedures. However, students were also required to justify their diagnostic plans and to provide mechanistic analyses. The use of ATLes met most of these objectives. Student acceptance was high, and students favorably reviewed the online ''Content Links'' that made useful information more readily accessible and level appropriate. Students came to the lab better prepared to engage in an in-depth and high-quality discussion and were better able to connect clinical problems to underlying changes in tissue (lesions). However, many students indicated that the required time on task prior to lab might have been excessive relative to what they thought they learned. The classroom discussion, although improved, was not elevated to the expected level-most likely reflecting other missing elements of the learning environment, including the existing student culture and the students' current discussion skills. This article briefly discusses the lessons learned from ATLes and how similar case-based exercises might be combined with other approaches to enhance and enliven classroom discussions in the veterinary curriculum.


Cytogenetic abnormalities in an ossifying fibroma from a patient with bilateral retinoblastoma.
Cytogenetic analysis of a cemento-ossifying fibroma from a patient with nonfamilial bilateral multicentric retinoblastoma revealed three reciprocal translocations with the karyotype 46,XY,t(1;18)(q21;q21.3),t(3;10)(p13;q22),t(6;11)(p22;p15). Routine and high-resolution cytogenetic analysis of peripheral blood leukocytes showed an apparently normal, 46,XY chromosome pattern with no deletion of chromosome 13. Molecular analysis demonstrated no gross differences in the retinoblastoma gene or the TP53 gene between constitutional and tumor DNA. This is the first cytogenetic analysis of a cemento-ossifying fibroma and the first report of this tumor in a retinoblastoma patient. The data may be added to the small, but growing literature on cytogenetic aberrations in benign tumors and may lend insight into genes involved in cell proliferation and neoplastic transformation.


Autonomic regulation predicts performance on Wisconsin Card Sorting Test (WCST) in adults with schizophrenia.
Although executive functions have been associated with autonomic regulatory capacity in healthy adults, there appear to be no reports of these relations in adults with schizophrenia to date. We tested whether baseline autonomic regulation was associated with performance on the Wisconsin Card Sorting Test (WCST) in a group of 42 stable community outpatients with schizophrenia. Patients exhibited faster resting heart rates and lower respiratory sinus arrhythmia (RSA) than age-matched controls, consistent with previous research. Patients also completed relatively few WCST categories and made many perseverative errors, replicating prior studies. Within the patient group, relatively better WCST performance was associated with slower resting heart rate and higher RSA, suggesting that inefficient executive and autonomic functioning in schizophrenia may be linked. WCST performance and autonomic regulatory capacity were further reduced in a subset of patients receiving clozapine, but relations between WCST performance and autonomic regulatory parameters did not differ from those of other patients. Findings extend the neurovisceral integration model of autonomic regulation to adults with schizophrenia and attest to the reliability of the model.


Interfacial structure in the liquid-liquid extraction of rare earth elements by phosphoric acid ligands: a molecular dynamics study.
Solvent extraction (SX), wherein two immiscible liquids, one containing the extractant molecules and the other containing the solute to be extracted are brought in contact to effect the phase transfer of the solute, underpins metal extraction and recovery processes. The interfacial region is of utmost importance in the SX process, since besides thermodynamics, the physical and chemical heterogeneity at the interface governs the kinetics of the process. Yet, a fundamental understanding of this heterogeneity and its implications for the extraction mechanism are currently lacking. We use molecular dynamics (MD) simulations to study the liquid-liquid interface under conditions relevant to the SX of Rare Earth Elements (REEs) by a phosphoric acid ligand. Simulations revealed that the extractant molecules and varying amounts of acid and metal ions partitioned to the interface. The presence of these species had a significant effect on the interfacial thickness, hydrogen bond life times and orientations of the water molecules at the interface. Deprotonation of the ligands was essential for the adsorption of the metal ions at the interface, with these ions forming a number of different complexes at the interface involving one to three extractant molecules and four to eight water molecules. Although the interface itself was rough, no obvious 'finger-like' water protrusions penetrating the organic phase were seen in our simulations. While the results of our work help us gain fundamental insights into the sequence of events leading to the formation of a variety of interfacial complexes, they also emphasize the need to carry out a more detailed atomic level study to understand the full mechanism of extraction of REEs from the aqueous to organic phases by phosphoric acid ligands.


