Forgetting ourselves: epistemic costs and ethical concerns in mindfulness exercises.
Mindfulness exercises are presented as being compatible with almost any spiritual, religious or philosophical beliefs. In this paper, we argue that they in fact involve imagining and conceptualising rather striking and controversial claims about the self, and the self's relationship to thoughts and feelings. For this reason, practising mindfulness exercises is likely to be in tension with many people's core beliefs and values, a tension that should be treated as a downside of therapeutic interventions involving mindfulness exercises, not unlike a side effect. Clients ought to be informed of these metaphysical aspects of the exercises, and mental health providers ought to take them into account in assessing which course of treatment to recommend. Given these concerns, the casual way in which mindfulness exercises are presently distributed by mental health providers to the general public is inappropriate.


[Organ and tissue regeneration in lower vertebrate animals during space flight and after its completion].
The most important data obtained in studies of the influence of space flight factors on the limb and lens regeneration in the newt Pleurodeles waltlii have been summarized. Regeneration of these organs under the conditions of space flight and after its termination proceeded just as on the ground. However after the 7th, 13th and 16th days of space flight, a trend was shown toward acceleration of the limb and lens regenerates development according to the regeneration stages and synchronization of the achieved stages, which was accompanied in some cases by an increased proliferative activity of the regenerate cells. It was shown that in two groups of animals operated before the 16-day space flight (I) and just after its termination (II) accelerated development of the limb and lens regenerates was observed. In group II, at the large bud stage, the index of 3H-thymidine labeled blastema cells was more than twice that in the control. The size of regenerates in groups I and II exceeded reliably those in the control. These results suggest a prolonged effect of space flight factors on the limb and lens regeneration. It was also shown that the capacity of the muscle minced 14 days before the flight for regeneration was not suppressed, although somewhat decreased. An electron microscopic study showed degenerative-atrophic changes in the intact hind limb muscle after the 16-day space flight. We believe that the phenomenon of synchronization and accelerated regeneration of the limb and lens observed in the most experiments are due to the effect of microgravity on the animals.


The Amazon Project: helping the patient to become an instrument of her own recovery.
The Amazon Project combines science, myth, and theater to explore problems linked to cancer and its surgical management in women from a social, political, and cultural point of view. This Project is concerned with change in the hope that one day it will be possible to discuss, along with the Science of Medicine, the Science of Patients as well.


Coping with potentially incompatible identities: accounts of religious, ethnic, and sexual identities from British Pakistani men who identify as Muslim and gay.
This study explores how a group of young British Muslim gay men (BMGM) of Pakistani background in non-gay affirmative religious contexts understood and defined their sexual, religious, and ethnic identities, focusing upon the negotiation and construction of these identities and particularly upon strategies employed for coping with identity threat. A total of 12 BMGM were interviewed using a semi-structured interview schedule. Transcripts were subjected to qualitative thematic analysis as described by Braun and Clarke. The aim was to explore participants' lived experiences through the interpretive lens of identity process theory. Four superordinate themes are reported, entitled 'I'm gay because … ': making sense of gay identity, 'It's all about temptation': invoking religious discourses to explain sexual identity, 'Going against God': fear of divine retribution, 'It's easier to be gay here': external attributions and British national identity. The data suggest the existence of an additional identity principle, which is referred to as the psychological coherence principle. This motive represents the need to ensure a sense of coherence between existing identities, and we discuss how individuals may adopt strategies to deal with threats to the principle.


Effect of expressing the water channel aquaporin-1 on the CO2 permeability of Xenopus oocytes.
It is generally accepted that gases such as CO2 cross cell membranes by dissolving in the membrane lipid. No role for channels or pores in gas transport has ever been demonstrated. Here we ask whether expression of the water channel aquaporin-1 (AQP1) enhances the CO2 permeability of Xenopus oocytes. We expressed AQP1 in Xenopus oocytes by injecting AQP1 cRNA, and we assessed CO2 permeability by using microelectrodes to monitor the changes in intracellular pH (pHi) produced by adding 1.5% CO2/10 mM HCO3- to (or removing it from) the extracellular solution. Oocytes normally have an undetectably low level of carbonic anhydrase (CA), which eliminates the CO2 hydration reaction as a rate-limiting step. We found that expressing AQP1 (vs. injecting water) had no measurable effect on the rate of CO2-induced pHi changes in such low-CA oocytes: adding CO2 caused pHi to fall at a mean initial rate of 11.3 x 10(-4) pH units/s in control oocytes and 13.3 x 10(-4) pH units/s in oocytes expressing AQP1. When we injected oocytes with water, and a few days later with CA, the CO2-induced pHi changes in these water/CA oocytes were more than fourfold faster than in water-injected oocytes (acidification rate, 53 x 10(-4) pH units/s). Ethoxzolamide (ETX; 10 microM), a membrane-permeant CA inhibitor, greatly slowed the pHi changes (16.5 x 10(-4) pH units/s). When we injected oocytes with AQP1 cRNA and then CA, the CO2-induced pHi changes in these AQP1/CA oocytes were approximately 40% faster than in the water/CA oocytes (75 x 10(-4) pH units/s), and ETX reduced the rates substantially (14.7 x 10(-4) pH units/s). Thus, in the presence of CA, AQP1 expression significantly increases the CO2 permeability of oocyte membranes. Possible explanations include 1) AQP1 expression alters the lipid composition of the cell membrane, 2) AQP1 expression causes overexpression of a native gas channel, and/or 3) AQP1 acts as a channel through which CO2 can permeate. Even if AQP1 should mediate a CO2 flux, it would remain to be determined whether this CO2 movement is quantitatively important.


Angiotensin-I converting enzyme inhibitory and antioxidant activities of peptide fractions extracted by ultrafiltration of cowpea Vigna unguiculata hydrolysates.
Enzymatic proteolysis of food proteins is used to produce peptide fractions with the potential to act as physiological modulators. Fractionation of these proteins by ultrafiltration results in fractions rich in small peptides with the potential to act as functional food ingredients. The present study investigated the angiotensin-I converting enzyme (ACE-I) inhibitory and antioxidant activities for hydrolysates produced by hydrolyzing Vigna unguiculata protein extract as well as ultrafiltered peptide fractions from these hydrolysates. Alcalase(®), Flavourzyme(®) and pepsin-pancreatin were used to produce extensively hydrolyzed V. unguiculata protein extract. Degree of hydrolysis (DH) differed between the enzymatic systems and ranged from 35.7% to 58.8%. Fractionation increased in vitro biological activities in the peptide fractions, with IC(50) (hydrolysate concentration in µg protein mL(-1) required to produce 50% ACE inhibition) value ranges of 24.3-123 (Alcalase hydrolysate, AH), 0.04-170.6 (Flavourzyme hydrolysate; FH) and 44.7-112 (pepsin-pancreatin hydrolysate, PPH) µg mL(-1), and TEAC (Trolox equivalent antioxidant coefficient) value ranges of 303.2-1457 (AH), 357.4-10 211 (FH) and 267.1-2830.4 (PPH) mmol L(-1) mg(-1) protein. The results indicate the possibility of obtaining bioactive peptides from V. unguiculata proteins by means of a controlled protein hydrolysis using Alcalase(®), Flavourzyme(®) and pepsin-pancreatin. The V. unguiculata protein hydrolysates and their corresponding ultrafiltered peptide fractions might be utilized for physiologically functional foods with antihypertensive and antioxidant activities.


[Clinical aspects and complete blood counts in children exposed to HIV-1: comparison between infected patients and seroreverters]
OBJECTIVE: To analyze the evolution of clinical and hematological aspects of children exposed to the vertical transmission of HIV-1, comparing infected patients with uninfected ones or seroreverters. METHODS: Prospective, descriptive, longitudinal study. We analyzed 79 children born from HIV-1 infected mothers, under clinical follow up from March, 1996 until November, 1997, at the Immunodeficiency division of the Hospital de Clínicas da Unicamp (State University Hospital of Campinas). RESULTS: Failure to thrive was observed in both groups, but was greater among seroreverters. Among the infected children, 23 mothers did not use AZT during pregnancy, 16 of them (61.5%) had been breastfed, four were classified into clinical category N, seven into A and fifteen into B. Clinical manifestations in patients younger than one year were seen in 18 infected children (69.2%). Anemia was observed in 73.1% of the infected group and in 41.5% of the seroreverters (P<0.008). The comparison between the groups showed that the most common hematologic alterations in the infected children was microcytosis and hypochromia (P<0.05), lymphopenia between 15 and 18 months (P<0.05), monocytosis between 9 and 12 months (P<0.05) and a tendency towards high ferritin levels, with no statistical significance. CONCLUSIONS: Microcytic and hypochromic anemia were observed in both groups: iron deficiency in the uninfected children, and chronic disease anemia in the infected ones. The infected children presented with monocytosis and lymphopenia at an earlier stage.


Can AFLP genome scans detect small islands of differentiation? The case of shell sculpture variation in the periwinkle Echinolittorina hawaiiensis.
Genome scans have identified candidate regions of the genome undergoing selection in a wide variety of organisms, yet have rarely been applied to broadly dispersing marine organisms experiencing divergent selection pressures, where high recombination rates can reduce the extent of linkage disequilibrium (LD) and the ability to detect genomic regions under selection. The broadly dispersing periwinkle Echinolittorina hawaiiensis exhibits a heritable shell sculpture polymorphism that is correlated with environmental variation. To elucidate the genetic basis of phenotypic variation, a genome scan using over 1000 AFLP loci was conducted on smooth and sculptured snails from divergent habitats at four replicate sites. Approximately 5% of loci were identified as outliers with Dfdist, whereas no outliers were identified by BayeScan. Closer examination of the Dfdist outliers supported the conclusion that these loci were false positives. These results highlight the importance of controlling for Type I error using multiple outlier detection approaches, multitest corrections and replicate population comparisons. Assuming shell phenotypes have a genetic basis, our failure to detect outliers suggests that the life history of the target species needs to be considered when designing a genome scan.


