Altered vascular reactivity induced by malaria parasites.
In this study, we have examined the possibility that there is altered vascular reactivity due to the direct interaction between parasitized erythrocytes and vascular endothelial cells. Ring preparations of rat aorta were studied using standard in vitro techniques, the rings were mounted in 20 ml organ baths containing PSS under an initial load of 1 g, maintained at 37 degrees C at pH 7.4 and isometric contractions were recorded electronically. Rings were allowed 90 minutes to equilibrate before the commencement of the various protocols: Dose responses to phenylephrine (PE) and other vasoactive agents (high-K+). Acetylcholine (Ach)--induced relaxation in phenylephrine-contracted rings (pre-contraction was induced by EC70 concentration of phenylephrine). Ach-induced relaxation in PE-precontracted, endothelium-denuded rings. Also, relaxation responses to acetylcholine was investigated through application of a single. (EC70) concentration of acetylcholine in rings exposed to blood with varying concentrations and dilutions of parasitized blood and varying durations of exposure. Incubation with parasitized blood resulted in a significant increase in maximum contractile response to phenylephrine in the rat aortic rings (p < 0.05) but no effect to the base line. Analysis of the whole dose-response curve (using paired t-test) showed a significant left-ward shift following the addition of parasitized blood (p < 0.05), EC70 (M) values increasing from 7 x 10(-7) to 5 x 10(-6)M. Following exposure to parasitized blood, the magnitude of Ach-induced relaxation responses reduced significantly from 73 +/- 3.6 to 24.75 +/- 7.25% in rat aortic rings (p < 0.05). Ach relaxations were significantly enhanced (p < 0.05) at 5-minute exposure; however at longer durations, Ach-relaxations were variable and inconsistent. The lesser the dilution, due to increased volume of parasitized blood, the lesser the relaxation response. Following endothelium removal, there was a marked impairment in endothelium-dependent relaxation responses to ACh in both the control and incubated vessels. Exposure to parasitized blood did not significantly alter contractile responses induced by potassium depolarization. This gives evidence in support of an endothelium-dependent action of malaria parasites as vascular effects of malaria parasites are mediated, at least in part, via endothelium-dependent mechanism(s).


Incomplete hippocampal inversion-is there a relation to epilepsy?
Incomplete hippocampal inversion (IHI) has been described in patients with epilepsy or severe midline malformations but also in nonepileptic subjects without obvious developmental anomalies. We studied the frequency of IHI in different epilepsy syndromes to evaluate their relationship. Three hundred patients were drawn from the regional epilepsy register. Of these, 99 were excluded because of a disease or condition affecting the temporal lobes or incomplete data. Controls were 150 subjects without epilepsy or obvious intracranial developmental anomalies. The coronal MR images were analysed without knowledge of the clinical data. Among epilepsy patients, 30% had IHI (40 left-sided, 4 right-sided, 16 bilateral). Of controls, 18% had IHI (20 left-sided, 8 bilateral). The difference was statistically significant (P < 0.05). Of temporal lobe epilepsy (TLE) patients, 25% had IHI, which was not a significantly higher frequency than in controls (P = 0.34). There was no correlation between EEG and IHI laterality. A total of 44% of Rolandic epilepsy patients and 57% of cryptogenic generalised epilepsy patients had IHI. The IHI frequency was very high in some epileptic syndromes, but not significantly higher in TLE compared to controls. No causality between TLE and IHI could be found. IHI can be a sign of disturbed cerebral development affecting other parts of the brain, maybe leading to epilepsy.


Studies on the 2,4-diamino-6-substituted quinazolines. II. Activities of selected derivatives against infections with various drug-susceptible and drug-resistant strains of Plasmodium falciparum and Plasmodium vivax in owl monkeys.
Four 6-thio-, one 6-sulfinyl-, and two 6-sulfonyl-substituted 2,4-diaminoquinazolines were evaluated for capacities to cure established infections with the chloroquine-resistant Vietnam Oak Knoll and pyrimethamine-resistant Malayan Camp-CH/Q strains of Plasmodium falciparum in owl monkeys. As compared with the doses of standard drugs required for cure of infections with drug-susceptible strains or doses of the newly developed aminoalcohols required for cure of either drug-susceptible or drug-resistant strains, each of these quinazolines effected cure of infections with the Oak Knoll strain at a remarkably small daily dose. However, doses required for cure of infections with the Camp-CH/O strain were from 4-48 times those required for cure of infections with the Oak Knoll strain, suggesting that the activities of these quizanolines, like those of 6-amino-substituted derivatives, were compromised by pyrimethamine resistance. This suggestion received support from expanded studies involving WR-158,122 and WR-159,412, the most active of the agents examined, and the multidrug-resistant Vietnam Smith strain of P. falciparum and Vietnam Palo Alto strain of P. vivax, as well as the Oak Knoll and Camp-CH/Q strains. These studies also showed that significant fractions of infections with the Oak Knoll, Camp-CH/Q, and Palo Alto strains treated previously with subcurative doses of the above derivatives failed to respond to doses that regularly cured previously untreated infections. These treatment failures proved to be due to emergence of parasites resistant to the quinazolines.


Early correlates of visual awareness following orientation and colour rivalry.
Binocular rivalry occurs when dissimilar images are presented to corresponding retinal regions of the two eyes: visibility alternates irregularly between the two images, interspersed by brief transitions when parts of both may be visible. We measured event-related potentials (ERPs) following binocular rivalry by changing the stimulus viewed by one eye to be identical to that in the other eye, eliciting binocular fusion. Because of the rivalry, observers either saw the change, when it happened to the visible stimulus, or did not see the change, when it happened to the invisible stimulus. The earliest ERP differences between visible and invisible changes occurred after about 100 ms (P1) when the rivalry was between stimuli differing in orientation, and after about 200 ms (N1) when the rivalry was between stimuli differing in colour. These differences originated from ventro-lateral temporal and prefrontal areas. We conclude that the rivalling stimulus property influences the timing of modulation of correlates of visual awareness in a property-independent cortical network.


GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis.
The post-translational modifications of histone tails generate a 'histone code' that defines local and global chromatin states. The resultant regulation of gene function is thought to govern cell fate, proliferation and differentiation. Reversible histone modifications such as methylation are under mutual controls to organize chromosomal events. Among the histone modifications, methylation of specific lysine and arginine residues seems to be critical for chromatin configuration and control of gene expression. Methylation of histone H3 lysine 4 (H3K4) changes chromatin into a transcriptionally active state. Reversible modification of proteins by beta-N-acetylglucosamine (O-GlcNAc) in response to serum glucose levels regulates diverse cellular processes. However, the epigenetic impact of protein GlcNAcylation is unknown. Here we report that nuclear GlcNAcylation of a histone lysine methyltransferase (HKMT), MLL5, by O-GlcNAc transferase facilitates retinoic-acid-induced granulopoiesis in human HL60 promyelocytes through methylation of H3K4. MLL5 is biochemically identified in a GlcNAcylation-dependent multi-subunit complex associating with nuclear retinoic acid receptor RARalpha (also known as RARA), serving as a mono- and di-methyl transferase to H3K4. GlcNAcylation at Thr 440 in the MLL5 SET domain evokes its H3K4 HKMT activity and co-activates RARalpha in target gene promoters. Increased nuclear GlcNAcylation by means of O-GlcNAc transferase potentiates retinoic-acid-induced HL60 granulopoiesis and restores the retinoic acid response in the retinoic-acid-resistant HL60-R2 cell line. Thus, nuclear MLL5 GlcNAcylation triggers cell lineage determination of HL60 through activation of its HKMT activity.


The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the testis: Localization of Bv8 receptors to endothelial cells.
We recently identified an angiogenic mitogen, endocrine-gland-derived vascular endothelial growth factor (EG-VEGF), with selective activity for endothelial cells of endocrine tissues. Here we describe the characterization of a highly related molecule, Bv8, also known as prokineticin-2. Human Bv8 shares 60% identity and 75% similarity with EG-VEGF. The human and mouse Bv8 genes share a common structure. Like EG-VEGF, Bv8 is able to induce proliferation, survival and migration of adrenal cortical capillary endothelial cells. Bv8 gene expression is induced by hypoxic stress. Bv8 expression occurs predominantly in the testis and is largely restricted to primary spermatocytes. Adenoviral delivery of Bv8 or EG-VEGF to the mouse testis resulted in a potent angiogenic response. We have localized the expression of the Bv8EG-VEGF receptors within the testis to vascular endothelial cells. The testis exhibits relatively high turnover of endothelial cells. Therefore, Bv8 and EG-VEGF, along with other factors such as VEGF-A, may maintain the integrity and also regulate proliferation of the blood vessels in the testis.


Comparative assessment of absolute cardiovascular disease risk characterization from non-laboratory-based risk assessment in South African populations.
All rigorous primary cardiovascular disease (CVD) prevention guidelines recommend absolute CVD risk scores to identify high- and low-risk patients, but laboratory testing can be impractical in low- and middle-income countries. The purpose of this study was to compare the ranking performance of a simple, non-laboratory-based risk score to laboratory-based scores in various South African populations. We calculated and compared 10-year CVD (or coronary heart disease (CHD)) risk for 14,772 adults from thirteen cross-sectional South African populations (data collected from 1987 to 2009). Risk characterization performance for the non-laboratory-based score was assessed by comparing rankings of risk with six laboratory-based scores (three versions of Framingham risk, SCORE for high- and low-risk countries, and CUORE) using Spearman rank correlation and percent of population equivalently characterized as 'high' or 'low' risk. Total 10-year non-laboratory-based risk of CVD death was also calculated for a representative cross-section from the 1998 South African Demographic Health Survey (DHS, n = 9,379) to estimate the national burden of CVD mortality risk. Spearman correlation coefficients for the non-laboratory-based score with the laboratory-based scores ranged from 0.88 to 0.986. Using conventional thresholds for CVD risk (10% to 20% 10-year CVD risk), 90% to 92% of men and 94% to 97% of women were equivalently characterized as 'high' or 'low' risk using the non-laboratory-based and Framingham (2008) CVD risk score. These results were robust across the six risk scores evaluated and the thirteen cross-sectional datasets, with few exceptions (lower agreement between the non-laboratory-based and Framingham (1991) CHD risk scores). Approximately 18% of adults in the DHS population were characterized as 'high CVD risk' (10-year CVD death risk >20%) using the non-laboratory-based score. We found a high level of correlation between a simple, non-laboratory-based CVD risk score and commonly-used laboratory-based risk scores. The burden of CVD mortality risk was high for men and women in South Africa. The policy and clinical implications are that fast, low-cost screening tools can lead to similar risk assessment results compared to time- and resource-intensive approaches. Until setting-specific cohort studies can derive and validate country-specific risk scores, non-laboratory-based CVD risk assessment could be an effective and efficient primary CVD screening approach in South Africa.


Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis.
CD3+ peripheral blood T lymphocytes were evaluated for expression of vascular endothelial growth factor (VEGF), an endothelial cell mitogen and potent angiogenic factor. VEGF mRNA expression was confirmed in CD3+ cells and Jurkat cells, a human T-cell line, by reverse transcription-PCR and in CD4+ and CD8+ T cell subtypes by Northern blot hybridization. Steady-state levels of VEGF mRNA were inducible in CD3+ T cells by hypoxia, a known inducer of VEGF mRNA accumulation. Secreted VEGF was detected in CD4+ and CD8+ T cell- and Jurkat cell-conditioned medium, indicating that T lymphocytes are capable of exporting bioactive concentrations of VEGF into the extracellular space. Human prostate and bladder cancers (prostatic adenocarcinoma and transitional cell carcinomas) were evaluated for VEGF mRNA expression by in situ hybridization. Tumor-infiltrating lymphocytes (TIL), identifiable immunocytochemically as T cells, along with tumor cells in these cancers, expressed VEGF mRNA. TIL in bladder cancers could be labeled with a specific anti-VEGF mAb, indicating that TIL are likely to be able to secrete VEGF protein in situ at bioactive concentrations. The finding that peripheral T cells and TIL in human tumors synthesize a factor known to be a specific mediator of neovascularization suggests a role for T lymphocytes as cellular effectors of angiogenesis.


Health-Related Behaviors Among School-Aged Children and Adolescents During the Spanish Covid-19 Confinement.
In response to the coronavirus disease 2019 (Covid-19) world pandemic, affected countries such as Spain enacted measures comprising compulsory confinement as well as restrictions regarding free movement. Such measures likely influence children's and adolescents' lifestyles. Our study aimed to investigate the impact that the Covid-19 confinement has on health-related behaviors (HRBs) among Spanish children and adolescents. An online survey was administered to 516 parents to collect data about 860 children and adolescents (49.2% girls) aged between 3 and 16 years in relation to physical activity, screen exposure, sleep time, and fruit and vegetable consumption during the Covid-19 confinement. Respectively, t-paired test and t-test between groups served to check differences between HRBs levels before and during the confinement as well as between strict and relaxed confinement. Significant differences were found for a reduction of weekly minutes of physical activity during the confinement (-102.5, SD 159.6) (p < 0.001), an increase of daily hours of screen exposure (2.9, SD 2.1) (p < 0.001), and a reduction of daily fruit and vegetable consumption (-0.2, SD 1.6) (p < 0.001). Sleep time showed a significant difference between strict and relaxed confinement (-0.3, SD 0.1) (p < 0.05), whereas binomial logistic regression adjusted for covariates (age, sex, education of the parents, siblings, current condition, exposure to Covid-19, and previous health risk behavior) showed significantly lower odds for screen exposure risk behavior with relaxed confinement (OR 0.60, 95%CI 0.40-0.91). The present study suggests that Covid-19 confinement reduced physical activity levels, increased both screen exposure and sleep time, and reduced fruit and vegetable consumption. Therefore, most HRBs worsened among this sample of Spanish children and adolescents. Closure of schools, online education, and the lack of policies addressing the conciliation between labor and family life could have played an important role in HRBs worsening among pupils, which might be mitigated with adequate conciliation policies, parental guidance, and community support.


Global processing of compound lettersin a patient with Balint's syndrome( ).
We report data on the ability of a patient with Balint's syndrome (GK) to process global information from compound letters. As with other patients with Balint's syndrome, GK was impaired at respond-ing to large, global letters. In Experiment 1 we show that this was due to local capture rather than the absolute size of the stimuli. Also, despite his impairment with global letters, GK showed global inter-ference on local judgements, indicating that some implicit processing took place at the global level. Interestingly, the inability to perceive large global letters was overcome when GK identified a solid, large prime letter prior to the onset of the compound figure (Experiment 2). This priming effect was temporary, and decreased as the interval between the prime and the compound letter increased (Experiment 3). When the prime was an English letter, the effect was maintained even when GK only had to identify the prime's colour, provided a colour-identification block of trials followed rather than preceded a block of trials where prime shapes had to be identified (Experiment 4). In contrast, there was no priming when GK had to identify the colour of English letter primes in a trial block following a block where the task was to identify the colour of Hebrew letter primes (Experiment 5). Overall the data indicate that local capture in Balint's syndrome can be overcome by actively priming a wide attentional window. The results can be interpreted in terms of an interaction between spatial attention and grouping processes that subserves the perception of global compound letters.


Possibilities of optical elements design using phase holograms.
Design principles of holographic optical elements are discussed. It is shown that a phase hologram with a high efficiency can be produced that transforms the input wavefront into an output of the required directivity. Such holograms can be used in laser systems instead of complex multilens objectives. Holograms have been obtained experimentally with a diffraction efficiency of 70%.


Plant and arthropod community sensitivity to rainfall manipulation but not nitrogen enrichment in a successional grassland ecosystem.
Grasslands provide many ecosystem services including carbon storage, biodiversity preservation and livestock forage production. These ecosystem services will change in the future in response to multiple global environmental changes, including climate change and increased nitrogen inputs. We conducted an experimental study over 3 years in a mesotrophic grassland ecosystem in southern England. We aimed to expose plots to rainfall manipulation that simulated IPCC 4th Assessment projections for 2100 (+15% winter rainfall and -30% summer rainfall) or ambient climate, achieving +15% winter rainfall and -39% summer rainfall in rainfall-manipulated plots. Nitrogen (40 kg ha(-1) year(-1)) was also added to half of the experimental plots in factorial combination. Plant species composition and above ground biomass were not affected by rainfall in the first 2 years and the plant community did not respond to nitrogen enrichment throughout the experiment. In the third year, above-ground plant biomass declined in rainfall-manipulated plots, driven by a decline in the abundances of grass species characteristic of moist soils. Declining plant biomass was also associated with changes to arthropod communities, with lower abundances of plant-feeding Auchenorrhyncha and carnivorous Araneae indicating multi-trophic responses to rainfall manipulation. Plant and arthropod community composition and plant biomass responses to rainfall manipulation were not modified by nitrogen enrichment, which was not expected, but may have resulted from prior nitrogen saturation and/or phosphorus limitation. Overall, our study demonstrates that climate change may in future influence plant productivity and induce multi-trophic responses in grasslands.


Developing red-emissive ruthenium(II) complex-based luminescent probes for cellular imaging.
Ruthenium(II) complexes have rich photophysical attributes, which enable novel design of responsive luminescence probes to selectively quantify biochemical analytes. In this work, we developed a systematic series of Ru(II)-bipyrindine complex derivatives, [Ru(bpy)(3-n)(DNP-bpy)(n)](PF(6))(2) (n = 1, 2, 3; bpy, 2,2'-bipyridine; DNP-bpy, 4-(4-(2,4-dinitrophenoxy)phenyl)-2,2'-bipyridine), as luminescent probes for highly selective and sensitive detection of thiophenol in aqueous solutions. The specific reaction between the probes and thiophenol triggers the cleavage of the electron acceptor group, 2,4-dinitrophenyl, eliminating the photoinduced electron transfer (PET) process, so that the luminescence of on-state complexes, [Ru(bpy)(3-n)(HP-bpy)(n)](2+) (n = 1, 2, 3; HP-bpy, 4-(4-hydroxyphenyl)-2,2'-bipyridine), is turned on. We found that the complex [Ru(bpy)(DNP-bpy)(2)](2+) remarkably enhanced the on-to-off contrast ratio compared to the other two (37.8 compared to 21 and 18.7). This reveals a new strategy to obtain the best Ru(II) complex luminescence probe via the most asymmetric structure. Moreover, we demonstrated the practical utility of the complex as a cell-membrane permeable probe for quantitative luminescence imaging of the dynamic intracellular process of thiophenol in living cells. The results suggest that the new probe could be a very useful tool for luminescence imaging analysis of the toxic thiophenol in intact cells.