Co-existing psychiatric problems in ADHD in the ADORE cohort.
To study the impact of co-existing psychiatric problems with ADHD on behavioural features, psychosocial functioning and quality of life in subjects of the ADORE cohort (N=1,478). The following six groups of associated psychiatric problems with ADHD were compared: oppositional-defiant disorder or conduct disorder only (ODD/CD); anxiety or depressive disorder only (ANX/DEP); tic/Tourette's disorder only (TIC/Tourette's); developmental co-ordination disorder only (DCD); two or more associated conditions; and none. Dependent variables included the ADHD Rating Scale-IV, the Strengths and Difficulties Questionnaire, the Clinical Global Impression-Severity scale, the Children's Global Assessment Scale and the Child Health Illness Profile-Child Edition. Having multiple co-existing psychiatric problems increased the severity of ADHD in all domains, be it behavioural features, psychosocial impairment or deterioration of quality of life. A similar though less consistent pattern applied to subjects with co-existing ODD/CD. The ADORE study provides impressive evidence for the far-reaching consequences of co-existing psychiatric problems in children with ADHD that warrant intensive consideration in clinical assessment and treatment.


The membrane molecule RCAS1 induces immune cell apoptosis via the RCAS1-RCAS1R pathway.
Tumor-associated antigen receptor-binding cancer antigen expressed on SiSo cells (RCAS1) has been identified as an estrogen-responsive gene and reportedly acts as a ligand for a putative receptor present in a variety of human cell lines and peripheral lymphocytes, thus leading them to apoptosis. In this study, we investigated the biological function of RCAS1 in vitro in inducing the apoptosis of immune cells. We detected the expression of the RCAS1 receptor (RCAS1R) in the cell lines, and investigated the mechanisms behind the apoptosis induced by RCAS1. HeLa cells were transfected with recombinant adenovirus Ad-RCAS1. RCAS1 induced the apoptosis of activated T cells, K562 cells and phytohemagglutinin (PHA)-activated Jurkat cells via the RCAS1-RCAS1R pathway. The expression of RCAS1R was induced. The intracellular overexpression of RCAS1 inhibited the growth of Jurkat and K562 cells. The expression of RCAS1 negatively correlated with the expression of glycogen synthase kinase 3β (GSK3β), but positively correlated with the expression of phosphorylated GSK3β (phGSK3β). RCAS1 expression was identified as a brown staining pattern in the breast cancer specimens. These findings may provide insight into the mechanisms through which tumor cells escape from immune surveillance.


Humanized UGT1 Mice, Regulation of UGT1A1, and the Role of the Intestinal Tract in Neonatal Hyperbilirubinemia and Breast Milk-Induced Jaundice.
Neonatal hyperbilirubinemia and the onset of bilirubin encephalopathy and kernicterus result in part from delayed expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the ability to metabolize bilirubin. It is generally believed that acute neonatal forms of hyperbilirubinemia develop due to an inability of hepatic UGT1A1 to metabolize efficiently bilirubin for clearance through the hepatobiliary tract. Newly developed mouse models designed to study bilirubin metabolism have led to new insight into the role of the intestinal tract in controlling neonatal hyperbilirubinemia. Humanization of mice with the UGT1 locus (hUGT1 mice) and the UGT1A1 gene provide a unique tool to study the onset of hyperbilirubinemia since the human UGT1A1 gene is developmentally regulated during the neonatal period in hUGT1 mice. A new mechanism outlying developmental expression of intestinal UGT1A1 is presented and its implications in the control of neonatal hyperbilirubinemia discussed. New findings linking breast milk protection against necrotizing enterocolitis and intestinal control of UGT1A1 may help explain the contribution of breast milk toward the development of neonatal hyperbilirubinemia. Our findings outline a new model that includes an active intestinal ROS /IκB kinase/nuclear receptor corepressor 1 loop that can be applied to an understanding of breast milk-induced jaundice.