Aberrant neuronal activity-induced signaling and gene expression in a mouse model of RASopathy.
Noonan syndrome (NS) is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and regulators of the Ras signaling pathway. Approximately 50% of NS cases are caused by mutations in PTPN11. However, the molecular mechanisms underlying cognitive impairments in NS patients are still poorly understood. Here, we report the generation and characterization of a new conditional mouse strain that expresses the overactive Ptpn11D61Y allele only in the forebrain. Unlike mice with a global expression of this mutation, this strain is viable and without severe systemic phenotype, but shows lower exploratory activity and reduced memory specificity, which is in line with a causal role of disturbed neuronal Ptpn11 signaling in the development of NS-linked cognitive deficits. To explore the underlying mechanisms we investigated the neuronal activity-regulated Ras signaling in brains and neuronal cultures derived from this model. We observed an altered surface expression and trafficking of synaptic glutamate receptors, which are crucial for hippocampal neuronal plasticity. Furthermore, we show that the neuronal activity-induced ERK signaling, as well as the consecutive regulation of gene expression are strongly perturbed. Microarray-based hippocampal gene expression profiling revealed profound differences in the basal state and upon stimulation of neuronal activity. The neuronal activity-dependent gene regulation was strongly attenuated in Ptpn11D61Y neurons. In silico analysis of functional networks revealed changes in the cellular signaling beyond the dysregulation of Ras/MAPK signaling that is nearly exclusively discussed in the context of NS at present. Importantly, changes in PI3K/AKT/mTOR and JAK/STAT signaling were experimentally confirmed. In summary, this study uncovers aberrant neuronal activity-induced signaling and regulation of gene expression in Ptpn11D61Y mice and suggests that these deficits contribute to the pathophysiology of cognitive impairments in NS.


Public health risks of ostrich and crocodile meat.
This paper discusses the infectious agents and chemical substances potentially capable of contaminating the meat of ostriches and crocodiles and which thus pose a danger to human handlers and consumers. For ostrich meat, there is no danger from Crimean-Congo haemorrhagic fever or spongiform encephalopathy. Contamination of ostrich meat with salmonellae, chlamydia, pasteurellae, mycobacteria and erysipelas might be possible, but has never been reported. No parasites are known which could be transmitted through ostrich meat to human consumers. Residues from growth hormones, antibiotics and acaricides are potential public health hazards. For crocodile meat, there is a distinct possibility of contamination with salmonellae, depending on housing, feed, slaughter technique and hygiene practices under which the animal is reared. Chlamydial infections are common on some crocodile farms in southern Africa. Mycobacteriosis is extremely rare. Tapeworm cysts have been found in crocodile meat in two cases only. Trichinellosis has been reported on several crocodile farms in Zimbabwe. A generalised coccidiosis with invasion of organs and tissues has been seen in several species of crocodiles, but should present no danger to consumers.


Genomic Bayesian functional regression models with interactions for predicting wheat grain yield using hyper-spectral image data.
Modern agriculture uses hyperspectral cameras that provide hundreds of reflectance data at discrete narrow bands in many environments. These bands often cover the whole visible light spectrum and part of the infrared and ultraviolet light spectra. With the bands, vegetation indices are constructed for predicting agronomically important traits such as grain yield and biomass. However, since vegetation indices only use some wavelengths (referred to as bands), we propose using all bands simultaneously as predictor variables for the primary trait grain yield; results of several multi-environment maize (Aguate et al. in Crop Sci 57(5):1-8, 2017) and wheat (Montesinos-López et al. in Plant Methods 13(4):1-23, 2017) breeding trials indicated that using all bands produced better prediction accuracy than vegetation indices. However, until now, these prediction models have not accounted for the effects of genotype × environment (G × E) and band × environment (B × E) interactions incorporating genomic or pedigree information. In this study, we propose Bayesian functional regression models that take into account all available bands, genomic or pedigree information, the main effects of lines and environments, as well as G × E and B × E interaction effects. The data set used is comprised of 976 wheat lines evaluated for grain yield in three environments (Drought, Irrigated and Reduced Irrigation). The reflectance data were measured in 250 discrete narrow bands ranging from 392 to 851 nm (nm). The proposed Bayesian functional regression models were implemented using two types of basis: B-splines and Fourier. Results of the proposed Bayesian functional regression models, including all the wavelengths for predicting grain yield, were compared with results from conventional models with and without bands. We observed that the models with B × E interaction terms were the most accurate models, whereas the functional regression models (with B-splines and Fourier basis) and the conventional models performed similarly in terms of prediction accuracy. However, the functional regression models are more parsimonious and computationally more efficient because the number of beta coefficients to be estimated is 21 (number of basis), rather than estimating the 250 regression coefficients for all bands. In this study adding pedigree or genomic information did not increase prediction accuracy.


Pastoral Herding Strategies and Governmental Management Objectives: Predation Compensation as a Risk Buffering Strategy in the Saami Reindeer Husbandry.
Previously it has been found that an important risk buffering strategy in the Saami reindeer husbandry in Norway is the accumulation of large herds of reindeer as this increases long-term household viability. Nevertheless, few studies have investigated how official policies, such as economic compensation for livestock losses, can influence pastoral strategies. This study investigated the effect of received predation compensation on individual husbandry units' future herd size. The main finding in this study is that predation compensation had a positive effect on husbandry units' future herd size. The effect of predation compensation, however, was nonlinear in some years, indicating that predation compensation had a positive effect on future herd size only up to a certain threshold whereby adding additional predation compensation had little effect on future herd size. More importantly, the effect of predation compensation was positive after controlling for reindeer density, indicating that for a given reindeer density husbandry units receiving more predation compensation performed better (measured as the size of future herds) compared to husbandry units receiving less compensation.


Insertions of hybrid P elements in the yellow gene of Drosophila cause a large variety of mutant phenotypes.
A series of yellow mutations associated with a great variety of tissue-specific phenotypes were obtained from several highly unstable Drosophila melanogaster strains carrying the gypsy-induced y2 allele. These mutations are caused by insertion of additional DNA sequences of variable size 69 bp upstream of the yellow transcription start site. These sequences are flanked by identical copies of a deleted 1.2-kb P element arranged in the same or inverted orientation. The central part of the inserted element consists of genomic sequences originating from different regions of the X chromosome. The mutant phenotype caused by these chimeric elements depends on the nature of the sequences present either in the P element or in the central part of the insertion, suggesting that these sequences are able to affect expression of the yellow gene. In addition, sequences present in the central region of the insertions strongly modify the effects of the gypsy-bound suppressor of Hairy-wing [su(Hw)] and modifier of mdg4 [mod(mdg4)] proteins on yellow transcription. Analyses of these mutations give new insights into the mechanisms by which su (Hw) and mod(mdg4) affect enhancer function.


Use of multiple orientation cues by juvenile loggerhead sea turtles Caretta caretta.
Although the orientation cues used by hatchling sea turtles have been studied extensively, little is known about the mechanisms of orientation and navigation that guide older turtles. To investigate the orientation cues used by juvenile loggerheads Caretta caretta L., captured turtles were tethered in a water-filled arena located outdoors. Turtles tested under these conditions established and maintained headings in specific directions in the absence of wave cues, familiar landmarks and chemical gradients. Distorting the magnetic field around the anterior part of a turtle's body did not disrupt orientation if vision remained unimpaired. Similarly, eliminating visual cues by attaching frosted goggles did not disrupt orientation if the magnetic environment was undisturbed. However, when turtles experienced a simultaneous disruption of magnetic and visual cues, their orientation was altered. These results imply that sea turtles, like migratory birds and homing pigeons, are able to maintain headings using multiple sources of directional information.


Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932.
AALL0932 evaluated two randomized maintenance interventions to optimize disease-free survival (DFS) while reducing the burden of therapy in children with newly diagnosed NCI standard-risk (SR) B-acute lymphoblastic leukemia (B-ALL). AALL0932 enrolled 9,229 patients with B-ALL; 2,364 average-risk (AR) patients were randomly assigned (2 × 2 factorial design) at the start of maintenance therapy to vincristine/dexamethasone pulses every 4 (VCR/DEX4) or every 12 (VCR/DEX12) weeks, and a starting dose of weekly oral methotrexate of 20 mg/m2 (MTX20) or 40 mg/m2 (MTX40). Five-year event-free survival and overall survival (OS) from enrollment (with 95% CIs), for all eligible and evaluable SR B-ALL patients (n = 9,226), were 92.0% (91.1% and 92.8%) and 96.8% (96.2% and 97.3%), respectively. The 5-year DFS and OS from the start of maintenance for randomly assigned AR patients were 94.6% (93.3% and 95.9%) and 98.5% (97.7% and 99.2%), respectively. The 5-year DFS and OS for patients randomly assigned to receive VCR/DEX4 (n = 1,186) versus VCR/DEX12 (n = 1,178) were 94.1% (92.2% and 96.0%) and 98.3% (97.2% and 99.4%) v 95.1% (93.3% and 96.9%) and 98.6% (97.7% and 99.6%), respectively (P = .86 and .69). The 5-year DFS and OS for AR patients randomly assigned to receive MTX20 versus MTX40 were 95.1% (93.3% and 96.8%) and 98.8% (97.9% and 99.7%) v 94.2% (92.2% and 96.1%) and 98.1% (97.0% and 99.2%), respectively (P = .92 and .89). The 0NCI-SR AR B-ALL who received VCR/DEX12 had outstanding outcomes despite receiving one third of the vincristine/dexamethasone pulses previously used as standard of care on Children's Oncology Group (COG) trials. The higher starting dose of MTX of 40 mg/m2/week did not improve outcomes when compared with 20 mg/m2/week. The decreased frequency of vincristine/dexamethasone pulses has been incorporated into frontline COG B-ALL trials to decrease the burden of therapy for patients and their families.


Cutaneous Melanomas Arising during Childhood: An Overview of the Main Entities.
Cutaneous melanomas are exceptional in children and represent a variety of clinical situations, each with a different prognosis. In congenital nevi, the risk of transformation is correlated with the size of the nevus. The most frequent type is lateral transformation, extremely rare before puberty, reminiscent of a superficial spreading melanoma (SSM) ex-nevus. Deep nodular transformation is much rarer, can occur before puberty, and must be distinguished from benign proliferative nodules. Superficial spreading melanoma can also arise within small nevi, which were not visible at birth, usually after puberty, and can reveal a cancer predisposition syndrome (CDKN2A or CDK4 germline mutations). Prognosis is correlated with classical histoprognostic features (mainly Breslow thickness). Spitz tumors are frequent in adolescents and encompass benign (Spitz nevus), intermediate (atypical Spitz tumor), and malignant forms (malignant Spitz tumor). The whole spectrum is characterized by specific morphology with spindled and epithelioid cells, genetic features, and an overall favorable outcome even if a regional lymph node is involved. Nevoid melanomas are rare and difficult to diagnose clinically and histologically. They can arise in late adolescence. Their prognosis is currently not very well ascertained. A small group of melanomas remains unclassified after histological and molecular assessment.