Education and decision making at the time of triptan prescribing: patient expectations vs actual practice.
Optimizing patient satisfaction with their medical care and maximizing patient adherence with treatment plans requires an understanding of patient preferences regarding education and their role in decision making when treatments are prescribed. To assess the congruence between patient expectations and actual practice regarding education and decision making at the time a triptan is prescribed. This multicenter cross-sectional survey was performed by headache fellow members of the American Headache Society Headache Fellows Research Consortium at their respective tertiary care headache clinics. Migraine patients who were new patients to the headache clinic and who were current triptan users (use within prior 3 months and for ≥1 year) or past triptan users (no use within 6 months; prior use within 2 years) completed questionnaires that assessed the education they received and their role in decision making at the time a triptan was first prescribed as well as their desire for education and participation in decision making when a triptan is prescribed. Consistent with patient preference, most participants received the majority of their education about the triptan from the prescriber's office (70.2%). In descending rank order, participants most desired to be informed about how to decide if a triptan should be taken, when during the course of migraine a triptan should be taken, possible side effects, cost, and how to obtain refills. Regarding side effects, most participants preferred to receive education about the most common side effects of a triptan rather than addressing all possible side effects. Regarding triptan dosing, participants desired to be informed in descending order of importance about taking other medications with triptans, how many doses can be taken for each migraine, how many doses can be taken each week/month, what to do if the triptan does not work, and the triptan mechanism of action. The vast majority of participants (92%) preferred that the decision to prescribe a triptan be a joint decision between the patient and the provider. In actual practice, participants were not as involved in decision making as they would like to be, with patients reporting that the prescriber was the sole decision maker 55.1% of the time. Participants had confidence in their providers (87.7%) and generally felt they did a good job educating them about the triptan (71.1%). Based on this study, it is clear that patients prefer the shared model approach to medical decision making in regards to the prescription of triptans. The majority of patients received education that was generally consistent with their desires. Patients preferred that the prescribing provider be the primary source of information. The most desired educational topics included when/if a triptan should be taken, the number of times a triptan can be taken for a single migraine, co-administration with other acute medications, and the most common side effects. Focusing on these topics should enhance patient satisfaction and may improve compliance.


Immunosuppressive niche engineering at the onset of human colorectal cancer.
The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune "cold" ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC.


Thermodynamics of the alkaline transition of cytochrome c.
The apparent equilibrium constant (Kapp) of the alkaline transition (AT) of beef heart cytochrome c, obtained from pH titrations of the current intensities in cyclic voltammetry experiments, has been measured as a function of the temperature from 5 to 65 degrees C, at different ionic strength (I = 0.01-0.2 M). The temperature profile of the pKapp values is biphasic and yields two distinct sets of DeltaH degrees 'AT and DeltaS degrees 'AT values below and above approximately 40 degrees C. In the low-temperature range, the process is endothermic and is accompanied by a small positive entropy change, while at higher temperatures it becomes less endothermic and involves a pronounced entropy loss. The temperature dependence of the transition thermodynamics is most likely the result of the thermal transition of native ferricytochrome c from a low-T to an high-T conformer which occurs at alkaline pH values at a temperature comparable with above (Ikeshoji, T., Taniguchi, I., and Hawkridge, F. M. (1989) J. Electroanal. Chem. 270, 297-308; Battistuzzi, G., Borsari, M., Sola, M., and Francia, F. (1997) Biochemistry 36, 16247-16258). Thus, it is apparent that the transitions of the two native conformers to the corresponding alkaline form(s) are thermodynamically distinct processes. It is suggested that this difference arises from either peculiar transition-induced changes in the hydration sphere of the protein or to the preferential binding of different lysines to the heme iron in the two temperature ranges. Extrapolation of the Kapp values at null ionic strength allowed the determination of the thermodynamic equilibrium constants (Ka) at each temperature, hence of the "true" standard thermodynamic parameters of the transition. The pKa value at 25 degrees C was found to be 8.0. A pKapp value of 14.4 was calculated for the alkaline transition of ferrocytochrome c at 25 degrees C and I = 0.1 M. The much greater relative stabilization of the native state in the reduced as compared to the oxidized form turns out to be almost entirely enthalpic in origin, and is most likely due to the greater affinity of the methionine sulfur for the Fe(II) ion. Finally, it is found that the Debye-Hückel theory fits the ionic strength dependence of the pKapp values, at least qualitatively, as observed previously for the ionic strength dependence of the reduction potential of this protein class. It is apparent that the increase in the pKapp values with increasing ionic strength is for the most part an entropic effect.


Enhancement of low spatial frequency signals with optical aperture tapering.
Detection of weak signals in an optical spectrum analyzer is impaired by sidelobes from nearby large signal components in the output spectrum. Strong sidelobes about the zero frequency component particularly inhibit detection of low frequency signals. Sidelobe response can be attenuated by suitable illumination tapering over the input data aperture. Changes of first and second sidelobe levels and main lobe width have been investigated for gaussian, lorentzian, and exponential tapers. Improved capability to distinguish weak low frequency signals in the presence of distortions introduced by component flaws is demonstrated for the exponential form.


Anesthetic considerations for magnetic seizure therapy: a novel therapy for severe depression.
Electroconvulsive therapy (ECT) is a highly effective treatment for severe depression. However, its use is associated with significant posttreatment cognitive impairment. Magnetic seizure therapy (MST) was developed as an alternative therapy that could reduce postseizure side effects through the induction of more "focal" seizure activity. Using an open-parallel study design, we compared 20 case-matched patients undergoing a series of either ECT or MST procedures with respect to their anesthetic, muscle relaxant, and cardiovascular drug requirements, effects on cardiovascular and electroencephalographic bispectral index (BIS) values, and early recovery times. We found that MST was associated with a reduced time to orientation (4 +/- 1 versus 18 +/- 5 min; P < 0.01) compared with ECT. To minimize residual muscle paralysis after MST, a reduction in the succinylcholine dosage (38 +/- 17 versus 97 +/- 2 mg; P < 0.01) was required. The BIS values were higher before, and lower immediately after, the stimulus was applied in the MST (versus ECT) group. The Hamilton depression rating scale score was significantly reduced from the baseline value in both treatment groups; however, the posttreatment score was lower after the series of ECT treatments (6 +/- 6 versus 14 +/- 10; P < 0.05). We conclude that MST was associated with a decreased requirement for muscle relaxants, reduced variability in the BIS values after seizure induction, and a more rapid recovery of cognitive function compared with ECT. Further studies are required to evaluate the antidepressant efficacy of MST versus ECT when they are administered at comparable levels of cerebral stimulation.


Gene expression profiles in normal and cancer cells.
As a step toward understanding the complex differences between normal and cancer cells in humans, gene expression patterns were examined in gastrointestinal tumors. More than 300,000 transcripts derived from at least 45,000 different genes were analyzed. Although extensive similarity was noted between the expression profiles, more than 500 transcripts that were expressed at significantly different levels in normal and neoplastic cells were identified. These data provide insight into the extent of expression differences underlying malignancy and reveal genes that may prove useful as diagnostic or prognostic markers.


Multidimensional epistasis and the disadvantage of sex.
Sex is thought to facilitate accumulation of initially rare beneficial mutations by allowing simultaneous allele replacements at many loci. However, this advantage of sex depends on a restrictive assumption that the fitness of a genotype is determined by fitness potential, a single intermediate variable to which all loci contribute additively, so that new alleles can accumulate in any order. Individual-based simulations of sexual and asexual populations reveal that under generic selection, sex often retards adaptive evolution. When new alleles are beneficial only if they accumulate in a prescribed order, a sexual population may evolve two or more times slower than an asexual population because only asexual reproduction allows some overlap of successive allele replacements. Many other fitness surfaces lead to an even greater disadvantage of sex. Thus, either sex exists in spite of its impact on the rate of adaptive allele replacements, or natural fitness surfaces have rather specific properties, at least at the scale of intrapopulation genetic variability.


Survey on oral hygiene measures for intubated patients in Swiss intensive care units.
Five to ten percent of all hospitalized patients are treated in intensive care units. The risk of nosocomial infections is inherent in the latter, especially in cases of intubation. In this context, impaired oral hygiene may play a pivotal role. Therefore, the purpose of this survey among representative Swiss intensive care units was to assess the standards and measures taken in this patient collective with reduced oral hygiene. To this end, a questionnaire was sent to 25 institutions which represented all A- and University hospitals in Switzerland as well as all accredited intensive care units in the canton of Zurich according to the register of the Swiss Society of Intensive Medicine. Intensive care units from pediatric departments were excluded. Twenty-one questionnaires were received and evaluated (84%). Only one quarter of all respondents reported having protocols available for preventing ventilation-associated pneumonia (VAP). Systemic antibiotic regimens were never performed. Ninety percent reported cleaning the patients' teeth mechanically with a toothbrush. Sixty-seven percent used chlorhexidine as a disinfectant (81% in liquid form). Seventy-five percent of the responding hospitals performed routine oral cleaning procedures three times a day (90% immediately after intubation). In summary, oral prophylaxis was neither standardized nor consistently implemented in the evaluated Swiss intensive care units of the responding hospitals. Only a small proportion had protocols available for preventing VAP, which is in accordance with similar surveys conducted in the US and Europe. Additional and improved measures have to be determined to confirm or optimize prophylactic oral strategies and to create standards and guidelines for this at-risk patient collective.


Diversity preferences among employees and ethnoracial workplace segregation.
Ethno-racial workplace segregation increases already existing ethno-racial inequality. While previous research has identified discriminatory employers as drivers of workplace segregation, this study addresses the role of the employees. Sociological and social psychological theory suggest that people prefer to surround themselves with people who positively confirm their social identity or who contribute with higher group status. Through web-based surveys, we measure employee attitudes and preferences concerning ethno-racial workplace diversity, to what extent they differ by ethnicity/race, and if they contain intersectional patterns. Thereafter, we use simulation models to analyze the consequences for workplace segregation that these preferences would have, if realized. The main survey results showed that all ethno-racial groups favored their own in-group as colleagues, especially European Americans. As a secondary choice, the respondents preferred the out-group with the highest labor market status. Intersectional patterns were identified, as minority women were preferred as colleagues over minority men. Our simulation model, based on the results of two surveys on stated vs. indirectly revealed preferences, showed that employee preferences were at best not diverse enough to desegregate workplaces. When based on the most common preferences (i.e. excluding a few outliers), the simulations even suggested that these preferences can cause segregation. We relate these findings to Schelling's model of segregation.