Identification of stromal differentially expressed proteins in the colon carcinoma by quantitative proteomics.
Tumor microenvironment plays very important roles in the carcinogenesis. A variety of stromal cells in the microenvironment have been modified to support the unique needs of the malignant state. This study was to discover stromal differentially expressed proteins (DEPs) that were involved in colon carcinoma carcinogenesis. Laser capture microdissection (LCM) was captured and isolated the stromal cells from colon adenocarcinoma (CAC) and non-neoplastic colon mucosa (NNCM) tissues, respectively. Seventy DEPs were identified between the pooled LCM-enriched CAC and NNCM stroma samples by iTRAQ-based quantitative proteomics. Gene Ontology (GO) relationship analysis revealed that DEPs were hierarchically grouped into 10 clusters, and were involved in multiple biological functions that were altered during carcinogenesis, including extracellular matrix organization, cytoskeleton, transport, metabolism, inflammatory response, protein polymerization, and cell motility. Pathway network analysis revealed 6 networks and 56 network eligible proteins with Ingenuity pathway analysis. Four significant networks functioned in digestive system development and its function, inflammatory disease, and developmental disorder. Eight DEPs (DCN, FN1, PKM2, HSP90B1, S100A9, MYH9, TUBB, and YWHAZ) were validated by Western blotting, and four DEPs (DCN, FN1, PKM2, and HSP90B1) were validated by immunohistochemical analysis. It is the first report of stromal DEPs between CAC and NNCM tissues. It will be helpful to recognize the roles of stromas in the colon carcinoma microenvironment, and improve the understanding of carcinogenesis in colon carcinoma. The present data suggest that DCN, FN1, PKM2, HSP90B1, S100A9, MYH9, TUBB, and YWHAZ might be the potential targets for colon cancer prevention and therapy.


CD4+ T cells from simian immunodeficiency virus disease-resistant sooty mangabeys produce more IL-2 than cells from disease-susceptible species: involvement of p300 and CREB at the proximal IL-2 promoter in IL-2 up-regulation.
IL-2 is an important cytokine required for the physiological function of CD4(+) T cells. Immunological unresponsiveness-anergy- of CD4(+) T cells is characterized by the inability of these cells to synthesize IL-2. Both progressive HIV infection leading to AIDS in humans and SIV infection in rhesus macaques (RM) are associated with dysregulation of IL-2 synthesis. In certain nonhuman primate species, such as sooty mangabeys (SM), SIV infection does not lead to AIDS. We have shown that this is associated with the resistance of the CD4(+) T cells from SM to undergo anergy in vitro. In this study, we show that CD4(+) T cells from SM spontaneously synthesize 2- to 3-fold higher levels of IL-2 than corresponding cells from RM. Proximal IL-2 promoter constructs derived from SM show significantly higher activity than the RM-derived constructs in primary CD4(+) T cells, which is associated with an element at approximately nt -200. Activity of both constructs was up-regulated by p300 and down-regulated by CREB to a similar degree. Chromatin immunoprecipitation analysis showed significantly higher binding of p300 and lower binding of CREB to the SM promoter in vivo. Two single nucleotide substitutions present in the SM sequence around position -200 and -180 seem to increase the affinity of these sites for the binding of transcription factors, one of which was identified as Oct-1. These unique characteristics of the proximal IL-2 promoter in SM therefore can represent one of the mechanisms contributing to the resistance of these cells to undergo anergy.