A(r)Ray of hope in analysis of the function and diversity of microbial communities.
The vast majority of microorganisms in the environment remain uncultured, and their existence is known only from sequences retrieved by PCR. As a consequence, our understanding of the ecological function of dominant microbial populations in the environment is limited. We will review microbial diversity studies and show that these may have moved from an extreme underestimation to a potentially severe overestimation of diversity. The latter results from a simple PCR-generated artifact: the cloning of heteroduplex molecules followed by Escherichia coli mismatch repair, which may generate an exponential increase in observed sequence diversity. However, simple modifications to current PCR amplification protocols minimize such artifactual sequences and may bring within our reach estimation of bacterial diversity in environmental samples. Such estimates may spur new culture-independent approaches based on genomic and microarray technology, allowing correlation of phylogenetic identity with the ecological function of unculturable organisms. In particular, we are developing a DNA microarray that enables identification of individual populations active in utilization of specific organic substrates. The array consists of 16S and 23S rDNA-targeted oligonucleotides and is hybridized to RNA extracted from samples incubated with (14)C-labeled organic substrates. Populations that metabolize the substrate can be identified by the radiolabel incorporated in their rRNA after only one to two cell doublings, ensuring realistic preservation of community structure. Thus, the microarray approach may provide a powerful means to link microbial community structure with in situ function of individual populations.


Effects of mutating leucine to threonine in the M2 segment of alpha1 and beta1 subunits of GABAA alpha1beta1 receptors.
The conserved leucine residues at the 9' positions in the M2 segments of alpha1 (L264) and beta1 (L259) subunits of the human GABAA receptor were replaced with threonine. Normal or mutant alpha1 subunits were co-expressed with normal or mutant beta1 subunits in Sf9 cells using the baculovirus/Sf9 expression system. Cells in which one or both subunits were mutated had a higher "resting" chloride conductance than cells expressing wild-type alpha1beta1 receptors. This chloride conductance was blocked by 10 mM penicillin, a recognized blocker of GABAA channels, but not by bicuculline (100 microm) or picrotoxin (100 microm) which normally inhibit the chloride current activated by GABA: nor was it potentiated by pentobarbitone (100 microM). In cells expressing wild-type beta1 with mutated alpha1 subunits, an additional chloride current could be elicited by GABA but the rise time and decay were slower than for wild-type alpha1beta1 receptors. In cells expressing mutated beta1 subunits with wild-type or mutated alpha1 subunits (alphabeta(L9'T) and alpha(L9'T)beta(L9'T)), no response to GABA could be elicited: this was not due to an absence of GABAA receptors in the plasmalemma because the cells bound [3H]-muscimol. It was concluded that in GABAA channels containing the L9'T mutation in the beta1 subunit, GABA-binding does not cause opening of channels, and that the L9'T mutation in either or both subunits gives an open-channel state of the GABAA receptor in the absence of ligand.


Decreased Mean Platelet Volume is Associated with Cervical Cancer Development
Background: Cervical cancer is the most common gynecological malignant disorder worldwide. Activated platelets play a key role in cancer development and progression. Mean platelet volume (MPV) is an early indicator of platelet activation. The aim of the present study was to evaluate MPV levels in patients with cervical cancer. Materials and methods: A total of 181 patients with cervical cancer and 181 controls between January 2015 and June 2015 were included in the study. Patient characteristics and hematologic test data at initial diagnosis were collected and odds ratios (ORs) and 95% confidence intervals (CIs) for risk of cervical cancer were calculated using multivariate logistic regression analyses across MPV quartiles. Results: MPV levels were decreased in patients with cervical cancer compared with control subjects. A significant correlation between MPV and FIGO stage was found. Moreover, after adjusting for other risk factors, the ORs (95%CIs) for cervical cancer according to MPV quartiles were 4.450 (1.975-10.026), 2.505 (1.206-5.202), 0.573 (0.261-1.259), and 1.000, respectively. Conclusions: MPV was found to be independently associated with the presence of cervical cancer. Our results suggest that MPV could be potential diagnostic screening tool.


Composition of free and adherent ruminal bacteria: inaccuracy of the microbial nutrient supply estimates obtained using free bacteria as reference samples and (15)N as the marker.
Previous studies have indicated that (15)N enrichment of solid-associated bacteria (SAB) may be predicted from the same value in liquid-associated bacteria (LAB). The aims of this study were to confirm this and to measure the error in the nutrient supply from SAB, when LAB are used as the reference sample. For this purpose, the chemical and amino acid (AA) compositions of both the bacterial populations were studied in four experiments carried out on different groups of three rumen cannulated wethers. Diets (one in Experiments 1 and 4 and three in Experiments 2 and 3) had forage-to-concentrate ratios (dry matter (DM) basis) between 2 : 1 and 40 : 60, and were consumed at intake levels between 40 and 75 g DM/kg (BW)(0.75). The bacteria samples were isolated after continuous infusion of ((15)NH(4))(2)SO(4) (40, 18, 30 and 25 mg (15)N/day, in Experiments 1 to 4, respectively) for at least 14 days. In all experiments, SAB had consistently higher concentrations of organic matter (826 v. 716 g/kg DM, as average) and total lipids (192 v. 95 g/kg DM, as average) than LAB. Similar CP concentrations of both populations were observed, except a higher concentration in SAB than in LAB in Experiment 3. A consistent (in Experiment 4 only as tendency) higher AA-N/total N ratio (on average 17.5%) was observed in SAB than in LAB. The (15)N enrichment in SAB was systematically lower than in LAB. On the basis of the results of all studies a close relationship was found between the (15)N enrichment in SAB and LAB, which was shown irrespective of experiments. This relationship was established from Experiments 1 and 2 and the above cited previous results (n = 20; P < 0.001; R(2) = 0.996), and then confirmed from the results of Experiments 3 and 4. These relationships between SAB and LAB demonstrate that CP supply from SAB is underevaluated by, on average, 21.2% when LAB are used as the reference. This underevaluation was higher for true protein and even higher for the lipid supply (32.5% and 59.6%, respectively, as an average of the four experiments). Large differences in AA profile were observed between SAB and LAB. The prediction equation obtained using (15)N as the marker may be used to correct the errors associated with the traditional use of LAB as the reference sample, and therefore to obtain more accurate estimates of the microbial nutrient supply to the ruminants.


Evaluation of an intravenous catheter for use in the horse.
A commercially available polyvinyl chloride intravenous catheter was studied in 9 horses for 3 to 10 days to evaluate the catheter's suitability for use in the horse, to develop a new insertion technique, and to establish a protocol for catheter care. Seven of the animals were clinically normal horses receiving parenteral nutrition; one was a horse with hypocalcemia receiving frequent intravenous injections of calcium gluconate, and one was a clinically normal horse receiving no infusions. The catheter dressings were changed every 48 hours, and an aspirate from the catheter and the catheter tip was cultured at the time of catheter removal. One catheter became infected following a break in the protocol. It was concluded that the polyvinyl catheter is suitable for use in the horse and that the proposed protocol for catheter insertion and maintenance may reduce the likelihood of complications such as catheter sepsis, thrombophlebitis, and embolism.


ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars.
The atypical protein kinase ALPK1 is activated by the bacterial nucleotide sugar ADP-heptose and phosphorylates TIFA to switch on a signaling pathway that combats microbial infection. In contrast, ALPK1 mutations cause two human diseases: the ALPK1[T237M] and ALPK1[Y254C] mutations underlie ROSAH syndrome (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis, and migraine headache), while the ALPK1[V1092A] mutation accounts for 45% of spiradenoma and 30% of spiradenocarcinoma cases studied. In this study, we demonstrate that unlike wild-type (WT) ALPK1, the disease-causing ALPK1 mutants trigger the TIFA-dependent activation of an NF-κB/activator protein 1 reporter gene in the absence of ADP-heptose, which can be suppressed by either of two additional mutations in the ADP-heptose binding site that prevent the activation of WT ALPK1 by ADP-heptose. These observations are explained by our key finding that although ALPK1[T237M] and ALPK1[V1092A] are activated by bacterial ADP-heptose, they can also be activated by nucleotide sugars present in human cells (UDP-mannose, ADP-ribose, and cyclic ADP-ribose) which can be prevented by disruption of the ADP-heptose binding site. The ALPK1[V1092A] mutant was also activated by GDP-mannose, which did not activate ALPK1[T237M]. These are new examples of disease-causing mutations permitting the allosteric activation of an enzyme by endogenous molecules that the WT enzyme does not respond to. We propose that the loss of the specificity of ALPK1 for bacterial ADP-heptose underlies ROSAH syndrome and spiradenoma/spiradenocarcinoma caused by ALPK1 mutation.


Non-muscle-invasive bladder cancer: a vision for the future.
The management of non-muscle-invasive bladder cancer (NMIBC) has evolved from the first reports on bladder endoscopy and transurethral resection to the introduction of adjuvant intravesical treatment. However, disease recurrence and progression remain an ongoing risk, placing a heavy burden on healthcare resources and on patients' quality of life. Deeper understanding of the molecular basis of the disease and developments in optics, lasers and computer science are already offering opportunities to revolutionize care and improve long-term prognosis. This article discusses developments likely to cause a paradigm shift towards the delivery of personalized care and reduced burden of disease in NMIBC.