Functional reorganization of marine fish nurseries under climate warming.
While climate change is rapidly impacting marine species and ecosystems worldwide, the effects of climate warming on coastal fish nurseries have received little attention despite nurseries' fundamental roles in recruitment and population replenishment. Here, we used a 26-year time series (1987-2012) of fish monitoring in the Bay of Somme, a nursery in the Eastern English Channel (EEC), to examine the impacts of environmental and human drivers on the spatial and temporal dynamics of fish functional structure during a warming phase of the Atlantic Multidecadal Oscillation (AMO). We found that the nursery was initially dominated by fishes with r-selected life-history traits such as low trophic level, low age and size at maturity, and small offspring, which are highly sensitive to warming. The AMO, likely superimposed on climate change, induced rapid warming in the late 1990s (over 1°C from 1998 to 2003), leading to functional reorganization of fish communities, with a roughly 80% decline in overall fish abundance and increased dominance by K-selected fishes. Additionally, historical overfishing likely rendered the bay more vulnerable to climatic changes due to increased dominance by fishing-tolerant, yet climatically sensitive species. The drop in fish abundance not only altered fish functional structure within the Bay of Somme, but the EEC was likely impacted, as the EEC has been unable to recover from a regime shift in the late 1990s potentially, in part, due to failed replenishment from the bay. Given the collapse of r-selected fishes, we discuss how the combination of climate cycles and global warming could threaten marine fish nurseries worldwide, as nurseries are often dominated by r-selected species.


Isolation and identification of infectious salmon anaemia virus (ISAV) from Coho salmon in Chile.
The isolation of infectious salmon anaemia virus (ISAV) from asymptomatic wild fish species including wild salmon, sea trout and eel established that wild fish can be a reservoir of ISAV for farmed Atlantic salmon. This report characterizes the biological properties of ISAV isolated from a disease outbreak in farmed Coho salmon in Chile and compares it with ISAV isolated from farmed Atlantic salmon in Canada and Europe. The virus that was isolated from Coho salmon tissues was initially detected with ISAV-specific RT-PCR (reverse transcription-polymerase chain reaction). The ability of the virus to grow in cell culture was poor, as cytopathology was not always conspicuous and isolation required passage in the presence of trypsin. Virus replication in cell culture was detected by RT-PCR and IFAT (indirect fluorescent antibody test), and the virus morphology was confirmed by positive staining electron microscopy. Further analysis of the Chilean virus revealed similarities to Canadian ISAV isolates in their ability to grow in the CHSE-214 cell line and in viral protein profile. Sequence analysis of genome segment 2, which encodes the viral RNA polymerase PB1, and segment 8, which encodes the nonstructural proteins NS1 and NS2, showed the Chilean virus to be very similar to Canadian strains of ISAV. This high sequence similarity of ISAV strains of geographically distinct origins illustrates the highly conserved nature of ISAV proteins PB1, NS1 and NS2 of ISAV. It is noteworthy that ISAV was associated with disease outbreaks in farmed Coho salmon in Chile without corresponding clinical disease in farmed Atlantic salmon. This outbreak, which produced high mortality in Coho salmon due to ISAV, is unique and may represent the introduction of the virus to a native wild fish population or a new strain of ISAV.


Implications of malnutrition in the surgical patient.
The substantial prevalence of malnutrition in the hospitalized patient population has only been recently recognized. Preoperative nutritional and immunological assessment was performed prospectively on admission in 64 consecutive surgical patients. Factors measured included weight loss, triceps skinfold, midarm muscle circumference, creatinine-height index, serum albumin level, serum transferrin level, total lymphocyte count, serum complement level, serum immunoelectrophoresis, lymphocyte T rosettes formation, neutrophil migration, and delayed hypersensitivity. Using these criteria for malnutrition, 97% of the patients had at least one abnormal measurement and 35% had at least three abnormal measurements. Patients were monitored for complications during their hospital course. Serum albumin level, serum transferrin level, and delayed hypersensitivity reactions were the only accurate prognostic indicators of postoperative morbidity and mortality. Substantial unrecognized malnutrition exists in the surgical patient population. An isolated indicator of malnutrition should be interpreted with caution. The visceral protein compartment (serum albumin and serum transferrin levels and delayed hypersensitivity) is the most accurate prognostic indicator of postoperative morbidity and mortality. Perioperative nutritional support may reduce operative morbidity and mortality in the malnourished operative candidate.


Fluorescence Activated Cell Sorting (FACS) in Genome-Wide Genetic Screening of Membrane Trafficking.
About one-third of cellular proteins in eukaryotic cells are localized to membrane-enclosed organelles in the endomembrane system. Trafficking of these membrane proteins (including soluble lumenal proteins) among the organelles is mediated by small sac-like vesicles. Vesicle-mediated membrane trafficking regulates a broad range of biological processes, many of which are still poorly understood at the molecular level. A powerful approach to dissect a vesicle-mediated membrane trafficking pathway is unbiased genome-wide genetic screening, which only recently became possible in mammalian cells with the isolation of haploid human cell lines and the development of CRISPR-Cas9 genome editing. Here, we describe a FACS-based method to select populations of live mutant cells based on the surface levels of endogenous proteins or engineered reporters. Collection of these mutant populations enables subsequent deep sequencing and bioinformatics analysis to identify genes that regulate the trafficking pathway. This method can be readily adapted to genetically dissect a broad range of mammalian membrane trafficking processes using haploid genetics or CRISPR-Cas9 screens. © 2018 by John Wiley & Sons, Inc.


CD30 expression on CD1a+ and CD8+ cells in atopic dermatitis and correlation with disease severity.
Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with cutaneous hyperreactivity to environmental stimuli, resulting in increased infiltration of inflammatory cells, IgE production and enhanced expression of costimulatory molecules, cytokines and chemokines. CD30, a TNF receptor superfamily member, is a costimulatory molecule expressed on activated T and B cells. A positive correlation between soluble CD30 (sCD30) levels in patient serum and AD disease severity has been described previously. However, the relative frequencies and identities of cells expressing CD30 in AD patients and the relationship between the frequency of CD30 positive cells and serum sCD30 levels with disease severity remained unknown. To address these questions, immunofluorescence analysis of AD skin lesions representing different disease stages, was conducted. In addition to the CD4+ T cells, CD1a+ Langerhans cells and CD8+ T cells were found to express CD30 in AD lesions and the cell numbers correlated with disease severity. FACS analysis of AD patient blood samples revealed expression of CD30 on memory T-cells and a correlation with disease severity was identified. Finally, serum analysis of soluble mediators revealed positive correlations between sCD30, IgE, MDC, TARC and PARC levels with disease severity. Combined, our data provide correlative evidence that CD30+ cells, including Langerhans cells and CD8+ T-cells, may contribute to AD disease severity and that therapeutic strategies targeting CD30+ cells may provide benefit to AD patients.


Carbon nanotubes induce inflammation but decrease the production of reactive oxygen species in lung.
With the rapid spread of carbon nanotubes (CNTs) applications, the respiratory toxicity of these compounds has attracted the attention of many scientists. Several studies have reported that after lung administration, CNTs could induce granuloma, fibrosis, or inflammation. By comparison with the mechanisms involved with other toxic particles such as asbestos, this effect could be attributed to an increase of oxidative stress. The aim of the present work was to test this hypothesis in vivo. Mice were intranasally instilled with 1.5mg/kg of double walled carbon nanotubes (DWCNTs). Six, 24, or 48h after administration, inflammation and localisation of DWCNTs in lungs were microscopically observed. Local oxidative perturbations were investigated using ESR spin trapping experiments, and systemic inflammation was assessed by measuring the plasma concentration of cytokines TNF-alpha, IL-1alpha, IL-1beta, IL-6, IGF-1, Leptin, G-CSF, and VEGF. Examination of lungs and the elevation of proinflammatory cytokines in the plasma (Leptin and IL-6 at 6h) confirmed the induction of an inflammatory reaction. This inflammatory reaction was accompanied by a decrease in the local oxidative stress. This effect could be attributed to the scavenger capability of pure CNTs.


Genetic structure and demographic history of the endangered and endemic schizothoracine fish Gymnodiptychus pachycheilus in Qinghai-Tibetan Plateau.
The endangered schizothoracine fish Gymnodiptychus pachycheilus is endemic to the Qinghai-Tibetan Plateau (QTP), but very little genetic information is available for this species. Here, we accessed the current genetic divergence of G. pachycheilus population to evaluate their distributions modulated by contemporary and historical processes. Population structure and demographic history were assessed by analyzing 1811-base pairs of mitochondrial DNA from 61 individuals across a large proportion of its geographic range. Our results revealed low nucleotide diversity, suggesting severe historical bottleneck events. Analyses of molecular variance and the conventional population statistic FST (0.0435, P = 0.0215) confirmed weak genetic structure. The monophyly of G. pachycheilus was statistically well-supported, while two divergent evolutionary clusters were identified by phylogenetic analyses, suggesting a microgeographic population structure. The consistent scenario of recent population expansion of two clusters was identified based on several complementary analyses of demographic history (0.096 Ma and 0.15 Ma). This genetic divergence and evolutionary process are likely to have resulted from a series of drainage arrangements triggered by the historical tectonic events of the region. The results obtained here provide the first insights into the evolutionary history and genetic status of this little-known fish.


High-dose oral vitamin D supplementation and mortality in people aged 65-84 years: the VIDAL cluster feasibility RCT of open versus double-blind individual randomisation.
Randomised controlled trials demonstrating improved longevity are needed to justify high-dose vitamin D supplementation for older populations. To demonstrate the feasibility of a large trial (n ≈ 20,000) of high-dose vitamin D in people aged 65-84 years through general practitioner (GP) practices, and to cluster randomise participating practices between open-label and double-blind randomisation to compare effects on recruitment, compliance and contamination. Twenty GP practices were randomised in matched pairs between open-label and double-blind allocation. Within each practice, patients were individually randomised to vitamin D or control (i.e. no treatment or placebo). Participants were invited to attend their GP practice to provide a blood sample and complete a lifestyle questionnaire at recruitment and again at 2 years. Randomisation by telephone followed receipt of a serum corrected calcium assay confirming eligibility (< 2.65 nmol/l). Treatment compliance was reported by quarterly follow-up forms sent and returned by e-mail or post (participant choice). GP visits and infections were abstracted from GP records. Hospital attendances, cancer diagnoses and deaths were ascertained by linkage to Hospital Episode Statistics and national registration through NHS Digital. GP practices in England. Recruitment opened in October 2013 and closed in January 2015. A total of 1615 registered patients aged 65-84 years were randomised: 407 to vitamin D and 421 to no treatment in open practices; 395 to vitamin D and 392 to placebo in blind practices. There was a 24-month treatment period: 12 monthly doses (100,000 IU of vitamin D3 or placebo as 5 ml oily solution) were posted after randomisation and at 1 year (100,000 IU per month corresponds to 3300 IU per day). Reminders were sent monthly by e-mail, text message or post. Recruitment, compliance, contamination and change in circulating 25-hydroxyvitamin D [25(OH)D] from baseline to 2 years. Participation rates (randomised/invited) were 15.0% in open practices and 13.4% in double-blind practices (p = 0.7). The proportion still taking study medication at 2 years was 91.2% in open practices and 89.2% in double-blind practices (p = 0.4). The proportion of control participants taking > 400 IU vitamin D per day at 2 years was 5.0% in open practices and 4.8% in double-blind practices. Mean serum 25(OH)D concentration was 51.5 nmol/l [95% confidence interval (CI) 50.2 to 52.8 nmol/l] with 82.6% of participants < 75 nmol/l at baseline. At 2 years, this increased to 109.6 nmol/l (95% CI 107.1 to 112.1 nmol/l) with 12.0% < 75 nmol/l in those allocated to vitamin D and was unaltered at 51.8 nmol/l (95% CI 49.8 to 53.8 nmol/l) in those allocated to no vitamin D (no treatment or placebo). A trial could recruit 20,000 participants aged 65-84 years through 200 GP practices over 2 years. Approximately 80% would be expected to adhere to allocated treatment (vitamin D or placebo) for 5 years. The trial could be conducted entirely by e-mail in participants aged < 80 years, but some participants aged 80-84 years would require postal follow-up. Recruitment and treatment compliance would be similar and contamination (self-administration of vitamin D) would be minimal, whether control participants are randomised openly to no treatment with no contact during the trial or randomised double-blind to placebo with monthly reminders. Current Controlled Trials ISRCTN46328341 and EudraCT database 2011-003699-34. This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 10. See the NIHR Journals Library website for further project information.


Translating global health research aims into action: the example of the ALPHA network.
There is increasing consensus on the importance of strengthening global health research to meet health and development goals. Three key global health research aims are to ensure that research (i) addresses priority health needs, (ii) contributes to policy development, and (iii) adds value to investments in developing countries through South-South collaboration and capacity-strengthening in the South. The ALPHA network (Analysing Longitudinal Population-based HIV/AIDS data on Africa) is an illustrative example of how these global health research aims can be translated into action. The network facilitates additional collaborative HIV epidemiological research among six independent research projects in Africa studying population-based cohorts. Under the first of the earlier mentioned aims, the network addresses key epidemiology research issues in HIV/AIDS which are crucial to making progress and monitoring progress in the response against HIV/AIDS. Under the second aim, the network's scientific programme of research has contributed to strengthening the evidence base on HIV epidemiology in Africa and has informed policy development in areas such as targeted HIV prevention, social support, monitoring epidemic response and epidemic forecasting. Under the third aim, investment in the network has added value to the research investment in the individual projects through capacity development among African researchers as well as through the collaborative research outputs of the individual projects. Lessons from the network are relevant to collaborations facing similar challenges in other areas of global health research. These include the importance of establishing transparent and efficient governance for research collaborations, developing advance consensus on data sharing, ensuring effective communication for networking and demonstrating the added value of research investment in South-South collaborations.


[The meaning of health in sexual relations according to women treated under the Unified National Health System in Natal, Rio Grande do Norte State, Brazil].
The aim of this article is to discuss the social representations of "health in sexual relations" as reported by women treated under the Unified National Health System (SUS) in Natal, Rio Grande do Norte, Brazil. A total of 150 women were tested using the free word recall test, with "health in sexual relations" as the stimulus. Women were also asked about their sources of information on the subject. The results were obtained with content analysis and the EVOC software. We identified three representational dimensions: prevention, relationship with the partner, and quality of life. The central nucleus of social representation consisted of the elements "prevention" and "condoms". Likely sources for representation were television, health services, and dialogue with family members and partners. Representations were composed of concepts related to prevention, a good partner relationship, and overall well-being. The results illustrate the need to expand women's sexual health aspects that are considered relevant by the health system.


Opening up the 'black box' of the electronic patient record: a linguistic ethnographic study in general practice.
One of the most pervasive changes in general practice is the introduction of the electronic patient record (EPR). The EPR supports both immediate clinical and anticipatory care (e.g. management of risk factors). Incorporating the EPR into social interaction is a complex task which is achieved discursively, clinician and patient responding to interactional contingencies as the consultation unfolds. Clinicians are presented with a 'dilemma of attention' as they seek to deal with the immediacy ('here and now') of the interpersonal interaction and the institutional demands ('there and then') of the EPR. We present data analysis which illuminates the EPR as an important presence in the clinic consultation context, one which places material and textual demands. Developing previous work on the triadic (three party) consultation, our novel multimodal analysis of the EPR-in-use suggests there is value in considering the EPR as a collection of silent but consequential voices. Micro-analytic attention to the way in which these different voices are managed, combined with understandings drawn from ethnographic observation of the primary care context, reveals the EPR as exhibiting a previously under-explored kind of 'agency' within the consultation.


A comparative analysis of complications after robot-assisted radical prostatectomy for men aged ≤69 and ≥70 years.
Robot-assisted radical prostatectomy (RARP) is a popular treatment option for localized prostate cancer. Literature is lacking on the effect of advanced age on complication rates in men undergoing robotic prostatectomy. We performed a comparative analysis of complication rates for men ≤69 and ≥70 years undergoing RARP. After IRB approval, we reviewed our initial 1000 consecutive patients who underwent RARP from 6/2002 to 6/2011 for intraoperative and postoperative complications, and we compared complication rates stratified by age ≤69 and ≥70 years. Complications were graded according to the Clavien-Dindo classification system. The Fischer's exact test was used to compare complication rates, and a p-value of <0.05 was considered statistically significant. In our cohort, 868 men were ≤69 and 129 men were ≥70. Overall, the intraoperative and postoperative complication rates for the entire cohort were 0.90% and 10.2%, respectively. There was no statistically significant difference in individual postoperative complications between the two groups, however, the overall postoperative complications rates for men ≤69 and ≥70 were 9.4% and 15.4%, respectively (p-value=0.043). Major complication rates for men ≤69 and ≥70 were 6.7% (58) and 10.8% (14), respectively (p=0.10); minor complications rates were 2.8% (22) and 4.6% (6), respectively (p=0.25). In our study, men ≥70 had a significantly higher overall complication rate after RARP compared with men ≤69 years; however, the individual, minor, and major complications were not different between the two groups. RARP is relatively safe in this older age group. Identifying complications and proposing insightful working solutions have decreased both minor and major complication rates after RARP.


Long 3'-UTRs target wild-type mRNAs for nonsense-mediated mRNA decay in Saccharomyces cerevisiae.
The nonsense-mediated mRNA decay (NMD) pathway, present in most eukaryotic cells, is a specialized pathway that leads to the recognition and rapid degradation of mRNAs with premature termination codons and, importantly, some wild-type mRNAs. Earlier studies demonstrated that aberrant mRNAs with artificially extended 3'-untranslated regions (3'-UTRs) are degraded by NMD. However, the extent to which wild-type mRNAs with long 3'-UTRs are degraded by NMD is not known. We used a global approach to identify wild-type mRNAs in Saccharomyces cerevisiae that have longer than expected 3'-UTRs, and of these mRNAs tested, 91% were degraded by NMD. We demonstrate for the first time that replacement of the natural, long 3'-UTR from wild-type PGA1 mRNA, which encodes a protein that is important for cell wall biosynthesis, with a short 3'-UTR renders it immune to NMD. The natural PGA1 3'-UTR is sufficient to target a NMD insensitive mRNA for decay by the NMD pathway. Finally, we show that nmd mutants are sensitive to Calcofluor White, which suggests that the regulation of PGA1 and other cell wall biosynthesis proteins by NMD is physiologically significant.


Endocannabinoid system in irritable bowel syndrome and cannabis as a therapy.
Irritable bowel syndrome (IBS) global burden is underestimated despite its high prevalence. It's a gastrointestinal disease having obscure pathophysiology with multiple therapies yet unsatisfactory remedies. The Endocannabinoid system (ECS) of our body plays a key role in maintaining normal physiology of the gastrointestinal tract as well as involves abnormalities including functional diseases like IBS. This review highlights the importance of the Endocannabinoid system, its connections with the normal gastrointestinal functions and abnormalities like IBS. It also discusses the role of cannabis as medical therapy in IBS patients. A literature search for articles related to endocannabinoids in IBS and medical cannabis in PubMed and Google Scholar was conducted. The studies highlighted the significant participation of ECS in IBS. However, the breach in obtaining the promising therapeutic model for IBS needed further investigation in ECS and uncover other treatments for IBS. This review summarizes ECS, highlights the relationship of ECS with IBS and explores cannabis as a potential therapy to treat IBS.