Kisspeptin modulates sexual and emotional brain processing in humans.
Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behavior. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviors, and is a likely candidate system for the integration of behavior with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behavior. Using a combination of functional neuroimaging and hormonal and psychometric analyses, we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men. We demonstrated that kisspeptin administration enhanced limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin's enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance. In addition, kisspeptin administration attenuated negative mood. Collectively, our data provide evidence of an undescribed role for kisspeptin in integrating sexual and emotional brain processing with reproduction in humans. These results have important implications for our understanding of reproductive biology and are highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function. National Institute for Health Research (NIHR), Wellcome Trust (Ref 080268), and the Medical Research Council (MRC).


pH-dependent stability of neuroserpin is mediated by histidines 119 and 138; implications for the control of beta-sheet A and polymerization.
Neuroserpin is a member of the serpin superfamily. Point mutations in the neuroserpin gene underlie the autosomal dominant dementia, familial encephalopathy with neuroserpin inclusion bodies. This is characterized by the retention of ordered polymers of neuroserpin within the endoplasmic reticulum of neurons. pH has been shown to affect the propensity of several serpins to form polymers. In particular, low pH favors the formation of polymers of both alpha(1)-antitrypsin and antithrombin. We report here opposite effects in neuroserpin, with a striking resistance to polymer formation at acidic pH. Mutation of specific histidine residues showed that this effect is not attributable to the shutter domain histidine as would be predicted by analogy with other serpins. Indeed, mutation of the shutter domain His338 decreased neuroserpin stability but had no effect on the pH dependence of polymerization when compared with the wild-type protein. In contrast, mutation of His119 or His138 reduced the polymerization of neuroserpin at both acidic and neutral pH. These residues are at the lower pole of neuroserpin and provide a novel mechanism to control the opening of beta-sheet A and hence polymerization. This mechanism is likely to have evolved to protect neuroserpin from the acidic environment of the secretory granules.


[Postpartum anestrus in dairy cattle--a review].
In modern high-yielding dairy herds fertility is of major economic importance. In order to gain maximum profit, calving intervals should not exceed 365 days. The achievement of a 365-day calving interval requires an early resumption of ovarian activity, an excellent oestrus detection, and a high first-service conception rate. Especially the inability to detect oestrus and to mate the cows by 60 to 80 days after calving is a common problem among dairy farmers nowadays. In this article a review is given about the occurrence, causes, treatment and prevention of post-partum anoestrus in dairy cows.


Molecular markers of neuronal subpopulations in layers 4, 5, and 6 of cat primary visual cortex.
Cat primary visual cortex has been used as an immunogen to produce monoclonal antibodies that detect subpopulations of neurons. When tested by immunofluorescence on tissue sections of areas 17 and 18, 2 of these antibodies, VC1.1 and VC5.1, outlined a rare subpopulation of neurons located mainly in layer 4 but also in layers 5 and 6. Double-labeling immunofluorescence experiments in area 17 revealed that all VC1.1-reactive cells were also VC5.1-reactive and 83% of VC5.1-reactive cells were VC1.1-reactive, suggesting that the antibodies were reacting with the same subpopulation of cells. Both antibodies labeled similar or identical subpopulations of cells in other areas of the cat CNS, including the superior colliculus, parts of hippocampus, cerebellar deep nuclei, and rostral spinal cord. Neither antibody labeled cell bodies in the lateral geniculate nucleus. In the retina, VC1.1 labeled cell bodies and processes of some horizontal and amacrine cells, whereas VC5.1 labeled only ganglion cell axons. In the cerebellar cortex, the most prominent labeling of VC1.1 was of Purkinje cells, whereas that of VC5.1 was of Lugaro cells. Immunoblotting analyses of cat cortical homogenates demonstrated that VC1.1 recognized a major polypeptide band of Mr 95,000-105,000 and additional bands of Mr 145,000 and Mr 170,000. VC5.1 recognized bands of Mr 97,000 and Mr 150,000. Subcellular fractionation and extraction studies showed that the VC1.1 antigens were integral membrane proteins preferentially located in a synaptosomal plasma membrane fraction. The VC5.1 antigens were preferentially located in a soluble cytoplasmic or extracellular fraction. The results indicate that antibodies VC1.1 and VC5.1 recognize unique epitopes in the cat CNS and define a previously unrecognized subpopulation of cells in cat visual cortex.


Activation and infection of B cells by Epstein-Barr virus. Role of calcium mobilization and of protein kinase C translocation.
Both the activation and the transformation of human B cells by EBV were inhibited by either the Ca2+ channel blocking agent verapamil or the combination of theophylline and dibutyryl cAMP: the day 4 and day 20 peaks of [3H]TdR incorporation were abolished; the EBNA marker was not expressed by day 10; lymphoblastoid cell lines did not arise. Short term incubation of B cells with EBV or verapamil showed that the effect of verapamil was reversible and took place early in the interaction between EBV and B cells. The effect of EBV on the early metabolic events of B cell response was thus examined in the presence and in the absence of the drugs. Compared to anti-mu stimulation, supernatant of the transforming B95-8 strain as well as that of the non-transforming P3HR1 strain induced a drug sensitive increase of the free cytosolic Ca2+ concentration. This increase was associated with a protein kinase C translocation from the cytosol to a membrane bound compartment. Moreover, B95-8 supernatant induced phosphatidyl inositol metabolism by human B cells but at least four times less than that induced by anti-mu antibody. These metabolic events induced by EBV were significantly inhibited by anti-CD21 antibodies whereas anti-mu induced metabolic events were not. The infection of EBV negative Ramos cell line was prevented by verapamil or by theophylline + dibutyryl cAMP. Verapamil did not modify the density of EBV receptors but negatively interfered with the penetration of the virus into B cells. Thus B cell activation through the EBV receptor and virus penetration share a common metabolic pathway which is also used for transduction of the signal delivered through the membrane Ig.


[Comparison of urine proteome in rats intraperitoneally infected by different microorganisms].
Different microorganisms can cause intraperitoneal infection. This study was to distinguish different microbial infections by urine analysis. Rats were intraperitoneally injected with Escherichia coli, Staphylococcus aureus, and Candida albicans, separately. Urine samples were collected from rats at 0, 12, 36 and 72 h after infection. Urinary proteins were profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Compared with the control (without infection), a total of 69 differential proteins were identified in rats injected with E. coli. A total of 31 differences proteins were identified in rats injected with S. aureus. A total of 38 differential proteins were identified in rats injected with C. albicans. Urine proteome was different when rats were infected by different microorganisms, suggesting that urine may have the potential for differential diagnosis of different intraperitoneal infections.


Validation of suitable genes for normalization of diurnal gene expression studies in Chenopodium quinoa.
Quinoa depicts high nutritional quality and abiotic stress resistance, attracting strong interest in the last years. To unravel the function of candidate genes for agronomically relevant traits, studying their transcriptional activities by RT-qPCR is an important experimental approach. The accuracy of such experiments strongly depends on precise data normalization. To date, validation of potential candidate genes for normalization of diurnal expression studies has not been performed in C. quinoa. We selected eight candidate genes based on transcriptome data and literature survey, including conventionally used reference genes. We used three statistical algorithms (BestKeeper, geNorm and NormFinder) to test their stability and added further validation by a simulation-based strategy. We demonstrated that using different reference genes, including those top ranked by stability, causes significant differences among the resulting diurnal expression patterns. Our results show that isocitrate dehydrogenase enzyme (IDH-A) and polypyrimidine tract-binding protein (PTB) are suitable genes to normalize diurnal expression data of two different quinoa accessions. Moreover, we validated our reference genes by normalizing two known diurnally regulated genes, BTC1 and BBX19. The validated reference genes obtained in this study will improve the accuracy of RT-qPCR data normalization and facilitate gene expression studies in quinoa.


Psychomotor Vigilance Test and Its Association With Daytime Sleepiness and Inflammation in Sleep Apnea: Clinical Implications.
Excessive daytime sleepiness (EDS) is a key symptom of obstructive sleep apnea (OSA). The Psychomotor Vigilance Task (PVT) has been suggested as an objective easy-to-use, inexpensive alternative to the Multiple Sleep Latency Test (MSLT) to measure EDS. In patients with OSA, physiological sleepiness, but not subjective EDS (Epworth Sleepiness Scale [ESS]), has been associated with increased levels of the sleep- inducing proinflammatory cytokine interleukin-6 (IL-6). The goal of this study was to assess the association of PVT with objectively measured sleepiness (MSLT) and subjectively measured sleepiness (ESS) and IL-6 levels in patients with OSA. We studied 58 untreated patients with OSA who underwent an 8-hour in-laboratory polysomnography for 4 consecutive nights. MSLT, PVT, and 24-hour serial profiles of IL-6 were assessed on the fourth day. PVT variables included number of lapses, mean reciprocal of the fastest 10% and slowest 10% reaction times, and median of 1/reaction time. ESS was assessed on day 1 of the study. Higher ESS scores were significantly associated with greater number of lapses (β = .34, P = .02) and lower values of 1/RT (β = -.36, P = .01) and slowest 10% RTs (β = -.30, P = .04). No significant association was observed between PVT and MSLT, nor PVT and IL-6 levels. Our findings suggest that PVT is associated with subjectively assessed daytime sleepiness, but not with physiological sleepiness nor IL-6 levels in patients with OSA. It appears that ESS and PVT may be useful in predicting risks associated with impaired performance, such as traffic accidents, in patients with OSA.


Impaired Intracellular Ca2+ Dynamics, M-Band and Sarcomere Fragility in Skeletal Muscles of Obscurin KO Mice.
Obscurin is a giant sarcomeric protein expressed in striated muscles known to establish several interactions with other proteins of the sarcomere, but also with proteins of the sarcoplasmic reticulum and costameres. Here, we report experiments aiming to better understand the contribution of obscurin to skeletal muscle fibers, starting with a detailed characterization of the diaphragm muscle function, which we previously reported to be the most affected muscle in obscurin (Obscn) KO mice. Twitch and tetanus tension were not significantly different in the diaphragm of WT and Obscn KO mice, while the time to peak (TTP) and half relaxation time (HRT) were prolonged. Differences in force-frequency and force-velocity relationships and an enhanced fatigability are observed in an Obscn KO diaphragm with respect to WT controls. Voltage clamp experiments show that a sarcoplasmic reticulum's Ca2+ release and SERCA reuptake rates were decreased in muscle fibers from Obscn KO mice, suggesting that an impairment in intracellular Ca2+ dynamics could explain the observed differences in the TTP and HRT in the diaphragm. In partial contrast with previous observations, Obscn KO mice show a normal exercise tolerance, but fiber damage, the altered sarcomere ultrastructure and M-band disarray are still observed after intense exercise.