Long-term maintenance of neuronally differentiated human adipose tissue-derived stem cells.
Recent studies reporting differentiation of early neural progenitors of human adipose tissue-derived stromal cells (ADSCs) has aroused interest among investigators for regenerative medicine. The aim of this study was to investigate the differentiation of ADSCs to neuron-like cells and to extend the life span of these differentiated ADSCs in vitro using our new DE-1 medium. After primary culture and expansion, ADSCs were incubated in a new long-term neuronal induction medium that maintains ADSCs in a differentiated state for 8 weeks. Neuronal differentiation was identified using immunocytochemistry, reverse-transcriptase polymerase chain reaction, and Western blotting. We found that the optimal differentiation protocol induced the ADSCs to express early neuronal markers, including nestin and neuronal nuclear antigen (NeuN), as well as the mature astrocyte marker glial fibrillary acidic protein (GFAP). Neuronal morphological characteristics were recognized in approximately 40% to 50% of the cell populations maintained over 8 weeks, and 60% to 80% of the differentiated cells expressed neuronal specific markers, including nestin, GFAP, NeuN, Trk-A, vimentin, and neuron-specific enolase. The data show that our DE-1 medium is capable of achieving a greater number of differentiated ADSCs for a longer period of time. This result bodes well for the application of ADSCs in in vivo peripheral nerve regeneration.


Tumor-associated macrophages in glioblastoma multiforme-a suitable target for somatostatin receptor-based imaging and therapy?
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM) have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10-tetraazacyclododecane-NN',N″,N'″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A) which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM. 15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68), proliferative activity (Ki67) as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET) imaging using 68Ga-DOTATATE was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry. The amount of microglia/macrophages ranged from <10% to >50% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns. SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM.


Localization of sperm whales in a group using clicks received at two separated short baseline arrays.
In this paper, a sperm whale click analysis scheme is proposed in order to calculate the position of individual sperm whales in a group using data received at two arrays deployed near the surface. The proposed method mainly consists of two parts: short baseline (SBL) with classification and long baseline (LBL) with class matching. In SBL with classification, a click is automatically detected, and its direction of arrival is calculated. The clicks are then classified based on their direction vectors. The class data are then sent together with direction data and matched to the other array's class data. LBL with class matching is used for localization. The classification algorithm can be used to estimate the number of whales clicking and to list potential candidates for LBL matching. As a result, the proposed method is able to localize the positions of the whales in a group. The performance of the proposed method is evaluated using data recorded off Ogasawara islands with two arrays near the surface. The three-dimensional underwater trajectories of six sperm whales are extracted to demonstrate the capability of the proposed method.


Leptin increases FA oxidation in lean but not obese human skeletal muscle: evidence of peripheral leptin resistance.
The adipocyte-derived hormone leptin has been shown to acutely increase fatty acid (FA) oxidation and decrease esterification in resting rodent skeletal muscle. However, the effects of leptin on human skeletal muscle FA metabolism are completely unknown. In these studies, we have utilized an isolated human skeletal muscle preparation combined with the pulse-chase technique to measure FA metabolism with and without leptin in lean and obese human skeletal muscle. Under basal conditions (in the absence of leptin), muscle from the obese demonstrated significantly elevated levels of total FA uptake (+72%, P = 0.038) and enhanced rates of FA esterification into triacylglycerol (+102%, P = 0.042) compared with lean subjects. In the presence of leptin, lean muscle had elevated rates of endogenous (+103%, P = 0.01) and exogenous (+150%, P = 0.03) palmitate oxidation. When the ratio of esterification to exogenous oxidation was examined, leptin reduced this ratio (-47%, P = 0.032), demonstrating the increased partitioning of FA toward oxidation and away from storage. Contrary to these findings in lean muscle, leptin had no effect on FA metabolism in skeletal muscle of the obese. This study provides the first evidence that leptin increases FA oxidation in skeletal muscle of lean, but not obese humans, thus demonstrating the development of leptin resistance in obese human skeletal muscle.


The value of the plasma circulating cell-free DNA concentration and integrity index as a clinical tool for prostate cancer diagnosis: a prospective case-control cohort study in an Iranian population.
Introduction: Prostate cancer (PCa) is the most common cancer among men and the second cause of cancer death among men. For early detection and differentiating PCa from benign prostate hyperplasia (BPH) tissue biopsy has been used for decades. However, circulating cell-free DNA (ccfDNA) testing is a noninvasive, fast, easily repeatable, and sensitive liquid biopsy for cancer detection. Hence, we aimed to investigate the value of the ccfDNA concentration and integrity index in peripheral blood of a population of Iranian prostatic patients for early diagnosis of the disease. Materials and methods: 100 subjects including 30 PCa, 40 BPH, and 30 healthy individuals were selected. ccfDNA was extracted from fresh blood plasma, and its total concentration and the integrity index were estimated by amplification of ALU115 and ALU247 repeat elements using quantitative real-time PCR. Results: In the PCa group, the ccfDNA concentration and its integrity were significantly higher than that of the BPH and healthy groups (P-value <0.001 and P-value <0.001). The ccfDNA concentration and its integrity were higher in BPH compared to the healthy group, although it was not statistically significant (P-value =0.836 and P-value =0.053, respectively). Conclusion: A significant relation between ccfDNA concentration, its integrity, and PCa suggests that the liquid biopsy can be used as a noninvasive early diagnostic biomarker. Determination of a cutoff or a diagnostic range value of the measured parameters for healthy, BPH, and PCa subjects in more samples of Iranian population results in timely, correct, and early detection, which results in better treatment outcomes. Moreover, this method may reduce overdiagnosis and overtreatment procedures.


Urban specialization reduces habitat connectivity by a highly mobile wading bird.
Mobile animals transport nutrients and propagules across habitats, and are crucial for the functioning of food webs and for ecosystem services. Human activities such as urbanization can alter animal movement behavior, including site fidelity and resource use. Because many urban areas are adjacent to natural sites, mobile animals might connect natural and urban habitats. More generally, understanding animal movement patterns in urban areas can help predict how urban expansion will affect the roles of highly mobile animals in ecological processes. Here, we examined movements by a seasonally nomadic wading bird, the American white ibis (Eudocimus albus), in South Florida, USA. White ibis are colonial wading birds that forage on aquatic prey; in recent years, some ibis have shifted their behavior to forage in urban parks, where they are fed by people. We used a spatial network approach to investigate how individual movement patterns influence connectivity between urban and non-urban sites. We built a network of habitat connectivity using GPS tracking data from ibis during their non-breeding season and compared this network to simulated networks that assumed individuals moved indiscriminately with respect to habitat type. We found that the observed network was less connected than the simulated networks, that urban-urban and natural-natural connections were strong, and that individuals using urban sites had the least-variable habitat use. Importantly, the few ibis that used both urban and natural habitats contributed the most to connectivity. Habitat specialization in urban-acclimated wildlife could reduce the exchange of propagules and nutrients between urban and natural areas, which has consequences both for beneficial effects of connectivity such as gene flow and for detrimental effects such as the spread of contaminants or pathogens.


Harmonized definition of occupational burnout: A systematic review, semantic analysis, and Delphi consensus in 29 countries.
Objective A consensual definition of occupational burnout is currently lacking. We aimed to harmonize the definition of occupational burnout as a health outcome in medical research and reach a consensus on this definition within the Network on the Coordination and Harmonisation of European Occupational Cohorts (OMEGA-NET). Methods First, we performed a systematic review in MEDLINE, PsycINFO and Embase (January 1990 to August 2018) and a semantic analysis of the available definitions. We used the definitions of burnout and burnout-related concepts from the Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT) to formulate a consistent harmonized definition of the concept. Second, we sought to obtain the Delphi consensus on the proposed definition. Results We identified 88 unique definitions of burnout and assigned each of them to 1 of the 11 original definitions. The semantic analysis yielded a first proposal, further reformulated according to SNOMED-CT and the panelists` comments as follows: "In a worker, occupational burnout or occupational physical AND emotional exhaustion state is an exhaustion due to prolonged exposure to work-related problems". A panel of 50 experts (researchers and healthcare professionals with an interest for occupational burnout) reached consensus on this proposal at the second round of the Delphi, with 82% of experts agreeing on it. Conclusion This study resulted in a harmonized definition of occupational burnout approved by experts from 29 countries within OMEGA-NET. Future research should address the reproducibility of the Delphi consensus in a larger panel of experts, representing more countries, and examine the practicability of the definition.


Short-term hemodynamic effects of hydralazine in infants with complete atrioventricular canal defects.
We evaluated the acute hemodynamic responses to hydralazine during cardiac catheterization in eight infants (ages 1.0 to 5.5 months) with congestive heart failure due to complete atrioventricular canal defect. Hydralazine administered intravenously (0.5 to 1.0 mg/kg body weight) increased heart rate and systemic blood flow and decreased mean right atrial pressure, systemic and pulmonic arterial pressures, systemic arteriolar resistance, and the ratio of pulmonary to systemic blood flow (p less than .05). The percentage of pulmonary flow contributed by shunted blood (percent left-to-right shunt; measured by indicator dilution) was decreased by hydralazine in six (mean = 85% before to 64% after hydralazine; p less than .01), but remained unchanged (79%) in two infants. The two infants with no change in percent left-to-right shunt had higher pulmonary arteriolar resistances (Rp) before hydralazine (mean = 12.8 vs 3.2 U/m2) and had greater declines in Rp (mean change = -5.1 vs + 0.3 U/m2) in response to hydralazine. Thus, if Rp does not fall, hydralazine reduces the percentage of left-to-right shunt over the short term and therefore might be useful for managing congestive heart failure in these infants. However, because the response varies, an evaluation of the short-term hemodynamic effects of hydralazine may be warranted in an attempt to select those infants who might respond favorably to long-term hydralazine therapy.


The clinical manifestations at the onset of antisynthetase syndrome: A chameleon with multiple faces.
The antisynthetase syndrome (ASS) is clinically characterized by fever, myositis, interstitial lung disease, joint involvement, mechanic's hands, or Raynaud's phenomenon, and the presence of antisynthetase autoantibodies. These clinical manifestations may not occur simultaneously. Therefore, the aim of this study was to analyze the sequence in which these clinical manifestations can develop at the onset of ASS. This retrospective, single-center cohort study enrolled 55 ASS patients. Their mean age at the onset of ASS symptoms was 42.3±11.8 years. There was a predominance of female patients (75.9%) and white patients (72.7%). At initial presentation, 41.8% of the patients had fever, 43.6% had joint symptoms, 38.2% had myositis, 36.4% had interstitial lung disease, 18.2% had Raynaud's phenomenon, and 16.4% had mechanic's hands. Subsequent clinical symptoms emerged at varying time points. In two out of 55 cases, joint, muscle, and lung manifestations developed simultaneously. The median time between the onset of symptoms and the complete ASS clinical manifestation was 19.9 (4.0-60.2) months; whereas, the timeframe between the onset of symptoms and the ASS diagnosis was 29.0 (11.0-63.0) months. The confounding misdiagnoses interfering with the initial diagnosis were polymyositis (52.7%), dermatomyositis (29.1%), nonspecific interstitial pneumopathy (23.6%), rheumatoid arthritis (18.2%), and others (10.9%). Clinical features at the onset of ASS are highly variable. Consequently, confounding factors can lead to significant delays for the final and definitive diagnosis of ASS. Therefore, ASS should be considered a differential diagnosis in patients with initial symptoms of joint, lung, and/or muscle involvements, as well as fever, mechanic's hands, and/or Raynaud's phenomenon manifestations.


Mitigation of prion infectivity and conversion capacity by a simulated natural process--repeated cycles of drying and wetting.
Prions enter the environment from infected hosts, bind to a wide range of soil and soil minerals, and remain highly infectious. Environmental sources of prions almost certainly contribute to the transmission of chronic wasting disease in cervids and scrapie in sheep and goats. While much is known about the introduction of prions into the environment and their interaction with soil, relatively little is known about prion degradation and inactivation by natural environmental processes. In this study, we examined the effect of repeated cycles of drying and wetting on prion fitness and determined that 10 cycles of repeated drying and wetting could reduce PrP(Sc) abundance, PMCA amplification efficiency and extend the incubation period of disease. Importantly, prions bound to soil were more susceptible to inactivation by repeated cycles of drying and wetting compared to unbound prions, a result which may be due to conformational changes in soil-bound PrP(Sc) or consolidation of the bonding between PrP(Sc) and soil. This novel finding demonstrates that naturally-occurring environmental process can degrade prions.


Density trends and demographic signals uncover the long-term impact of transmissible cancer in Tasmanian devils.
1. Monitoring the response of wild mammal populations to threatening processes is fundamental to effective conservation management. This is especially true for infectious diseases, which may have dynamic and therefore unpredictable interactions with their host. 2. We investigate the long-term impact of a transmissible cancer, devil facial tumour disease (DFTD), on the endemic Tasmanian devil. We analyse trends in devil spot-light counts and density across the area impacted by the disease. We investigate the demographic parameters which might be driving these trends, and use spatial capture-recapture models to examine whether DFTD has affected home range size. 3. We found that devils have declined by an average of 77% in areas affected by DFTD, and that there is a congruent trend of ongoing small decline in spotlight counts and density estimates. Despite this, devils have persisted to date within each of nine monitoring sites. One site is showing as yet unexplained small increases in density 8-10 years after the emergence of DFTD. 4. We also found the prevalence of DFTD has not abated despite large declines in density and that diseased sites continue to be dominated by young devils. The long-term impact of the disease has been partially offset by increased fecundity in the form of precocial breeding in 1-year-old females, and more pouch young per female in diseased sites. The lower densities resulting from DFTD did not affect home range size. 5. Synthesis and applications. Transmission of devil facial tumour disease continues despite large declines in devil density over multiple generations. Plasticity in life history traits has ameliorated the impact of devil facial tumour disease, however broad-scale trends in density show ongoing decline. In light of this, devil facial tumour disease and the impact of stochastic events on the reduced densities wrought by the disease, continue to threaten devils. In the absence of methods to manage disease in wild populations, we advocate managing the low population densities resulting from disease rather than disease per se.


Health, sleep, and professional career in female white-collar workers back to work after long-term sick-listing due to minor mental disorders.
This study is a 3-year follow up of female white-collar workers, who were on long-term sick leave in 2004 due to stress-related and minor mental disorders. The aim is to show what promotes return-to-work (RTW) and the impact of a long period of sickness absence on professional career. The study includes a cohort of 233 women who were currently on medically certified sick leave lasting ≥90 days in 2004. A postal questionnaire was sent out after 34 months, regarding self-rated health, quality of sleep, sick-listing status, occupational status, etc. After 34 months, 69% of the women had fully returned to working life. One of the most salient findings is that almost half of those had changed jobs and more than a third were in a new profession. Those who were back in working life rated less negative consequences of the long-term sick-listing on their professional career and their quality of sleep was better (OR 2.90, 95% CI 1.50-5.60 "sleeping all night"). Self-rated health did not show significant association with RTW (OR 2.83, 95% CI 0.91-8.77). Those who had returned to working life reported more control over their lives (OR 1.98, 95% CI 1.01-3.88). The findings imply that, in work health promotion and rehabilitation and efforts to prevent sickness absence due to stress-related disorders, important factors to be considered are job mobility, changes in present work, improved sleep, and control over one's own life.


Moderate dietary vitamin B-6 restriction raises plasma glycine and cystathionine concentrations while minimally affecting the rates of glycine turnover and glycine cleavage in healthy men and women.
Glycine is a precursor of purines, protein, glutathione, and 1-carbon units as 5,10-methylenetetrahydrofolate. Glycine decarboxylation through the glycine cleavage system (GCS) and glycine-serine transformation by serine hydroxymethyltransferase (SHMT) require pyridoxal 5'-phosphate (PLP; active form of vitamin B-6) as a coenzyme. The intake of vitamin B-6 is frequently low in humans. Therefore, we determined the effects of vitamin B-6 restriction on whole-body glycine flux, the rate of glycine decarboxylation, glycine-to-serine conversion, use of glycine carbons in nucleoside synthesis, and other aspects of 1-carbon metabolism. We used a primed, constant infusion of [1,2-(13)C(2)]glycine and [5,5,5-(2)H(3)]leucine to quantify in vivo kinetics in healthy adults (7 males, 6 females; 20-39 y) of normal vitamin B-6 status or marginal vitamin B-6 deficiency. Vitamin B-6 restriction lowered the plasma PLP concentration from 55 +/- 4 nmol/L (mean +/- SEM) to 23 +/- 1 nmol/L (P < 0.0001), which is consistent with marginal deficiency, whereas the plasma glycine concentration increased (P < 0.01). SHMT-mediated conversion of glycine to serine increased from 182 +/- 7 to 205 +/- 9 micromol x kg(-1) x h(-1) (P < 0.05), but serine production using a GCS-derived 1-carbon unit (93 +/- 9 vs. 91 +/- 6 micromol x kg(-1) x h(-1)) and glycine cleavage (163 +/- 11 vs. 151 +/- 8 micromol x kg(-1) x h(-1)) were not changed by vitamin B-6 restriction. The GCS produced 1-carbon units at a rate (approximately 140-170 micromol x kg(-1) x h(-1)) that greatly exceeds the demand for remethylation and transmethylation processes (approximately 4-7 micromol x kg(-1) x h(-1)). We conclude that the in vivo GCS and SHMT reactions are quite resilient to the effects of marginal vitamin B-6 deficiency, presumably through a compensatory effect of increasing substrate concentration.


Dabigatran in atrial fibrillation: pharmacology and clinical trials.
The central pharmacologic approach to stroke prevention in atrial fibrillation has recently changed with the approval of dabigatran by the US Food and Drug Administration (FDA). Dabigatran is an oral anticoagulant that belongs to the class of direct thrombin inhibitors. Dabigatran has predictable pharmacokinetics, without significant drug and food interactions, rapid onset, and requires twice-daily administration without the need for monitoring. The only drug contraindicated with dabigatran is rifampin. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, dabigatran at a dose of 150 mg bid is statistically superior to warfarin in preventing strokes and systemic embolism in patients with atrial fibrillation and has a lower non-statistically significant rate of major bleeding. There is significantly lower rate of intracranial bleeding. The FDA recently approved the 150-mg bid dose for patients with a creatinine clearance above 30 mL/min and 75 mg bid for use in patients with a creatinine clearance of 15 to 30 mL/min. A prespecified subanalysis in both warfarin-experienced and warfarin-naive subgroups mirrored the main results. For cardioversions, a post hoc analysis showed that the rate of thromboembolism and major bleeding within 30 days of cardioversion for dabigatran 150 mg bid was low and comparable to that of warfarin, with or without transesophageal echocardiography guidance. Dabigatran, therefore, is the first novel anticoagulant to offer an alternative to warfarin.


Influence of Cassia grandis galactomannan on the properties of sponge cakes: a substitute for fat.
Here we have proposed to evaluate potential replacers of fat in sponge cake formulations. Our investigation consisted initially of monitoring the physical-chemical changes in sponge cake batters caused by gradually replacing the vegetable fat/margarine of a control sample (standard sponge cake recipe) with galactomannan extracted from the seeds of Cassia grandis. Several samples were prepared where a 100% concentration of vegetable fat was substituted with galactomannan in different concentrations. We then compared both microscopic and macroscopic characteristics of pure fat cake batter formulations and formulations with controlled fat/galactomannan mixtures. At this first stage, rheometry and optical microscopy were employed to characterize the rheological features and air bubble distribution in the batters. In the second stage, the effects of fat substitution with galactomannan, now for the final baked cakes, were also monitored. Scanning electron microscopy (SEM) and standard sensorial tests were performed in order to correlate the final color, texture, and taste characteristics of the final sponge cake and those characteristics obtained initially for the batter. According to the statistical analysis of the data, a 75% fat replacement with galactomannan at only 1.0% concentration was achieved, while successfully maintaining surface microstructure, sensory acceptance, and rheological behavior similar to the original formulation containing only fat. Regarding vegetable fat substitution with galactomannan, our results allow us to conclude that rheometry and bubble distribution tests on the initial batters are useful indicators of the final cake quality.