Interferon-gamma 1b: impact of new indications (idiopathic pulmonary fibrosis).
Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease with inadequate response to conventional treatment with corticosteroids and/or immunosuppressive agents in most patients. Interferon-gamma (IFN-gamma), an antifibrotic agent, has been proposed as a novel therapeutic approach. Several investigators have shown a relative decrease in systemic and pulmonary IFN-gamma activity in patients with IPF. Experimental evidence from animal and human studies also suggests that IFN-gamma administration may ameliorate lung fibrosis. Clinical experience is, however, limited to a single clinical trial that showed objective functional improvement in a small number of patients treated with IFN-gamma and low-dose corticosteroids. Further research is needed to characterise the efficacy, safety and optimum route of administration of this agent before it can be recommended for use in routine clinical practice.


Time of birth and risk of neonatal death at term: retrospective cohort study.
To determine the effect of time and day of birth on the risk of neonatal death at term. Population based retrospective cohort study. Data from the linked Scottish morbidity records, Stillbirth and Infant Death Survey, and birth certificate database of live births in Scotland, 1985-2004. Liveborn term singletons with cephalic presentation. Perinatal deaths from congenital anomalies excluded. Final sample comprised 1,039,560 live births. All neonatal deaths (in the first four weeks of life) unrelated to congenital abnormality, plus a subgroup of deaths ascribed to intrapartum anoxia. The risk of neonatal death was 4.2 per 10,000 during the normal working week (Monday to Friday, 0900-1700) and 5.6 per 10 000 at all other times (out of hours) (unadjusted odds ratio 1.3, 95% confidence interval 1.1 to 1.6). Adjustment for maternal characteristics had no material effect. The higher rate of death out of hours was because of an increased risk of death ascribed to intrapartum anoxia (adjusted odds ratio 1.7, 1.2 to 2.3). Though exclusion of elective caesarean deliveries attenuated the association between death ascribed to anoxia and delivery out of hours, a significant association persisted (adjusted odds ratio 1.5, 1.1 to 2.0). The attributable fraction of neonatal deaths ascribed to intrapartum anoxia associated with delivery out of hours was 26% (95% confidence interval 5% to 42%). Delivering an infant outside the normal working week was associated with an increased risk of neonatal death at term ascribed to intrapartum anoxia.


Rabbits protecting birds: Hypopredation and limitations of hyperpredation.
Biological invasions often damage island ecosystems. One such damaging consequence of biological invasions is hyperpredation. Hyperpredation is the increase in predation pressure from a generalist predator following the introduction of an alternative prey, typically a consequence of apparent competition between the two prey. Models for this have been devised that demonstrate this effect. However, hyperpredation may not always occur or may not always occur at the same strength. Here, we investigate how different mechanisms affect the magnitude of hyperpredation: (i) saturation of the predator's functional response, (ii) predator interference and (iii) non-predatory competition among predators. We find that all three mechanisms generally reduce hyperpredation. Predator saturation can actually overturn hyperpredation into hypopredation, an increase in native prey, as a result of apparent predation between the two prey. This occurs when the alternative prey is 'poisoned prey', i.e. prey that have a handling time cost greater than the nutritional benefit for the predator. Consuming 'poisoned prey' can result in an increase or decrease in predator density. Conversely, we also identify scenarios in which interference and competition may increase hyperpredation. Based on these insights, we conclude that the invasion of established ecosystems by non-native prey can lead to more diverse consequences than previously thought. Potential control measures should take these effects into account.


Educating nurses to undertake clinical supervision in practice.
Alongside interest in the process of clinical supervision, there is a growing recognition of the need for education for practitioners undertaking the role of supervisor. This article describes a module accredited by the Welsh National Board and the University of Wales, Swansea, which was designed to achieve this aim and help practitioners design structures for supervision applicable to their practice settings. The structure and content of the module are described, as well as an evaluation of the first intake.


Value of magnetic resonance imaging in assessing efficacy in clinical trials of multiple sclerosis therapies.
Magnetic resonance imaging (MRI) has become an important technique for monitoring the effectiveness of putative treatments for multiple sclerosis (MS) because of its high sensitivity, objectivity, and noninvasive nature. Its importance as a surrogate measure of disease, however, is an issue that is more difficult to validate than might seem to be the case. In this review, we describe the role of MRI in the assessment of putative therapies for MS. New magnetic resonance techniques and methods of image analyses aimed at better demonstrating the nature and extent of disease are discussed, and the role of MRI in published MS therapeutic trials is examined. MRI is a frequently used secondary outcome measure for putative treatment strategies for MS. Although it is sensitive to changes in the inflammatory component of the MS disease process, poor correlation has been noted between MRI findings and long-term patient outcome. There is a widespread expectation that new magnetic resonance techniques--such as fluid-attenuated inversion recovery, magnetization transfer imaging, and magnetic resonance spectroscopy--will ultimately be useful for characterization of pathologic changes within the MS lesion and more generally of the MS disease process. Whether magnetic resonance changes seen in experimental therapies predict the long-term clinical course of the disease remains to be determined.


Stability of antibiotics and chemotherapeutics in agar plates.
The stability of chemotherapeutic agents incorporated into agar plates was studied by comparison of minimum inhibitory concentrations on fresh and stored plates and by direct bioassay of the chemotherapeutic agar plates. Plates were stored in sealed bags at 4 C. No loss of bioactivity was demonstrated after 30 days of storage in plates containing methicillin, erythromycin, cephalothin, tetracycline, chloramphenicol, kanamycin, streptomycin, polymyxin B, or nalidixic acid. Penicillin G, ampicillin, and nitrofurantoin showed statistically significant losses of activity after 4 weeks. None of the chemotherapeutics tested showed significant loss in activity after 1 week.


Femoral Vessel Blood Flow Is Preserved Throughout Direct Anterior Total Hip Arthroplasty.
Posterolateral and anterolateral approach THA disrupts femoral vessel blood flow, however, this has not been established for the direct anterior (DA) approach. Ten patients undergoing primary DA THA had peak vascular flow rates for the femoral artery and vein calculated via Doppler ultrasound at specified points: incision, acetabular preparation, femoral preparation and final reduction. Peak femoral arterial and venous flow decreased over baseline, but not significantly, during acetabular preparation (P=0.88, P=0.98) and femoral preparation (P=0.97, P=0.97). At final reduction, arterial peak flow was restored (P=1) with an increase in venous flow (P=0.55). Although there were alterations to peak flow, no vessel occlusion occurred at any point during DA THA.


[Immunological parameters in the diagnosis of silicotuberculosis].
The study has defined criteria for the concomitant development of tuberculosis as secondary to silicosis. Factorial and discriminant analyses identified the most significant factors of immune homeostasis in silicotuberculosis. The major signs of possible development of tuberculosis in the presence of silicosis are the elevated levels of total IgE and IgG, fibronectin; the cells expressing CD4+ and CD20+ markers; and the decreased concentration of the mucinic antigen 3EG5. The findings were used to construct models of immunity in tuberculosis, silicosis, and silicotuberculosis. The use of a complex of immunological studies promoted the better early diagnosis of silicotuberculosis.


Dietary genistein results in larger MNU-induced, estrogen-dependent mammary tumors following ovariectomy of Sprague-Dawley rats.
Due to the estrogenic properties of soy-derived isoflavones, many postmenopausal women are using these compounds as a natural alternative to hormone replacement therapy (HRT). How isoflavones impact breast cancer in postmenopausal women is important, because a majority of breast cancer cases occur in this age group. Chemical induction of mammary tumors in female rats has been used to determine that exposure of the mammary gland to soy isoflavones prior to tumor induction is protective against tumor formation. Here we investigate the effect of dietary genistein on mammary tumors that have already formed. The study was designed to determine the action of dietary genistein in a low endogenous estrogen environment as is observed in postmenopausal women. Animals were ovariectomized (OVX) after mammary tumor development and were then placed into one of three treatment groups: positive-control (OVX+ estradiol implant), genistein (OVX+ 750 p.p.m. genistein) and negative-control (OVX alone). Tumors were distinguished as malignant or benign by histopathological examination and were further characterized as either estrogen-dependent or estrogen-independent using immunohistochemistry to identify the presence of both estrogen receptor (ER) alpha and the progesterone receptor (PR). Genistein at 750 p.p.m. increased the weight of estrogen-dependent adenocarcinomas in ovariectomized rats compared with the negative-control animals. Genistein treatment also resulted in a higher percentage of proliferative cells in tumors and increased uterine weights when compared with negative-control animals. Collectively, these effects are probably due to the estrogenic activity of genistein. Plasma genistein concentrations in animals fed the isoflavone-containing diet were at physiological levels relevant to human exposure. Estradiol concentrations in ovariectomized animals not receiving an estradiol supplement were similar to those observed in postmenopausal women. The data suggest that in an endogenous estrogen environment similar to that of a postmenopausal woman, dietary genistein can stimulate the growth of a mammary carcinogen MNU-induced estrogen-dependent mammary tumors.


The power of compassion in group psycotherapy.
Research has repeatedly demonstrated that individual and group psychotherapy are equally effective. Compassion-focused therapy (CFT) has been shown to be an effective approach to treating individuals with a wide range of presenting mental health concerns. In this study, we discuss the basic tenets of CFT and introduce a 12-module CFT group psychotherapy approach for college counseling centers. We use a clinical vignette to provide an example of how psychotherapists may implement this approach. We then discuss clinical applications, including strengths and limitations of this approach.


Effects of a single dose of a flavonoid-rich blueberry drink on memory in 8 to 10 y old children.
Recent evidence from animals and adult humans has demonstrated potential benefits to cognition from flavonoid supplementation. The aim of this study was to investigate whether these cognitive benefits extended to a sample of school-aged children. Using a crossover design, with a washout of at least 7 d between drinks, 14 children ages 8 to 10 y consumed either a flavonoid-rich blueberry drink or a matched vehicle. Two h after consumption, the children completed a battery of five cognitive tests comprising the Go-NoGo, Stroop, Rey's Auditory Verbal Learning Task, Object Location Task, and a Visual N-back. In comparison to the vehicle, the blueberry drink produced significant improvements in the delayed recall of a previously learned list of words, showing for the first time a cognitive benefit for acute flavonoid intervention in children. However, performance on a measure of proactive interference indicated that the blueberry intervention led to a greater negative impact of previously memorized words on the encoding of a set of new words. There was no benefit of our blueberry intervention for measures of attention, response inhibition, or visuospatial memory. Although findings are mixed, the improvements in delayed recall found in this pilot study suggest that, following acute flavonoid-rich blueberry interventions, school-aged children encode memory items more effectively.


High-intensity interval training and β-hydroxy-β-methylbutyric free acid improves aerobic power and metabolic thresholds.
Previous research combining Calcium β-hydroxy-β-methylbutyrate (CaHMB) and running high-intensity interval training (HIIT) have shown positive effects on aerobic performance measures. The purpose of this study was to examine the effect of β-hydroxy-β-methylbutyric free acid (HMBFA) and cycle ergometry HIIT on maximal oxygen consumption (VO2peak), ventilatory threshold (VT), respiratory compensation point (RCP) and time to exhaustion (Tmax) in college-aged men and women. Thirty-four healthy men and women (Age: 22.7 ± 3.1 yrs ; VO2peak: 39.3 ± 5.0 ml · kg(-1) · min(-1)) volunteered to participate in this double-blind, placebo-controlled design study. All participants completed a series of tests prior to and following treatment. A peak oxygen consumption test was performed on a cycle ergometer to assess VO2peak, Tmax, VT, and RCP. Twenty-six participants were randomly assigned into either a placebo (PLA-HIIT) or 3 g per day of HMBFA (BetaTor™) (HMBFA-HIIT) group. Eight participants served as controls (CTL). Participants in the HIIT groups completed 12 HIIT (80-120% maximal workload) exercise sessions consisting of 5-6 bouts of a 2:1 minute cycling work to rest ratio protocol over a four-week period. Body composition was measured with dual energy x-ray absorptiometry (DEXA). Outcomes were assessed by ANCOVA with posttest means adjusted for pretest differences. The HMBFA-HIIT intervention showed significant (p < 0.05) gains in VO2peak, and VT, versus the CTL and PLA-HIIT group. Both PLA-HIIT and HMBFA-HIIT treatment groups demonstrated significant (p < 0.05) improvement over CTL for Tmax, and RCP with no significant difference between the treatment groups. There were no significant differences observed for any measures of body composition. An independent-samples t-test confirmed that there were no significant differences between the training volumes for the PLA-HIIT and HMBFA-HIIT groups. Our findings support the use of HIIT in combination with HMBFA to improve aerobic fitness in college age men and women. These data suggest that the addition of HMBFA supplementation may result in greater changes in VO2peak and VT than HIIT alone. The study was registered on ClinicalTrials.gov (ID NCT01941368).


Improving spot-scanning proton therapy patient specific quality assurance with HPlusQA, a second-check dose calculation engine.
The purpose of this study was to validate the use of HPlusQA, spot-scanning proton therapy (SSPT) dose calculation software developed at The University of Texas MD Anderson Cancer Center, as second-check dose calculation software for patient-specific quality assurance (PSQA). The authors also showed how HPlusQA can be used within the current PSQA framework. The authors compared the dose calculations of HPlusQA and the Eclipse treatment planning system with 106 planar dose measurements made as part of PSQA. To determine the relative performance and the degree of correlation between HPlusQA and Eclipse, the authors compared calculated with measured point doses. Then, to determine how well HPlusQA can predict when the comparisons between Eclipse calculations and the measured dose will exceed tolerance levels, the authors compared gamma index scores for HPlusQA versus Eclipse with those of measured doses versus Eclipse. The authors introduce the αβγ transformation as a way to more easily compare gamma scores. The authors compared measured and calculated dose planes using the relative depth, z∕R × 100%, where z is the depth of the measurement and R is the proton beam range. For relative depths than less than 80%, both Eclipse and HPlusQA calculations were within 2 cGy of dose measurements on average. When the relative depth was greater than 80%, the agreement between the calculations and measurements fell to 4 cGy. For relative depths less than 10%, the Eclipse and HPlusQA dose discrepancies showed a negative correlation, -0.21. Otherwise, the correlation between the dose discrepancies was positive and as large as 0.6. For the dose planes in this study, HPlusQA correctly predicted when Eclipse had and had not calculated the dose to within tolerance 92% and 79% of the time, respectively. In 4 of 106 cases, HPlusQA failed to predict when the comparison between measurement and Eclipse's calculation had exceeded the tolerance levels of 3% for dose and 3 mm for distance-to-agreement. The authors found HPlusQA to be reasonably effective (79% ± 10%) in determining when the comparison between measured dose planes and the dose planes calculated by the Eclipse treatment planning system had exceeded the acceptable tolerance levels. When used as described in this study, HPlusQA can reduce the need for patient specific quality assurance measurements by 64%. The authors believe that the use of HPlusQA as a dose calculation second check can increase the efficiency and effectiveness of the QA process.


UFMylation: a ubiquitin-like modification.
Post-translational modifications (PTMs) add a major degree of complexity to the proteome and are essential controllers of protein homeostasis. Amongst the hundreds of PTMs identified, ubiquitin and ubiquitin-like (UBL) modifications are recognized as key regulators of cellular processes through their ability to affect protein-protein interactions, protein stability, and thus the functions of their protein targets. Here, we focus on the most recently identified UBL, ubiquitin-fold modifier 1 (UFM1), and the machinery responsible for its transfer to substrates (UFMylation) or its removal (deUFMylation). We first highlight the biochemical peculiarities of these processes, then we develop on how UFMylation and its machinery control various intertwined cellular processes and we highlight some of the outstanding research questions in this emerging field.


Organization of skin stratum corneum extracellular lamellae: diffraction evidence for asymmetric distribution of cholesterol.
Lipid suspensions containing 2:1:1 skin ceramides:palmitic acid:cholesterol, similar to the lipid composition found in the extracellular matrix of skin stratum corneum, were analyzed by X-ray diffraction methods. These suspensions gave a sharp wide-angle reflection at 4.1 A, indicating tight hydrocarbon chain packing that would function as a water barrier, and low-angle lamellar diffraction with a repeat period near 130 A, similar to that previously recorded from intact stratum corneum. The lamellar repeat increased from 121 A at pH 6 to 133 A at pH 8.5, allowing phase angles of the lamellar data to be obtained by a sampling theorem "swelling" analysis. Electron density profiles showed that each repeating unit contained two asymmetric bilayers, with a fluid space on one side of the bilayer that increased with increasing pH, due to electrostatic repulsion between bilayers because of ionization of the palmitic acid. Profiles obtained from lamellae with cholesterol sulfate partially substituted for cholesterol showed large density increases on that same side of the bilayer, indicating that cholesterol is asymmetrically distributed in each bilayer. A molecular model was developed postulating that this asymmetry is due to the exclusion of cholesterol from lipid monolayers containing the ester-linked unsaturated (linoleic) hydrocarbon chain of skin ceramide 1. This model can explain the altered organization of extracellular lamellae in epidermal cysts (P. W. Wertz, D. C. Swartzendruber, K. C. Madison, D. T. Downing. 1987. J. Invest. Dermatol. 89:419-425) where the ester-linked chains have a higher percentage of saturated fatty acids than found in normal epidermis.


Gut hormones, appetite suppression and cachexia in patients with pulmonary TB.
Cachexia is a hallmark of pulmonary tuberculosis and is associated with poor prognosis. A better understanding of the mechanisms behind such weight loss could reveal targets for therapeutic intervention. The role of appetite-regulatory hormones in tuberculosis is unknown. 41 subjects with newly-diagnosed pulmonary TB (cases) were compared to 82 healthy controls. We measured appetite, body mass index (BMI), % body fat (BF), plasma peptide YY (PYY), leptin, ghrelin, and resistin for all subjects. Measurements were taken at baseline for controls and at treatment days 0, 30, and 60 for cases. Baseline appetite, BMI, and BF were lower in cases than in controls and improved during treatment. PYY, ghrelin, and resistin were significantly elevated in cases and fell during treatment. Leptin was lower in cases and rose with treatment. Appetite was inversely related to PYY in cases. High pre-treatment PYY predicted reduced gains in appetite and BF. PYY was the strongest independent predictor of appetite in cases across all time points. Appetite-regulatory hormones are altered in TB patients. As hormones normalize during treatment, appetite is restored and nutritional status improves. High baseline PYY is an indicator of poor prognosis for improvement in appetite and nutrition during treatment. Wasting in TB patients may partly be mediated by upregulation of PYY with resulting appetite suppression.


Forecasting intensifying disturbance effects on coral reefs.
Anticipating future changes of an ecosystem's dynamics requires knowledge of how its key communities respond to current environmental regimes. The Great Barrier Reef (GBR) is under threat, with rapid changes of its reef-building hard coral (HC) community structure already evident across broad spatial scales. While several underlying relationships between HC and multiple disturbances have been documented, responses of other benthic communities to disturbances are not well understood. Here we used statistical modelling to explore the effects of broad-scale climate-related disturbances on benthic communities to predict their structure under scenarios of increasing disturbance frequency. We parameterized a multivariate model using the composition of benthic communities estimated by 145,000 observations from the northern GBR between 2012 and 2017. During this time, surveyed reefs were variously impacted by two tropical cyclones and two heat stress events that resulted in extensive HC mortality. This unprecedented sequence of disturbances was used to estimate the effects of discrete versus interacting disturbances on the compositional structure of HC, soft corals (SC) and algae. Discrete disturbances increased the prevalence of algae relative to HC while the interaction between cyclones and heat stress was the main driver of the increase in SC relative to algae and HC. Predictions from disturbance scenarios included relative increases in algae versus SC that varied by the frequency and types of disturbance interactions. However, high uncertainty of compositional changes in the presence of several disturbances shows that responses of algae and SC to the decline in HC needs further research. Better understanding of the effects of multiple disturbances on benthic communities as a whole is essential for predicting the future status of coral reefs and managing them in the light of new environmental regimes. The approach we develop here opens new opportunities for reaching this goal.