Grain boundary melting in ice.
We describe an optical scattering study of grain boundary premelting in water ice. Ubiquitous long ranged attractive polarization forces act to suppress grain boundary melting whereas repulsive forces originating in screened Coulomb interactions and classical colligative effects enhance it. The liquid enhancing effects can be manipulated by adding dopant ions to the system. For all measured grain boundaries this leads to increasing premelted film thickness with increasing electrolyte concentration. Although we understand that the interfacial surface charge densities q(s) and solute concentrations can potentially dominate the film thickness, we cannot directly measure them within a given grain boundary. Therefore, as a framework for interpreting the data we consider two appropriate q(s) dependent limits; one is dominated by the colligative effect and other is dominated by electrostatic interactions.


Influence of calcium in extracellular DNA mediated bacterial aggregation and biofilm formation.
Calcium (Ca(2+)) has an important structural role in guaranteeing the integrity of the outer lipopolysaccharide layer and cell walls of bacterial cells. Extracellular DNA (eDNA) being part of the slimy matrix produced by bacteria promotes biofilm formation through enhanced structural integrity of the matrix. Here, the concurrent role of Ca(2+) and eDNA in mediating bacterial aggregation and biofilm formation was studied for the first time using a variety of bacterial strains and the thermodynamics of DNA to Ca(2+) binding. It was found that the eDNA concentrations under both planktonic and biofilm growth conditions were different among bacterial strains. Whilst Ca(2+) had no influence on eDNA release, presence of eDNA by itself favours bacterial aggregation via attractive acid-base interactions in addition, its binding with Ca(2+) at biologically relevant concentrations was shown further increase in bacterial aggregation via cationic bridging. Negative Gibbs free energy (ΔG) values in iTC data confirmed that the interaction between DNA and Ca(2+) is thermodynamically favourable and that the binding process is spontaneous and exothermic owing to its highly negative enthalpy. Removal of eDNA through DNase I treatment revealed that Ca(2+) alone did not enhance cell aggregation and biofilm formation. This discovery signifies the importance of eDNA and concludes that existence of eDNA on bacterial cell surfaces is a key facilitator in binding of Ca(2+) to eDNA thereby mediating bacterial aggregation and biofilm formation.


Molecular characterization of ThIPK2, an inositol polyphosphate kinase gene homolog from Thellungiella halophila, and its heterologous expression to improve abiotic stress tolerance in Brassica napus.
Inositol polyphosphate kinases play important roles in diverse cellular processes. In this study, the function of an inositol polyphosphate kinase gene homolog named ThIPK2 from a dicotyledonous halophyte Thellungiella halophila was investigated. The deduced translation product (ThIPK2) shares 85% identity with the Arabidopsis inositol polyphosphate kinase AtIPK2beta. Transient expression of ThIPK2-YFP fusion protein in tobacco (Nicotiana tabacum) protoplasts indicates that the protein is localized to the nucleus and plasma membrane, with a minor localization to the cytosol. Heterologous expression of ThIPK2 in ipk2Delta (also known as arg82Delta), a yeast mutant strain that lacks inositol polyphosphate multikinase (Ipk2) activity, rescued the mutant's salt-, osmotic- and temperature-sensitive growth defects. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) revealed ubiquitous expression of ThIPK2 in various tissues, including roots, rosette leaves, cauline leaves, stem, flowers and siliques, and shoot ThIPK2 transcript was strongly induced by NaCl or mannitol in T. halophila as exhibited by real-time PCR analysis. Transgenic expression of ThIPK2 in Brassica napus led to significantly improved salt-, dehydration- and oxidative stress resistance. Furthermore, the transcripts of various stress responsive marker genes increased in ThIPK2 transgenic plants under salt stress condition. These results suggest that ThIPK2 is involved in plant stress responses, and for the first time demonstrate that ThIPK2 could be a useful candidate gene for improving drought and salt tolerance in important crop plants by genetic transformation.


A Cochrane review of manipulation and mobilization for mechanical neck disorders.
Our systematic review of randomized trials assessed whether manipulation and mobilization relieve pain or improve function/disability, patient satisfaction, and global perceived effect in adults with mechanical neck disorders. Neck disorders are common, disabling, and costly. Computerized bibliographic databases were searched up to March 2002. Two independent reviewers conducted study selection, data abstraction, and methodologic quality assessment. Relative risk and standardized mean differences were calculated. In the absence of heterogeneity, pooled effect measures were calculated using a random effects model. Of the 33 selected trials, 42% were high quality trials. Single or multiple (3-11) sessions of manipulation or mobilization showed no benefit in pain relief when assessed against placebo, control groups, or other treatments for acute/subacute/chronic mechanical neck disorders with or without headache. There was strong evidence of benefit favoring multimodal care (mobilization and/or manipulation plus exercise) over a waiting list control for pain reduction [pooled standardized mean differences -0.85 (95% CI: -1.20 to -0.50)], improvement in function [pooled SMD -0.57 (95% CI: -0.94 to -0.21)] and global perceived effect [standardized mean differences -2.73 (95% CI: -3.30 to -2.16)] for subacute/chronic mechanical neck disorders with or without headache. Mobilization and/or manipulation when used with exercise are beneficial for persistent mechanical neck disorders with or without headache. Done alone, manipulation and/or mobilization were not beneficial; when compared to one another, neither was superior. There was insufficient evidence available to draw conclusions for neck disorder with radicular findings. Factorial design would help determine the active agent(s) within a treatment mix.


Adhesion molecules in inflammatory bowel disease.
The ability of leucocytes to adhere to endothelium is essential for leucocyte migration into inflammatory sites. Some of these adhesion molecules are released from the cell surface and can be detected in serum. The soluble adhesion molecules intercellular adhesion molecule 1 (ICAM-1), E selectin, and vascular cell adhesion molecule 1 (VCAM-1) were studied in the serum of patients with Crohn's disease, ulcerative colitis, and healthy controls. A second blood sample was taken from patients with active disease after one month of treatment and a third two months after remission was achieved. Tissue expression of the same adhesion molecules was studied by immunohistology. Circulating VCAM-1 concentrations were significantly higher in patients with active ulcerative colitis (n = 11, median = 165 U/ml) compared with patients with inactive ulcerative colitis (n = 10, median = 117 U/ml, p < 0.005), active Crohn's disease (n = 12, median = 124 U/ml, p < 0.02), and controls (n = 90, median = 50 U/ml, p < 0.0001). Within each disease group there were no significant differences in E selectin or ICAM-1 concentrations between the active and inactive states, however, patients with active Crohn's disease had significantly higher ICAM-1 concentrations (n = 12, median = 273 ng/ml) than controls (n = 28, median = 168, p < 0.003). VCAM-1 concentrations fell significantly from pretreatment values to remission in active ulcerative colitis (p < 0.01). In Crohn's disease there was a significant fall in ICAM-1 both during treatment (p < 0.01) and two months after remission (p < 0.02). Vascular expression of ICAM-1 occurred more often and was more intense in inflamed tissue sections from patients with ulcerative colitis and Crohn's disease than from controls. Vascular labelling with antibody to E selectin also occurred more often in patients with active inflammatory bowel disease. In conclusion, increased circulating concentrations of selected adhesion molecules are associated with inflammatory bowel disease. There is also evidence of local upregulation, particularly of ICAM-1. Differential expression of adhesion molecules in tissue may play a part in the initiation of leucocyte migration and local inflammation; the function of circulating adhesion molecules is unknown, but may play a physiological part in blocking adhesion.


Normal and language-impaired children's use of reference: syntactic versus pragmatic processing.
The present study investigates children's syntactic and pragmatic processing when specifying referents presented in short video clips. Within Relevance theory, the assumption of 'optimal relevance' implies that utterances are intended to involve the least processing effort on the part of the listener. In the present context, lexically specified NPs are assumed to be more in line with optimal relevance than pronouns. Subjects were 48 normally developing children aged 3;4-8;10 and 30 SLI children aged 5;1-8;9, divided into a low and a normal MLU group. Children's responses were coded according to levels of pragmatic processing and syntactic positions. Normally developing children's referent specifications were found to be increasingly relevant with increasing age. Differences between SLI and normal children were only found for the low MLU group with SLI who used fewer pronouns than the younger children, thereby showing that syntactic limitations alone cannot account for children's specification of referents.


The small GTP-binding protein RacG regulates uroid formation in the protozoan parasite Entamoeba histolytica.
Entamoeba histolytica is a protozoan parasite that invades human intestine leading to ulceration and destruction of tissue. Amoebic movement and phagocytosis of human cells is accompanied by characteristic changes in cell morphology. Amoebae become polarized, developing a frontal pseudopod and a well-defined rear zone of membrane accumulation designated the uroid. In motile eukaryotic cells, a phenomenon that contributes to movement is the capping of receptors at the cell surface. During the capping process, E. histolytica concentrates ligand-receptor complexes in the uroid. Interestingly, some of these surface receptors are involved in the survival of the parasite. While looking for regulators of capping and uroid formation, we identified RacG, an E. histolytica protein that is homologous to human Rac1. This protein belongs to the Rac subfamily of small GTPases implicated in interactions between the actin cytoskeleton and the membrane of mammalian cells. Cloning of the EhracG gene and analysis of the protein activity either in murine fibroblasts or in E. histolytica revealed that EhRacG induces a characteristic Rac phenotype. When expressed in amoebae, an EhRacG-V12 mutant protein not only deregulated cell polarity, but also caused a defect in cytokinesis. Analysis of the cytoskeleton in amoebae bearing this mutant revealed that F-actin concentrated at the periphery of the cell. In addition, the number and localization of uroids were modified. These results suggest a role for EhRacG in amoebic morphogenesis and cytokinesis.