Improved performance of prostate DCE-MRI using a 32-coil vs. 12-coil receiver array.
To assess whether acquisition with 32 receiver coils rather than the vendor-recommended 12 coils provides significantly improved performance in 3D dynamic contrast-enhanced MRI (DCE-MRI) of the prostate. The study was approved by the institutional review board and was compliant with HIPAA. 50 consecutive male patients in whom prostate MRI was clinically indicated were prospectively imaged in March 2015 with an accelerated DCE-MRI sequence in which image reconstruction was performed using 12 and 32 coil elements. The two reconstructions were compared quantitatively and qualitatively. The first was done using signal-to-noise ratio (SNR) and g-factor analysis to assess sensitivity to acceleration. The second was done using a five-point scale by two experienced radiologists using criteria of perceived SNR, artifact, sharpness, and overall preference. Significance was assessed with the Wilcoxon signed rank test. Extension to T2-weighted spin-echo and diffusion sequences was assessed in phantom studies. Reconstruction using 32 vs. 12 coil elements provided improved performance in DCE-MRI based on intrinsic SNR (18% higher) and g-factor statistics (14% higher), with a median 32% higher overall SNR within the prostate volume over all subjects. Reconstruction using 32 coils was qualitatively rated significantly improved (p<0.001) vs. 12 coils on the basis of perceived SNR and radiologist preference and equivalent for sharpness and artifact. Phantom studies suggested the improvement in intrinsic SNR could extend to T2-weighted spin-echo and diffusion sequences. Reconstruction of 3D accelerated DCE-MRI studies of the prostate using 32 independent receiver coils provides improved overall performance vs. using 12 coils.


Economic assessment of thrombocytopenia: CATCH Registry.
Thrombocytopenia is associated with increased patient risk. However, the costs of this complication are not well defined. This study assessed the impact of thrombocytopenia on in-hospital costs using results from CATCH, an observational study that examined 1988 consecutive patients receiving prolonged heparin therapy (> or =96 h). Thrombocytopenia was defined as: (group 1) an absolute reduction in platelet count to <150 x 10(9)/L; (group 2) a relative reduction in platelet count of >50% from admission levels; or (group 3) both criteria. We found that the development of thrombocytopenia was associated with significantly higher total in-hospital costs for all groups: (group 1) (difference, $8,222; 95% CI, $5,020-$11,425; P<.001); (group 2) (difference, $15,429; 95% CI, $7,472-$23,385; P<.001); and (group 3) (difference, $27,077; 95% CI, $22,901-$31,252; P<.001). However, in our adjusted model, longer lengths-of-stay and greater use of blood transfusions accounted for most incremental in-hospital cost differences.


TomoEED: fast edge-enhancing denoising of tomographic volumes.
TomoEED is an optimized software tool for fast feature-preserving noise filtering of large 3D tomographic volumes on CPUs and GPUs. The tool is based on the anisotropic nonlinear diffusion method. It has been developed with special emphasis in the reduction of the computational demands by using different strategies, from the algorithmic to the high performance computing perspectives. TomoEED manages to filter large volumes in a matter of minutes in standard computers. TomoEED has been developed in C. It is available for Linux platforms at http://www.cnb.csic.es/%7ejjfernandez/tomoeed. Supplementary data are available at Bioinformatics online.


The role of antigen-presenting B cells in T cell priming in vivo. Studies of B cell-deficient mice.
Mice rendered B cell deficient by treatment with rabbit anti-mouse IgM (anti-mu) antibodies from birth fail to respond when primed with soluble protein antigens in CFA, as measured by T cell proliferation when challenged with antigen in vitro. The role of B cells in T cell priming in vivo was examined by adoptively transferring hapten-specific B cells into anti-mu mice, followed by immunization with haptenated Ag in CFA. The T cell proliferative response to OVA of anti-mu BALB/c mice was partially restored by the administration of TNP or FITC-specific B cells and immunization with TNP-OVA or FITC-OVA, respectively. This reconstitution was Ag-specific, inasmuch as hapten-binding B cells restored the T cell responses to OVA in mice immunized with the same hapten coupled to OVA. The mechanism of B cell reconstitution of T cell priming in anti-mu mice was addressed using parental to F1 B cell transfers. The Ia restriction pattern of the activated T cells from these mice indicated that both direct presentation of Ag by transferred B cells and antibody-mediated enhancement of Ag presentation by non-B, host Ag-presenting cells occurred. Thus, Ag-specific B lymphocytes play a critical role in priming of T cells in vivo.


Effect of melatonin in the prevention of post-operative adhesion formation in a rat uterine horn adhesion model.
Our main aim was to investigate the effects of melatonin (ME), possibly the most powerful free-radical scavenger, on the prevention of i.p. adhesion formation in rat uterine horn. Our secondary aim was to determine whether different methods of administration of ME were beneficial. Animals were randomly assigned into seven groups, each consisting of 13 rats. Measured serosal injury was created using a standard technique. While control and two sham groups were not given ME, two of the remaining four groups were given a single dose of 10 mg/kg (2 mg) of ME i.p. immediately after injury and 30 min prior to injury respectively. In the two other groups, ME treatment was continued daily for 5 days. All animals were killed 2 weeks after surgery and adhesions were determined and scored by a examiner blinded to the test. The extent, severity and total scores of adhesion were found to be significantly reduced in all of the ME treatment groups when compared with control and sham groups. There were no statistically significant differences between the treatment groups. This study showed that even single dose ME therapy was effective in the prevention of post- operative i.p. adhesion formation.


Polyphenols and Sesquiterpene Lactones from Artichoke Heads: Modulation of Starch Digestion, Gut Bioaccessibility, and Bioavailability following In Vitro Digestion and Large Intestine Fermentation.
Artichoke is a relevant source of health-promoting compounds such as polyphenols and sesquiterpene lactones. In this study, the bioaccessibility and gut bioavailability of artichoke constituents were evaluated by combining in vitro digestion and large intestine fermentation, metabolomics, and Caco-2 human intestinal cells model. Moreover, the ability of artichoke polyphenols to modulate the in vitro starch digestibility was also explored. An untargeted metabolomic approach based on liquid chromatography quadrupole-time-of-flight (UHPLC/QTOF) mass spectrometry coupled with multivariate statistics was used to comprehensively screen the phytochemical composition of raw, digested, and fermented artichoke. Overall, a large abundance of phenolic acids and sesquiterpene lactones was detected, being 13.77 and 11.99 mg·g-1, respectively. After 20 h of in vitro large intestine fermentation, a decrease in polyphenols and sesquiterpene lactones content was observed. The most abundant compounds characterizing the raw material (i.e., chlorogenic acid and cynaropicrin equivalents) showed an average % bioaccessibility of 1.6%. The highest % bioaccessibility values were recorded for flavonoids such as anthocyanin and flavone equivalents (on average, 13.6%). However, the relatively high bioavailability values recorded for flavonols, phenolic acids, and sesquiterpene lactones (from 71.6% up to 82.4%) demonstrated that these compounds are able to be transported through the Caco-2 monolayer. The phenolic compounds having the highest permeation rates through the Caco-2 model included low molecular weight phenolics such as tyrosol and 4-ethylcatechol; the isoflavonoids 3'-O-methylviolanone, equol 4'-O-glucuronide, and hydroxyisoflavone; together with the methyl and acetyl derivatives of glycosylated anthocyanins. Therefore, although human in vivo confirmatory trials are deemed possible, current findings provide insights into the mechanistic effects underlying artichoke polyphenols and sesquiterpenoids bioavailability following gastrointestinal and large intestine processes.


Association Between Tobacco Consumption and Self-Reported Visual Impairment in Adults of High-Altitude Andean Communities of Peru.
To determine the association between tobacco consumption and self-reported visual impairment. We performed a cross-sectional study based on an original cohort study. A non-probabilistic sampling was performed to invite 413 patients of 60 years or more from 11 high-altitude Andean communities (altitude higher than 1500 m above sea level) of Peru between 2013 and 2017. Demographic data and information on tobacco consumption were collected. Associations were determined using a Poisson regression model with 95% confidence intervals (CI). Of the 413 participants, 141 (34.14%) were men and 49 (11.86%) were tobacco users. In the adjusted model, tobacco users presented a high probability of visual impairment with a prevalence ratio of 1.32 (95% CI: 1.18-1.97). We also found that having two or more comorbidities 2.19 (95% CI: 1.53-3.15), receiving health assistance in a pharmacy 3.75 (95% CI: 1.97-7.16), and coffee consumption 1.67 (95% CI: 1.26-2.21) were factors significantly associated with self-reported visual impairment. We determined that in Peruvian high-altitude Andean communities, visual impairment was more frequent in individuals reporting tobacco consumption, taking alternative medicine, going directly to a drug store without primary care physician consultation, having more than one comorbidity, and coffee consumption.


Population based case-control study of serious non-fatal motorcycle crashes.
Motorcycle sales, registration and use are increasing in many countries. The epidemiological literature on risk factors for motorcycle injury is becoming outdated, due to changes in rider demography, licensing regulations, traffic mix and density, road environments, and motorcycle designs and technologies. Further, the potential contribution of road infrastructure and travel speed has not yet been examined. A population based case-control study together with a nested case-crossover study is planned. Cases will be motorcycle riders who are injured but not killed in a motorcycle crash on a public road within 150 km radius of Melbourne, Australia, and admitted to one of the study hospitals. Controls will be motorcycle riders who ride through the crash site on the same type of day (weekday or weekend) within an hour of the crash time. Data on rider, bike, and trip characteristics will be collected from the participants by questionnaire. Data on crash site characteristics will be collected in a structured site inspection, and travel speed for the cases will be estimated from these data. Travel speed for the controls will be measured prior to recruitment with a radar traffic detection device as they ride through the crash site. Control sites for the case-crossover study will be selected 1 km upstream from the crash site and matched on either intersection status or road curvature (either straight or cornered). If the initial site selected does not match the case site on these characteristics, then the closest matching site on the case route will be selected. Conditional multivariate logistic regression models will be used to compare risk between the matched case and control riders and to examine associations between road infrastructure and road environment characteristics and crash occurrence. Interactions between type of site and speed will be tested to determine if site type is an effect modifier of the relationship between speed and crash risk. The relationship between rider factors and travel speed generally will be assessed by multivariate regression methods. In the context of the changing motorcycling environment, this study will provide evidence on contemporary risk factors for serious non-fatal motorcycle crashes.


Amphiphilic hyperbranched fluoropolymers as nanoscopic 19F magnetic resonance imaging agent assemblies.
Three hyperbranched fluoropolymers were synthesized and their micelles were constructed as potential (19)F MRI agents. A hyperbranched star-like core was first synthesized via atom transfer radical self-condensing vinyl (co)polymerization (ATR-SCVCP) of 4-chloromethyl styrene (CMS), lauryl acrylate (LA), and 1,1,1-tris(4'-(2''-bromoisobutyryloxy)phenyl)ethane (TBBPE). The polymerization gave a small core with M n of 5.5 kDa with PDI of 1.6, which served as a macroinitiator. Trifluoroethyl methacrylate (TFEMA) and tert-butyl acrylate (tBA) in different ratios were then "grafted" from the core to give three polymers with M(n) of about 120 kDa and PDI values of about 1.6-1.8. After acidolysis of the tert-butyl ester groups, amphiphilic, hyperbranched star-like polymers with M(n) of about 100 kDa were obtained. These structures were subjected to micelle formation in aqueous solution to give micelles having TEM-measured diameters ranging from 3-8 nm and DLS-measured hydrodynamic diameters from 20-30 nm. These micelles gave a narrow, single resonance by (19)F NMR spectroscopy, with a half-width of approximately 130 Hz. The T1/T2 parameters were about 500 and 50 ms, respectively, and were not significantly affected by the composition and sizes of the micelles. (19)F MRI phantom images of these fluorinated micelles were acquired, which demonstrated that these fluorinated micelles maybe useful as novel (19)F MRI agents for a variety of biomedical studies.


Tracking Healthy Days -- a window on the health of older adults.
In collaboration with its partners in the public health and aging services communities, the Centers for Disease Control and Prevention (CDC) Health Care and Aging Studies Branch has developed and validated a brief set of health-related quality of life (CDC HRQOL) measures for tracking the perceived physical and mental health of adults over time. For the past 12 years, these measures -- also called the Healthy Days measures -- have been used in an expanding set of population health surveys, surveillance systems, performance report cards, and evaluation studies, and they have provided useful disease and disability burden data to inform decision making and provide new insights for prevention research. Although now used continuously to assess health-related quality of life for Americans aged 12 years and older, the measures and population data have been especially valuable in applications affecting older adults, for which health-related quality of life is an outcome of primary importance. The CDC HRQOL measures are recommended to public health and social service professionals as a feasible way to assess perceived physical and mental health needs of older adults and to document the effects of policies and interventions.


[The work process in health and the production of care in a Family Health Unit: limits to the reception and reflections on the emergency service].
This study examines the work process of a Family Health Unity (USF) in a small municipality, inland the state of Rio de Janeiro. We would like to start with the question of what is causing the population registered in a family health program to look for the Emergency Service (SE) of a General Hospital. Semi-structured individual interviews were conducted with doctors who worked on duty and users in the Emergency Service and group interviews with users of a Family Health Unit and its staff. In addition, information was also collected by participant observation. The theoretical fields of Health Management and Psycho-sociology were the grounds of this research. It was concluded that the "modus operandi" of the USF, the geographical and organizational accessibility, and the technological apparatus of the SE ended up leading the population to seek the General Hospital emergency service of the municipality mentioned in this study in acute situations of suffering and distress.


Preparation and crystallization of dynamic NF-kappa B.Ikappa B complexes.
The formation of single, well-diffracting crystals is a requirement for any molecular structure determination by x-ray crystallography. Crystallization of biological macromolecules can represent a significant obstacle when the subject exhibits internal flexibility or indiscriminate self-association. In such cases, the removal of inherently flexible regions and the addition of stabilizing ligands can improve the probability of crystal formation and ordered growth. We have applied these principles in order to form crystals of the Rel homology region of transcription factor NF-kappaB in complex with its inhibitors IkappaBalpha and IkappaBbeta. None of these molecules crystallizes in the absence of a binding partner. Recombinant overexpression of truncated IkappaBalpha required selection of the correct start site. NF-kappaB.IkappaBalpha complex crystals formed under relatively stringent conditions. NF-kappaB. IkappaBbeta complex crystals were formed by analogy to NF-kappaB. IkappaBalpha, although some modifications in purification and complex formation were necessary due to differences between the inhibitors.


An unexpected role for angiotensin II in the link between dietary salt and proximal reabsorption.
We set out to confirm the long-held, but untested, assumption that dietary salt affects proximal reabsorption through reciprocal effects on the renin-angiotensin system in a way that facilitates salt homeostasis. Wistar rats were fed standard or high-salt diets for 7 days and then subjected to renal micropuncture for determination of single-nephron GFR (SNGFR) and proximal reabsorption. The tubuloglomerular feedback (TGF) system was used as a tool to manipulate SNGFR in order to distinguish primary changes in net proximal reabsorption (Jprox) from changes due to glomerulotubular balance. The influence of Ang II over Jprox was determined by the sensitivity of Jprox to the AT1 receptor antagonist, losartan. Plasma, whole kidneys, and fluid from midproximal tubules were assayed for Ang II content by radioimmunoassay. In rats on the standard diet, losartan reduced Jprox by 25% and reduced the maximum range of the TGF response by 50%. The high-salt diet suppressed plasma and whole-kidney Ang II levels. But the high-salt diet failed to reduce the impact of losartan on Jprox or the TGF response and actually caused tubular fluid Ang II content to increase. The persistent effect of Ang II on Jprox prevented a major rise in late proximal flow rate in response to the high-salt diet. These observations challenge the traditional model and indicate that the role of proximal tubular Ang II in salt-replete rats is to stabilize nephron function rather than to contribute to salt homeostasis.


Direct Inhibitory Effects of Carbon Monoxide on Six Venoms Containing Fibrinogenolytic Metalloproteinases.
Since the introduction of antivenom administration over a century ago to treat venomous snake bite, it has been the most effective therapy for saving life and limb. However, this treatment is not always effective and not without potential life-threatening side effects. We tested a new paradigm to abrogate the plasmatic anticoagulant effects of fibrinogenolytic snake venom metalloproteinases (SVMP) by inhibiting these Zn+2 -dependent enzymes directly with carbon monoxide (CO) exposure. Assessment of the fibrinogenolytic effects of venoms collected from the Arizona black rattlesnake, Northern Pacific rattlesnake, Western cottonmouth, Eastern cottonmouth, Broad-banded copperhead and Southern copperhead on human plasmatic coagulation kinetics was performed with thrombelastography in vitro. Isolated exposure of all but one venom (Southern copperhead) to CO significantly decreased the ability of the venoms to compromise coagulation. These results demonstrated that direct inhibition of transition metal-containing venom enzymes by yet to be elucidated mechanisms (e.g. CO, binding to Zn+2 or displacing Zn+2 from the catalytic site, CO binding to histidine residues) can in many instances significantly decrease fibrinogenolytic activity. This new paradigm of CO-based inhibition of the anticoagulant effects of SVMP could potentially diminish haemostatic compromise in envenomed patients until antivenom can be administered.


Advantages of supplementary CT in myelography of intraspinal masses.
Computed tomographic (CT) myelography subsequent to nonionic water-soluble contrast medium myelography has provided additional diagnostic information for evaluating intraspinal mass lesions. In 20 patients thus studied, there were eight intramedullary tumors, eight intradural extramedullary masses, and four extradural neoplasms. In intramedullary tumors CT enabled more precise delineation of the extent and location of expansion of the spinal cord. In intradural and extradural tumors, rotation and compression of the spinal cord as well as bony and paraspinal soft-tissue changes were more accurately demonstrated in the axial plane. When a complete block was present, the greater contrast sensitivity of CT permitted visualization beyond the level of the block. Histologic prediction is not feasible by CT myelography except for hyperlucent lipoma. CT can provide useful supplemental information to conventional metrizamide myelography.


Regulation of neural progenitor cell development in the nervous system.
The mammalian telencephalon, which comprises the cerebral cortex, olfactory bulb, hippocampus, basal ganglia, and amygdala, is the most complex and intricate region of the CNS. It is the seat of all higher brain functions including the storage and retrieval of memories, the integration and processing of sensory and motor information, and the regulation of emotion and drive states. In higher mammals such as humans, the telencephalon also governs our creative impulses, ability to make rational decisions, and plan for the future. Despite its massive complexity, exciting work from a number of groups has begun to unravel the developmental mechanisms for the generation of the diverse neural cell types that form the circuitry of the mature telencephalon. Here, we review our current understanding of four aspects of neural development. We first begin by providing a general overview of the broad developmental mechanisms underlying the generation of neuronal and glial cell diversity in the telencephalon during embryonic development. We then focus on development of the cerebral cortex, the most complex and evolved region of the brain. We review the current state of understanding of progenitor cell diversity within the cortical ventricular zone and then describe how lateral signaling via the Notch-Delta pathway generates specific aspects of neural cell diversity in cortical progenitor pools. Finally, we review the signaling mechanisms required for development, and response to injury, of a specialized group of cortical stem cells, the radial glia, which act both as precursors and as migratory scaffolds for newly generated neurons.


Association and dissociation kinetics of bobwhite quail lysozyme with monoclonal antibody HyHEL-5.
The anti-hen egg lysozyme monoclonal antibody HyHEL-5 and its complexes with various species-variant and mutant lysozymes have been the subject of considerable experimental and theoretical investigation. The affinity of HyHEL-5 for bobwhite quail lysozyme (BWQL) is over 1000-fold lower than its affinity for the original antigen, hen egg lysozyme (HEL). This difference is believed to arise almost entirely from the replacement in BWQL of the structural and energetic epitope residue Arg68 by lysine. In this study, the association and dissociation kinetics of BWQL with HyHEL-5 were investigated under a variety of conditions and compared with previous results for HEL. HyHEL-5-BWQL association follows a bimolecular mechanism and the dissociation of the antibody-antigen complex is a first-order process. Changes in ionic strength (from 27 to 500 mM) and pH (from 6.0 to 10.0) produced about a 2-fold change in the association and dissociation rates. The effect of viscosity modifiers on the association reaction was also studied. The large difference in the HEL and BWQL affinities for HyHEL-5 is essentially due to differences in the dissociation rate constant.


CO blocking of D2 dissociative adsorption on Ru(0001).
The influence of pre-adsorbed CO on the dissociative adsorption of D(2) on Ru(0001) is studied by molecular-beam techniques. We determine the initial dissociation probability of D(2) as a function of its kinetic energy for various CO pre-coverages between 0.00 and 0.67 monolayers (ML) at a surface temperature of 180 K. The results indicate that CO blocks D(2) dissociation and perturbs the local surface reactivity up to the nearest-neighbour Ru atoms. Non-activated sticking and dissociation become less important with increasing CO coverage, and vanish at theta(CO) approximately 0.33 ML. In addition, at high D(2) kinetic energy (>35 kJ mol(-1)) the site-blocking capability of CO decreases rapidly. These observations are attributed to a CO-induced activation barrier for D(2) dissociation in the vicinity of CO molecules.